Essais Cliniques et COVID-19

Accueil Essais Cliniques et COVID-19




Mise à jour le 30 avril 2020 à 17h15

Téléchargez le support de présentation du Point d’Information « Covid19 et Essais Cliniques » du 7 et 9 avril 2020.

Pour ses propres besoins, Sunnikan maintient une Base de Connaissances d’analyse réglementaire portant sur plus de 800 thèmes relatifs à la recherche clinique et la pharmacovigilance.

Dans le contexte actuel, Sunnikan met à votre disposition l’analyse réglementaire relative à l’impact de l’épidémie de Covid-19 sur les essais cliniques.

Il s’agit des textes applicables à ce jour.

Merci par avance de nous remonter vos commentaires pour améliorer cette page mise au service de tous !

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Sites Internet et contacts

  fr France ANSM : questions.clinicaltrials@ansm.sante.fr en mentionnant COVID-19 dans le sujet de votre message
DGS : ccs-pole-recherche@sante.gouv.fr
BE Belgique FAMHP : ct.rd@fagg-afmps.be
DE Allemagne CT-COVID@bfarm.de (Questions seulement, ne pas soumettre les demandes d’autorisation ou d’amendements par cette adresse) / +49 (0)228 99 307 4318
DK Danemark Danish Medical Agency : +45 70 20 02 33 (pour les
renseignements relatifs au Covid-19)
BG Bulgarie clintrialsquestions@bda.bg / 0894195544
UK Royaume-Uni clintrialhelpline@mhra.gov.uk (pour les renseignements relatives au Covid-19)
devices.regulatory@mhra.gov.uk (pour les dispositifs médicaux uniquement)
NHS : 020 7972 2545 (Procédure Fast-Track, heures d’ouverture)
NHS : 020 7104 8322 (Procédure Fast-Track, hors des heures d’ouverture)
ES Espagne aecaem@aemps.es (pour les essais cliniques) en mentionnant « URGENTE COVID19 »
area_bpc_bpfv@aemps.es (pour l’inspection et le contrôle des médicaments) en mentionnant « URGENTE COVID19 »
us Etats-Unis Clinicaltrialconduct-COVID19@fda.hhs.gov (pour les questionnements concernant la politique de gestion d’essais)
AU Australie clinical.trials@health.gov.au / 02 6289 4614

Référentiels applicables

2020 BG Bulgarie Reporting suspected side effects of medicines in patients with COVID-19, BDA, Bulgarie, 29 April 2020
2020 fr France Ordonnance n° 2020-460 du 22 avril 2020 portant diverses mesures prises pour faire face à l’épidémie de covid-19, JO, France
2020 fr France Organisation et fonctionnement du système de santé dans le contexte du COVID-19 : publication d’un arrêté après avis de la CNIL, CNIL, France, 22 avril 2020
2020 eu Europe Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020
2020 fr France Arrêté du 21 avril 2020 complétant l’arrêté du 23 mars 2020 prescrivant les mesures d’organisation et de fonctionnement du système de santé nécessaires pour faire face à l’épidémie de covid-19 dans le cadre de l’état d’urgence sanitaire, Journal Officiel, France
2020 fr France Essais cliniques dans la prise en charge des patients atteints du COVID-19 : point d’étape sur les projets autorisés par l’ANSM – Point d’Information, ANSM, France, 21 avril 2020
2020 UK Royaume-Uni Covid-19 research – Fast track review guidance for COVID-19 studies, NHS, Royaume-Uni, Last Updated on 16 April 2020
2020 UK Royaume-Uni The ICO’s regulatory approachduring the coronavirus public health emergency, ICO, Royaume-Uni, 15 April 2020
2020 UK Royaume-Uni Covid-19 Research – Seeking consent in COVID-19 research, NHS, Royaume-Uni, Last updated on 14 April 2020
2020 PE Pérou Decreto supremo N° 014-2020 S.A. – Medidas para asegurar el adecuado desarrollo de los ensayos clínicos de la enfermedad COVID-19 en el país, Perou, 12 April 2020
2020 UK Royaume-Uni Approval of GxP documents when working from home during the coronavirus (COVID-19) outbreak, MHRA, Royaume-Uni, 9 April 2020
2020 NL Pays-Bas Coronavirus (COVID-19): impact op het verrichten en uitvoeren van klinisch onderzoek dat onder de Wet medisch-wetenschappelijk onderzoek met mensen (WMO) valt, IGJ, Pays-Bas, 8 April 2020
2020 IT Italie  Gestione degli studi clinici in Italia in corso di emergenza COVID-19 (coronavirus disease 19), AIFA, Italie, Versione 2.1, 7 aprile 2020
2020 IT Italie  Circolare sulle procedure semplificate per gli studi e gli usi compassionevoli per l’emergenza da Covid-19, AIFA, Italie, 6 aprile 2020
2020 UK Royaume-Uni Covid-19 research – Guidance for using patient data, NHS, Royaume-Uni, Last updated on 27 April 2020
2020 fr France « COVID-19 – Essais cliniques en cours – Quel est le circuit préconisé en cas de délivrance à domicile ? », ANSM – DGS – CNRIPH – CNIL, 3 avril 2020, MAJ le 6 avril 2020
2020 NL Pays-Bas Emergency regulation for authorisation of research into COVID-19-targeted gene therapy or medicinal product containing GMO, CCMO, Pays-Bas, 3 April 2020
2020 UK Royaume-Uni Covid-19 resarch – Pharmacy and Radiation Assurance for COVID-19 studies, NHS, Royaume-Uni, Last Updated on 3 April 2020
2020 UK Royaume-Uni Guidance – MHRA regulatory flexibilities resulting from coronavirus (COVID-19), MHRA, Royaume-Uni, 1 April 2020, Updated 2 April 2020
2020 eu Europe ICH M1 Points to Consider Working Groupand MedDRA MSSOCommunication on Coronavirus, MedDRA – Europe, 1 April 2020
2020 AU Australie  Coronavirus (COVID-19): Information on medicines and medical devices, TGA, Australie, 31 March 2020
2020 UK Royaume-Uni Guidance – Medical devices clinical investigations during the coronavirus (COVID-19) outbreak, MHRA, Royaume-Uni, 30 March 2020
2020 top Monde General Meeting – Trial Master File Reference Model, 30 March 2020
2020 DE Allemagne Clinical Trials during the COVID-19 Pandemic – Information on the authorisation and conduct of clinical trials of medicinal products during the COVID-19 pandemic (Version 2.1), BFarm, Allemagne, 30 March 2020, Updated on 7 April 2020
Klinische Prüfungen während der COVID-19 Pandemie – Hinweise zur Genehmigung und Durchführung klinischer Arzneimittelprüfungen während der COVID-19 Pandemie (Version 2.1), 30. März 2020
2020 PE Pérou Covid-19 – Communicado N° 003-2020-OGITT/INS, Ministerio de Salud, 30 de Marzo 2020
2020 NL Pays-Bas Regeling van de Minister van Infrastructuur en Waterstaat van 28 maart 2020, nr. IENW/BSK-2020/57427, houdende spoedmaatregelen met betrekking tot gentherapie ter bestrijding van COVID-19 (Tijdelijke regeling afwijkende behandeling vergunningaanvragen gentherapie in verband met bestrijding COVID-19),
Pays-Bas
2020 NL Pays-Bas Accelerated procedure (fast track) review of coronavirus research files, CCMO, Pays-Bas, 27 mars 2020
2020 fr France Recherches sur le COVID-19 : la CNIL se mobilise, CNIL, France, 26 mars 2020
2020 Suisse Joint Guidance of Swissmedic and swissethics on the management of clinical trials with medicinal drug products in Switzerland during the COVID-19 pandemic, 26 March 2020, SwiwsMedic, Suisse, Updated to Version 2.1 on 7 April 2020
2020 PE Pérou Covid-19 – Communicado N° 002-2020-OGITT/INS, Ministerio de Salud, 26 de Marzo 2020
2020 DK Danemark COVID-19: Danish Medicines Agency puts inspection and control tasks on hold, DMA, Danemark, 26 March 2020
2020 BE Belgique Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020
2020 Afrique du Sud SAHPRA Policy on Conduct of Clinical Trials of Health Product during the current COVID-19 pandemic, SAHPRA, 25 mars 2020
2020 AU Australie COVID-19 : Guidance on clinical trials for institutions, HRECs, researchers and sponsors, CTPRG, Australia, 24 mars 2020
2020 CA Canada Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors, Health Canada, 23 March 2020, Updated on 3 April 2020
2020 UK Royaume-Uni MHRA Good Practice (GxP) inspections during the COVID19 outbreak, MHRA, Great-Britain, 23 March 2020
2020 fr France FAQ – Covid 19 – Essais cliniques en cours, ANSM, France, 20 mars 2020, Mise à Jour du
3 avril 2020
QnA – Covid 19 – Ongoing clinical, ANSM, France, 20 March 2020,
Updated on 8 April 2020
2020 fr France Essais cliniques : procédures accélérées pour l’évaluation des traitements du COVID-19 et recommandations aux promoteurs sur les essais en cours – Point d’information, ANSM, France, 20 mars 2020
2020 eu Europe Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 28 April 2020
2020 eu Europe DRAFT – Points to consider on implications of Coronavirus disease 4 (COVID-19) on methodological aspects of ongoing clinical 5 trials,
EMA, Europe, 25 march 2020
2020 DE Allemagne Supplementary recommendations to the document European Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 1.0, Bfarm, Allemagne, 26 March 2020
2020 eu Europe Guidance to sponsors on how to manage clinical trials during the COVID-19 pandemic – Press Release – EMA, 20 March 2020
2020 DE Allemagne « Genehmigungsverfahren », BfARM Internet site, Germany, 19 März 2020
2020 UK Royaume-Uni Guidance – Clinical trials applications for Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020
2020 UK Royaume-Uni Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 22 avril 2020
2020 PE Pérou Covid-19 – Comunicado n° 001-2020-OGITT/INS, Ministerio de Salud, Pérou, 18 mars 2020
2020 BG Bulgarie Recommandations aux commanditaires concernant la conduite des essais cliniques dans le cadre du risque complexe de Covid-19 d’une déclaration de l’état d’urgence dans le pays, BDA, Bulgarie, 18 mars 2020 (Traduction)
ПРЕПОРЪКИ КЪМ СПОНСОРИТЕ ОТНОСНО ПРОВЕЖДАНЕТО НА КЛИНИЧНИ ИЗПИТВАНИЯ ВЪВ ВРЪЗКА С УСЛОЖНЕНАТА ОБСТАНОВКА ОТ ПОВИШЕН РИСК ОТ COVID-19 И ОБЯВЕНОТО ИЗВЪНРЕДНО ПОЛОЖЕНИЕ В СТРАНАТА, BDA, Bulgaria, 18  March 2020
Recommendations to the Sponsors for managing of Clinical Trials during the COVID-19 pandemic and the declared State of emergency in the Republic of Bulgaria, BDAn Bulgarie, 24 March 2020
2020 us Etats-Unis FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 16 April 2020
2020 us Etats-Unis Coronavirus (COVID-19) Update: FDA Issues Guidance for Conducting Clinical Trials, FDA, USA, 18 March 2020
2020 DK Danemark Fast-track Approval of Clinical Trials investigating COVID-19, Danish Medicines Agency, Denmark, 17 March 2020
2020 UK Royaume-Uni COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020, Updated to v2.2 on 26 March 2020
2020 eu Europe Call to pool research resources into large multi-centre, multi-arm clinical trials to generate sound evidence on COVID-19 treatments, European Commission, 16 March 2020
2020 ES Espagne Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020, Mis à jour le 7 avril 2020
2020 us Etats-Unis Guidance for NIH-funded Clinical Trials and Human Subjects Studies Affected by COVID-19, NIH, Etats-Unis, 16 March 2020
2020 BE Belgique Directive sur la délivrance directe de médicaments aux patients dans le cadre d’essais cliniques, AFMPS, Belgique, 16 mars 2020
2020 DK Danemark Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated on 24 avril 2020
2020 NL Pays-Bas Information CCMO due to coronavirus outbreak, CCMO, The Netherlands, March 2020
2020 NL Pays-Bas Recommendations for the conduct of clinical research at the time of restrictive measures due to the coronavirus, CCMO, The Netherlands, 16 March 2020
Updated on 28 April 2020
2020 UK Royaume-Uni Advice for Management of Clinical trials in relation to Coronavirus, MHRA, United Kingdom, 12 March 2020
2020 IT Italie Notice – Clinical trials’ management in Italy during the COVID-19 (coronavirus disease 19) emergency, AIFA, Italia, 12 march 2020
2020 IT Italie Guidance on submission of Marketing Authorization/Extension, MA Variation and Renewal applications, up to the end of the restrictions related to COVID-19 emergency, AIFA, Italia, 12 march 2020
2020 UK Royaume-Uni Research in a public health emergency, MHRA, United Kingdom, 8 March 2020
2020 us Etats-Unis Coronavirus Disease 2019 (COVID-19) Update: Foreign Inspections, FDA, Etats-Unis, 10 March 2020
2020 BR Brésil Informe aos comitês de ética em pesquisa, Comissão National de ética em pesquisa, Brésil, 7 février 2020

Délivrance du médicament / produit de santé

Des mesures doivent être prises par les promoteurs concernant la distribution du médicament expérimental pour éviter les ruptures de stock de produits commercialisés

eu Europe « Changes in distribution of IMP may include:

  • The following measures could be considered provided that they do not create shortages of marketed medicinal products:
    • Larger amounts of trial medications than normally foreseen can be provided to the participant (in particular IMP, when prepared specifically for the purposes of the trial). This is to sustain the trial participant for a longer period and thereby avoid non-critical visits by the participant to the investigator site. This may be done providing that the continuation of treatment is under adequate supervision of the responsible investigator.
    • It is recommended for all IMPs and non-IMPs in clinical trials that appropriate stock is maintained to ensure treatment in case of distribution failure«  (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 27 March 2020)

DK Danemark « Stock of trial related medicinal products and medical devices
We recommend that stocks of IMP and other necessary medicinal products (NIMP) be kept appropriately high to ensure continuity in the event of shortage. It is important, as stated above, that it is taken into account that certain marketed drugs are used in the treatment of COVID-19 and other critical illnesses. The same applies for medical devices, including IVDs, which are used for safety/efficacy monitoring and other data collection. « 
(Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

Des mesures spécifiques doivent être mises en place au regard de la comptabilité des Médicaments Expérimentaux

UK Royaume-Uni « Accountability of Investigational Medicinal Products (IMP)

If COVID-19 related issues affect the ability of the investigator or institution to perform IMP accountability, then a risk assessment needs to be undertaken. If accountability is not critical, then the drug can be destroyed instead of being returned to minimise exposure to the virus. The sponsor should be involved in this decision.

If accountability is important, the sponsor should consider whether there are other ways this can be achieved whilst mitigating risks to virus exposure. For example, asking the participants to make a count, or submit a photograph.

If the reconciliation is critical (eg for controlled drugs) and needs to be done by the site or sponsor staff, then this would need to be handled appropriately. A risk-based approach should be taken for example conducting in an environment specialised for this or put in quarantine for some time so that virus on packaging is no longer viable (based on research literature review).

If additional resources are required to manage potentially contaminated IMPs then this should be managed by the sponsor. For example, the sponsor may make arrangements for collection and management of returns under these circumstances. » (Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 22 avril 2020)

La livraison au domicile du patient est possible sous certaines conditions

fr L’ANSM accepte la livraison à domicile du traitement expérimental auto-administrable (sous réserve de prise de Mesures Urgentes de Sécurité (MUS), puis de soumission d’une Modification Substantielle (MSA), dans des conditions garantissant la sécurité du patient, la protection des données personnelles, la traçabilité des produits envoyés, la gratuité…

fr France « La délivrance à domicile des traitements expérimentaux est-elle autorisée ?
Oui dans le respect des consignes de sécurité, de l’information du patient et de la traçabilité ainsi que des instructions du promoteur, établies si nécessaire en lien avec le fabricant, en accord avec le lieu de recherches.

  • MUS puis MSA précisant les conditions de délivrance, de suivi et d’information des participants

Pour plus de détails sur les exigences à respecter et les circuits envisageables, voir le document complémentaire établi par ANSM / DGS / CNRIPH / CNIL

La version actuelle de ces recommandations ne s’applique pas à la mise en place d’une administration à domicile des médicaments expérimentaux non auto-administrables.
Si exceptionnellement de telles modalités devaient être considérées, il est demandé de soumettre au préalable une MSA à l’ANSM afin de s’assurer que toutes les conditions de sécurité sont assurées pour l’administration parentérale au domicile du patient. »
(FAQ – Covid 19 – Essais cliniques en cours, ANSM, France, 20 mars 2020, Mise à jour du 3 avril 2020)

fr France « Principes généraux

La délivrance des produits nécessaires à la recherche au patient reste sous la responsabilité de l’investigateur et, si le lieu de recherche en dispose, de la pharmacie à usage intérieur (PUI).

Le promoteur met à disposition du lieu de recherches un appui logistique pour le transport des produits nécessaires à la recherche à destination du patient. Si le lieu de recherches/la PUI le demande, le promoteur organise la fourniture des emballages et des étiquettes. Il assure dans tous les cas le financement du transport.

Les promoteurs industriels simplifieront autant que faire se peut leurs procédures d’acheminement des produits nécessaires à la recherche. Les solutions retenues, y compris pour la prise en charge financière, doivent limiter autant que possible la charge de travail supplémentaire pour les lieux de recherches et les PUI et doivent tenir compte de la situation de chaque lieu de recherches

Les solutions retenues seront toujours évaluées au fur et à mesure de la pandémie au regard de la sécurité des patients et de la situation de tension de l’établissement du lieu de recherches mais aussi des capacités de transport. Pour les produits injectables une vigilance particulière sera apportée et des recommandations spécifiques seront élaborées.

Les exigences qui sous-tendent les circuits possibles sont :

  • l’absence de déplacement inutile des patients ou déplacement limité au maximum ;
  • le transport des produits dans le respect des conditions de température et d’environnement définies par le promoteur en lien avec le fabricant.
    Le transport de produits à température ambiante pourra s’effectuer sans enregistrement particulier de température si les données de stabilité dont dispose le fabricant montrent l’absence d’impact des déviations de température éventuelles pendant une durée correspondant à la durée de transport.
    Les conditions spéciales de transport (i.e. stupéfiants, psychotropes) et le transport de produits thermosensibles devront faire l’objet de procédures appropriées définies par les principes de bonnes pratiques de préparation et de distribution ;
  • le respect des dispositions du Règlement Général sur la protection des données (RGPD), de la loi n° 78-17 du 6 janvier 1978 relative à l’informatique, aux fichiers et aux libertés modifiée et des principes posés dans la méthodologie de référence (MR 001) adoptée par la CNIL quelle que soit la formalité préalable ayant permis l’essai clinique (autorisation ou conformité à la MR001), notamment :
    • information des patients ;
    • modalités sécurisées de transmission des données vers des destinataires habilités ;
    • séparation des données nominatives et des données de santé.
    • Le lieu de recherche prend contact avec le patient préalablement à l’envoi des produits, informe le patient sur la nécessité de communiquer à un sous-traitant son identité et adresse et documente sa non-opposition.
    • Le patient est ensuite informé par l’intermédiaire d’une note circonstanciée placée dans l’emballage (ou un courrier d’information à part ou tout autre moyen écrit, utilisé pour échanger habituellement avec les personnes concernées – par exemple : site web avec questionnaires en ligne à compléter régulièrement dans le cadre de l’étude). Cette information pourra mentionner uniquement la modification, à savoir le recours à un nouveau sous-traitant, les catégories de données qu’il traite et la finalité associée, la durée de conservation des données et les droits des personnes (article 14 du RGPD).
  • la documentation des dispositions choisies, dans le respect des bonnes pratiques en vigueur ;
  • la traçabilité des produits de santé jusqu’à leur réception et des circuits mis en œuvre ;
  • la gratuité des produits et de leur transport pour les patients.

Les circuits et solutions possibles sont notamment :

  • l’expédition des produits du lieu de recherche vers le domicile du patient ;
  • l’expédition des produits du lieu de recherche vers la pharmacie d’officine désignée par le patient, sous réserve de l’accord préalable de celle-ci ;
  • l’expédition des produits de la PUI, d’un distributeur de médicaments expérimentaux ou pour les produits hors médicaments d’une structure de distribution vers la pharmacie à usage intérieur de l’établissement de santé dans lequel le patient sera suivi de façon temporaire durant la période de confinement;
  • dans le cas de recherches conduites en ouvert, l’approvisionnement par le patient en produits commercialisés auprès de la pharmacie d’officine de son choix, sur prescription de l’investigateur.
    A l’exception des recherches à finalité non commerciale conduites dans les conditions du III de l’article L. 1121-16-1 du code de la santé publique, la prise en charge financière des médicaments devra être organisée par le promoteur.
    Des dispositions devront être mises en place par le promoteur et le lieu de recherches afin de maintenir le suivi de l’observance au traitement, tel que prévu par le protocole de la recherche. »
    (COVID-19 – Essais cliniques en cours – Quel est le circuit préconisé en cas de délivrance à domicile ? », ANSM – DGS – CNRIPH – CNIL, 3 avril 2020 MAJ le 6 avril 2020)

fr France « Is delivery of investigational products to the patient’s home allowed?

Yes in compliance with all safety instructions, patient information, traceability and the sponsor’s instructions, established if necessary in conjunction with the manufacturer, in agreement with the research site.

  • USM then SM-A specifying the conditions for delivery, monitoring and information of participants.
    The delivery of the products necessary for the research to the patient remains the responsibility of the investigator and, if available at the research site, of the site’s pharmacy.

The sponsor provides the research site with logistical support for the transport of the products necessary for the research to the patient. If requested by the research site/pharmacy, the sponsor provides the packaging and labels.
In all cases, the promoter finances the transport.Industrial sponsors will simplify as much as possible their procedures for transporting the products needed for the research. The solutions chosen, including financial support, must limit as far as possible the additional workload for the research site and pharmacy, and must take into account the situation of each research site.
For more details on the requirements to be met and the possible circuits, see the complementary document drawn up by ANSM / DGS / CNRIPH / CNIL (in French)
The current version of these recommendations does not apply to the implementation of home delivery of non-self-administered investigational drugs. If exceptionally such modalities should be considered, it is requested to submit a SM-A to the ANSM to ensure that all safety conditions are met for parenteral administration in the patient’s home. »
(QnA – Covid 19 – Ongoing clinical, ANSM, France, 20 March 2020)

eu L’EMA accepte la livraison du produit expérimental au patient Par le site d’investigation, sous conditions (respect de l’insu, information et éducation thérapeutique du patient le cas échéant, respect des normes relatives au transport, …

eu Europe « In line with the reduction of physical site visits, we foresee that there will be a need for delivery of the IMP directly to trial participants’ homes during the COVID-19 pandemic to avoid that the trial participant has to reach the site with the consequent risk of spreading/acquiring infection. The following should be considered for the direct shipment of IMP to trial participants:

  • It should also be determined whether further education or training of the trial participants will be necessary for IMP receipt, handling and self-administration. Written information on the dose regimen needs to be provided to trial participants along with contact information to site for any questions they may have. The same contact should be used for trial participant to inform the investigator if there is any damage to the IMP packaging, containers or the IMP itself.
  • The delivery should be done from trial sites (hospital pharmacies as applicable) to trial participants. The sponsor should bear the cost of the shipment and should provide logistical assistance to the trial site if needed, for instance for the selection of an appropriate courier or transporter.
  • If, due to the COVID-19 pandemic, a trial site is not able to handle the additional burden of IMP shipment to trial participants, the IMP may as an exception be shipped to the trial participants by a distributor independent from and acting on behalf of the sponsor in line with national law or temporary national emergency measures. The following then applies:
    • IMP shipment to the trial participants should be described in a contract between the sponsor and the distributor. The contract should identify all involved investigators/ trial sites. The contract should set out what documents or other materials are permitted to be supplied to the site. The contract and procedures involved should be documented in the sponsor trial master file.
    • The IMP may only be dispatched to trial participants after agreement with the investigator and on the basis of the investigator’s prescription. The agreement and the procedure should be recorded in the investigator site file;
    • The investigator should explain the process to the trial participant or carer orally and should obtain her/his oral consent before agreeing with the sponsor, including for the investigator to provide the trial participant’s name, address and contact details (phone and or e-mail) to the distributor. When possible, consent should be confirmed in writing by e-mail, mail or letter sent via a courier. The oral or written consent should be documented in the trial participant’s medical records;
    • The distributor should not store the personal data of the trial participant for a longer period than is required for the purpose of dispatching the IMP (should be destroyed as soon as no longer needed and in no case longer that the duration of the public health crisis) and should only use this information for the purpose of making the IMP deliveries during the period of the pandemic. It should not be used for any other purpose or disclosed to a third party for another purpose, other than monitors, auditors or inspectors verifying the conduct of the trial. This should be set out in the contract between the sponsor and distributor.
    • The trial participants’ names, address and contact details should never be provided to the sponsor, and the distributor should not have access to the trial participants’ health information.
  • The organisational measures agreed between the sponsor and the contracted distributor should protect blinding and ensure compliance with the randomisation.
  • Dedicated couriers should be contracted for IMP shipment with procedures in place. These procedures should ensure timely delivery directly to the trial participant or her/his designated caregiver to avoid that e.g. the IMP is handed over to the neighbour etc. The investigator should receive confirmation of all deliveries by the courier and confirm the receipt with the trial participant/caregiver by e.g. phone-call or e-mail. The investigator is responsible for proper IMP administration.
  • The shipment should be done under conditions that safeguard the integrity of the IMP, whether physically or with regards to temperature. Temperature records should be maintained during shipment for temperature-sensitive products. The investigator should be immediately informed in case the temperature departs from the specified conditions and should advise the trial participant at the earliest on the possibility to use or not the IMP, after consultation with the sponsor.
  • The courier should be informed of, and commit to, the shipment conditions (in particular regarding temperature) and maximum duration.
  • Procedures for the accountability of the IMP must be in place (among others for compliance monitoring). Accountability of the IMP should be maintained. Clear records of shipment from the trial site or from the distributor should be kept in the investigator site file, itemising the medication being delivered and the quantity involved. Documentation of receipt by the trial participant should be kept. Participants should retain unused IMP and containers and return them to the investigator when they next have a visit to the investigator site » (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 28 April 2020)

eu Europe « In line with the reduction of physical site visits, we foresee that there will be a need for delivery of the IMP directly to trial participants during the COVID-19 pandemic to avoid that the trial participant has to reach the site with the consequent risk of spreading/acquiring infection. The delivery is generally expected to happen from investigator sites (e.g. via hospital (or other) pharmacies as applicable) to trial participants;
Direct from sponsor to trial participant IMP delivery is accepted in a few member states under this emergency situation. The sponsor should check the NCA guidance regarding the possibility of direct sponsor to trial participant shipment, as it is likely that such measures can only be implemented under specified conditions (e.g. agreement with sites, dedicated couriers with procedures to only allow delivery directly to a trial participant or his/her carer, solid shipment and receipt procedures, informed consent provisions if necessary for the sponsor’s third party to handle personal information etc.), and for a limited period. Alternative shipping and storage arrangements should not compromise the treatment blinding. »
(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

BE L’Autorité Compétente belge autorise l’envoi de médicaments expérimentaux au domicile du patient, sous la forme d’amendement non substantiel, dans des conditions garantissant la confidentalité de la recherche, l’intégrité et la traçabilité des produits envoyés à partir du site d’investigation (interdiction de l’envoi par le Promoteur)

BE Belgique « Si un patient ne peut pas accéder à l’hôpital, ou si cela n’est pas souhaitable dans le contexte actuel, il est permis d’envoyer des médicaments expérimentaux (Investigational Medicinal Products, IMP) directement au patient. Cela relève de la responsabilité du chercheur principal. Le promoteur d’un essai clinique ne peut intervenir dans ce processus pour des raisons de confidentialité et d’intégrité. Bien entendu, les conditions d’expédition appropriées doivent être respectées. Ce processus doit être documenté et entièrement traçable. » (Directive sur la délivrance directe de médicaments aux patients dans le cadre d’essais cliniques, AFMPS, Belgique, 16 mars 2020)

BE Belgique « Direct shipment from sponsor to patient is not allowed in Belgium. What is allowed under these exceptional COVID-19 times under exceptional conditions:
In cases where, for the protection of the rights (confidentiality) and the safety of the participants, a continued supply of trial medication needs to be maintained at home, trial medication may also be shipped directly, under responsibility of the principal investigator, from the trial site to the trial participants via courier. This is only possible provided that the product is suitable for transport, storage at home and administration at home use.

In case of home administration by the participant, a care giver, nurse or physician, training on administration at home (i.e. trained in terms of the protocol) must be provided to the participant, care giver, nurse or physician.Any additional training from the participant, care giver, nurse or physician must be documented. Special attention should be paid to capturing adverse events and informing the PI of the subject’s health and wellbeing in this off-site setting.The GMDP and GCP requirements for transport and storage of investigational medicinal products remain in place.

Concluding:

  • Under PI’s responsibility
  • Shipment without sponsor involvement (personal data protection)
  • Under correct shipping conditions
  • With correct & traceable documentation
  • Patient is trained for storage, administration at home or administration is conducted by a trained (i.e. trained in terms of the protocol) care giver, nurse or physician

To emphasize: documentation is paramount. A courier under contract of the sponsor may be implied for the shipment upon condition that documentation is present before shipment, that the PI is informed, that the patient’s personal data are protected and that the sponsor under no circumstances can obtain the personal data (like name and address) of the patient. The responsibilities of each party in this have to be documented.It must be clear that this shipment cannot happen on the expenses of the patient

Administratively:

  • The shipping arrangements can be considered as a non-substantial amendment to be included with the next substantial amendment
  • If any training is provided to the participant, care giver, nurse or physician that is not mentioned in the protocol, a substantial amendment is required.
  • If it concerns temporary changes to the informed consent, these changes are preferably described in an addendum to the ICF which is temporarily valid. Non-substantial and substantial amendments on the ICF have to be submitted to the EC as soon as possible

Apart from the investigational treatment (IMP and any other medication and material specifically used for the trial), this rule can also be applied – under the same conditions mentioned above – for patient diaries, pregnancy tests.
Administrations of study medication by site staff / general practitioner / nursing staff are indeed possible outside the site (for example at home, alternative location). This should be requested by the study site. A substantial amendment should be submitted to the FAHMP and the EC in accordance with questions 10 and 11 of the Q&A: Good clinical practice (GCP): https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-clinical-practice/qa-good-clinical-practice-gcp
“All of these changes in shipment should be budgeted for by the sponsor if they are necessary to ensure the continuity of the studies.”
(Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

UK Au Royaume-Uni, les mesures temporaires mises en place pour l’envoi à domicile ou la récupération du traitement par une personne désignée, doivent être traitées comme des Modifications Non Substantielles (MNS)

UK Royaume-Uni  » 3.1.3. Studies where treatment or investigational medicinal product need to be sent by courier direct to participants or other alternative mechanisms of provision
Sponsors must assess the risks relating to the product and consider any shipping and storage arrangements. Participants must consent verbally to providing contact details for shipping purposes. Where participants are self-isolating or in quarantine, arrangements for a nominated person to collect product may be implemented with the participant’s verbal consent. Any such temporary arrangements should be handled as a non-substantial amendment that does not require HRA/HCRW Approval or R&D agreement. For studies involving the NHS/HSC, these should be marked by the sponsor as category C and not requiring assessment and sent directly to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor. »
(COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020)

UK Royaume-Uni « Providing investigational medicinal product (IMP) to trial participants

If a trial participant cannot attend a trial site, then delivery of IMP to a participant’s home is acceptable and no substantial amendment notification to the MHRA will be required. This applies to supply from the trial site or directly from the sponsor.

Sponsors should do a risk-assessment and record this internally.

Participants must consent verbally (and this should be documented in their notes) to providing contact details for shipping purposes. If the participant does not want to sign for the delivery due to self-isolation, then a follow up phone call could be used to confirm they have received the package. The sponsor should also consider if any training is required for administration of the IMP.

The following factors need to be taken into consideration if providing an IMP to a participant at home:

  • Storage requirements:
    • whether the medicine has any specific storage requirements, and how those are managed during posting
    • What assurance can be given about the integrity of the product during transit, for example should a temperature monitoring device be used
    • The stability of the product and margin of safety: for example a product with a very stable profile at temperature extremes would require less monitoring than one with a narrow stability range. The expiry of the product may need to be shortened if is delivered in ambient temperature
  • Delays in posting
    • This will depend on the trial, but it is worth considering if there is potential to affect continuity of supply. Shortage of the medicine may be crucial for some trials but not others.
  • Medicine accountability
    • The mechanism for confirming that the subjects have received the IMP, and it has not been delivered to someone else
    • Whether the medicine needs to be signed for and sent by courier or recorded delivery
    • Whether there needs to be a follow-up call to the subject

The HRA has provided guidance on this topic. » (Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 22 avril 2020)

DE En Allemagne, l’envoi des médicaments expérimentaux au domicile du patient est autorisé sous réserve du respect de la traçabilité et de conditions de transports adéquates

DE Allemagne « 2. Shipment of investigational medicinal products to trial subjects

Owing to the impact of the COVID 19 pandemic, it may become necessary to send IMP directly to trial subjects in individual clinical trials, either to ensure the safety and well-being of trial subjects and/or to maintain the continuation of clinical trials in accordance with the protocol and thus to ensure the evaluability of clinical trial data.

The shipment of IMP to trial subjects requires that adequate medical supervision of the subject by the investigator, in accordance with the protocol, is ensured.

The following recommendations refer exclusively to IMP used autonomously by trial subjects.

If it is necessary to ship IMPto trial subjects directly, shipment by the trial site itself is preferred under this exception due to the pandemic. Shipment should be made in a manner that allows tracking of both transport and delivery. The subject should acknowledge receipt of the shipment to the trial site (e.g. by returning a dated and signed receipt form).

In case adequate shipment by the trial site is not possible (for example, owing to capacity limitations, logistics or special transport conditions for the IMP), direct transport by the sponsor may be accepted in justified exceptional cases, provided that the sponsor appoints a suitably qualified service provider as a trustee. The sponsor must contractually oblige this service provider to maintain the pseudonymisation and, if necessary, blinding of the trial subjects towards the sponsor by means of appropriate measures. Both the transport and handover conditions for the IMP should be part of the contractual arrangements, so that pharmaceutical drug safety of the IMP as well as protection of the privacy and personal data of the trial subjects are adequately safeguarded. IMP must be delivered to the trial subject directly or to a person authorized by the subject and must not be given to neighbours or deposited at a storage location. Written confirmation of dose and dose regimens by the investigator should also be obtained prior to shipment.

The personnel of the service provider in charge of the transport should be trained and instructed accordingly.

As personal data are transferred to the service provider, this requires a contract of assignment with the sponsor or his legal representative.

For direct shipment of IMP to trial subjects, written instructions on storage and return of used and unused IMP should be provided to trial subjects.

When IMP is shipped by trial sites or by contracted service providers, their receipt, consumption and return must be documented in a form that allows the trial site to meet its documentation requirements (drug accountability), as defined in ICH GCP 4.6.3.

Usually, the dispensing of IMP at the trial site is associated with other trial-related activities (e.g. diagnostic investigations and/or clinical evaluations). A change in the trial protocol in this regard, for example by the introduction of a previously unplanned remote treatment or the discontinuation of previously planned trial-related measures (e.g. laboratory tests, medical consultation, etc.), requires in all cases approval by the higher federal authority and a favourable opinion by the ethics committee. Therefore, the intended trial protocol amendments must be submitted together with the intended amendments regarding IMP supply to the trial subjects as asubstantial amendment according to § 10 GCP-V. When using telemedicine, the necessary standards, including the requirements for data protection, must be adhered to. If external service providers, e.g. home-care services, as sumetrial-related tasks, it must be ensured that the source data collected by them are transmitted to the investigator and that the persons employed are subject to the investigator’s instructions and reporting obligations towards the investigator. The descriptions of trial sites (which are part of the submission to the ethics committees)must be adapted accordingly. In justified individual cases, these measures can be taken to protect against immediate hazards in accordance with §11GCP-V. The obligation to immediately provide post-hoc information on these measures in accordance with § 13, paragraph 5 GCP-V remains unchanged.

The trial subjects must be informed about the changed procedures with a supplement to the patient information and should give their consent to this. » (Supplementary recommendations to the document European Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 1.0, Bfarm, Allemagne, 26 March 2020)

ES En Espagne, l’envoi à domicile ou la réception par une personne autorisée sont possibles durant les mesures prises pour lutter contre le Covid-19 sous réserve que le Promoteur et la PUI puissent s’assurer de la bonne réception et de la bonne administration du traitement au patient

ES Espagne « 3. Acceso al tratamiento del ensayo
Los Servicios de Farmacia de los hospitales podrán tomar las medidas que consideren necesarias, por ejemplo, la dispensación a una persona autorizada por el paciente del ensayo de un tratamiento que deba tomarse en casa o el envío desde el Servicio de Farmacia del tratamiento al domicilio del paciente cuando sus circunstancias lo hagan aconsejable. En relación con esto último, deberá asegurarse la conservación del tratamiento durante el transporte y la comunicación con el paciente que permita la recepción y adecuada administración del mismo. Se tendrá en cuenta la sección 10 del documento “Q&A: Good clinicalpractice (GCP)” – GCP Matters”. Deberá valorarse la situación en cada caso particular, por parte del promotor, el investigador principal y el Servicio de Farmacia. »
(Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020)

DK Au Danemark, l’envoi au domicile du patient est toléré jusqu’au 17 juin 2020 sous conditions

DK Danemark « 4. Changes to shipment/handling/stock of IMP
In case of urgent shortage of IMP at some sites, we acknowledge the need to potentially re-distribute IMP between sites in accordance with GMP annex 13 (section 47). Sponsors should assess whether sites can handle and control such a redistribution process, especially in case of restricted conditions for storage, such as the need for specific conditions out of room temperature (e.g. 2-8° C).
Redistribution should follow a written procedure established in cooperation with the Qualified Person or the person responsible for distribution of IMP, and sites should be provided with sufficient information to ensure that the process can be performed securely. (…)

Temporary option to distribute directly to clinical trial subjects (temporary ex-emption from § 23 (2), of the GDP executive order because of COVID-19):
We acknowledge that clinical trials may experience acute IMP shortages caused by COVID-19 related quarantines and cancellations of on-site visits. Considering these highly unusual circumstances, we have decided upon a temporary possibility for sponsors to distribute trial medicine directly to the trial subjects without involving the investigator or hospital pharmacies.

This temporary option is valid until 01 september 2020.
We will assess whether an extension is needed two weeks before expiry. Sponsors may avail themselves of this option on the following terms:

  • Sponsor has a MIA (manufacturing authorisation) or a WDA (wholesale au-thorisation) that covers distribution of investigational medicinal products.
  • Sponsor may only distribute investigational medicinal products for clinical trials on Danish sites and should be on the basis of a risk assessment with patient safety as utmost priority.
  • Prior to the direct distribution, the viability of distribution via investigator/hos-pital pharmacy should have been investigated.
  • A courier needs to ensure that the shortest possible route of transportation is used and that the terms of storage are met in all parts of the supply chain. This must be documented.
  • The Danish Medicines Agency Q&A guidelines on supplying trial medicine directly to trial subjects (within the section ‘virtual/telemedicine trials’) must be followed to the greatest extent possible with patient safety as utmost pri-ority: https://laegemiddelstyrelsen.dk/en/licensing/clinical-trials/clinical-tri-als-questions-and-answers/. Among other things, this entails that proce-dures are in place ensuring that the trial medicine is delivered to the trial subject or their relatives only, and that it is possible for the trial subject to store the medicine in a suitable way. In other words, the trial medicine must be delivered personally and not delivered to neighbours or placed outside the door. In addition, sponsor must make sure that the trial subject has the required training to self-administrate trial medicine or otherwise assess if assistance from a nurse may be required (see section 5).
  • Direct distribution to trial subjects is implemented as an urgent safety meas-ure. Notification to us on this procedure must comply with the general re-quirements set in this guidance (see section 2).
  • The trial medicine may only be dispatched to trial subjects after agreement with the investigator and on the basis of the investigator’s prescription. Fur-thermore, procedures for the accountability of the trial medicine must be in place (among other for compliance monitoring).
  • Sponsor may not store the personal data of the trial subject for a longer period than is required for the purpose of dispatching the medicine to the subject. Sponsor may only authorise a limited number of employees to pro-cess the personal data in order to dispatch the medicine
  • Sponsor must ensure that trial subjects is informed that the trial medicine will be delivered directly to their homes.

Trial subjects assigned to a Danish site but living abroad
We do not limit the delivery of IMPs to trial subjects, who are assigned to a Danish site, but who are staying abroad. However, it is important that the sponsor in these cases consult the authorities of the country concerned, whether they impose require-ments or restrictions »
(Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated
24 avril 2020)

DK Danemark « Hand-out of IMP at on-site visits:
If on-site visits are required, but the frequency of visits is limited, it should be consid-ered whether the trial participant can be given IMP for a longer period than normal. It should be considered for all trials whether the trial participants should have IMP handed out for a longer period than usual in the event of a deterioration of the current situation. However, it should be taken into account that certain marketed drugs are used in the treatment of COVID-19 and other critical illnesses. The primary concern is that no deficiencies arise, so that COVID-19 treatment is prevented. »
(Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

NL Aux Pays-Bas, l’envoi du traitement à domicile ne doit pas faire l’objet d’une information du Review Commitee mais la procédure doit être enregistrée par écrit

NL Pays-Bas « Study medication can be sent directly to the research subject by courier from the (hospital) pharmacy for reasons of subject safety; you need not inform the review committee about this, but do record this temporary procedure in writing » (Recommendations for the conduct of clinical research at the time of restrictive measures due to the coronavirus, CCMO, The Netherlands, March 2020)

us Aux Etats-Unis, l’envoi du médicament
auto-administrable à domicile doit faire l’objet d’un amendement au Protocole qui peut être soumis en urgence ou dans le cadre d’un “cumulative” amendment comprenant toutes les mesures liées au Covid-19

us Etats-Unis « Q7. If patients are currently dispensed investigational product through a pharmacy for self-administration at home, can a sponsor switch that to home delivery without amending the protocol?

If there is concern about risk of exposure to COVID-19, home delivery of investigational productthat would not raise any new safety risks may be implemented to protect patients from coming to clinical trial sites. In all cases, requirements under FDA regulations for maintaining required investigational product storage conditions and investigational product accountability remain; these requirements must be addressed and documented (21 CFR 312.60; 312.62, and 812.140). If the protocol indicates pharmacy dispensing for self-administration at home, and this is changed to direct-to-patient shipments, then a protocol amendment would be required to permit home delivery of investigational product.5 If the extent of home delivery is limited to certain participants and not the entire population described in the protocol, documenting the change in the mechanisms of distribution of investigational product administration through protocol deviations may also be acceptable. If the change in the mechanisms of investigational product distribution is then included in a protocol amendment, such a change may be part of a “cumulative” amendment that includes a number of changes that accrue, rather than an urgent protocol change.«  (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

CA Le Canada autorise l’envoi directement chez le patient
des médicaments auto-administrables si les conditions de transport et de traçabilité sont remplies

CA Canada « The FDR do not prohibit the shipment of clinical trial investigational products (IP) from Canadian sites directly to patients. This approach would be acceptable for all product formulations (e.g., tablets, injectables); however, the following considerations and/or requirements should be kept in mind:

  • This approach can only be considered for drugs that a subject could take on their own (e.g., subject already in a trial and on medication, and if the trial uses a medication that doesn’t have to be administered in a hospital/clinic setting or have any special conditions for handling).
  • Record keeping must comply with regulatory requirements of section C.05.012 of the FDR. As per C.05.012(3)(e), the sponsor must maintain complete and accurate records in respect of the use of a drug in a clinical trial, including records respecting the shipment, receipt, disposition, return and destruction of the drug.
  • The trial must always be conducted in accordance with Good Clinical Practices (GCP) and must comply with regulatory requirements of section C.05.010 of the FDR. It is the sponsor’s responsibility to ensure that the drug is administered in accordance with these Regulations.
  • Products must be transported, handled and stored in a manner that mitigates the risk of exposure to temperatures outside labelled storage conditions (please refer to the
    Health Canada Guidelines for Temperature Control of Drug Products during Storage and Transportation (GUI-0069)).

For detailed guidance on how to comply with Part C, Division 5 of the FDR, please refer to the Guidance Document: Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving Human Subjects” (GUI-0100) » (Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors, Health Canada, 23 March 2020)

CA Canada « Getting investigational product to participant

  • The Food and Drug Regulations (FDR) do not prohibit the shipment of clinical trial investigational products (IP) from Canadian sites directly to patients.
  • This approach would be acceptable for all product formulations (e.g. tablets, injectables).
  • This approach can only be considered for specific trial designs and drugs that a subject could take on their own (e.g. subject already in a trial and on medication, and if the trial uses a medication that doesn’t have to be administered in a hospital/clinic setting or have any special conditions for handling).
  • The investigational products must be transported, handled and stored in a manner that mitigates the risk of exposure to temperatures outside labelled storage conditions.
  • Verification that the investigational drug has been received by the participant is required.
  • Accurate documentation of the process in the participant’s study record is required. » (Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors, Health Canada, 23 March 2020, Updated on 3 April 2020)

Possibilité, lors des visites programmées, de fournir au patient le traitement pour une durée plus longue qu’initialement prévue

fr France « La délivrance des traitements expérimentaux pour des durées supérieures est-elle autorisée ?
Oui dans le respect des consignes de sécurité, de l’information du patient et de la traçabilité.
En cas de suppression des visites lors desquelles les médicaments ou dispositifs expérimentaux auraient dû être délivrés aux patients, des dispositions doivent être prévues afin d’évaluer la tolérance au traitement et d’adapter celui-ci si nécessaire, par exemple par téléconsultation.

  • Notification pour information à l’ANSM (MSI) incluant des mesures additionnelles sur le suivi.

Attention : les produits stupéfiants sont exclus de cette mesure.«  (FAQ – Covid 19 – Essais cliniques en cours, ANSM, France, 20 mars 2020, Mise à jour du 3 avril 2020)

fr France « Is the delivery of investigational products for longer durations allowed?
Yes in compliance with safety instructions, patient information and traceability.

If visits during which the investigational medicinal products or devices should have been delivered to patients are skipped, arrangements must be made to assess the tolerability of the treatment and to adjust the treatment if necessary, for example by teleconsultation.

  • Notification to ANSM (SM-I) including additional measures on follow-up.

Caution : narcotic products are excluded from this measure.«  (QnA – Covid 19 – Ongoing clinical, ANSM, France, 20 March 2020)

ES Espagne « 3. Acceso al tratamiento del ensayo
Se debe garantizar el acceso de los pacientes a la medicación del ensayo en las mismas condiciones en las que se estaba dando. Se recomienda que el investigador valore la posibilidad y conveniencia de que, cuando el paciente acuda a una visita programada reciba una cantidad de medicamento que permita cubrir un periodo mayor de tratamiento.
Los Servicios de Farmacia de los hospitales podrán tomar las medidas que consideren necesarias, por ejemplo, la dispensación a una persona autorizada por el paciente del ensayo de un tratamiento que deba tomarse en casa o el envío desde el Servicio de Farmacia del tratamiento al domicilio del paciente cuando sus circunstancias lo hagan aconsejable. En relación con esto último, deberá asegurarse la conservación del tratamiento durante el transporte y la comunicación con el paciente que permita la recepción y adecuada administración del mismo. Se tendrá en cuenta la sección 10 del documento “Q&A: Good clinical practice (GCP)” – GCP Matters”. Deberá valorarse la situación en cada caso particular, por parte del promotor, el investigador principal y el Servicio de Farmacia. »
(Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020)

IT Italie « 1. Investigational medicinal product (IMP) management
If possible, when the patient goes to the study site for a visit, it may be useful to provide an amount of medicinal product covering a longer period of time than is normally estimated.
According to current legislation (article 7 of the Ministerial Decree 21st December 2007), the Sponsors must send investigational drugs needed for the trial to the pharmacy of the investigational site, that is in charge for their registration, appropriate storage and delivery to the investigator. Therefore, considering the COVID-19 serious emergency, even if the priority mode remains the delivery to the hospital pharmacy that then proceeds to the subsequent delivery to the investigational centre, direct deliveries from the hospital pharmacy to the trial subjects also through dedicated couriers can be arranged, upon indications of both the hospital pharmacy Director and the Principal Investigator (PI). It is intended that the hospital pharmacy is responsible for the process supervision; the pharmacy and the PI must be constantly informed on the delivery, according to procedures established for the correct conduction of the trial and by the above-said risk plan, that must take into account the IMP typology, administration methods, conservation and transport. Adequate remote communication ways with involved subjects must be implemented to replace the information that will no longer be provided in person. Depending on the case, telephone and/or video call can be used to inform the patient, where deemed necessary. Adequate tracking of what is being implemented in this emergency situation is recommended. All this without prejudice, if possible, to conditions set out in FAQ 10 of the EMA Document “Q&A: Good clinicalpractice (GCP)” – GCP Matters (https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-clinical-practice/qa-good-clinical-practice-gcp).
If the CRA of the study is not able to carry out the control on the final accounting of the investigational medicinal product for the purpose of reconciliation, and this operation is considered as impossible to be postponed, it can be carried out by a pharmacist of the hospital pharmacy or by the study coordinator/data manager, appropriately trained. The IMP can be returned to the Sponsor directly by the hospital pharmacy. »
(Notice – Clinical trials’ management in Italy during the COVID-19 (coronavirus disease 19) emergency, AIFA, Italia, 12 march 2020)

PE Pérou « 3. Acceso al tratamiento del ensayo
Se debe garantizar el acceso de los pacientes a la medicación del ensayo bajo las mismas condiciones estipuladas en el protocolo de estudio aprobado. Se recomienda que el investigador valore la posibilidad y conveniencia cuando sea posible, que el paciente acuda a una visita programada reciba una cantidad de medicamento que permita cubrir un periodo mayor de tratamiento. »
(Covid-19 – Communicado N° 002-2020-OGITT/INS, Ministerio de Salud, 26 de Marzo 2020)

Possibilité de redistribuer les médicaments expérimentaux entre différents sites

eu Europe « In case of urgent shortage of IMP at some sites or transfer of trial participants from one clinical trial site to another site, there might be a need to potentially re-distribute the IMP between sites in accordance with GMP annex 13 (section 47). This should only be considered in cases where a direct distribution of the IMP to a trial site by the usual distributor is not possible or in the exceptional circumstance where a trial participant is transferred from one site to another. Sponsors should assess whether sites can handle and control such a re-distribution process, especially in case of restricted conditions for storage such as the need for specific conditions other than room temperature (e.g. -20°C, +2-8°C).

Re-distribution should follow a written procedure established in cooperation with the Qualified Person or the person responsible for distribution of the IMP, and sites should be provided with enough information to ensure that the process can be performed securely. Appropriate associated records should be included in the transfer and retained. Adequate documentation of the transfer needs to be included in the investigators’ and the sponsor’s trial master file. » (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 28 April 2020)

eu Europe « In case of urgent shortage of IMP at some sites or transfer of trial participants from one site to another clinical trial site, there might be a need to potentially re-distribute the IMP between sites in accordance with GMP annex 13 (section 47). This should only be considered in cases where a direct distribution of the IMP to a trial site by the usual distributor is not possible or in the exceptional circumstance where a trial participant is transferred from one site to another. Sponsors should assess whether sites can handle and control such a re-distribution process, especially in case of restricted conditions for storage such as the need for specific conditions other than room temperature (e.g. +2-8° C). Re-distribution should follow a written procedure established in cooperation with the Qualified Person or the person responsible for distribution of the IMP, and sites should be provided with sufficient information to ensure that the process can be performed securely. Associated records should be included in the transfer » (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

DK Danemark « 4. Changes to shipment/handling/stock of IMP
In case of urgent shortage of IMP at some sites, we acknowledge the need to potentially re-distribute IMP between sites in accordance with GMP annex 13 (section 47). Sponsors should assess whether sites can handle and control such a redistribution process, especially in case of restricted conditions for storage, such as the need for specific conditions out of room temperature (e.g. 2-8° C).
Redistribution should follow a written procedure established in cooperation with the Qualified Person or the person responsible for distribution of IMP, and sites should be provided with sufficient information to ensure that the process can be performed securely. (…)

Hand-out of IMP at pharmacies:
In open trials (it is not appropriate if IMP is blinded), it may be an advantage to supply IMP through the Danish pharmacies. Such procedure is subject to the following terms:

  • This only applies to clinical trials on Danish sites during the COVID-19 pan-demic and a risk assessment must be carried out with priority to patient safety.
  • The trial drug must be marketed and used within the approved indication (according to the SmPC).
  • A simple process for reimbursement of the expense should be implemented.
  • It must be ensured that the name of the sponsor or investor is printed on the label together with a reference code, that ensure identification of the site, investigator and trial subject
  • There must be procedures in place at the investigator site to ensure that the IMP is accounted for (for compliance monitoring). » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

BG Bulgarie « 6. Il est recommandé de maintenir les médicaments et les dispositifs médicaux des essais cliniques en quantité appropriée pour assurer la continuité du traitement en cas de difficulté de livraison. Dans des cas exceptionnels, en cas de pénurie, une redistribution des quantités entre centres agréés est autorisée. Le promoteur doit s’assurer que les conditions de stockage et la sécurité de l’approvisionnement sont maintenues, en suivant une procédure écrite et une documentation bien établies à chaque étape du processus. Ces actions nécessitent une notification à la BDA. » (Traduction des Recommandations aux commanditaires concernant la conduite des essais cliniques dans le cadre du risque complexe de Covid-19 d’une déclaration de l’état d’urgence dans le pays, Version Bulgare )

BG Bulgarie « 6. It is recommended that the medicinal products and the medical devices in the clinical trials should be maintained in appropriate quantities in order to ensure the continuity of treatment in case of difficulty in the delivery. In exceptional cases, in the case of shortages, redistribution of quantities between sites is permitted. The sponsor should guarantee that the storage conditions and the security of the delivery are ensured, following an established written procedure and documenting each stage of the process. A notification to BDA is required. » (Recommendations to the Sponsors for managing of Clinical Trials during the COVID-19 pandemic and the declared State of emergency in the Republic of Bulgaria, BDAn Bulgarie, 24 March 2020)

Afrique du Sud « Impact of social distancing measures on investigational and other products administration: If scheduled visits at clinical sites will be significantly impacted, certain investigational and other products, such as those that are typically distributed for self-administration, may be amenable to alternative secure delivery methods. For investigational and other products that are normally administered in a health care setting, consulting SAHPRA on plans for alternative administration (e.g. home nursing or alternative sites by trained but non-study personnel) is recommended. In all cases, existing regulatory requirements for maintaining investigational and other product accountability remain and should be addressed and documented. (SAHPRA Policy on Conduct of Clinical Trials of Health Product during the current COVID-19 pandemic, SAHPRA, 25 mars 2020)

us Etats-Unis « If scheduled visits at clinical sites will be significantly impacted, certain investigational products, such as those that are typically distributed for self-administration, may be amenable to alternative secure delivery methods. For other investigational products that are normally administered in a health care setting, consulting FDA review divisions on plans for alternative administration (e.g., home nursing or alternative sites by trained but non-study personnel) is recommended. In all cases, existing regulatory requirements for maintaining investigational product accountability remain and should be addressed and documented. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

Possibilité de recourir à des soins à domicile ou par un professionnel de santé de ville

us Etats-Unis « If scheduled visits at clinical sites will be significantly impacted, certain investigational products, such as those that are typically distributed for self-administration, may be amenable to alternative secure delivery methods. For other investigational products that are normally administered in a health care setting, consulting FDA review divisions on plans for alternative administration (e.g., home nursing or alternative sites by trained but non-study personnel) is recommended. In all cases, existing regulatory requirements for maintaining investigational product accountability remain and should be addressed and documented. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q8. If patients are currently receiving an investigational product infusion at the clinical trial site, can a sponsor switch to home infusion?

Sponsors should consider the safety risk to trial participants who would miss an investigational product infusion because of the inability to come to the clinical trial site. In general, for investigational product that is usually administered in a health care setting, consulting the appropriateFDA review divisions is recommended regarding plans for alternative sites for administration (e.g., home nursing or alternative sites by trained but non-study personnel). For example, consulting FDA would be strongly advised for complex investigational products (e.g. cellular therapy and gene therapy products) where potentially altered storage and handling conditions could adversely affect product stability. In all cases, applicable requirements for maintaining required investigational product storage conditions (prior and after reconstitution), investigational product reconstitution specifications per the Investigational Brochure, and investigational product accountability remain and must be addressed and documented. Storage conditions and investigational productaccountability should be considered if the protocol is amended to permit alternative site infusions. Defining circumstances when discontinuing investigational product treatment, while continuing study participation albeit with potentially delayed assessments, may be an appropriate option when suitable alternative arrangements cannot be made. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q15. During the COVID-19 public health emergency, certain patients may no longer be able to travel to a central location for protocol-based treatment that is scheduled on a recurring basis. Can the investigational product intended for infusion be shipped to a local health care provider who is not a sub-investigator to administer the infusion to a patient while still maintaining integrity of the trial? If so, what else would be needed regarding trial monitoring and institutional review board (IRB) oversight?

Specific circumstances for a given clinical trial would affect the feasibility and appropriateness of shipping investigational products (IP) to locations other than clinical trial sites as specified under an IND, as well as administering the IP. If the IPs being evaluated in the trial are administered by infusion, then it would be important that any alternative infusion center have appropriately trained personnel and oversight by physicians with sufficient experience regarding the class of products involved to assure subject safety comparable to administration at a trial site.

For the purposes of this guidance, local health care providers (HCPs) who are administering drugs in a manner that does not differ from their normal clinical practices would not be considered sub-investigators and need not be listed on Form FDA 1572. FDA recommends that these HCPs be listed in site records, such as a log of activities delegated by the investigator. Any changes to a trial protocol to permit an HCP to administer the investigational drug generally must be reviewed and approved by an IRB.

The above paragraph described administration of the investigational product by local HCPs who arepracticing medicine within their scope of practice. In contrast, if a sponsor will be asking local HCPs to perform study-specific research procedures or assessments that represent a direct and significant contribution to the clinical data for the study (e.g., assessing drug response for a patient or performing a procedure unique to the study and not part of routine medical care), these HCPs would be considered sub-investigators and should be listed on Form FDA 1572.

IP may be shipped from a central distribution site directly to an HCP, provided that such shipping is done under the supervision of the investigator using procedures that assure accountability and product quality (i.e., that storage conditions, as defined in the protocol, for the IP were maintained during shipping, and the drug packaging was intact upon receipt).

If the HCP administering the IP is not considered a sub-investigator, the investigator should ensure that they can obtain records regarding administration of the IP by requesting that the trial participants provide consent to allow access to medical records from their local HCPs involving trial-related data such as measuring vital signs, and results of evaluations of any symptoms or signs occurring with the infusion. Communicating the intent to request such records from the HCP in advance may facilitate this process.

Consulting the appropriate FDA review division(s) on plans for alternative administration is also recommended as per Q8 above » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 16 April 2020)

Possibilité pour le patient de s’approvisionner dans une officine de ville si le produit existe sous une forme commercialisée

us Etats-Unis « Q16. If a subject is unable to receive the investigational drug from the trial site but the product is FDA-approved for other uses, can the patient or health care provider secure the product commercially or is this considered the sponsor charging for the investigational drug under 21 CFR 312.8? Can the sponsor reimburse trial subjects for their out of pocket expenses in getting the drug commercially?

If the product(s) under investigation in a clinical trial is FDA-approved, and the study does not require blinding, then local sourcing of the product(s) would be acceptable to FDA (e.g., by having the local physician write a prescription for the product instead of shipping the product directly to the patient). FDA does not consider a trial participant’s commercial procurement of the study drug when unable to secure it from the trial site during the COVID-19 public health emergency to be a sponsor charging for an investigational drug under an IND per FDA regulations at 21 CFR 312.8. FDA also would not object if the sponsor reimburses the patient for any costs incurred by commercially purchasing the product or for charges related to an infusion.

Per FDA regulations at 21 CFR 312.6, the immediate package of an investigational new drug intended for human use must bear a label with the statement “Caution: New Drug–Limited by Federal (or United States) law to investigational use.” FDA recognizes that a commercially obtained product will not have this statement on its container. In the setting of the COVID-19 public health emergency, where alternative arrangements are being made to provide an investigational agent to a participant who is unable to come to the trial site, FDA intends to exercise flexibility without sponsors needing to seek a waiver under 21 CFR 312.10 of the investigational labeling requirements under 21 CFR 312.6. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 16 April 2020)

Procédures révisées d’autorisations initiales et d’amendements au Protocole

Examen des demandes d’amendements rendues nécessaires par l’épidémie de Covid-19

fr En France, des conventions de nommage ont été appliquées pour les demandes d’amendements

fr France « Soumission à l’agence dans le cadre d’un essai clinique nécessitant une adaptation en lien avec COVID-19 :

fr France « Submission to ANSM when related to COVID-19
National recommendation are available on ANSM website

eu La règlementation européenne clarifie les mesures prises durant l’essai devant être soumises comme des modifications substantielles

eu Europe « 6. COMMUNICATION WITH AUTHORITIES
Priority is given to any (new) clinical trial application for the treatment or prevention of COVID-19 infection, and/or substantial amendment applications to existing clinical trials necessary as a result of COVID-19.

For ongoing trials, the guidance given by EC CT-18 on substantial amendments remains applicable. A single submission by the same sponsor with the list of concerned trials and an aggregated list of changes is acceptable and encouraged in case of substantial amendments as well as of urgent safety measures.

Two important aspects need to be taken into account:

  1. It is up to the sponsor to assess whether an amendment is to be regarded as ‘substantial’. A change is substantial when it has a potential impact on the safety or physical or mental integrity of the clinical trial participant, or on the scientific value of the trial (CT-1 section 3.3, CT-2 section 59). Substantial amendments relate to amendments of documents/information that are part of the clinical trial application dossier.
  2. Submission of information is only obligatory if the amendment is a substantial amendment. Directive 2001/20/EC does not require notification, or immediate submission of information on non-substantial amendments. In other words, the only communication mechanism of substantial changes to information in the protocol or clinical trial dossier is through the submission of a substantial amendment. Non-substantial amendments, or changes that do not relate to information submitted in the clinical trial application dossier should be recorded in the documentation when it is subsequently submitted, for example in the subsequent submission of a substantial amendment (CT-1 section 3.1). »
    (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020,
    Updated on 28 April 2020)

eu Europe « The following table provides a non-exhaustive list of examples for the classification of different mitigating measures – more information on specific approaches can be found in the chapters 3, 9 and 11 below, and/or in the national recommendations, where applicable :

Urgent safety measures (a)
(in light of the conditions described above)
Substantial amendments (b)
(in light of the conditions described above)
Other measures (c)
(in light of the conditions described above)
Temporary halt due to shortage of trial medication Temporary halting of a trial, when it is not linked to the safety of trial participants
Direct distribution of IMP to trial participants/carer home or residence by a distributor in case of exceptional emergency situations (please refer to chapter 9 for more detail) Direct distribution of IMP to trial participants/carer home or residence by a distributor (please refer to chapter 9)  
Testing is performed in local laboratories instead of at the trial site    
  Introducing remote SDV (in exceptional cases, see chapter 11)  
Transfer of trial participants to another trial site, but treatment is continued    
Temporary de-activation of the trial site with discontinuation of treatment
  Changes to the as per protocol informed consent process  
Opening of new trial sites or relocation to existing trial sites to accommodate for the transfer of existing trial participants in case of emergency situations    
    Supplying trial participants with larger amounts of IMP under the supervision of the investigator »

(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 28 April 2020)

BE En Belgique, les mesures prises dans les essais en cours doivent être seulement documentées et non soumises si elles ne sont pas destinées à être permanentes

BE Belgique « All measures taken for the ongoing trials due to the COVID-19 pandemic need to be documented by the sponsor together with a justification and benefit/risk evaluation. A summary report of all measures should be available in the site master file of the trial and provided to the FAMHP and EC by the national end of trial.

In order to avoid over-reporting it is asked to the sponsors to keep a listing/overview of all mitigation measures taken due to the COVID-19 situation that are not permanent amendment/modification of the protocol and not urgent safety measures, with description, explanation and justification of each taken measure.

As we do not know how long the current crisis may last and as the virus may be seasonal, it is also asked to the sponsor to provide the listing/overview of measures taken, at regular basis, every 4 months to CT.RD@fagg-afmps.be. « (Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

DE En Allemagne, les demandes d’amendements consécutives à la situation pandémique sont prioritaires et doivent être si possible faites électroniquement

DE Allemagne « 2. Notifications of variation of ongoing clinical trials due to COVID-19
Due to the current situation, notifications of variations necessary due to the pandemic are given utmost priority. Applicants are requested to include a short reference to « COVID-19 » in the subject line of their cover letter. If possible, such submissions should be made electronically via the European CESP portal. »
(Clinical Trials during the COVID-19 Pandemic – Information on the authorisation and conduct of clinical trials of medicinal products during the COVID-19 pandemic (Version 2.1), BFarm, Allemagne, 30 March 2020)

DE Allemagne Les demandes d’amendements consécutives à la situation pandémique seront considérées comme prioritaires (une référence « COVID-19 » est requise en objet). (« Genehmigungsverfahren », BfARM Internet site, Germany, 19 März 2020)

BG En Bulgarie, les demandes de modifications substantielles sont prioritaires

BG Bulgarie « 3. Le promoteur, en collaboration avec le chercheur principal, devrait déterminer si les visites physiques (visites sur place dans les centres) peuvent être transformées en suivi à distance, appels téléphoniques, différés ou annulés entièrement en appliquant l’approche basée sur les risques, les capacités du protocole de test ou son amendement visant à garantir que seules les visites nécessaires soient effectuées dans les centres. En cas de modification substantielle du protocole, dans ces cas, accompagné de la documentation pertinente, il sera considéré comme prioritaire.
4. En l’absence d’alternative, le transfert des participants d’un centre à un autre – un centre nouveau / déjà approuvé dans le règlement est possible en cas d’urgence. Dans de tels cas, il est important de s’assurer que les patients sont traités en continu. Les participants au test et les deux chercheurs principaux doivent s’entendre sur la relocalisation, et le centre d’accueil devrait avoir un accès rapide aux informations – données collectées auprès des participants au test. Si une ou des demandes de modification substantielle sont nécessaires dans ces cas-là, elles devront être accompagnées d’une documentation pertinente, et leur examen sera priorisé.« 
(Traduction des Recommandations aux commanditaires concernant la conduite des essais cliniques dans le cadre du risque complexe de Covid-19 d’une déclaration de l’état d’urgence dans le pays, Version Bulgare )

BG Bulgarie « 3. The sponsor, in collaboration with the Principal Investigator, should consider if the physical visits (on-site visits) can be converted in remote tracking/visits, phone visits, postponed or canceled completely in applying the risk-based approach, the capabilities of the clinical trial’s protocol or its amendment, to ensure that only the strictly necessary visits are performed at sites. If a substantial amendment in the protocol in these cases is applied (accompanied by the relevant documentation), it will be prioritized as assessment by BDA.
4. In the absence of an alternative (applying the risk-based approach), the transfer of patients from one site to another, e.g. to a new site or existing site in the same settlement, could occur. In such cases it is important to ensure the treatment continuity of the patients. Both the trial participants and the two Principal Investigators must agree on the relocation, and the receiving site must have the possibility to access previously collected information/collected data for the trial participants. In these cases a submission of substantial amendments, accompanied by the relevant documentation, is needed and will be prioritized as assessment by BDA. »
(Recommendations to the Sponsors for managing of Clinical Trials during the COVID-19 pandemic and the declared State of emergency in the Republic of Bulgaria, BDAn Bulgarie, 24 March 2020)

UK Au Royaume-Uni les demandes d’amendements concernant le Covid-19 sont prioritaires

UK Royaume-Uni « 2. Amendments to existing studies to address COVID-19 elements
There are a number of possible scenarios where there may be a need to rapidly amend an existing study.

  • All amendments requiring submission should use the usual email route, clearly marking them with the subject header: IRAS ref# Amendment – COVID-19, so that they can be expedited.
  • For non-substantial amendments, the template non-substantial amendment form may be used. It is acceptable for the form to only be authorised by the sponsor.

All amendments should be sent to participating sites in accordance with existing guidance. To support site implementation it is important that:

  • The changes and local implications are made clear
  • Any changes to documentation are provided in tracked changes
  • For multi-centre studies in Scotland or Northern Ireland, amendments should be provided to the national coordinating functions for dissemination to the participating R&D offices as usual. Sponsors should continue to share with the PI/delivery teams.
    For single centre studies all correspondence to sites should be copied to R&D/I department and the PI/delivery teams. »
    (COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020, Updated to v2.2 on 26 March 2020)

UK Royaume-Uni « Amendments
If there are any actions you need to take in response to COVID-19 that are considered an amendment, tell us by emailing devices.regulatory@mhra.gov.uk and we will expedite the review. Please make it clear in your cover letter that the amendment is in response to COVID-19.
You must tell us about any changes made to:

  • the device under investigation
  • study documentation, including the clinical investigation plan
  • investigators or investigating institutions
  • changes requested by an ethics committee

We will assess any amendments that are not related to COVID-19 within normal MHRA processing times. » (Guidance- Medical devices clinical investigations during the coronavirus (COVID-19) outbreak, MHRA, Royaume-Uni, 30 March 2020)

DK Au Danemark, tout changement doit passer comme une Mesure Urgente de Sécurité et être soumise en priorité (à l’exclusion des changements abordés dans la Guidance « Extraordinary Mesures for clinical trials due to COVID-19 » qui ne doivent plus être soumises)

DK Danemark « We recommend that changes due to COVID-19 should be handled as ’Urgent Safety Measures’. Consequently, they can be implemented without approval from the Danish Medicines Agency. We should only be notified of changes implemented during the COVID-19 pandemic, that does not comply with this guidance and its terms, and have a significant impact on the benefit-risk of the trial (see section 2.1). (…) If substantial changes to patient safety or data integrity occur without requiring immediate changes in the trial, these should be submitted in accordance with normal substantial amendment procedures. We do not consider addition of COVID-19 testing substantial and we do not wish to be notified, if trial subjects are diagnosed with COVID-19. » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

DK Danemark « 2.1 Updated notification procedure
Based on the notifications received until now, we have decided that it is no longer necessary to submit changes covered by this guidance. However, changes must be continuously documented in the Trial Master File.
Specifically, this means that, for example, stopping inclusion at one or several sites (study halt), changes to the visit schedule (see section 5) and delivering medicine directly to participants will no longer be subject to notification requirements. Please note that sponsors are obliged to submit notifications when the situation has stabilised (see sub-section 2.3).

The requirement of submitting notifications within 7 days is still valid in those cases where other substantial changes are made, which significantly impact the benefit-risk or this guidance and its terms are not followed. In addition, we must be notified if there is an acute shortage of IMP without any substitution possibilities. In the notification, sponsor must explain how safety is monitored for trial participants who are deprived of treatment. Furthermore, we always need to be informed if the trial is terminated prematurely in accordance to normal practice. » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated on 1 April 2020)

DK Danemark « 2.2 Format and content of notifications
You should not submit documentation such as SOPs or instructions for those changes implemented because of the COVID-19 pandemic. We do expect an over-view of the substantial changes, which should be justified on account of the trial population and indication. In addition, it should be clearly stated that our recommendations from this guideline have been taken into consideration, accompanied with thorough justification in the event of non-compliance.

Notifications submitted is allowed to cover multiple clinical trials. However, First in Human trials must be addressed individually (please see section 5). The notification can be carried out by, for example, an Excel sheet (it might be ap-propriate using the same documentation added to the TMF with the overview of deviations), where all clinical trials are listed and it is noted which general and specific measures have been implemented. Please note that it is up to the sponsor how these orientations are most easily prepared » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated on 1 April 2020)

DK Danemark « 2.3 COVID-19 stabilisation and restoring normal practice
When the normal procedures are restored, a notification must be submitted describ-ing all actions taken in the trial due to the COVID-19 pandemic. These must follow the same requirements as given above, why a risk assessment is expected for both patient safety and data integrity. Furthermore, the notification must clarify how spon-sor plan to follow-up on, among other things, the lack of on-site monitoring (see sec-tion 3).

The notification can be submitted as a comprehensive list of deviations in each trial. The documentation submitted may be the same as added to the TMF. However, if the studies are extended due to delays in handling COVID-19, it is im-portant that the Expected Last Patient Last Visit (LPLV) is reported for each EudraCT number » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated on 1 April 2020)

us Aux Etats-Unis, les amendements visant à minimiser ou éliminer les dangers liés au Covid peuvent-être mis en oeuvre avant approbation mais doivent tout de même être soumis

us Etats-Unis « COVID-19 screening procedures that may be mandated by the health care system in which a clinical trial is being conducted do not need to be reported as an amendment to the protocol even if done during clinical study visits unless the sponsor is incorporating the data collected as part of a new research objective.

Changes in a protocol are typically not implemented before review and approval by the IRB/IEC, and in some cases, by FDA. Sponsors and clinical investigators are encouraged to engage with IRBs/IEC as early as possible when urgent or emergent changes to the protocol or informed consent are anticipated as a result of COVID-19. Such changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to COVID-19) may be implemented without IRB approval or before filing an amendment to the IND or IDE, but are required to be reported afterwards.4 FDA encourages sponsors and investigators to work with their IRBs to prospectively define procedures to prioritize reporting of deviations that may impact the safety of trial participants. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q4. How should a sponsor submit a change in protocol that results from challenges related to the COVID-19 pandemic?

For IND studies, the sponsor should submit a formal amendment to its IND, with the following information added to the cover letter in the subject line:

PROTOCOL AMENDMENT – COVID-19

TITLE OF PROTOCOL

Sponsors should summarize the major changes made to the protocol related to COVID-19 in the cover letter and should include a tracked changes version of the protocol to facilitate review. As with other protocol amendments, sponsors may implement protocol amendments due to COVID-19 upon submission to FDA if approved by the IRB. Sponsors seeking FDA input prior to implementation should indicate that in the cover letter.

For IDE studies, the sponsor should submit a supplement to its existing IDE, with the following information added to the cover letter in the subject line:

CHANGE IN PROTOCOL SUPPLEMENT – COVID-19 or
NOTICE OF IDE CHANGE – COVID-19, as applicable

TITLE OF PROTOCOL

The submission to the IDE should contain a tracked changes version of the protocol to facilitate review. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

En Afrique du Sud, l’impact sur les participants détermine la soumission des amendements au SAHPRA et au comité d’éthique soit pour autorisation soit pour information

Afrique du Sud « Sponsors and principal investigators are encouraged to consider alternative approaches or changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g. to limit exposure to COVID-19). Protocol amendments should typically not be implemented before review and approval by SAHPRA and relevant ethics committees.
Protocol amendments occasioned by COVID-19 may include:

AU En Australie, les demandes d’examen qui seront indentifiées comme relatives au Covid-19 seront examinées de façon prioritaire

AU Australie « CTN processes
The vast majority of clinical trials of unapproved therapeutic goods in Australia are conducted through the Clinical Trial Notification (CTN) scheme. This is also the case for clinical trials relating to treatment or prevention of COVID-19.

The CTN scheme is a notification scheme and, as such, we do not review or evaluate any data relating to the clinical trials at the time of submission. All material relating to the proposed trial, including the trial protocol, must be submitted directly to the relevant Human Research Ethics Committee (HREC).

Under the Therapeutic Goods Regulations 1990, once a CTN form is submitted and the relevant fee is paid, the trial is deemed to be ‘notified’ and the unapproved therapeutic good/s can be lawfully supplied for the purposes of the trial.

The TGA’s acknowledgement of the trial is an administrative process and, for our purposes, is not required before the trial can begin. However, we appreciate that some HRECs and Approving Authorities do require TGA acknowledgement prior to commencement. We will accept CTN form submissions while the sponsor is obtaining any required approvals from the HREC and Approving Authority.

To submit a CTN, login to the online TBS portal menu. Refer to the Clinical trial notification (CTN) form – user guide for guidance. If you do not have access to the online TBS portal menu, please contact TBS Helpdesk at ebs@tga.gov.au or 1800 010 624. The target time to process online CTNs is 5-7 working days.

For COVID-19 related trials, once you have submitted the online CTN form and paid the relevant fee, contact our Clinical Trials team on 02 6289 4614 or email clinical.trials@health.gov.au and we will ensure the trial is processed as a priority.

See the TGA’s Clinical Trials web page for further information about clinical trials undertaken through the Clinical Trial Exemption (CTX) scheme. CTX requires an evaluation process by the TGA and timeframes and data requirements may vary. Trial sponsors should contact us about COVID-19 clinical trials proposed to be conducted under the CTX scheme as early as possible. » (Coronavirus (COVID-19): Information on medicines and medical devices, TGA, Australie, 31 March 2020)

Demande d’examen des demandes d’autorisation d’essais cliniques relatifs au Covid-19

fr En France, mise en place d’une procédure accélérée pour l’évaluation initiale des demandes d’autorisation et dérogations mises en place

Mise en place d’une procédure accélérée pour les essais cliniques portant sur la prise en charge de patients Covid-19

fr France Modalités d’évaluation des essais cliniques en lien avec la prise en charge de la pandémie COVID-19
Des procédures accélérées pour l’évaluation initiale des demandes d’autorisations ont été mises en place par l’ANSM, la DGS et l’ensemble des CPP. Afin de garantir le bon suivi de ces dossiers, il convient de prendre contact avec l’ANSM et la DGS afin de prioriser l’essai clinique, d’orienter l’évaluation et d’établir si des informations additionnelles sont nécessaires.
Modalités de soumission

Comme demandé à l’Organisation Mondiale de la Santé, le promoteur doit veiller inclure dans le titre de la recherche la mention COVID-19.
Un contact avec la DGOS est possible pour information sur les lieux de recherche sélectionnés: DGOS-PF4@sante.gouv.fr
De même pour les déclarations de vigilance (cas individuels, faits nouveaux et RAS) relatives à ces essais, ajouter au début du nommage des mails habituels la mention « COVID-19_
Les équipes développant des médicaments ou des vaccins sont invitées à contacter l’EMA dès que possible pour partager des informations sur leur projet en envoyant un courriel à 2019-ncov@ema.europa.eu.
L’EMA offre une dispense de frais et une procédure accélérée pour les avis scientifiques . »
(FAQ – Covid 19 – Essais cliniques en cours, ANSM, France, 20 mars 2020, Mise à jour du 27 mars 2020)

fr France « Modalities for the evaluation of clinical trials related to the management of the pandemic COVID-19
Accelerated procedures for the initial assessment of applications for authorisation have been put in place by ANSM, DGS and all ECs.
In order to ensure the proper follow-up of these dossiers, contact should be made in order to prioritize the clinical trial, guide the evaluation and determine whether additional information is needed.
Submission of an initial clinical trial application

As requested by the WHO, sponsor must ensure that the WHO official acronym for the coronavirus disease (COVID-19) is entered in the title field of the trial registration data set.
A contact with Ministery of Health (DGOS) is possible for information on the selected research sites: DGOS-PF4@sante.gouv.fr .
Similarly for the vigilance statements (individual cases, news events and annual safety report) relating to these tests, add at the beginning of the naming of the usual emails the mention « COVID-19 ».
It should be noted that the developers of medicines or vaccines are invited to contact EMA as soon as possible with information about their proposed development by emailing 2019-ncov@ema.europa.eu . EMA provides a full fee waiver and a fast-track procedure for scientific advice . »
(QnA – Covid 19 – Ongoing clinical, ANSM, France, 20 March 2020, Updated on 27 march 2020)

Les CPP ne sont plus désigné spar tirage au sort (jusqu’à une date fixée par décret) pour les recherches portant sur le Covid-19

fr France « I. – Lorsqu’un projet de recherche impliquant la personne humaine vise à lutter contre l’épidémie de covid-19, il est soumis, par dérogation aux dispositions de l’article L. 1123-6 du code de la santé publique et jusqu’à une date fixée par décret, et au plus tard jusqu’au 31 décembre 2021, à l’avis d’un comité de protection des personnes désigné par le ministre chargé de la santé, qui se prononce dans les conditions prévues à l’article L. 1123-7 du code de la santé publique. » (Ordonnance n° 2020-460 du 22 avril 2020 portant diverses mesures prises pour faire face à l’épidémie de covid-19, JO, France)

Dossier allégé pour les Recherches Non Interventionnelles ne portant pas sur un produit de santé

fr France « II. – Par dérogation aux dispositions de l’article L. 1123-7 du code de la santé publique et jusqu’à la date de cessation de l’état d’urgence sanitaire déclaré en application de l’article 4 de la loi du 23 mars 2020 susvisée, le cas échéant prolongé dans les conditions prévues par cet article, le dossier des recherches non interventionnelles ne portant pas sur un produit mentionné à l’article L. 5311-1 du code de la santé publique soumis au comité de protection des personnes comprend :

  1. Un document attestant que la recherche est conçue et réalisée conformément aux dispositions du titre II du livre Ier de la première partie du code de la santé publique;
  2. Une déclaration attestant la conformité des traitements de données ayant pour finalité la réalisation de la recherche à une méthodologie de référence homologuée par la Commission nationale de l’informatique et des libertés en application de l’article 73 de la loi du 6 janvier 1978 susvisée;
  3. Un questionnaire d’auto-évaluation défini par arrêté du ministre chargé de la santé.

Le comité rend son avis au regard des éléments de ce dossier. Le comité s’assure, pour rendre son avis, que la recherche n’est pas interventionnelle, ne porte pas sur un produit mentionné à l’article L. 5311-1 et répond aux conditions applicables à ces recherches.

Un contrôle des dossiers, sur lesquels les comités de protection des personnes ont rendu un avis, est assuré dans des conditions fixées par décret, notamment afin de vérifier que la mise en oeuvre de ces recherches respecte les règles applicables aux recherches mentionnées au premier alinéa du présent II.

III. – Les dispositions des I et II du présent article sont applicables en Nouvelle-Calédonie, en Polynésie française et à Wallis-et-Futuna.

Les références aux articles L. 1123-6, L. 1123-7 et L. 5311-1 du code de la santé publique mentionnées aux I et II s’entendent de la rédaction de ces articles résultant:

eu En Europe, les Promoteurs sont encouragés à utiliser l’évaluation rapide de la Voluntary Harmonisation Procedure (VHP)

eu Europe « The Member States support the submission of large, multinational trial protocols for the investigation of new treatments for COVID19.
In addition, sponsors are encouraged to consider the submission of such applications for an accelerated Voluntary Harmonisation Procedure (VHP) assessment when possible. In order to avoid or minimise delays due to the harmonised review, sponsors are recommended to prospectively contact the proposed Ref NCA to explore the feasibility of an accelerated VHP (plus) process.
It should be noted that the developers of medicines or vaccines are invited to contact EMA as soon as possible with information about their proposed development by emailing 2019-ncov@ema.europa.eu. EMA provides a full fee waiver and a fast-track procedure for scientific advice. »
(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

BE En Belgique, les Promoteurs sont encouragés à passer leurs projets de recherche nationaux concernant le Covid-19 via la phase pilote du Règlement européen n°536/2014 et encouragés à les faire passer par la voie de la VHP lorsqu’ils concernent plusieurs pays

BE Belgique « 2.Procedure and communication with authorities

Priority is given to any (new) clinical trial applications for the treatment or prevention of COVID-19 infection, and/or substantial amendment applications and notifications to existing clinical trials necessary as a result of COVID-19.

Please contact the FAMHP (ct.rd@fagg-afmps.be) prior to submitting a COVID-19 related trial.
When considering submitting a multi-country COVID-19 related trial, please consider the accelerated Voluntary Harmonisation Procedure.

For the FAMHP: Please submit exclusively electronically via CESP, clearly mark all applications with ‘COVID-19’ in the subject field and indicate this in the cover letter as well.

For national COVID-19 related trials: the accelerated CTR Pilot is strongly recommended. The pilot has the benefit that a single submission to the national contact point is sufficient and that a single review by the selected evaluating EC (without possible local ECs) is foreseen. The structure of the submitted dossier can follow the requirements of the law of 7 May 2004 or the structure of the CTR. If the structure of the dossier of the law of 7 May 2004 is followed, please provide additionally the document in annex (written statement) for each site.

The FAMHP commits to validate and review in four working days, as will do the evaluating EC.

The CT-College may use adapted criteria to select the evaluating EC and send the dossier to an EC of the CTR Pilot who has applied to take part in this procedure and committed to perform the review in four working days after submission. This may be the EC of the site.

At the validation of the dossier, it will be accepted that a written statement of the suitability of the site is lacking. The sponsor is requested to provide any lacking written statement together with the answers to the Request For Information (RFI)-letter.It is to be reminded that Scientific Technical Advice (sta-wta@fagg-afmps.be) can be requested, where upon submission of the corresponding CTA for the pilot in the following two years, the fee does not have to be paid. »(Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

DE En Allemagne, les projets concernant le Covid-19 et les demandes de réduction de taxe concernant ces recherches sont prioritaires

DE Allemagne « 3. Clinical trials of medicinal products related to COVID-19
The BfArM treats all applications and requests for advice in direct connection with clinical trials and drug development related to COVID-19 with utmost priority and flexibility. We have installed the special e-mail address CT-COVID@bfarm.de for questions in connection with clinical trials related to COVID-19. Please use this address only for inquiries and not for submission of variation notifications or applications for authorisation. For clinical trial applications there is the possibility of a fee reduction according to Section 3 (2) AMGKostV. Such applications for fee reductions are processed with priority. The same applies to scientific advisory procedures prior to clinical trials. »
(Clinical Trials during the COVID-19 Pandemic – Information on the authorisation and conduct of clinical trials of medicinal products during the COVID-19 pandemic (Version 2.1), BFarm, Allemagne, 30 March 2020)

DK Au Danemark, les projets de recherche clinique portant sur le Covid-19 seront étudiés sous 3 jours

DK Danemark « Clinical trials investigating treatments for COVID-19 will be processed within 3 days. The processing time is extended if major objections is raised but we prioritise to have these solved immediately. (…)
We prioritise all inquiries about COVID-19 (please clearly mark the topic ‘COVID-19’) at . We can also be contacted by phone (4488 9123). »
Fast-track Approval of Clinical Trials investigating COVID-19, Danish Medicines Agency, Denmark, 17 March 2020)

NL Aux Pays-Bas, une procédure accélérée est mise en place pour les recherches portant sur le développement de vaccins contre le Covid-19

NL Pays-Bas « Given the current developments around the outbreak of the new coronavirus (COVID-19), CCMO facilitates an accelerated review of research files concerning studies on COVID-19 (fast-track procedure).
If you would like to make use of this fast-track procedure, please contact CCMO via ccmo@ccmo.nl. CCMO will then determine whether your research qualifies for the fast-track procedure. The fast-track procedure means that the time at which the review normally starts can be brought forward and the procedure is handled by a subcommittee of CCMO. More information about the fast-track procedure for review of research files within the authorisation of CCMO can be found here.
For a fast-track review by the competent authority, please send a message to bi@ccmo.nl or info-bi@cbg-meb.nl stating: ‘FAST TRACK COVID-19′ »
(Accelerated procedure (fast track) review of coronavirus research files, CCMO, Pays-Bas, 27 mars 2020)

NL Pays-Bas « Accelerated procedure (fast track) assessment of coronavirus research files
Given the current developments around the outbreak of the new coronavirus (COVID-19), CCMO facilitates an accelerated assessment of research files on the development of vaccines against this coronavirus (fast-track procedure).
If you would like to make use of this fast-track procedure, please contact CCMO via ccmo@ccmo.nl or telephone number 070 340 6700. CCMO will then determine whether your research qualifies for the fast-track procedure. The fast-track procedure means that the time at which the assessment normally starts can be brought forward and the procedure is handled by a subcommittee mandated by CCMO.
For a fast-track assessment by the competent authority, please send a message to bi@ccmo.nl stating FAST TRACK COVID-19. »
(Information CCMO due to coronavirus outbreak, CCMO, The Netherlands, March 2020)

ES En Espagne, l’évaluation des recherches (interventionnelles ou observationnelles) portant sur le Covid-19 est priorisé

ES Espagne « 6. Ensayos clínicos dirigidos a la investigación de nuevos medicamentos frente al coronavirus

En estos momentos es de extremada importancia conseguir que la práctica clínica habitual sea generadora de conocimiento. Por ello, es importante sumar esfuerzos en torno a grandes ensayos clínicos con poder estadístico para identificar en el plazo más breve posible los medicamentos más eficaces para curar o prevenir esta enfermedad.

La AEMPS está priorizando junto con los CEIm la evaluación de los ensayos clínicos destinados a tratar o prevenir la enfermedad por coronavirus. Los promotores o investigadores que tengan un proyecto de investigación de este tipo deben enviar un resumen del ensayo a Área de Ensayos Clínicos, indicando en el asunto: URGENTE nuevo EC COVID-19 y el nombre del medicamento en investigación. La Agencia valorará el interés de llevar a cabo el ensayo de forma individual, indicando la documentación a presentar para que pueda ser autorizado o propondrá al promotor que se sume a alguno ya en marcha o que se esté organizando. Se dará una respuesta lo antes posible en un plazo máximo de 48 horas.

Las solicitudes de autorización de un ensayo clínico deben incluir en el título la palabra COVID-19.

Con el fin de facilitar la puesta en marcha de los ensayos clínicos de promotor sin ánimo comercial, se recomienda la exención de tasas y simplificación de los contratos entre el promotor y el centro. En los ensayos clínicos de promotor sin ánimo comercial, el contrato podrá sustituirse por un documento de conformidad de la dirección del centro.

Es indispensable acelerar en lo posible el análisis de los resultados de estos ensayos y presentarlos a la AEMPS tan pronto como estén disponibles. «  (Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020, Mis à jour le 7 avril 2020)

ES Espagne « 7. Estudios observacionales de seguimiento prospectivo con medicamentos relacionados con el coronavirus

En el correo electrónico de la solicitud de clasificación de estudios observacionales de seguimiento prospectivo con medicamentos relacionados con el coronavirus, se indicará en el asunto URGENTE COVID-19.

Las Resoluciones de Clasificación de estos estudios se enviarán al solicitante por vía electrónica y se resolverán en el plazo más breve posible, normalmente en el mismo día de la solicitud y en un máximo de dos días hábiles.

Los estudios observacionales de seguimiento prospectivo en los que el promotor sea un investigador de una organización independiente (grupos de investigación, sociedades científicas) serán considerados de interés sanitario y clasificados como EPA-AS. La AEMPS se ofrece a prestar apoyo metodológico a aquellos investigadores que así lo soliciten.

Para la evaluación/autorización de los EPA-AS del COVID-19, la AEMPS solicitará únicamente, además del protocolo, el dictamen favorable del CEIM y la resolución de autorización se emitirá en un plazo máximo de 7 días naturales desde la recepción del dictamen del CEIm.

Con el fin de contribuir a mejorar la calidad y la eficiencia de la investigación de tipo observacional sobre COVID-19, la AEMPS va a intentar facilitar la colaboración entre investigadores de distintos centros que proponen estudios con objetivos comunes. Para ello, estamos poniendo en contacto a dichos investigadores, por si fuera factible que entre ellos se materialice algún tipo de colaboración y en su caso la realización de estudios multicéntricos. » (Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020, Mis à jour le 7 avril 2020)

IT En Italie, une procédure simplifiée d’autorisation des essais portant sur le Covid-19 a été mise en place

Etudes interventionnelles

IT Italie « 1.DOMANDE DI AUTORIZZAZIONE ALLA SPERIMENTAZIONE CLINICA

Ogni domanda di autorizzazione alla sperimentazione clinica deve essere inoltrata ad AIFA tramite le seguenti modalità:

  • inserimento in OsSC: è unico e vale sia per AIFA che per Comitato etico nazionale dell’INMI Spallanzani
  • in caso di problemi tecnici inOsSC,è accettatol’invio in cartaceoad AIFA e CE Spallanzani.
  • In caso di problemi tecnici in OsSC e impossibilità di invio cartaceo a causa delle restrizioni vigenti, èaccettato l’invio mediante PEC. In tale caso la documentazione va mandata contemporaneamente ad AIFA (apa@pec.aifa.gov.it, in ccsperimentazione.clinica@aifa.gov.it) e al Comitato etico nazionale dell’INMI Spallanzani (comitatoetico@inmi.it). In questo casoAIFA provvederàad inoltrare la domandaal Comitato etico nazionale dell’INMI Spallanzani.

Nell’oggetto della PEC e di tutte lecomunicazioni deve essere presente all’inizio il termine COVID-19.

Si suggerisce di inseriretaletermine anchenel titolo delle sperimentazioni.Le domande di autorizzazione alla sperimentazione dovranno contenere almeno laseguentedocumentazione:

  • Lettera di trasmissione ad AIFA e Comitato eticonazionale dell’INMI Spallanzani(cover letter)
  • EudraCT number
  • Modulo di Domanda OsSC (Appendice 5) (tramite
    https://www.aifa.gov.it/web/guest/osservatorio-nazionale-sperimentazione-clinica)
  • Eventuale delega del Promotore alla CRO
  • Protocollo di studio
  • Sinossi dello studio
  • Foglio Informativo per il paziente e modulo per il consenso informato
  • CV e dichiarazione conflitto di interessi dello Sperimentatore Principale
  • Investigator Brochure (IB)se disponibile(in alternativa i dati a supporto di non clinica e clinica potranno essere inseriti direttamente nel protocollo);
  • Investigational Medicinal Product Dossier (IMPD), eventualmente semplificato, o Riassunto delle Caratteristiche Prodotto (RCP) per il prodotto medicinale sperimentale con autorizzazione all’immissione in commercio e utilizzato nell’ambito delle condizioni autorizzative
  • Autorizzazione GMP alla produzione/importazioneove applicabile
  • Etichetta del prodotto medicinale sperimentale » (Circolare sulle procedure semplificate per gli studi e gli usi compassionevoli per l’emergenza da Covid-19, AIFA, Italie, 6 aprile 2020)

Etudes observationnelles

IT Italie « 4.REQUISITI MINIMI PER PROPOSTE DI SPERIMENTAZIONE CLINICA E STUDI OSSERVAZIONALI

I requisiti minimi per una proposta di sperimentazione clinica e studi osservazionali devono contenere almeno le seguenti informazioni: il razionale;la tipologia di trattamento proposto (medicinale o composto, dosaggio e modalità di somministrazione); il beneficio attesoed i rischi prevedibili; se il medicinale è già autorizzato per indicazioni differenti o se è in fase di sviluppo e, nell’ultimo caso, se sono disponibili risultati di studi preclinici e clinici; il target dei soggettia cui dovrebbe essere somministrato. Dovrà inoltre essere specificata l’origine e la modalità di fornitura del farmaco.Infine, si segnala che gli studi dovrebbero concentrarsi su esiti di rilievo (decessi,intubazione/estubazione ecc.) e su una numerosità in grado di fornire risposte chiare. Al fine di accelerare la valutazione, è preferibile che le proposte siano presentante utilizzando il modello allegato (link ipertestuale).

Le proposte di sperimentazione clinica o studio osservazionale il cui protocollo è ancora in via di definizione devono essere inviate alla casella di posta apa@pec.aifa.gov.it. Nell’oggetto della PEC e di tutte lecomunicazioni deve essere presente all’inizio il termine COVID-19.Si suggerisce di inserire tale termine anchenel titolo delle proposte.

PUBBLICAZIONE DEI PROTOCOLLI AUTORIZZATIE MODALITA’ DI ADESIONEAGLI STUDI

Al fine di favorire la massima conoscenza e partecipazione, AIFA pubblica sul proprio sito istituzionale l’elenco aggiornato di tutte le sperimentazioni cliniche e i programmi di uso compassionevole autorizzatida AIFA e approvatidal Comitato eticonazionale.

Per ciascuno studio sono reperibili sul sito dell’Agenzia le informazioni principali: protocollo di studio, sinossi dello studio, approvazione del Comitato etico nazionale e, ove appropriato, una breve nota recante le informazioni per la partecipazione alla sperimentazione.

MODALITA’ DI MONITORAGGIO E ACQUISIZIONE DEI DATI

Le modalità di accesso, da parte di AIFA, ai dati raccolti all’interno delle sperimentazioni cliniche, studi osservazionali farmacologici e programmi di uso compassionevolesaranno definite successivamente. »(Circolare sulle procedure semplificate per gli studi e gli usi compassionevoli per l’emergenza da Covid-19, AIFA, Italie, 6 aprile 2020)

UK Le Royaume-Uni a mis en place une procédure d’examen accélérée pour les recherches sur le Covid-19 présentant un intérêt de santé publique

UK Royaume-Uni « Researchers who have a study that they would like to be considered for fast-track review should contact us using the telephone numbers at the bottom of this page.

We’ll take some basic information and ask you to send us an email copying in your research sponsor. Your application will be triaged and, if approved in principle for fast-track review, we will follow up with you by phone for more information.

Please register the proposed study on the IRAS website and be ready to discuss:

  • A brief summary of the study (if you have a protocol or one-page summary already please let us know)
  • Your current working title, and IRAS ID
  • When you expect you will be able to submit the full study via IRAS
  • Whether the study involves the NHS and, if so, if you have agreement in principle from the relevant Research & Development offices and clinical services that they have the capacity to support this study now
  • Whether you have applied for prioritisation of this project from the Chief Medical Officer
  • Whether the study is a Clinical Trial of an Investigational Medicinal Product (CTIMP). If so then you will also need submit to the Medicines and Healthcare products Regulatory Agency (MHRA). We will liaise with them to expedite the review. If it is a CTIMP, our Pharmacy Assurance process can support site set up.
  • Whether the study involves ionising radiation. If so, our Radiation Assurance process can support site set up.

We will also ask you to:

  • Confirm if the study will include Adults Lacking Capacity
  • Confirm if the study is funded by the United States Department of Health and Human Services (USDHHS)
  • Confirm which nations the study will include (if this is Scotland, Northern Ireland or Wales please also contact the research operations lead in the relevant nation)
  • Give us a predicted date when you may be able to start the study.

If you intend to use confidential patient information without consent, we can advise.

We will consider requests for fast-track review as soon as possible. During office hours please contact our mainline on 020 7972 2545. Out of office hours please contact 020 7104 8322 (open 5.30-8pm on weekday evenings and 10am-4pm on weekends and bank holidays). »(Covid-19 research – Fast track review guidance for COVID-19 studies, NHS, Royaume-Uni, Last Updated on 16 April 2020)

UK Royaume-Uni « An expedited review process is available for studies relating to COVID-19 where there are public health grounds for rapid review. The full process for fast-track reviews is set out in the Standard Operating Procedures for Research Ethics Committees.
Researchers should contact the HRA Director of the Approvals Service (who will liaise with colleagues in Scotland, Wales or Northern Ireland if applicable), copying in their research sponsor, as early as possible to request expedited review. »
(COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020)

UK Royaume-Uni « New submissions for clinical investigations
Any new submissions for clinical investigations that will have a direct impact on the COVID-19 emergency will get a fast-track review.

However, you must still provide the documentation detailed in guidance on compiling a submission and guidance for manufacturers.

You must submit your application electronically using the Integrated Research Application System (IRAS).

Give us advanced notice of your intention to apply and ensure your study title clearly identifies it as related to COVID-19.

If you are considering submitting an application for a medical device that is not related to COVID-19, contact us first. We might ask you to defer the submission if there is a resource issue.

We will assess any clinical investigation submissions that are not related to COVID-19 within standard statutory processing times. » (Guidance- Medical devices clinical investigations during the coronavirus (COVID-19) outbreak, MHRA, Royaume-Uni, 30 March 2020)

Le processus d’assurance pour la recherche fait également l’objet de procédure accélérée pour les recherches portant sur le Covid-19

UK Royaume-Uni « To support sponsors and sites in the quick set up of COVID-19 studies, the Pharmacy and Radiation Assurance process has been expanded. Technical assurances enables rapid set-up of NHS sites and reduces the pressure on organisations.

We have reviewers in place to support fast-tracked applications, so please contact a member of the Technical Assurance team to support you through the process if you are submitting a research project for COVID-19 that includes pharmacy or radiation. Studies will be able to be processed through the self-managed route, where the sponsor is an NHS organisation.

We continue to accept all other eligible studies through both Pharmacy and Radiation Assurance, so sponsors can still receive the benefits these reviews provide, though are prioritising studies:

  • COVID-19 studies
  • Studies submitted through the combined ways of working pilot (CWoW)
  • Studies currently going through Technical Assurance
  • New applications (non COVID-19) where it is confirmed that the study can be supported in principle by the proposed NHS sites
  • New applications (non COVID-19) where it is planned to set up the study once the current pressures on the system have eased

Please be aware that timelines for non COVID-19 studies could be longer than usual at this time.

For further information on eligible study types, please visit the HRA Technical Assurances webpage.

If you have any questions, please contact a member of the Technical Assurance team (pharmacy.assurance@hra.nhs.uk / radiation.assurance@hra.nhs.uk). » (Covid-19 resarch – Pharmacy and Radiation Assurance for COVID-19 studies, NHS, Royaume-Uni, Last Updated on 3 April 2020)

CA Au Canada, l’évaluation des études visant à diagnostiquer / traiter / prévenir le Covid-19 sont évalués de façon prioritaire

CA Canada « Clinical trial applications

  • Health Canada will prioritize the review of clinical trial applications designed to investigate the diagnosis, treatment and/or prevention of COVID-19.
  • Sponsors may continue to file other CTA and CTA amendments according to Health Canada guidance
  • During the course of a CTA review, if sponsors are unable to respond to an Information Request (IR) within specified time lines, consider withdrawing the submission without prejudice and refiling when the information is available. » (Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors, Health Canada, 23 March 2020, Updated on 3 April 2020)

BR Au Brésil, l’évaluation éthique pour des recherches portant sur le Covid-19 sont faite par le Comité d’Ethique national via une procédure accélérée

BR Brésil « 1. Todos os protocolos de pesquisa sobre a referida virose deverãoser encaminhados para apreciação ética por essa Comissão, mesmo que não se enquadrem em áreas de análise ética obrigatória pela Conep(conforme a Resolução CNS n°466, item IX.10). Nesse sentido, os CEP são aqui instruídos a nãorealizar a apreciação éticadestes protocolosde pesquisa.

2. Os coordenadores dos CEP serão os relatores dos protocolos e deverão assinalar no parecer do colegiado a opção « Sim » no campo « Necessita Apreciação da Conep? » e incluir no campo « Justificativa para envio a Conep » a redação: « Tramitação prioritária por solicitação da Conep -2019-nCoV ». Portanto, no âmbito dos CEP, os Pareceres Consubstanciados deverão ser emitidos com a situação « Aprovado », cabendo à Conep deliberar sobre tais protocolos de pesquisaem regime especial de tramitação.

3. Nos casos de protocolos de pesquisa que possuam « centros participantes »e/ou « centros coparticipantes », não deverá serrealizadanova análise ética pelos respectivos CEP vinculados. Devido ao caráter excepcional adotado, os CEP referendarãoo parecer de aprovado, quando for o caso, emitido pela Conep. » (Informe aos comitês de ética em pesquisa, Comissão National de ética em pesquisa, Brésil, 7 février 2020)

PE Au Pérou, les évaluations des essais cliniques portant sur le Covid-19 sont prioritaires

PE Pérou « Así mismo, se informa que la OGITT está priorizando, la evaluación de todo ensayo clínico destinado al diagnóstico, tratamiento o prevención de la enfermedad ocasionada por coronavirus. En ese sentido, los patrocinadores o sus representantes que tengan un proyecto de investigación de este tipo deben enviar un mensaje al correo ensayosclinicoscovid@ins.gob.pe indicando en el asunto: URGENTE nuevo EC COVID19. Se dará una respuesta el mismo día, comunicando los procedimientos a seguir. » (Covid-19 – Communicado N° 003-2020-OGITT/INS, Ministerio de Salud, 30 de Marzo 2020)

Procédure d’autorisation pour les recherches portant sur des Organismes Génétiquement Modifiés (OGM)

NL Pays-Bas « Due to the exceptional circumstances, the Ministry of Infrastructure and Water Management (IenW) has decided to accelerate the authorisation procedure for research into gene therapy or a medicinal product containing a genetically modified organism (GMO), that is aimed at combating COVID-19.
Clinical research into gene therapy or a medicinal product containing a GMO requires a license from the Ministry of IenW. The Ministry of IenW has now set up an emergency regulation (in Dutch) accelerating the procedure of granting a license and enabling investigators to start clinical trials with such products earlier. The emergency regulation has been published in the Staatscourant (Government Gazette) and has been in effect since March 31.
The time limit on the application will be shortened to a maximum of 28 days. This regulation does not make any concessions to safety in working with GMOs. The regulation only applies to permit applications for research aimed at the preventive or curative control of the pandemic of COVID-19. »
(Emergency regulation for authorisation of research into COVID-19-targeted gene therapy or medicinal product containing GMO, CCMO, Pays-Bas, 3 April 2020)

NL Pays-Bas « Article 2

  1. L’article 3.4 de la loi générale sur le droit administratif, l’article 13.2 de la loi sur la gestion de l’environnement et l’article 3.10 du décret ne s’appliquent pas à la préparation d’une demande d’autorisation, telle que visée à l’article 3.2, premier paragraphe, du décret, pour l’application de substances et de préparations médicamenteuses consistant en des organismes génétiquement modifiés ou contenant de tels organismes à usage humain, si la demande concerne des applications visant le contrôle préventif ou curatif du COVID-19.
  2. Le ministre envoie un résumé de la demande à la Commission européenne dans les 30 jours suivant la réception d’une demande visée au paragraphe 1.
  3. e ministre se prononce sur une demande visée au paragraphe 1 dans les 28 jours suivant la réception de la demande. La décision est une décision visée à l’article 20.3, paragraphe 2.b) de la loi sur la gestion de l’environnement et est publiée au Journal officiel néerlandais. » (Traduction
    du Règlement temporaire portant dérogation aux demandes d’autorisation de traitement de thérapie génique dans le cadre de la lutte contre la COVID-19,
    Pays-Bas, 28 mars 2020
    )

Procédure accélérée pour les demandes de renouvellement et d’extentions d’Autorisations de Mise sur le Marché (AMM)

IT Italie « Please be informed that, due to COVID-19 emergency and the difficulties that some MA holders are facing, as exception to the provisions given in the guidance published the 7th May 2019, the Marketing Authorizations Department will accept:

  1. the submission of MA variation and renewal applications/noifications through the relevant portals; the submission of what required in the above mentioned guidance can be postponed
  2. the submission through CESP of MA/extension applications (N,MR,DC); the submission of what required in the above mentioned guidance can be postponed

    The provisions given above are also applicable to responses/additional documents

The provisions given above are also applicable to responses/additional documents » (Guidance on submission of Marketing Authorization/Extension, MA Variation and Renewal applications, up to the end of the restrictions related to COVID-19 emergency, AIFA, Italia, 12 march 2020)

Procédure d’usage compationnel face au Covid-19

IT Italie « 2.PROGRAMMI DI USO COMPASSIONEVOLE

Con riferimento all’uso compassionevole, ai sensi del DM7/9/2017,si riportano le seguenti definizioni:

  • Programma di uso terapeutico: presentato, da parte dell’industria farmaceutica, per l’impiego di medicinali nell’ambito dell’uso compassionevole in più pazienti, sulla base di un protocollo clinico predefinito e identico per tutti i pazienti.
  • Uso terapeutico nominale: impiego di medicinali nell’ambito dell’uso compassionevole su base nominaleper singolipazienti, in base alle evidenze scientifiche e non nell’ambito di un protocollo clinico definito.

Nel primo caso (programmi di uso terapeutico) le richieste di uso compassionevole devono essere inviate, complete di breve sinossi e protocollo, all’AIFA e al Comitato etico nazionale dell’INMI Spallanzanialle seguenti caselle di posta usocompassionevole@aifa.gov.ite comitatoetico@inmi.it. Il modello di consenso informato deve essere disponibile per valutazione da parte del Comitato etico nazionale. Le modalità di raccolta dati possono essere inviate anche in fase successiva al primo invio ai fini di valutazione. Nell’oggetto della mail deve essere presente il termine COVID-19.Si ricorda che l’approvazione di un programma di uso terapeutico da parte del Comitato Etico nazionale individuato dal DL 17 marzo 2020 n.18 all’Art. 17 ha valenza immediata su tutto il territorio nazionale.

Gli usi terapeutici nominali, invece,NON devono essere sottoposti per valutazione al Comitato etico nazionale, ma rimangono di competenza dei Comitati etici locali. »(Circolare sulle procedure semplificate per gli studi e gli usi compassionevoli per l’emergenza da Covid-19, AIFA, Italie, 6 aprile 2020)

Conduite de la recherche

Le Promoteur doit envisager la suspension ou l’arrêt d’une recherche en cours si la poursuite de la recherche entrainait la mise en danger des participants

FR France « Un essai peut-il être suspendu en raison de la pandémie ?
Oui
Une décision de suspension des inclusions peut être justifiée par le contexte de l’étude et/ou l’indisponibilité des équipes (sponsor ou investigateurs).
La poursuite ou non des traitements en cours doit être précisée et justifiée. Une décision d’arrêt des traitements en cours doit en effet être impérativement évaluée en fonction du contexte clinique de chaque patient et des risques alors encourus.

FR France« May a trial be suspended because of the pandemic?
Yes
A decision to suspend inclusions may be justified by the context of the study and/or the unavailability of teams (sponsor or investigators).
The continuation or not of ongoing treatments must be specified and justified. A decision to discontinue ongoing treatments must be evaluated according to the clinical context of each patient and associated risks.

eu Europe « The sponsors should consider in their risk assessment whether the following measures could be the most appropriate during COVID-19. Measures should generally be agreed with investigators and could be: (…)

BE Belgique « 5.Temporary halts and urgent safety measures (USM) need to be notified

A temporary halt (e.g. recruitment halt, halt of the trial on a site) of the trial shall be submitted to the FAMHP and the EC within 15 days of the decision. A temporary halt is not a substantial amendment but it is communicated via CESP to the FAMHP through the Substantial Amendment Notification Form (Annex II Section E.4.). Only a confirmation of receipt is sent, no official approval » (Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

NL Pays-Bas« If the trial is (partially) suspended, this must be reported immediately to the review committee;
If the study is terminated prematurely, this must be reported to the review committee as soon as possible, but at the latest within 15 days; »
(Recommendations for the conduct of clinical research at the time of restrictive measures due to the coronavirus, CCMO, The Netherlands, March 2020)

UK Royaume-Uni « Stop or suspend the trial

Withdraw participants from the trial and halt the trial temporarily (ensuring appropriate care of participants– e.g. prescribing alternative treatment via the GP.) This could be prioritised based on the length of participation and meeting the endpoint of the trial. For example, if sufficient data has already been gathered, or if a participant had just started, participation could be withdrawn as opposed to those who, if they remain in the trial for a little longer, could generate data to meet the trial objectives.

Where subjects are near to completion of their participation in the trial, consideration could be given to ensuring end of trial activities are completed as much as possible so that the participant’s trial data is as useful as possible. These could include final blood tests or assessments assuming that trial team availability permits this. » (Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 22 avril 2020)

UK Royaume-Uni « 3.1.4. Studies where sponsors need to implement a temporary halt to all or some of the study or extend the duration of a study due to COVID-19.
Sponsors must decide when they need to implement a formal temporary halt. For CTIMPs the MHRA provides advice. For non-CTIMPs consider reporting a formal halt if there are safety considerations for existing participants, or actions that sites need to take. Simply pausing recruitment does not need to be reported as a temporary halt, although sponsors should record such decisions for their records.
For CTIMPs, where MHRA have advised this is a substantial amendment, such amendments will be categorised and assessed according to existing guidance, but the process will be expedited. They should be sent to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor.
For non-CTIMPs where a formal halt is required, this should be handled as a non-substantial amendment that does not require HRA/HCRW Approval or R&D agreement. For studies involving the NHS/HSC, these should be marked by the sponsor as category C and not requiring assessment and sent directly to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor.
3.1.5. Studies that need to be closed
For any studies not involving provision of treatment to participants, a notification to the REC or study-wide review (for non-REC studies) should be provided, and an end of study report should subsequently be provided.
For any studies involving provision of treatment to participants, careful consideration should be given to post-study care. If this cannot be in line with the information provided in the participant-information sheet, a substantial amendment should be submitted. Such amendments will be categorised and assessed according to existing guidance, but the process will be expedited. They should be sent to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor. »
(COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020)

UK Royaume-Uni « Pausing ongoing clinical investigations
If a clinical investigation needs to be paused, notify us as soon as possible and keep good records of your actions.
Once you are ready to re-start, inform us and provide a summary of the actions taken and whether there was any patient safety impact. »
(Guidance- Medical devices clinical investigations during the coronavirus (COVID-19) outbreak, MHRA, Royaume-Uni, 30 March 2020)

DK Danemark « Consideration should be given to whether inclusion should be halted. In addition, it might be necessary to terminate studies if, for example, the primary effect parameters of the study cannot be monitored on site or using a local laboratory
Furthermore, in case it is not feasible for a site to continue participation at all, the sponsor should consider if the trial site should be terminated and how this can be done to best ensure patient safety and data validity. »
(Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

AU Australie « Decisions by researchers to halt a study or suspend recruitment can be dealt with administratively between institutions and sponsors; however, a decision to close a study where an investigational product (IP) or an unregistered device, diagnostic or biological is being provided is a substantial amendment requiring HREC review.

In assessing the proposed closure of a study where an IP or an unregistered device, diagnostic or biological is being provided, careful consideration should be given to any post-trial care or access to the IP, device or biological that is planned, or not planned, for relevant participants (COVID-19 : Guidance on clinical trials for institutions, HRECs, researchers and sponsors, CTPRG, Australia, 24 mars 2020)

us Etats-Unis « Sponsors, in consultation with clinical investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), may determine that the protection of a participant’s safety, welfare, and rights is best served by continuing a study participant in the trial as per the protocol or by discontinuing the administration or use of the investigational product or even participation in the trial. Such decisions will depend on specific circumstances, including the nature of the investigational product, the ability to conduct appropriate safety monitoring, the potential impact on the investigational product supply chain, and the nature of the disease under study in the trial. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q1. What are some of the key factors that a sponsor should consider when deciding whether to suspend or continue an ongoing study or to initiate a new study during the COVID-19 pandemic?

Central to any decision should be ensuring that the safety of clinical trial participants can be maintained. Sponsors, in consultation with clinical investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), should assess whether the protection of a participant’s safety, welfare, and rights is best served by continuing a study participant in the trial as per the protocol or by discontinuing the administration or use of the investigational product or even participation in the trial. Such decisions will depend on specific circumstances, including the nature of the investigational product, the ability to conduct appropriate safety monitoring, the potential impact on the investigational product supply chain, and the nature of the disease under study in the trial. As part of this assessment, sponsors should carefully consider the following aspects of clinical trial conduct when deciding how or whether to proceed with a clinical trial:

  • Assessing whether the limitations imposed by the COVID-19 pandemic on protocol implementation pose new safety risks to trial participants, and whether it is feasible to mitigate these risks by amending study processes and/or procedures.
  • Assessing the continued availability of the clinical investigator/sub-investigators to provide oversight of the trial, and properly assess and manage safety issues that may emerge.
  • Assessing whether there will be sufficient clinical trial support staff given the evolving COVID-19 situation and its impact on staff availability. Are there appropriately trained staff that could be available to handle the expected tasks? Is there adequate equipment and materials for clinical trial support staff?
  • Assessing whether clinical investigator sites will remain open to trial participants for required in-person assessments or whether the clinical investigator has the ability to provide required in-person assessments at an acceptable alternate location(s), or whether such protocol- specified in-person assessments can instead be conducted virtually.
  • Assessing the continued availability of clinical trial supplies and continued operations of vendors, especially related to supply of the investigational product and/or to clinical trial supplies that are essential to maintaining appropriate safety monitoring or other key trial procedures. This should include consideration of product stability (shelf life) if the treatment schedule is revised, or if the clinical site is unable to properly store the product for the needed duration.
  • Assessing the continued availability of, and support for, information technology systems and any other technological tools that are needed to support the trial. Are current contingency plans adequate for the types of disruptions that might be anticipated? What other plans can be put in place to minimize any potential disruptions?
  • Assessing whether there will be continued operations of, and adequate communications with, IRB) IEC and Data Monitoring Committee (DMC) staff, if applicable, to support trial needs.
  • Assessing whether it is feasible to conduct the trial in light of any COVID-19 public health measures implemented by Federal and State authorities to control the virus.

Involvement of a study’s DMC, if one has been established, can provide support for the assessments discussed above. Since a primary responsibility of the DMC is assuring the safety of participating trial participants, the DMC’s assessment of the impact of modifications of trial conduct due to COVID-19 on patient safety is important to consider.

The risks and benefits of continuing a trial are likely different than a decision to initiate a trial (other than trials intended to evaluate investigational treatments or vaccines for COVID-19). Given the evolving situation, with likely increasing impacts on investigators, staff, and supply chains, sponsors should carefully consider the ability to effectively mitigate risks such that patient safety and trial integrity are assured. In addition, it is important to consider whether initiation of the trial could interfere with public health measures implemented by Federal and State authorities to control the virus. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q2. What key factors should sponsors consider when deciding whether to continue administering or using an investigational product that appears to be providing benefit to the trial participant during the COVID-19 pandemic?

There may be circumstances in which an investigational product (either a drug, biological product or medical device) appears to be providing benefit to the trial participant. A sponsor deciding whether to continue administering or using such a product during the COVID-19 pandemic should carefully consider context-dependent issues, including whether a trial participant appears to be benefitting from treatment with the investigational product, whether there are reasonable alternative treatments,the seriousness of the disease or condition being treated, and the risks involved in switching to an alternative treatment if necessary. FDA recognizes that in some circumstances it may be necessary (e.g., based on lack of product supply or inability to administer or ensure the safe use of the investigational product) to discontinue investigational product administration in a trial. If there are individual trial participants for whom discontinuing the investigational product might present a substantial risk (e.g., trial participants perceived by the investigator as having a clinical benefit to the investigational product), the sponsor should consider amending the protocol, after discussion with the relevant review division, to limit investigational product use to those patients with apparent benefit and discontinue investigational product use to other participants. In all cases, if a trial participant is discontinued from an investigational therapy, it is important that there be appropriate managementafter discontinuation. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

CA Canada « Placing study on hold

PE Pérou « Respecto a las actividades propias de iniciación, el mantenimiento y conclusión de los ensayos clínicos estas deberán continuar bajo responsabilidad del patrocinador, quien podrá implementar estrategias en el marco del mencionado decreto, a fin de no afectar el perfil de riesgo-beneficio del sujeto de investigación; además estas deberán ser comunicadas a la OGITT/INS a través del correoconsultaensayos@ins.gob.pe. » (Covid-19 – Comunicado n° 001-2020-OGITT/INS, Ministerio de Salud, Pérou, 18 mars 2020)

Redémarrage de l’essai

UK Royaume-Uni « Submitting paperwork for trials which have been halted
If your trial has been halted due to issues related to COVID-19, you will not normally need to inform us.
The trial master file should include a note that the trial was halted and the reason.
If a halt is due to either of the below scenarios however, you do need to inform us:

  • A direct participant safety issue, especially if there is the potential to impact other trials; please inform us in the normal way
  • A medicines supply issue, as we can escalate this to DHSC. Inform us of this directly by phone or email rather than an amendment form

Restart of the trial may require changes to the trial conduct, for example to participant monitoring or clinic visits as described below. If the restart of the study does not involve any substantial changes to the Clinical Trial Authorisation (CTA), then a substantial amendment notification to MHRA will not be necessary. If substantial changes do need to be made, for example to protect participant safety or data integrity moving forward then this should be submitted as a substantial amendment in the normal way. If a substantial amendment has been approved to halt the trial then another to restart will always be necessary.

If the sponsor decides not to recommence a halted trial, they should notify us via an End of Trial declaration form within 15 days of the decision. » (Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 22 avril 2020)

Restarting a trial after it has been halted
If the restart of the study does not involve any substantial changes to the Clinical Trial Authorisation (CTA), then a substantial amendment notification to MHRA will not be necessary. If changes do need to be made to protect participant safety moving forward, then this should be submitted as a substantial amendment in the normal way. »
(Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 24 March 2020)

BE Belgique « In order to restart the trial after temporary halt, a substantial amendment must therefore be submitted. The trial can only restart upon approval by the EC and if no motivated objections have been raised by the FAMHP within legal deadline.If the temporary halt of recruitment is only due to the COVID-19 crisis, it will be acceptable to restart the recruitment when again possible after a notification only to the FAMHP and to the EC »(Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

Le Promoteur doit évaluer la possibilité de poursuivre ou non le recrutement de patients

eu Europe « The sponsors should consider in their risk assessment whether the following measures could be the most appropriate during COVID-19. Measures should generally be agreed with investigators and could be: (…)
Suspension or slowing down of recruitment of new trial participants; »
(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

BE Belgique « 5.Temporary halts and urgent safety measures (USM) need to be notified

A temporary halt (e.g. recruitment halt, halt of the trial on a site) of the trial shall be submitted to the FAMHP and the EC within 15 days of the decision. A temporary halt is not a substantial amendment but it is communicated via CESP to the FAMHP through the Substantial Amendment Notification Form (Annex II Section E.4.). Only a confirmation of receipt is sent, no official approval

If the rational to discontinue the recruitment into the ongoing clinical trials is the same for all clinical trials, it is needed and sufficient that the applicant sends only one temporary halt notification that lists all the concerned clinical trials. » (Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

DE Allemagne « 5. Discontinuation of patient recruitment
Sponsors of clinical trials are requested to evaluate whether continuation of patient recruitment during the pandemic is reasonable or should be discontinued. Should it become necessary to discontinue recruitment, this will require a notification of variation, but in order to simplify matters, the BfArM does not insist on use of the amendment form for submission. It is also possible to apply for discontinuation of recruitment together for several clinical trials by way of a collective letter. Should you wish to do this by e-mail, please begin the subject line of e-mail and cover letter with the term « COVID-19″. Resumption of recruitment will require a renewed variation notification subject to approval with competent federal higher authority and competent Ethics Committee. »
(Clinical Trials during the COVID-19 Pandemic – Information on the authorisation and conduct of clinical trials of medicinal products during the COVID-19 pandemic (Version 2.1), BFarm, Allemagne, 30 March 2020)

BG Bulgarie « 2. Sur la base de l’évaluation des risques, le promoteur devrait déterminer si le recrutement des participants au test peut être suspendu. » (Traduction des Recommandations aux commanditaires concernant la conduite des essais cliniques dans le cadre du risque complexe de Covid-19 d’une déclaration de l’état d’urgence dans le pays, Version Bulgare )

BG Bulgarie « 2. On the basis of the risk assessment it should be considered by the sponsor whether recruitment of new patients/trial subjects in ongoing clinical trials can be temporary suspended. » (Recommendations to the Sponsors for managing of Clinical Trials during the COVID-19 pandemic and the declared State of emergency in the Republic of Bulgaria, BDAn Bulgarie, 24 March 2020)

DK Danemark « Consideration should be given to whether inclusion should be halted. In addition, it might be necessary to terminate studies if, for example, the primary effect parame-ters of the study cannot be monitored on site or using a local laboratory » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

ES Espagne « 2. Reclutamiento de nuevos pacientes
Las desviaciones al protocolo previstas con carácter prospectivo no son aceptables y es esperable que todos los sujetos que se incluyan en un ensayo clínico cumplan todos los criterios de selección. El promotor junto con el investigador, en base a una valoración beneficio/riesgo que considere las características del ensayo y las circunstancias de los centros participantes podrá interrumpir el reclutamiento e incluso interrumpir el tratamiento de los pacientes del ensayo en aras a evitar riesgos innecesarios y garantizar la mejor asistencia sanitaria posible a los pacientes. Este análisis es especialmente pertinente en los ensayos clínicos que conlleven el tratamiento con inmunosupresores y por tanto un riesgo mayor de infección, sin expectativa de beneficio para los participantes.
En el caso de una interrupción del ensayo que conlleve la paralización del tratamiento en parte de los pacientes, el promotor tendría que notificar dichas medidas como “medidas urgentes de seguridad” explicando las medidas adoptadas para garantizar el tratamiento alternativo de los pacientes enviando un informe Ad Hoc tanto a la AEMPS como al Comité de Ética de la Investigación con medicamentos. (CEIm) en los 15 días siguientes a la interrupción o finalización. »
(Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020)

UK Royaume-Uni « 3.2.1. Studies where sites need to suspend recruitment
Sites must raise such issues with the sponsor as early as possible if this is likely to occur. No further action by sites is required except where instructed by sponsors.
It is for the sponsor to decide whether or not to temporarily halt or close a study (see 3.1.4 or 3.1.5 above). »
(COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020)

CA Canada « Participant recruitments

CA Canada « Halting recruitment or temporarily halting the trial may be required in some circumstances. If this happens, sponsors are to inform Health Canada using a clinical trial application notification (CTA-N) » (Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors, Health Canada, 23 March 2020)

AU Australie « Recruitment of new participants

PE Pérou « 2. El reclutamiento
El reclutamiento podrácontinuar en base a una valoración beneficio/riesgo que considere las características del ensayo y las circunstancias de los centros participantes. De ser decisión del patrocinador interrumpir el reclutamiento de nuevos participantes, a fin de evitar riesgos innecesarios y garantizar la mejor asistencia sanitaria posible a los participantes del ensayo que ya se encuentran enroladosen el estudio, esta deberá de ser comunicada a la OGITT »
(Covid-19 – Communicado N° 002-2020-OGITT/INS, Ministerio de Salud, 26 de Marzo 2020)

Le Promoteur doit envisager la fermeture de sites d’investigation, si la sécurité des patients ou la continuité de l’essai ne peuvent être assurées

eu Europe « The sponsors should consider in their risk assessment whether the following measures could be the most appropriate during COVID-19. Measures should generally be agreed with investigators and could be: (…)

BG Bulgarie « 5. Dans le cas où il n’est pas possible pour un centre de poursuivre son implication, le promoteur devrait envisager de fermer le centre et comment cela sera fait pour garantir au mieux la sécurité des patients et la validité des données notifiées. à la BDA. » (Traduction des Recommandations aux commanditaires concernant la conduite des essais cliniques dans le cadre du risque complexe de Covid-19 d’une déclaration de l’état d’urgence dans le pays, Version Bulgare )

BG Bulgarie « 5. In case it is not feasible for a site to continue participation at all, the sponsor should consider if the site should be terminated and how this scan be done to best ensure patient safety and data validity. A notification to BDA is required. » (Recommendations to the Sponsors for managing of Clinical Trials during the COVID-19 pandemic and the declared State of emergency in the Republic of Bulgaria, BDAn Bulgarie, 24 March 2020)

IT Italie « 3. Sites closing
If a site is closed to the public for COVID-19 containment measures, it should be carefully assessed if the clinical trial staff is able to guarantee the continuity of the trial itself. In case the site is unable to follow the patients undergoing the trial, the study should be temporarily halted or, where possible, enrolled patients should be transferred to the nearest active trial site. Information exchange between PIs must be assured, as well as the transmission of clinical documentation and other trial material (e.g. IMPs) between sites. Contacts between Sponsor and health structures involved must be updated according to new agreements.
A site not authorized to participate in the specific clinical trial is not considered as suitable as back-up, since it is not active, it does not know the trial and could not ensure a proper therapeutic continuity for the patient. »
(Notice – Clinical trials’ management in Italy during the COVID-19 (coronavirus disease 19) emergency, AIFA, Italia, 12 march 2020)

Nécessité ou non de soumettre la « Dear Investigator » Letter aux autorités avant la mise en œuvre des mesures

UK Au Royaume-Uni, la « Dear Investigator » Letter portant sur les mesures prises en réponse à la pandémie n’est pas à soumettre pour autorisation

UK Royaume-Uni « ‘Dear Investigator’ Letters
During the COVID -19 pandemic it is acknowledged that Sponsors may need to send ‘Dear Investigator’ Letters to inform investigator sites of changes to trial conduct. These do not require regulatory oversight and should not be submitted to the MHRA. »
(Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 24 March 2020)

BE En Belgique, la « Dear Investigator » Letter portant sur les mesures prises en réponse à la pandémie est à soumettre si elle entre dans le cadre d’un amendement substantiel ou de Mesures Urgentes de Sécurité (MUS)

BE Belgique « An individual DIL (dear investigator letters, per study/compound) has to be reported to FAMHP and EC if it is part of an USM and/or a substantial amendment. Once again only DIL related to measures that are really impacting safety of the participants have to be submitted as part of USM or of a substantial amendment. If it is not, the DIL is considered as non-substantial. The sponsor does not have to notify non-substantial amendments to the national competent authority or the Ethics Committee. However, non-substantial amendments should be recorded and contained in the documentation when it is subsequently submitted, for example in the subsequent notification of a substantial amendment. »(Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

Les déviations prospectives au protocole portant sur les critères d’éligibilité ne sont pas acceptées

eu Europe « Please note that prospective protocol waivers remain unacceptable and that patients should not be included in trials without proper eligibility assessment, including performance of planned tests, and written informed consent according to national laws and regulations. » (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

eu Europe « We acknowledge that the COVID-19 situation is likely to introduce more protocol deviations than normal. We expect that the sponsor escalates and manages such protocol deviations in accordance with their standard procedures. A proportionate approach will be taken by the GCP inspectors when such deviations are reviewed during inspections, in particular where the best interest of the participant is maintained, and the participant is not put at risk.
An increase in protocol deviations in relation to the COVID-19 situation will in itself not trigger the actions required by GCP § 5.20. They will however need to be assessed and reported in the clinical study report, following ICH E3. »
(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

UK Royaume-Uni « Prospective protocol waivers remain unacceptable, we would not expect you to bypass the eligibility process due to difficulties in assessing subjects and carrying out tests. Safety of patients of course remains a priority and they should not be included into a trial unless you can confirm they meet the inclusion and exclusion criteria. Similarly, if the safety of a trial subject is at risk because they cannot complete key evaluations or adhere to critical mitigation steps, then consideration to discontinuing that subject must be discussed. This may also extend to the whole trial in some cases, and a Sponsor and Investigator should not forget they are able to use Urgent Safety Measures, or even temporarily halt a trial, or halt recruitment, if this is the best way forward. » (Research in a public health emergency, MHRA, United Kingdom, 8 March 2020)

UK Royaume-Uni « Protocol waivers
Prospective protocol waivers remain unacceptable. We would not expect you to bypass the eligibility process due to difficulties in assessing subjects and carrying out tests.

Safety of patients remains a priority and they should not be included into a trial unless you can confirm they meet the inclusion and exclusion criteria.

Similarly, if the safety of a trial subject is at risk because they cannot complete key evaluations or adhere to critical mitigation steps, then consideration to discontinuing that subject must be discussed.

This may also extend to the whole trial in some cases, and a Sponsor and Investigator should remember they can use Urgent Safety Measures, or even temporarily halt a trial, or halt recruitment, if this is the best way forward. » (Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 24 March 2020)

CA Canada « Eligibility assessment is to be carried out as usual. Persons should not enroll in a trial if they do not meet the pre-set inclusion/exclusion criteria. If by missing a pre-defined study visit, the safety of a participant may be put at risk despite implementation of appropriate mitigation measures, the sponsor needs to consider having the participant discontinue taking part in the study. » (Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors, Health Canada, 23 March 2020)

Possibilité de transférer en urgence des patients vers un autre centre

fr France « Un patient peut-il changer de lieu de recherche pour décharger un centre en tension ou afin de limiter ses déplacements ? »
Oui

fr France « May a patient change his trial site in order to unburden a centre in tension or in order to limit his journeys?
Yes

fr France « De nouveaux lieux de recherche (centres investigateurs) peuvent-ils être ouverts rapidement pour décharger des centres en tension ou pour limiter les déplacements des patients en cours de traitement ?
Oui

fr France « May new trial sites be opened quickly in order to unburden centers under stress or to limit journeys for patient on treatment?
Yes

eu Europe « The sponsors should consider in their risk assessment whether the following measures could be the most appropriate during COVID-19. Measures should generally be agreed with investigators and could be: (…)
If unavoidable (it should be justified that this is a truly exceptional situation based on the personal risk-benefit ratio for the individual trial participant), transfer of participants to investigational sites away from risk zones, or closer to their home, to sites already participating in the trial, or new ones could occur. Initiation of new trial sites is generally not expected in the current situation unless no other solution exists for the trial participant. If there is an urgent need to open a new trial site for critical trial visits for example outside the hospital, this may be implemented as an urgent safety measure (USM) first, with a substantial amendment (SA) application submitted later as for the approval and initiation of an additional site later. The exceptional situation could involve e.g. a trial participant who urgently needs to stay in the trial and for whom no other sites are available. In such cases, it is important that trial participants as well as investigators (both receiving and sending) are in agreement about the transfer and that the receiving site has the possibility to access previously collected information/collected data for the trial participant and that any eCRF can be adjusted accordingly to allow the receiving site to enter new data. The impact on trial participants should be considered and arrangements made to e.g. appropriate transportation; transport »
(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

DK Danemark « We recommend the sponsor to consider whether there could be a need (in certain cases) to transfer trial subjects from one site to another e.g. to new sites or existing sites in less affected areas. In such cases, it is important that both trial subjects and both investigators (receiving and providing) agree about the transfer and that the receiving site has the possibility to access previously information/collected data for the trial subject and that any eCRF can be adjusted accordingly to allow the receiving site to enter new data. Such agreement can be documented e.g. in email corre-spondence filed in the TMF » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

BG Bulgarie « 4. En l’absence d’alternative, le transfert des participants d’un centre à un autre – un centre nouveau / déjà approuvé dans le règlement est possible en cas d’urgence. Dans de tels cas, il est important de s’assurer que les patients sont traités en continu. Les participants au test et les deux chercheurs principaux doivent s’entendre sur la relocalisation, et le centre d’accueil devrait avoir un accès rapide aux informations – données collectées auprès des participants au test. Des changements substantiels sont nécessaires dans ces cas, accompagnés d’une documentation pertinente, qui sera priorisée. » (Traduction des Recommandations aux commanditaires concernant la conduite des essais cliniques dans le cadre du risque complexe de Covid-19 d’une déclaration de l’état d’urgence dans le pays, Version Bulgare )

BG Bulgarie « 4. In the absence of an alternative (applying the risk-based approach), the transfer of patients from one site to another, e.g. to a new site or existing site in the same settlement, could occur. In such cases it is important to ensure the treatment continuity of the patients. Both the trial participants and the two Principal Investigators must agree on the relocation, and the receiving site must have the possibility to access previously collected information/collected data for the trial participants. In these cases a submission of substantial amendments, accompanied by the relevant documentation, is needed and will be prioritized as assessment by BDA » (Recommendations to the Sponsors for managing of Clinical Trials during the COVID-19 pandemic and the declared State of emergency in the Republic of Bulgaria, BDAn Bulgarie, 24 March 2020)

ES Espagne « 5. Transferencia de pacientes de unos centros a otros
Si fuera necesario el traslado de un paciente de un centro del ensayo a otro, éste se podrá realizar siempre que: a) se firme un acuerdo de transferencia entre centros, b) el nuevo centro tenga acceso al cuaderno de recogida de datos y a la historia clínica del paciente (o en su defecto el centro original le envíe una copia de la misma); c) el centro original envíe un informe de transferencia que resuma los datos médicos más relevantes del paciente en relación con el ensayo para facilitar su seguimiento al nuevo centro; d) la transferencia del paciente quede documentada en el archivo del ensayo de los dos centros. »
(Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020)

UK Royaume-Uni « 3.2.2. Studies where sites need to move participant visits due to re-allocation of staff and resources to clinical care or limiting participant contact
Sites must raise such issues with the sponsor as early as possible if this is likely to occur.
Where possible such arrangements should be handled prospectively, and, where required, submitted as an amendment. In cases where there is no time to arrange for such review, changes should be implemented as urgent safety measures and reported retrospectively. In any such situation the impact on participants should be considered and arrangements made to cover this, for example additional transport.
Where participant visits can be done remotely rather than face to face this does not need to be reported as an amendment, although it may be appropriate to record this if it might affect the study data, for example subjective interview responses.
Where individual sites need to arrange to courier treatment to patients, this does not need to be reported as an amendment, but should be agreed with the sponsor and a risk assessment documented.
If patient visits need to be moved, the options are to set up as a sub-contracted site of the existing site if oversight can be maintained by the existing site, or to set up new sites, or to implement direct home care arrangements by the sponsor. For study types where addition of new sites is a substantial amendment, existing guidance for submitting a substantial amendment for new sites should be followed. In all other cases, existing guidance for non-substantial amendments and addition of new sites should be followed.
Establishing subsidiary sites is a non-substantial amendment. These should be handled as a non-substantial amendment that does not require HRA/HCRW Approval or R&D agreement. For studies involving the NHS/HSC, these should be marked by the sponsor as category C and not requiring assessment and sent directly to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor. »
(COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020)

Le Promoteur doit déterminer si les visites des patients doivent être maintenues ou faire l’objet d’aménagement

fr France « Les visites de suivi des patients peuvent-elles être adaptées ?
Oui
Le recueil d’information par téléconsultation est recommandé à titre exceptionnel, centrée sur les critères de vigilance et le critère principal.
Toute donnée non évaluable à distance sera notée manquante.
La non réalisation d’une visite protocolaire ne sera pas considérée comme un motif de sortie d’étude et au-delà de la nécessaire documentation, ne sera pas considérée comme une déviation majeure devant être notifiée à l’ANSM selon les BPC § 5.20.
Les déviations devront néanmoins être signalées et évaluées dans le rapport final de l’essai (Cf. guideline ICH E3).

fr France « May patient follow-up visits be adapted?
Yes
The collection of information by teleconsultation is recommended on an exceptional basis, with a focus on safety data and primary objective endpoints.
Any data that cannot be assessed remotely will be noted as missing.
The failure to complete a protocol visit will not be considered as a reason for study discontinuation and, beyond the necessary documentation, will not be considered as a major deviation that must be notified to the ANSM according to GCP § 5.20.
Deviations shall nevertheless be reported and evaluated in the final study report (see ICH guideline E3).

eu Europe « The sponsors should consider in their risk assessment whether the following measures could be the most appropriate during COVID-19. Measures should generally be agreed with investigators and could be:
Conversion of physical visits into phone or video visits, postponement or complete cancellation of visits to ensure that only strictly necessary visits are performed at sites; »
(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

UK Royaume-Uni « 3.1.2. Studies making changes to how or when patients are seen to avoid exposing patients or to reduce burden on clinical services

  • In some cases changes will be deemed by the sponsor to reduce risk of potential exposure to COVID-19 by participants, for example changing participant site visits to phone calls or postal questionnaires. Sponsors must not make any such changes that would create additional burden to NHS staff or resources. These should be handled as a non-substantial amendment that does not require HRA/HCRW Approval or R&D agreement. For studies involving the NHS/HSC, these should be marked by the sponsor as category C and not requiring assessment and sent directly to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor.
  • In some cases changes will be deemed by the sponsor to potentially increase risk to participants, eg less frequent participant checks. Sponsors must not make any such changes that would create additional burden to NHS staff or resources. These should be handled as a substantial amendment. Such amendments will be categorised and assessed according to existing guidance, but the process will be expedited. They should be sent to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor. » (COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020, Updated to v2.2 on 26 March 2020)

UK Royaume-Uni « Replacing in-person visits with phone calls
Using phone calls instead of protocol-directed in-person study visits is acceptable where possible. This will not constitute a serious breach of the protocol. A substantial amendment to update the protocol will not be required. We would however expect that any protocol deviations are well documented internally. »
(Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 24 March 2020)

BE Belgique « 3.Restrictions of visits to healthcare facilities

In those conditions where it is not advised to have the subjects going to the investigator site, or where they would not be allowed to do so (e.g. due to quarantine conditions), home nursing/contact via phone may be required to identify adverse events and ensure continuous medical care and oversight. This is already foreseen in the European Guidance.

There might be particular cases: as e.g. a Belgian patient is enrolled in a trial in another member state. Owing to the COVID-19 situation the foreign site closes. The Belgian patient returns to Belgium. The same trial is not launched in Belgium. The patient wants to continue the experimental treatment, as he benefits from it. The principal investigator and the sponsor are invited to obtain a solution in the best interest of the participating patient. In this case there are two possibilities: either a new trial is launched in Belgium (initial CTA dossier to be submitted to both EC and FAMHP) which is in current circumstances not recommended, or one relies on (i) the patient drops out of the clinical trial and (ii) on the Royal Decree of 14th Dec 2006 Art 105 or Art 107/1 (Compassionate use). « (Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

BG Bulgarie « 3. Le promoteur, en collaboration avec le chercheur principal, devrait déterminer si les visites physiques (visites sur place dans les centres) peuvent être transformées en suivi à distance, appels téléphoniques, différés ou annulés entièrement en appliquant l’approche basée sur les risques, les capacités du protocole de test ou son amendement visant à garantir que seules les visites nécessaires soient effectuées dans les centres. En cas de modification substantielle du procès-verbal, dans ces cas, accompagné de la documentation pertinente, il sera considéré comme prioritaire. » (Traduction des Recommandations aux commanditaires concernant la conduite des essais cliniques dans le cadre du risque complexe de Covid-19 d’une déclaration de l’état d’urgence dans le pays, Version Bulgare )

BG Bulgarie « 3. The sponsor, in collaboration with the Principal Investigator, should consider if the physical visits (on-site visits) can be converted in remote tracking/visits, phone visits, postponed or canceled completely in applying the risk-based approach, the capabilities of the clinical trial’s protocol or its amendment, to ensure that only the strictly necessary visits are performed at sites. If a substantial amendment in the protocol in these cases is applied (accompanied by the relevant documentation), it will be prioritized as assessment by BDA » (Recommendations to the Sponsors for managing of Clinical Trials during the COVID-19 pandemic and the declared State of emergency in the Republic of Bulgaria, BDAn Bulgarie, 24 March 2020)

ES Espagne « 1. Visitas presenciales programadas de los pacientes de un ensayo clínico
El promotor junto con el investigador deberá considerar la conveniencia de posponer dichas visitas, o transformarlas en visitas telefónicas, reprogramándolas en el calendario de visitas del ensayo clínico. Deberá garantizarse que las visitas programadas in situ que sean críticas se lleven a cabo. En el caso de reprogramar las visitas estas desviaciones del protocolo no se considerarán incumplimientos graves a menos que pongan en riesgo la seguridad del paciente. »
(Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020)

DK Danemark « The sponsor (in cooperation with the principal investigator) should also consider whether physical visits can be converted to phone visits, postponed or cancelled completely to ensure that only strictly necessary visits are performed at sites. It may be considered to use electronic systems, such as video/telecommunications or e.g. electronic diaries if considered to relief burden from the trial staff. This is, of course, provided that the IT systems used are secure and valid.This consideration should also be part of the sponsor’s risk assessment in relation to the COVID-19 pandemic. » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

us Etats-Unis « Since trial participants may not be able to come to the investigational site for protocol-specified visits, sponsors should evaluate whether alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) could be implemented when necessary and feasible, and would be sufficient to assure the safety of trial participants. Sponsors should determine if in-person visits are necessary to fully assure the safety of trial participants (for example to carry out procedures necessary to assess safety or the safe use of the investigational product appropriately); in making the decision to continue use or administration of the investigational product, the sponsor should consider whether the safety of trial participants can be assured with the implementation of the altered monitoring approach. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q5. Can a sponsor initiate virtual clinical trial visits for monitoring patients without contacting FDA if there is an assessment by the sponsor and investigator that these visits are necessary for the safety of the trial participant and it will not impact data integrity?

FDA regulations allow for changes to be made to the investigational plan or protocol without prior FDA review or approval, if the change is intended to eliminate an apparent immediate hazard or to protect the life and well-being of subjects.Therefore, changes in protocol conduct necessary to immediately assure patient safety, such as conducting telephone or video contact visits for safety monitoring rather than on-site visits, can be immediately implemented with subsequent review by the IRB and notification to FDA. Since this reflects a protocol deviation (until the amendment is approved), documentation of the required deviations, as described above, would generally be acceptable (i.e., a document that lists each deviation (study reference ID, patient ID, and date)). For example, documenting that all protocol-specified visits will be done by telephone contact rather than on-site visits, and that procedures requiring in-person visits will either not be conducted, or performed by other means (specified, as appropriate). Since the change to telephone or video contact visits would likely result in some protocol-required procedures not being conducted (e.g., vital signs, blood samples for safety laboratory studies, etc.), the sponsor must evaluate the potential impact on patient safety, and consider how to mitigate risks to patients, including the need to discontinue the investigational product. For IDE studies, sponsors are required to report deviations implemented to address the imminent safety risk to FDA within 5 working days after learning of the deviations. We recognize that challenges related to the COVID-19 pandemic may make it difficult to meet this timeframe. Sponsors may consolidate implemented deviations when submitting 5-day reports and should update FDA as soon as possible. (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

CA Canada « Clinical trial visits

  • Investigators may need to evaluate whether alternative methods for safety assessment are feasible should participants not be able to come to the investigational sites as specified in the study protocol. Alternative methods may include phone contact, virtual visits via telemedicine or alternative care sites. Alternative locations for imaging studies and laboratory tests may need to be considered.
  • If alternative monitoring is done, careful documentation will be required to capture the reason why it was done; the method used to collect the information; what data was collected; who provided the information; how the source of the information was verified and the reason why. Study protocol amendments will not be needed.
  • The use of alternative sites may create issues of confidentially related to participant’s medical records (Electronic Health Record).
  • Trial participants will need to consent to any identifiers leaving the original site and be assured that their confidentially will be protected. » (Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors, Health Canada, 23 March 2020, Updated on 3 April 2020)

Afrique du Sud « Impact of social distancing measures on study logistics: Since trial participants may not be able to come to the investigational site for protocol-specified visits, sponsors should evaluate whether alternative methods for safety assessments (e.g. telephone contact, virtual visit, alternative location for assessment, including local laboratories or imaging facilities) could be implemented when necessary and feasible, and would be sufficient to assure data integrity and safety of participants.
Sponsors should determine if in-person visits are necessary to fully assure the safety of trial participants (for example to carry out procedures necessary to assess safety or the safe use of the investigational product appropriately); in making the decision to continue use or administration of the investigational or other products, both the sponsor and principal investigator(s) should consider whether the safety of trial participants can be assured with the implementation of the amended monitoring approach. »
(SAHPRA Policy on Conduct of Clinical Trials of Health Product during the current COVID-19 pandemic, SAHPRA, 25 mars 2020)

PE Pérou « 1. Visitas presenciales programadas de los participantes de un ensayo clínico
El patrocinador o su representante, junto al Investigador principal deberán considerar la conveniencia de posponer o reprogramar dichas visitas, o transformarlas en visitas telefónicas, reprogramándolas en el calendario de visitas del ensayo clínico.

Para los sujetos de investigación en los cuales es necesaria su asistencia a los centros de investigación para que se le aplique un tratamiento o toma de muestra, los patrocinadores o sus representantes deberán suministrar los elementos de protección personal para minimizar el riesgo de infección y garantizar un medio de trasporte para que el sujeto en investigación tenga contacto mínimo con otras personas.

En todos los casos se debe garantizar el acceso de los sujetos se investigación a la medicación y procedimientos propios del ensayo en las mismas condiciones de seguridad contempladas en los protocolos aprobados. » (Covid-19 – Communicado N° 002-2020-OGITT/INS, Ministerio de Salud, 26 de Marzo 2020)

Modalités spécifiques de recueil du consentement

eu Europe « 8. Changes to informed consent

The informed consent procedure in all trials needs to remain compliant with the trial protocol as well as with EU and national rules. It is acknowledged that national provisions and approaches differ.
Sponsors should be mindful of the current pressure on the medical profession and should carefully assess the pertinence of adding new subjects in ongoing clinical trials. Absolute priority should be given to clinical trials for the prevention or treatment of COVID-19 and COVID19- related illnesses, or trials on serious diseases with no satisfactory treatment option. In case a sponsor plans to initiate a trial aiming to test new treatments for COVID-19, advice should be sought on alternative procedures to obtain informed consent, as it is likely that the physical consent cannot leave the isolation room, and therefore is not appropriate as trial documentation.
However, the following specific aspects should be taken into account with trials involving COVID-19 patients.
If written consent by the trial participant is not possible (for example because of physical isolation due to COVID-19 infection), consent could be given orally by the trial participant (Art 2(j) of Directive 2001/20/EC) in the presence of an impartial witness. In such cases, the witness is required to sign and date the informed consent document and the investigator is expected to record how the impartial witness was selected.
In addition, it could be considered that the trial participant and the person obtaining consent sign and date separate informed consent forms. In either case, all relevant records should be archived in the investigator site’s Trial Master File. A correctly signed and dated informed consent form should be obtained from the trial participant later, as soon as possible.
Where potential COVID-19 trial participants lack capacity to consent due to the severity of their medical condition, or when minors are included, consent has to be obtained from the legal representative(s) according to the Articles 4 and 5 of Directive 2001/20/EC and national rules. In case of acute life-threatening situations, where it is not possible within the therapeutic window to obtain prior informed consent from the patient (or her/his legal representatives(s)), informed consent will need to be acquired later, when this is allowed in national legislation. In these cases, the investigator is expected to record why it was not possible to obtain consent from the participant prior to enrollment.
For other ongoing trials, there may be a need to re-consent already included trial participants. However, avoid the need for trial participants to visit investigator sites for the sole purpose of obtaining re-consent. If re-consents are necessary for the implementation of new urgent changes in trial conduct (mainly expected for reasons related to COVID-19), alternative ways of obtaining such re-consents should be considered during the pandemic e.g. contacting the trial participants via phone or video-calls and obtaining oral consents supplemented with email confirmation. Approved updated patient information sheet and consent form should be provided to trial participants by e-mail, mail or courier before re-consent is obtained. Any consent obtained this way should be documented and confirmed by way of normal consent procedures at the earliest opportunity when the trial participants will be back at the regular sites.
Any validated and secure electronic system already used in the trial in the particular member state for obtaining informed consent can be used as per usual practice and if in compliance with national legislation. »
(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 27 March 2020)

UK Royaume-Uni « Information and consent in emergency research projects

Emergency research is when:

  • treatment needs to be given urgently, and
  • it is necessary to take urgent action for the purposes of the study.

In this situation, participants may or may not have capacity to consent.

Where research participants do have capacity to consent in emergency research, there will be limited time available for them to consideration participation. Information about the study should therefore be short and easy to read but contain enough detail for the participant to be able to make an informed decision.

Further guidance about this is in our consent and participant information guidance.

Where research participants do not have capacity to consent in emergency research, the law and associated requirements depend upon whether the research is a Clinical Trial of an Investigational Medicinal Product (CTIMP) and where in the UK your research will take place. Obtaining consent from a legal representative or consultee may not be reasonably practicable.

Further guidance about this is in our consent and participant information guidance.

Information and consent in other, non-emergency research projects

Although COVID-19 research is taking place as part of a public health emergency, that does not mean all studies are classed as emergency research. The requirements for providing information and seeking consent depend upon the type of research project, whether or not your research participants will have capacity to consent and where in the UK the research will take place.

For information about general principles of consent, see our consent and participant information guidance. This guidance includes information about:

Research involving participants who are adults unable to consent

  • Research involving participants who are children and young people
  • Research involving the use of patient data
  • Research involving the collection of tissue from deceased person(s)

It also includes example consent documentation for different types of research.

Providing information to participants and recording consent

You should provide information to participants about your research using a format that is best suited to supporting the consent process and aiding understanding.

Text-based information on paper is not always be the best format for informing participants. Alternative formats, such as using images, diagrams, audio or online materials, may be more appropriate. For further guidance, see the informing participants and seeking consent section of our website.

 You can use electronic methods for seeking, confirming and documenting informed consent in research studies. For further guidance, please see the MHRA, HRA and Devolved Administrations joint statement on seeking consent by electronic methods. Our consent and participant information guidance also has links to examples of providing information in different formats.

Gathering tissue samples and/or data for COVID-19 bioresources

If your COVID-19 research activity is to gather tissue samples and/or data without a specific research project in mind, this is classed as establishing a research tissue bank (a collection of tissue and/or data) or research database (a collection of data only).

It is best practice to apply for voluntary Research Ethics Committee (REC) review as this may facilitate programmes of research without the need for individual project-specific REC review. Fast-track REC review is available in this instance.

If you are seeking to amend the scope of an existing research tissue bank or research database to include tissue samples and/or data for COVID-19 research, you should submit a substantial amendment for fast-track review.

For research tissue banks and research databases, it is likely that you will be seeking generic consent from potential participants. Generic consent is non-specific consent, where potential participants are given information about how the tissue samples and/or data might be used. Further guidance is about this is in our consent and participant information guidance.

You may choose to seek tiered consent where you describe a number of discrete research activities that the tissue sample and/or data could be used for and enable potential donors to agree to some but not necessarily all. You should only offer tiered consent if you are confident that you will be able to deliver on all aspects of consent in any combination the donor specifies.

If you are gathering patient data, see our guidance for using patient data.

For further guidance about consent, ethical review and licensing requirements in relation to human tissue in research and the use of material from diagnostic archives, see the use of human tissue in research section of our website.

DNA analysis

If you intend to use tissue samples for DNA analysis, whether for diagnosis, treatment or research, you need to seek consent from the participant/donor. Where the participant lacks the capacity to consent, advice from a consultee will be required. «  (Covid-19 Research – Seeking consent in COVID-19 research, NHS, Royaume-Uni, Last updated on 14 April 2020)

NL Pays-Bas « In case a subject is unable to provide (re)consent to (continue to) participate in a clinical trial in an emergency situation, obtaining consent can be deferred under specific conditions. The applicable conditions for such a deferred consent are described in the CCMO memorandum with flow chart Deferred Consent (in Dutch). To be able to use the possibility of deferred consent it is mandatory to obtain approval by the review committee (MREC/CCMO). » (Recommendations for the conduct of clinical research at the time of restrictive measures due to the coronavirus, CCMO, The Netherlands, 16 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q.10 How do I obtain a signed informed consent from a patient who is in isolation and the COVID-19 infection control policy would prevent us from removing a document signed by the patient from their hospital room?

FDA regulations generally require that the informed consent of a participant be documented by the use of a written consent form approved by the IRB and signed and dated by the subject or the subject’s legally authorized representative at the time of consent (21 CFR 50.27(a)). In light of COVID-19 infection control measures, the following procedure would satisfy documentation of this requirement if the patient signing the informed consent is in COVID-19 isolation

  • If the technology is available, electronic methods of obtaining informed consent should be considered
  • When it is not possible to obtain informed consent electronically, the sponsor should consider taking the following steps:
    1. An unsigned consent form is provided to the patient by a heath care worker who has entered the room
    2. If direct communication with the patient in isolation is not feasible or safe, the investigator (or their designee) obtains the patient’s phone number and arranges a three-way call or video conference with the patient, an impartial witness, and if desired and feasible, additional participants requested by the patient, (e.g. next of kin)
    3. To ensure that patients are approached in a consistent fashion, a standard process should be used that will accomplish the following:
      • Identification of who is on the call
      • Review of the informed consent with the patient by the investigator (or their designee) and response to any questions the patient may have
      • Confirmation by the witness that the patient’s questions have been answered
      • Confirmation by the investigator that the patient is willing to participate in the trial and sign the informed consent document while the witness is listening on the phone
      • Verbal confirmation by the patient that they would like to participate in the trial and that they have signed and dated the informed consent document that is in their possession.

If the signed informed consent document cannot be collected from the patient’s location and included in the study records, FDA considers the following two options acceptable to provide documentation that the patient signed the informed consent document:

  • Attestations by the witness who participated in the call and by the investigator that the patient confirmed that they agreed to participate in the study and signed the informed consent

    OR
  • A photograph of the informed consent document with attestation by the person entering the photograph into the study record that states how that photograph was obtained and that it is a photograph of the informed consent signed by the patient.

A copy of the informed consent document signed by the investigator and witness should be placed in the patient’s trial source documents, with a notation by the investigator of how the consent was obtained, e.g. telephone. The trial record at the investigational site should document how it was confirmed that the patient signed the consent form (i.e., either using attestation by the witness and investigator or the photograph of the signed consent). The note should include a statement of why the informed consent document signed by the patient was not retained, e.g., due to contamination of the document by infectious material.

If the patient is unable to provide informed consent and there is a legally authorized representative,investigators must obtain consent from the participant’s legally authorized representative in accordance with 21 CFR 50.27(a). » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q.11 How do I obtain informed consent from a patient unable to travel to a clinical trial site where electronic informed consent is not an option?

Investigators may also need to obtain informed consent from a potential trial participant or their legally authorized representative when these individuals are unable to travel to the site where the investigator is located due to COVID-19 illness or travel restrictions. When investigators do not have electronic informed consent (eIC) capabilities, methods of obtaining informed consent other than a face-to-face consent interview may still be acceptable if those methods allow for an adequate exchange of information and documentation, and a method to ensure that the signer of the consent form is the person who plans to enroll as a subject in the clinical investigation or is the legally authorized representative of the subject. For example, the consent form may be sent to the subject or the subject’s legally authorized representative by facsimile or e-mail, and the consent interview may then be conducted by telephone when the subject or subject’s legally authorized representative can read the consent form during the discussion. After the consent discussion, the subject or the subject’s legally authorized representative can sign and date the consent form. Options for returning the document to the clinical investigator may include facsimile, scanning the consent form and returning it through a secure e-mail account, or posting it to a secure internet address. Alternatively, the subject may bring the signed and dated consent form to his/her next visit to the clinical site, if restrictions on traveling to the clinical trial site are alleviated, or mail it to the clinical investigator.The case history for each subject must document that informed consent was obtained prior to participation in the trial. In addition, the person signing the consent form must receive a copy of the consent form. Although FDA regulations do not require the subject’s copy to be a signed copy, FDA recommends that a copy of the signed consent form be provided.

If concerns exist about having subjects mail to the investigator potentially contaminated consent documents from the subject’s location, the investigator may employ the procedures described above for enrolling patients in isolation through the use of a photographic image of the signed consent formtransmitted through electronic means.

The subject or the subject’s legally authorized representative must sign and date the informed consent form before the investigator may conduct any study-related procedures involving the subject. Where it is not feasible for investigators to receive the signed consent form prior to beginning study-related procedures, the investigators should have the subject or legally authorized representative confirm verbally during the consent interview that the subject or legally authorized representative has signed and dated the form. In addition, the overseeing IRB must review and approve the planned informed consent process. »(FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 16 April 2020)

Afrique du Sud « In-study Informed Consent: In all cases, it is critical that trial participants are kept informed of amendments to the study protocol and any monitoring plans that could impact them. Sponsors, in consultation with Principal Investigators, including National Principal Investigators, and Research Ethics Committees, may determine that the protection of a participant’s safety, welfare, and rights is best served by continuing a study participant in the trial as per the protocol or by discontinuing the administration or use of investigational or other products or even participation in the trial. Such decisions will depend on specific circumstances, including the nature of the investigational and other products, the ability to conduct appropriate safety monitoring, the potential impact on the investigational and other products supply chains, and the nature of the disease under study in the trial. » (SAHPRA Policy on Conduct of Clinical Trials of Health Product during the current COVID-19 pandemic, SAHPRA, 25 mars 2020)

Le choix peut-être laissé au participant de continuer, d’arrêter ou de suspendre sa participation

AU Australie « Participants

  • The safety and well-being of trial participants, other patients, family members, researchers and other clinical and support staff is paramount.
  • In trials that proceed without modification, participants should explicitly be given the following options:
    • continuing to participate in the trial
    • suspending their participation, if this is viable, or
    • withdrawing from the trial
  • Participants who do not attend clinic visits or complete other trial activities may be reminded that these are required; however, if a patient declines or actively refuses to participate in trial activities, then their decision should be respected and they should be considered to have withdrawn from the trial. These participants should be informed that their decision will not affecttheir ongoing treatment or participation in future clinical trials.
  • Participants who choose to move off the investigational product and onto standard care, and who do not wish to continue with site visits may be able to remain on trial for follow-up only
  • Participants should be informed of any modifications to the trial, including medical and other trial procedures, ongoing treatment or care and any tests or assessments that will have, or have the potential to have, an impact on them
  • In trials that have been modified, participants should explicitly be given the following options:

Le processus de gestion des déviations au protocole doit être révisé

UK Royaume-Uni « Protocol deviations
We appreciate that the impact of COVID-19 will likely result in an increase in protocol deviations. You should maintain good records of these deviations. Unless there is an impact onto patient safety, you do not need to notify MHRA of COVID-19 related deviations.
However, all other protocol deviations must be reported to us as normal. »
(Guidance- Medical devices clinical investigations during the coronavirus (COVID-19) outbreak, MHRA, Royaume-Uni, 30 March 2020)

UK Royaume-Uni « An increase in protocol deviations in relation to coronavirus will not constitute a serious breach, therefore there is no need to report this to us (unless of course patients are being put at risk). » (Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 24 March 2020)

BE Belgique « A protocol deviation (control of visits,…) should be considered as an USM if the change has to be directly implemented for the patient’s safety and if it is considered as a substantial amendment (cf. definition of substantial amendment, national and European coronavirus guidelines). The protocol deviations need to be included in the ICH E3 clinical study report. A substantial amendment shall only be submitted for critical protocol deviations (those which are really impacting safety), not for minor deviations. »(Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

us Etats-Unis « The implementation of alternative processes should be consistent with the protocol to the extent possible, and sponsors and clinical investigators should document the reason for any contingency measures implemented. Sponsors and clinical investigators should document how restrictions related to COVID-19 led to the changes in study conduct and duration of those changes and indicate which trial participants were impacted and how those trial participants were impacted.

Changes in study visit schedules, missed visits, or patient discontinuations may lead to missing information (e.g., for protocol-specified procedures). It will be important to capture specific information in the case report form that explains the basis of the missing data, including the relationship to COVID-19 for missing protocol-specified information (e.g., from missed study visits or study discontinuations due to COVID-19). This information, summarized in the clinical study report, will be helpful to the sponsor and FDA. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q3. How should sponsors manage protocol deviations and amendments to ongoing trialsduring the COVID-19 pandemic?

FDA recognizes that during the COVID-19 pandemic, sponsors of clinical trials may need to modify protocol-specified procedures. As in discussed in the main body of this guidance, for protocol deviations necessitated by the impact of the current COVID-19 pandemic, the sponsor should document the specific protocol deviation and the reason for the deviation. The sponsor can document protocol deviations using its standard processes, or given the larger expected number of such deviations, use alternative documentation approaches. For example, if visits are to be conducted by telephone/video contact rather than at the investigational site as specified in the protocol, documentation that provides a listing of all study visits (e.g., listing study reference number, patient ID, date of visit) that are deviations from the protocol due to the current COVID-19 situation generally would be acceptable.

For a study-wide change in protocol conduct, protocol amendments that are necessary to prevent imminent hazards to trial participants can generally be immediately implemented with subsequent submission and formal approval by the IRB and notification to FDA through filing a protocol amendment to the IND or IDE.

For studies under an IND, 21 CFR § 312.30(b) specifies that sponsors need to submit a protocol amendment describing any change in a phase 1 protocol that significantly affects the safety of subjects, or any change in a phase 2 and 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. Pausing enrollment in a trial to decrease potential exposure to COVID-19 would not generally be expected to significantly affect subject safety, the scope of the investigation, or the scientific quality of the study; therefore, submitting a protocol amendment would not be required under the regulation for such a pause.

Protocol amendments that are not required to prevent imminent safety risks to patients can be implemented once they are submitted to FDA and IRB approval has occurred. FDA recognizes that during the rapidly evolving circumstances of a pandemic, a sequence of changes may be needed to address those circumstances. Consolidating several protocol modifications in a single protocolamendment would be acceptable but should be done expeditiously. Clinical investigators mustdocument as protocol deviations any modifications to protocol-specified procedures that occur prior to IRB approval and FDA submission of the protocol amendment implementing the modification.

For studies under an IDE, 21 CFR 812.35(a) generally requires prior FDA approval before implementing changes to the investigational plan. However, under 21 CFR 812.35(a)(3), changes to the protocol that the sponsor determines, based on credible information, do not affect the validity of the results from the study, the likely patient risk to benefit relationship, the scientific soundness of the investigational plan, or the rights, safety or welfare of the subjects may be made without prior FDA approval, if the sponsor reports the modifications to the agency within 5 days of implementing the changes. Because of the unique and evolving circumstances surrounding the impact of COVID-19, we understand that it may be challenging to submit 5-day Notices within the required timeframe. Sponsors may consolidate implemented changes when submitting 5-day Notices and should update the IDE as soon as possible. «  (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

CA Canada « The clinical trial site(s) should have a system in place to identify, document, assess and report all protocol deviations to the sponsor and REB in accordance with sponsor and REB requirements. These deviations need to be documented, to facilitate future analysis of the study findings. The sponsor should define and identify the protocol deviations to be reported. Unless the deviations may place participants at risk, sponsors will not be required to report these deviations to Health Canada. » (Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors, Health Canada, 23 March 2020)

CA Canada « Increased number of protocol deviations

AU Australie « For clinical trials notified under the CTN scheme, the TGA acknowledges that there may be deviations from trial protocols relating to the supply of the Investigational Medicinal Product (IMP) and resulting from potential quarantine and travel restrictions (for example, patients may need to be managed remotely). These deviations do not need to be notified to the TGA.
Other variations to the CTN in response to COVID-19 that do not need to be notified to the TGA include changes to:

  • trial start/finish dates
  • Product Information
  • numbers of participants
  • name of the trial approving authority.

Variations to the trial, such as changes to existing therapeutic goods, addition of therapeutic goods or addition of sites and those variations that are not in response to COVID-19 will continue to require notification to the TGA. » (Coronavirus (COVID-19): Information on medicines and medical devices, TGA, Australie, 31 March 2020)

AU Australie « The use of strategies to pre-approve certain categories of amendments is encouraged and should be adopted subject to the directions of jurisdictional health departments. Amendments eligible for pre-approval would be at the discretion of the institution and/or HREC and might include modification of a trial to: »

  • employ virtual visits, telehealth, electronic consent or otherwise implement teletrials
  • change the ‘site’ to a location outside of a hospital or clinic or permit referral to another hospital or clinic
  • extend protocol timeframes for visits, procedures, trial medication delivery or follow-up to accommodate isolation periods or other disruptions
  • ensure that all returned investigational medical product is destroyed in accordance with standard protocols for the destruction of biohazards, and
  • any other changes that do not implicate participants’ safety or well-being and are intended for the purpose of safeguarding the health of participants, researchers and staff or the community via infection control or reducing the burden of participation in a trial for the participants or researchers

Amendments to existing protocols that are designed to limit exposure of participants, researchers or staff to infectious agents or to change methodology, procedures or project activity to ease the burden on participants, researchers or staff do not need to be approved by HRECs before being implemented, if timing does not enable this. In addition, necessary amendments that suspend recruitment or testing of participants, or that modify research locations or staffing and other administrative matters can be implemented as necessary. If there is time for an amendment of this type to be reviewed in accordance with existing administrative amendment approval processes, that is optimal; but, participant and staff safety are the paramount concerns in all cases.

If such changes are made, they should be reported to the sponsor in accordance with usual processes and to the HREC, when that becomes possible, in accordance with usual processes and in conformance with the National Statement.

Protocol deviations can be reported to HRECs in the usual manner or collected and submitted in bulk form at the end of the crisis.

Researchers are reminded that, although all deviations must to be reported to the trial sponsor, only the sub-set of deviations that have a significant impact on the continued safety or rights of participants or the reliability and robustness of the data generated in the clinical trial must be reported to the HREC. These deviations (also known as ‘serious breaches’) should also be reported by the PI to their institution, as they may impact on medico-legal risk, the responsible conduct of research, or adherence to contractual obligations. » (COVID-19 : Guidance on clinical trials for institutions, HRECs, researchers and sponsors, CTPRG, Australia, 24 mars 2020)

Afrique du Sud « Record of in-study protocol deviations: SAHPRA encourages sponsors and principal investigators to work with their Research Ethics Committees to prospectively define procedures to prioritize reporting of deviations that may impact the safety of trial participants. The implementation of alternative processes should be consistent with the protocol to the maximum extent possible, and sponsors and principal investigators should document the reason for any contingency measures implemented. » (SAHPRA Policy on Conduct of Clinical Trials of Health Product during the current COVID-19 pandemic, SAHPRA, 25 mars 2020)

Le Plan de Monitoring doit être adapté et actualisé (possibilité de visites de monitoring, révision des procédures…)

fr France « Les visites de monitoring sont-elles possibles dans les lieux de recherche ?

  • Les consignes de confinement actuellement en place doivent être respectées. Il convient de considérer un report des visites sur site selon les recommandations nationales et contraintes locales.
  • Le promoteur est incité à contacter les investigateurs afin de s’adapter aux contraintes de chaque lieu de recherche.
  • Le monitoring centralisé reste possible avec contact promoteur / centre sous réserve de la disponibilité des équipes investigatrices en situation de tension. L’envoi de copies des dossiers médicaux, même pseudonymisés, n’est pas autorisé.

fr France « Are monitoring visits to trial sites possible?

  • Existing containment guidelines must be followed. Postponement of site visits should be considered according to national recommendations and local constraints.
  • The sponsor is encouraged to contact the investigators in order to adapt to the constraints of each trial site.
  • Centralised monitoring remains possible with sponsor/site contact subject to the availability of the research teams in tense situations. Sending copies of medical records, even pseudonymised, is not authorised.

eu Europe « 11. CHANGES TO MONITORING
Certain sponsor oversight responsibilities, such as monitoring and quality assurance activities need to be re-assessed and temporarily, alternative proportionate mechanisms of oversight may be required.

The first priority when considering any change is to protect the rights, safety and well-being of trial participants.

As part of the risk assessment outlined in chapter 5, a risk-based approach to monitoring should be taken, focusing on certain sites, certain data points and certain processes that are critical to ensure the rights, safety and well-being of trial participants and the integrity of the trial (and trial data). The sponsor should consider the extent and nature of monitoring that would be eligible in each specific trial under this exceptional situation, and weigh this against the extra burden that introduction of any alternative measures would put on site staff and facilities. The monitoring plan should then be revised in accordance with these considerations, in order to strike an acceptable balance between appropriate oversight and the capacity of the trial site.

Results of adjusted monitoring/review measures and their impact should be reported to the sponsor in monitoring reports and in the clinical study report, where applicable.

It is essential that robust follow-up measures are planned and ready to be implemented when the situation is normalised. This should include increased on-site monitoring for a period that is sufficient to ensure that the impact of the reduced monitoring can be rectified, and problems resolved or properly documented. Data subject to remote source data verification are likely to require re-monitoring, in particular if it was based on pseudonymised documents, which cannot be considered as source documents, and considering that remote monitoring is expected to only have focused on the most critical information.

Adjusting monitoring activities may include a combination of the following:

a) On-site monitoring

Cancelling or postponing of on-site monitoring visits and extending of the period between monitoring visits are likely to be necessary.

To the extent on-site monitoring remains feasible, it should take into account national, local and/or organisational social distancing restrictions, the urgency (e.g. source data verification can often be postponed) and the availability of site staff and should only be performed as agreed with trial sites.

Additional measures regarding on-site monitoring may include limited, targeted on-site monitoring identifying higher risk clinical sites, if not already applicable for the trials of concern.

The on-site monitoring plan will need to be adapted and alternative measures (like those outlined in b), c) and d) below) put in place, or relied on to a greater extent if already present.

b) Centralised monitoring and central review of data collected

Centralised monitoring of data acquired by electronic data capture systems (e.g. eCRFs, central laboratory or ECG / imaging data, ePROs etc.) that are in place or could be put in place provides additional monitoring capabilities that can supplement and temporarily replace on-site monitoring through a remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely manner.

c) Off-site monitoring

Additional off-site monitoring activities could include phone calls, video visits, e-mails or other online tools in order to discuss the trial with the investigator and site staff. These activities could be used to get information on the clinical trial progress, to exchange information on the resolution of problems, review of procedures, trial participant status as well as to facilitate remote site selection and investigator training for critical trials.

d) Remote source data verification

Remote source data verification (SDV) will currently only be considered necessary for very few trials when in line with national law (or temporary national emergency measures). Remote SDV may be considered only during the public health crisis for trials involving COVID-19 treatment or prevention or in the final data cleaning steps before database lock in pivotal trials investigating serious or life-threatening conditions with no satisfactory treatment option. It should focus on the quality control of critical data such as primary efficacy data and important safety data. Important secondary efficacy data may be monitored simultaneously, provided this does not result in a need to access additional documents and therefore in an increased burden for trial site staff.

The sponsor should determine the extent and nature of remote SDV that they consider needed for each trial under this exceptional situation and should carefully weigh it against the extra burden that introduction of any alternative measures would put on site staff and facilities.

In the case of these very few trials, principal investigators should make their own determination as to whether or not the situation at their clinical site allows any of the following options for remote SDV:

  • Sharing pseudonymised copies of trial related source documents with the monitor; this may be done electronically where manageable by the site staff;
  • Direct, suitably controlled remote access to trial participants’ electronic medical records;
  • Video review of medical records with clinical site team support, without sending any copy to the monitor and without the monitor recording images during the review.

For COVID-19 trials starting now, when remote SDV is foreseen, it should be described in the initial protocol application (and informed consent form). In case of ongoing trials introduction of remote source data verification should be submitted, in line with national law or temporary national emergency measures, via a substantial amendment. These provisions should be in line with the principles of necessity and proportionality and in a way that protects trial participants’ rights and should not place any disproportionate burden on site staff as determined by the investigator and trial site staff. Investigators should not be put under undue pressure to accept remote SDV and should always give priority to the care to be given to trial participants and other patients.

Refer to Annex 1 for controls that, where applicable, can protect trial participants’ rights while permitting remote SDV. »(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 28 April 2020)

eu Europe « Certain sponsor oversight responsibilities, such as monitoring and quality assurance activities need to be re-assessed and temporary, alternative proportionate mechanisms of oversight may be required. The extent of on-site monitoring, if it remains feasible, should take into account national and local restrictions, the urgency (e.g. source data verification can often be postponed) and the availability of site staff, and should only be performed as agreed with investigator sites. The burden of the introduction of any alternative measures for the site staff and facilities should also be considered in order to strike an acceptable balance between appropriate oversight and the capacity of and possibilities at the site.
Possible temporary, alternative measures could include:

  • Cancelling of on-site monitoring visits and extending of the period between monitoring visit;
  • Implementing phone and video visits (without unnecessarily increased burden to the investigator site and taking into account trial participant integrity);
  • Adapting the on-site monitoring plan when it is impossible to follow, supplementing it with (additional/increased) centralised monitoring and central review of data if possible and meaningful.

Results of adjusted monitoring/review measures should be reported to the sponsor in monitoring reports and in the clinical study report.
It is essential that robust follow-up measures are planned and ready to be implemented when the situation is normalised. This should likely include increased on-site monitoring for a period that is sufficient to ensure that the impact of the reduced monitoring could be rectified and problems resolved or properly documented for reporting in the clinical study report.
So-called remote source data verification (e.g. providing sponsor with copies of medical records or remote access to electronic medical records) is currently not allowed in most member states as it might infringe trial participants’ rights. In addition, provision of redacted/ de-identified pdfs files will not be acceptable as it puts disproportionate burden on site staff.
Nevertheless, since the coronavirus emergency situation and containment measures are likely to last for a prolonged period, several NCAs have started to look into possible, temporary solutions related to remote access and conditions for such, providing that methods can be used that restricts access to trial participant records, in line with the principles of necessity and proportionality. This should however also be clarified with other relevant authorities in this area (such as, without limitation, Ethics Committees and data protection agencies) and is consequently not allowed unless a member state has given specific guidance allowing this.
 » (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020)

eu Europe « Possible temporary, alternative measures could include: (…)

UK Royaume-Uni « 3.1.1. Studies where sponsors need to change their site monitoring arrangements, or make changes to administrative arrangements to reduce burden or physical contact with sites
Any such changes should not increase the burden on NHS sites.
Any change to remote monitoring must not result in confidential patient information being sent to the sponsor if this has not already been addressed in the participant information sheet. Source data verification may be done remotely by electronic means if the necessary security arrangements can be put in place, if the arrangements are in line with the participant information sheet.
Such changes should be handled as a non-substantial amendment that does not require HRA/HCRW Approval or R&D agreement. For studies involving the NHS/HSC, these should be marked by the sponsor as category C and not requiring assessment and sent directly to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor.
Sponsors should consider what monitoring needs to be done in real time, and what checks can be undertaken later, taking a risk-based approach. Where a change to access to confidential patient information will arise as a result of changes to remote monitoring, the revised participant information sheet and consent form, along with the risk assessment justifying the changes to access to confidential patient information, should be submitted as a substantial amendment. Such amendments will be categorised and assessed according to existing guidance, but the process will be expedited. They should be sent to sites following the instructions above. These should be implemented at sites on the date specified by the sponsor. »
(COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020, Updated to v2.2 on 26 March 2020)

UK Royaume-Uni « Remote monitoring for trials

We support remote monitoring where appropriate but consider the following:

Direct access to patients EHR (Electronic Health Record) away from the site creates issues around confidentiality. Consider where this access takes place, for example will CRAs (Clinical Research Associates) be accessing records in an open plan office, public space or other location where others who are not authorised could view sensitive information. There should be explicit instructions from the sponsor and the host organisation (with input from their Caldicott Guardian) as to what can be accessed where and an agreement from the CRAs that this will be complied with. Access from home can be acceptable, provided that there is somewhere private that this can be done, away from family etc. The device through which this is accessed must have adequate security, such as adequate firewalls, secure log-in and passwords etc, and must not be left unattended and accessible. The instructions should not allow printing, emailing or downloading of any records, or that this is disabled by the system

  • Trial participants will need to consent to any identifiers leaving the site and be assured that their confidentiality will be protected
  • It is likely that there will be increased pressures on clinical staff during this period, so it is important to make sure that extra burdens are not placed on investigators around scanning and uploading many documents.
  • The use of alternative means of oversight such as teleconferences/videoconferences is encouraged

Please refer to the MHRA blog, the HRA blog and the MHRA GCP Forum FAQs on monitoring/remote monitoring for further guidance. » (Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 22 avril 2020)

UK Royaume-Uni « Reducing the number of participant monitoring visits
CT-1 guidance does regard a reduction in the number of monitoring visits as a substantial amendment.
If participant monitoring visits need to be reduced due to COVID-19, this will not require a substantial amendment. However, do please ensure that your risk assessment and rationale is appropriately documented. »
(Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 24 March 2020)

BE Belgique « 6.Remote Source Data Verification

Several investigators have cancelled on-site monitoring at their study site. Remote source data verification (e.g. providing sponsor with copies of medical records or remote access to electronic medical records) is currently not allowed in Belgium as it violates trial participants’ rights. In addition, requiring the site staff to redact all medical charts would most likely put too much burden on the sites at this time, nor does it allows sufficient verification by monitors. Therefore this process is not recommended. Special attention to on-site monitoring will be required once allowed again.Please note that with source we mean the medical dossier, the charts of the participant. « (Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

DE Allemagne « 1. Recommendations for conducting remote monitoring
It must first be determined through a risk analysis for what purpose, at what times and to what extent monitoring remains necessary in the clinical trial in question, despite the restrictions imposed by the COVID 19 pandemic. Where this is the case, it is strongly recommended that remote monitoring in form of telephone and/or video visits will be limited to essential core data and processes to avoid an unnecessary burden on the investigator and the trial team. This usually includes data required for the continuous benefit-risk assessment, such as verification of compliance with inclusion and exclusion criteria, the doses and dose regimens of IMP(s) used and the complete recording of (serious) adverse events (pharmacovigilance) and key outcomeparameters.

The possibility of remote access to source data may exceptionally be considered as a temporary solution duringthe COVID 19 pandemic. A possibilityto provide such direct accesswould be camera access to prepared study documents and records. However, the essential requirements of data protection must be guaranteed. Documents or recordings containing personal data of trial subjects mustnot leave the trial site, not even as copies; thus, such datamustnot be permanently stored outside the trial site. Transmission of data and/or documents ofany kind that goesbeyond the mere transmission of a camera image content as well as the use of cloud solutions remain fundamentally inadmissible. The same applies to the transfer of such camera image content to third countries. The information and communication technology must be designed to ensure DSGVO(German name for General Data Protection Regulation)-compliant transmission. As a general rule, the establishedmessenger services are not suitable for this purpose. In this context, please be referredto the « Whitepaper—TechnicalData Protection Requirements for Messenger Services in the Hospital Sector » published by the Conference of Independent Data Protection Supervisors of the Federal and State Governments on November 7 2019.

It must also be ensured that monitoringby video camerais performed exclusively by the sponsor’s authorized personnel(i.e. the clinical monitor) in accordance with the written consent of trial subjects.

The specific procedure must be included in the list of processing activities as a defined exception with start and end dates; however,it is not known whether the responsible data protection authorities will assess this.

Before implementing monitoring by video camera, it is necessary to extend and/or adapt the monitoring plan and/or the monitoring manual accordingly. The instructions provided in these documentsshould ensure a structured approach and adequatedocumentation. The amended monitoring plan and/or monitoring manual, as well as the documentation on the implementation of video monitoring or other adapted monitoring measures, should be stored in the Trial Master File. The necessity, suitability of and compliance with the specified changes shall be reviewed periodically.

The monitoring adaptationsdue to the COVID 19 pandemic shall be summarized in the trial report after completion of the clinical trial.

In Germany, the temporary adaptation of the monitoring plan and/or the monitoring manual does not require the submission of an amendmentto the responsible higher federal authority and ethics committee according to § 10 GCP-V(Ordinance on the implementation of GCPin the conduct of clinical trials on medicinal products for use in humans), as these documents are usually not subject of the clinical trial authorisationand opinion, respectively. » (Supplementary recommendations to the document European Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 1.0, Bfarm, Allemagne, 26 March 2020)

BG Bulgarie « En ce qui concerne le suivi des essais, il est recommandé que le plan de suivi soit suivi des procédures du promoteur etdes options pour diluer les visites de suivi ou les faire à distance conformément aux règles de bonnes pratiques cliniques. Les modifications du plan de surveillance ne sont pas soumises à la déclaration de la BDA. » (Traduction des Recommandations aux commanditaires concernant la conduite des essais cliniques dans le cadre du risque complexe de Covid-19 d’une déclaration de l’état d’urgence dans le pays, Version Bulgare )

BG Bulgarie « Regarding the monitoring of the trials – it is recommended the monitoring plan to be adjust to the sponsor procedures and the options for diluting the monitoring visits or conducting them remotely in compliance with Good Clinical Practice guidelines should be obtained. Changes to the monitoring plan are not subject to BDA reporting. » (Recommendations to the Sponsors for managing of Clinical Trials during the COVID-19 pandemic and the declared State of emergency in the Republic of Bulgaria, BDAn Bulgarie, 24 March 2020)

ES Espagne « 4. Visitas de monitorización
Se recomienda al promotor actualizar los planes de monitorización del ensayo para los cuatro próximos meses priorizando la monitorización centralizada y la monitorización remota de los centros participantes que no conlleve sobrecargar de tareas al personal del centro ni la revisión de datos fuente y posponiendo en la medida de lo posible la verificación de datos fuente hasta poder acceder a la historia médica de forma presencial. El promotor acordará con los centros y equipos participantes las condiciones para dichas monitorizaciones. »
(Medidas excepcionales aplicables a los ensayos clínicos para gestionar los problemas derivados de la emergencia por COVID-19, AEMPS, Espana, 16 de marzo de 2020)

IT Italie « 4. Clinical trial monitoring
By analogy with what stated in the previous paragraph, Sponsors are invited to draw up a risk evalutation plan and implement an action plan taking into account the need to reduce unnecessary contacts in this period of COVID-19 epidemiological emergency. First of all, it should be assessed whether in-situ monitoring visits can be replaced by an enhanced centralised monitoring or whether such local visits can be postponed.
Exceptional methods such as telephone contacts or, even better, videoconferences with the trial site staff can be implemented for the purpose of source data verification. These methods must be described in a specific SOP by the Sponsor/CRO and must be evaluated and approved by the Personal Data Protection Officer of the trial site.
Other unusual monitoring methods involving more risky ways of accessing sensitive data, such as video recording of source document or making available to monitors original documents in shared electronic areas, must always be agreed with the Personal Data Protection Officer of the hospital, but it is considered appropriate that a specific opinion by the Italian Data Protection Authority be obtained. »
(Notice – Clinical trials’ management in Italy during the COVID-19 (coronavirus disease 19) emergency, AIFA, Italia, 12 march 2020 )

DK Danemark « 3. Changes in monitoring and audits

Monitoring

We acknowledge the need to adjust the monitoring of clinical trials. It is important that the overall risk assessment address any need for changes to monitoring strate-gies due to COVID-19. This risk assessment should take into consideration whether recruitment should be stopped temporarily. In addition, agreement with investigator sites on any changes should be obtained. Decisions should be driven based on pa-tient safety considerations.

  • On-site monitoring can be performed to the extent possible and as agreed with investigator sites. If it is not possible to follow the on-site monitoring plan, monitoring should be supplemented with centralised monitoring and central review of data, if possible.
  • Remote SDV (Source Data Verification) is allowed in accordance with below section

Sponsors should be aware that these requirements might be subject to change dur-ing the evolution of the pandemic.

It is essential that robust follow-up measures are planned for when the situation is normalised, especially in regards to data collection. This should likely include in-creased on-site monitoring for a period that is sufficient to ensure that the impact of the reduced monitoring has been established and handled.

Remote Source Data Verification

The COVID-19 pandemic is a long-term burden for the Danish health care system. This means that there will continue to be restrictive access to most clinical trial sites. As a result, onsite monitoring might be disrupted for a long period, which can have serious consequences for data validity in some clinical trials. Therefore, in dialog with the Danish Data Protection Agency, we have decided to allow remote access to source data and prepared the following prerequisites for sponsors to establish remote access to source data.

Sponsor shall assess if ongoing trials, or soon to launch critical trials, where verifi-cation of source data is needed to ensure the quality of the final data. If this is the case, the sponsor must prepare a monitoring plan for remote SDV. Such plan should identify critical data that is going to be verified. Critical data are considered by the Danish Medicines Agency to be primary efficacy parameters, important safety data as well as any important secondary efficacy data to the extent that these can be verified in the same documents as the primary efficacy data. Only these data must be requested by the sponsor and verified.

Remote SDV should at this point only be required for a few clinical trials:

  • Clinical trials investigating treatment and prevention of COVID-19
  • Pivotal clinical trials soon reaching Data Lock Point and thereby trial com-pletion, analysis and reporting of trial data.

Implementation of remote access must be carried out in close collaboration with the site investigators. The investigators should consult relevant personnel at the hospi-tal’s regarding possible solutions, practicality and security.

We also point out that sponsor is responsible for ensuring that remote SDV complies with GDPR. In this connection, a separate risk assessment must be prepared re-garding data protection for the established procedures. Consideration should be made whether access is contemplated at the monitor’s home or office. In case of doubt regarding data protection, the investigator and sponsor/monitor can contact the Danish Data Protection Agency.

This temporary option is valid until 01 September 2020. We will assess whether an extension is needed two weeks before expiry. A substantial amendment must be submitted to the Danish Medicines Agency if sponsor introduce re-mote access to source data.

For non-commercial sponsors in Denmark, which are monitored by the Danish GCP units, other conditions apply regarding remote access to e.g. patient records. The GCP unit monitors is employed by the Danish health care system and their contrac-tual conditions are expected to include appropriate safeguards.

The following general conditions must be met in addition to the specific terms mentioned by each of the three different procedures

  • Establishing remote access must be in accordance with the principles of ne-cessity and proportionality and must always be done in a way that protects the rights of the participants and does not place unnecessary burden on site staff. The sponsor must never put pressure on the investigator to establish remote access to source data.
  • Remote access to Danish source data may only take place from a location within EU/EEA.
  • Access must be established under secure conditions. This include a secure connection on a machine protected from unauthorized access. The location must ensure that outsiders cannot overlook the process.
  • Monitor and involved site staff must be trained in the process.
  • The principal investigator and the institutions data officer must assess the necessity for monitors to sign a written confidentiality agreement committing to securely destroy any documents, whether paper or electronic, as soon as they have been used for SDV and committing not to make any additional copies (or recording in the case of video access) of any non-pseudonymised document, etc.
  1. Electronic remote access to patient records and other source data

Conditions for method 1.

  • The access shall be restricted to read-only. Furthermore, monitors access should be restricted for trial subjects only to the extent possible.
  • The IT system must have an event log that shows when the monitor has accessed specific information.
  • Monitor must have personal access to the system.
  • The personal access must be provided with 2-factor authentication.
  • The system shall not, to the possible extent, allow the monitor to make local copies. Any data storage on the monitor’s computer should be limited to the extent possible.
  • A log must document which data the monitor has accessed if not possible to restrict monitors access exclusively to the data of the trial subjects. This should proof that the monitor has not accessed other data than relevant for the SDV task for the specific trial subjects. This must be documented in the TMF.
  • It must be clarified that no data may be deducted/archived from the systems for monitoring purposes. This also applies to images/screenshots of source data.
  • Monitors remote access shall be terminated immediately when the need for remote access is no longer present.
  1. Video conference where source data is reviewed with help of site staff

Conditions for method 2.

  • The video connection must be capable to provide high quality video to en-sure readability. Screen sharing functionality can be used.
  • It must be clarified that no data may be deducted/archived from the systems for monitoring purposes. This also applies to images/screenshots of source data.
  1. Transfer of pseudo-anonymised copies of source documents

Conditions for method 3.

  • Monitor must prepare a written request to investigator site about the source data needed for specific study participants to conduct SDV.
  • The site staff must pseudo-anonymise the requested documentation, do a quality check that anonymised areas cannot be read, and then deliver the documentation to the monitor in an encrypted form of communication.
  • A statement must be signed by the monitor that all documents has been destroyed or returned to the site. This statement must be submitted to the site as documentation.
  • At the earliest opportunity, when the possibility of on-site monitoring is re-established, the pseudo-anonymised documentation must be checked to re-late to the subjects concerned. » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 24 avril 2020)

us Etats-Unis « Q9. Considering that there will be likely delays to on-site monitoring of clinical trials during the COVID-19 pandemic, what are FDA’s expectations in such circumstances?

FDA recognizes that monitors may not be able to access the trial sites for on-site visits in a timely manner during the COVID-19 pandemic. Sponsors should work to find alternative approaches to maintain trial participant safety and trial data quality and integrity, such as enhanced central monitoring, telephone contact with the sites to review study procedures, trial participant status, and study progress, or remote monitoring of individual enrolled trial participants, where appropriate and feasible. FDA recognizes that delays in on-site monitoring may result in delayed identification of GCP non-compliance (including major protocol deviations) at the clinical trial site(s) (including protocol deviations not due to the impact of COVID-19). Sponsors should carefully document situations where monitors were unable to access, or had to delay, monitoring of a clinical site. Sponsors/monitors should also include in their documentation of protocol deviations or other GCP non-compliance issues identified at clinical sites whether delayed identification was due to postponed monitoring. FDA recognizes that unique situations at clinical sites will occur due to COVID-19 control measures and will consider these circumstances when evaluating inspectional observations. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « If planned on-site monitoring visits are no longer possible, sponsors should consider optimizing use of central and remote monitoring programs to maintain oversight of clinical sites. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

us Etats-Unis « Q13. I am a study monitor and am unable to conduct on-site monitoring visits due to the COVID-19 public health emergency. May I remotely perform the site monitoring visit? What recommendations does FDA have for how I can remotely perform source document review?

FDA regulations require sponsors to monitor the conduct and progress of their clinical investigations. The regulations are not specific about how sponsors must conduct such monitoring and are therefore compatible with a range of approaches to monitoring that may vary depending on multiple factors. Therefore, certain aspects of site monitoring visits may be done remotely if technically feasible. FDA understands that there may be deviations from the timing of on-site monitoring visits set forth in the trial monitoring plan and procedures, and that sponsors may consider ways to replace on-site monitoring visits with remote monitoring visits during the COVID-19 public health emergency. Further, there may be components of an on-site monitoring visit, as outlined in the trial monitoring plan, that cannot be completed remotely.

During the COVID-19 public health emergency, traditional on-site monitoring might be difficult for reasons such as (1) sites may not be able to accommodate monitoring visits (e.g., due to staffing limitations or site closures) or (2) monitors may not be able to travel to trial sites. When planned on-site monitoring visits are not possible, the reason should be documented and available for review by the sponsor and during FDA inspections.

The sponsor should consider using a risk-based approach to prioritize sites for remote monitoring, including as many study sites as feasible (and with a frequency as close to that described in the site monitoring plan as feasible). The decision regarding which sites to prioritize for remote monitoring should be guided by centralized monitoring or other information available about site performance(e.g., frequency and severity of protocol deviations previously identified during monitoring visits or currently identified by centralized monitoring, number of randomized active trial participants, experience of site staff, known history of prior major audit or inspection findings).

Remote monitoring should be focused on review of critical study site documentation and source data. If the materials identified for review include participants’ medical records that normally would be reviewed at the site (and such a review is consistent with the trial participants’ informed consent documents) then, as discussed below, remote review of medical records may be explored with trial sites to complete source document review. When the study monitor cannot access the site to review critical source documents, requests for review of source documents that may include private health information should be consistent with requirements for source document validation and review as described in the current study monitoring plan or other appropriate study-specific document. When remote monitoring processes and procedures have not previously been described by the sponsor, these processes and procedures should be established (e.g., in a revised study monitoring plan or in updates to existing sponsor policies and procedures).

During remote monitoring, the study monitor should focus on trial activities that are essential to the safety of trial participants and/or data reliability. Sponsors and monitors may wish to consider one or more of the following options to facilitate remote monitoring access to clinical site records:

  • If the site can provide appropriate resources and technical capabilities, consider establishing a secure remote viewing portal that would permit site staff to provide access to the site’s study documentation and/or trial participants’ source documents for the study monitor’s review. In addition, the potential for remote access to trial participants’ electronic health records may be explored with trial sites
  • Sites could upload certified copies of source records to a sponsor-controlled electronic system or other cloud-based repository that contains appropriate security controls. In the setting of a blinded or partially blinded study, if source documents contain potentially unblind information, controls to protect the study blind should be in place prior to transfer of source documents (e.g., use of an unblinded study monitor to review source documents, restricted access to folders containing copies of source documents). It is not necessary for the clinical site to have control of certified copies of source documents uploaded to such a repository; however, the clinical investigator should maintain control of the original source records.

Regarding retention of copies of source documents used for remote review, it would not be necessary to retain the certified copies of source documents used for remote review, provided the clinical investigator retains the original source documents according to FDA regulations for the retention of records.

In addition, processes and procedures should be established for the handling of source document copies that were placed in temporary storage locations for remote review and that are no longer needed after the remote monitoring has concluded.

Remote monitoring activities, including remote review of source documents, should be documented in the same level of detail as on-site monitoring activities, and any resulting actions to address issues identified from the remote source document review should be consistent with procedures and processes described in the study monitoring plan » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 16 April 2020)

CA Canada « Site monitoring not possible

Afrique du Sud « iv. Impact of social distancing measures on study logistics: Since trial participants may not be able to come to the investigational site for protocol-specified visits, sponsors should evaluate whether alternative methods for safety assessments (e.g. telephone contact, virtual visit, alternative location for assessment, including local laboratories or imaging facilities) could be implemented when necessary and feasible, and would be sufficient to assure data integrity and safety of participants. Sponsors should determine if in-person visits are necessary to fully assure the safety of trial participants (for example to carry out procedures necessary to assess safety or the safe use of the investigational product appropriately); in making the decision to continue use or administration of the investigational or other products, both the sponsor and principal investigator(s) should consider whether the safety of trial participants can be assured with the implementation of the amended monitoring approach.
v. Impact of social distancing measures on participant monitoring: In some cases, trial participants who no longer have access to the investigational or other products, or to the investigational site, may need additional safety monitoring (e.g. withdrawal of an active investigational treatment). If planned on-site monitoring visits are no longer possible, sponsors should consider optimizing use of central and remote monitoring programmes to maintain oversight of clinical sites.« 
(SAHPRA Policy on Conduct of Clinical Trials of Health Product during the current COVID-19 pandemic, SAHPRA, 25 mars 2020)

AU Australie« Site monitoring visits

  • Remote monitoring visits are encouraged as the first option in all cases and sponsors and institutions should ensure that these are facilitated, taking into account the need to avoid undue burden on hospital or institutional resources. These arrangements must adhere to patient confidentiality protocols already in place. Remote source data verification may be done electronically as long as appropriate security arrangements either are or can be put in place.
  • If remote monitoring visits are not feasible, then clinical research associates may continue to undertake on-site monitoring visits as long as they are not symptomatic, have not returned from overseas in the last 14 days or had contact with a known case of COVID-19, in accordance withthe most current public health guidance and advice from jurisdictional health departments. » (COVID-19 : Guidance on clinical trials for institutions, HRECs, researchers and sponsors, CTPRG, Australia, 24 mars 2020)

Le Promoteur doit documenter les cas positifs de Covid-19

fr En France, les cas positif de Covid doivent être documentés et déclarés en tant que fait nouveau si le Promoteur prend des mesures particulières

fr France « Quelle attitude en cas de diagnostic d’infection COVID-19 chez un patient inclus dans un essai et en cours de traitement expérimental ?
La poursuite ou la suspension des traitements expérimentaux doit être évaluée par l’investigateur en lien avec le promoteur en fonction du contexte clinique.
Les modalités de dépistage des patients en cours d’essai thérapeutique doivent être alignées sur les recommandations nationales.

  • Documentation dans le dossier
  • Recommandation actualisée le 27/03/20 :

Un cas individuel d’infection par le SARS-CoV-2 ne doit pas être déclaré comme fait nouveau sauf en cas de mesures particulières prises par le promoteur.
Cependant, si cet évènement répond à la définition de cas individuel à notifier immédiatement à l’ANSM (par exemple SUSAR-suspicion d’effet indésirable grave inattendu pour les essais portant sur les médicaments) il reste à déclarer à l’ANSM selon les modalités habituelles »
(FAQ – Covid 19 – Essais cliniques en cours, ANSM, France, 20 mars 2020, Updated 27 mars 2020)

fr France « What should be done if a patient included in a trial and under treatment becomes infected with SARS-CoV-2?
The continuation or suspension of investigational products should be evaluated by the investigator in liaison with the sponsor based on the clinical context.
Testing strategy for clinical trials patients have to be in line with national recommendations.

DK Au Danemark, les patients diagnostiqués au Covid-19 ne doivent plus être notifiés à l’Autorité Compétente

DK Danemark « We do not consider addition of COVID-19 test-ing substantial and we do not wish to be notified, if trial subjects are diagnosed with COVID-19. » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

us Aux Etats-Unis, les cas de patients diagnostiqués au Covid-19 doivent être documentés

us Etats-Unis « C. For all trials that are impacted by the COVID-19 pandemic:
Sponsors should describe in appropriate sections of the clinical study report (or in a separate study-specific document):

  1. Contingency measures implemented to manage study conduct during disruption of the study as a result of COVID-19 control measures.
  2. A listing of all participants affected by the COVID-19 related study disruption by unique subject number identifier and by investigational site, and a description of how the individual’s participation was altered.
  3. Analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., trial participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study.

Robust efforts by sponsors, investigators, and IRBs/IECs to maintain the safety of trial participants and study data integrity are expected, and such efforts should be documented. As stated above, FDA recognizes that protocol modifications may be required, including unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures. Efforts to minimize impacts on trial integrity, and to document the reasons for protocol deviations, will be important. »(FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

CA Au Canada, les cas de patients diagnostiqués au Covid-19 doivent être documentés

CA Canada « Participants affected with COVID19

Le Promoteur doit vérifier si les soins / fournitures de produits
postérieurs à l’étude peuvent être réalisés conformément au document d’information fourni au patient (ou soumission d’une modification substantielle le cas échéant)

UK Royaume-Uni « 3.2.3. Studies where sites need to withdraw participants
Sites must raise such issues with the sponsor as early as possible if this is likely to occur.
For any studies involving provision of treatment to participants, careful consideration should be given to post-study care. If this cannot be in line with the information provided in the participant-information sheet, a substantial amendment should be submitted. Such amendments will be categorised and assessed according to existing guidance, but the process will be expedited. They should be sent to sites following the instructions above. »
(COVID-19: Guidance for sponsors, sites and researchers V2, MHRA, United Kingdom, 17 March 2020, Updated to v2.2 on 26 March 2020)

Réalisation des soins et risques infectieux

DK Danemark « Use of qualified and trained personnel to administer trial medications and conducting other diagnostic tests at the trial subject’s residence
We recognise the increased need to collect blood tests, side effects, etc. at the trial subject’s residence. Furthermore, it might be appropriate to administer IMP at the trial subject’s residence with assistance from qualified and trained personnel This is acceptable if carried out under the terms set in the EMA GCP Q&A (ques-tion 10), with the following changes under COVID-19:

  • The justification for using such procedures may be based on the excep-tional circumstances of the COVID-19 pandemic (in relation to question 10 of the Q&A)
  • The qualified and trained personnel must comply with the strict require-ments for containment of COVID-19
  • Consent is not expected, but the subjects need to be informed of the pro-cedural change (in relation to question 10 of the Q&A).

If an external supplier of the above mentioned service is used, the contractual con-ditions must comply with questions 11 and 12 in the same Q&A. Sponsor should facilitate this to the greatest extent possible during the COVID-19 pandemic.

Blood sampling and other diagnostics tests can be transferred to a local laboratory
There may be a need for blood sampling and other diagnostics tests to be per-formed locally because of the changes to the visit schedule. It is acceptable that blood sampling and other diagnostic tests are done at a local laboratory if author-ised/certified to perform such tests routinely and the local facility have the neces-sary precautions in place to ensure COVID-19 containment. If the protocol uses a central lab for analysis but it is not feasible for the sample to be shipped, then this should be clearly stated in the clinical study report in accord-ance with ICH E3 (Structure and content of clinical study reports).

Special precautions for First in Human trials
It is a requirement in First in Human (FiH) trials that an agreement has been made with the intensive care unit in the event that serious side effects should occur. We foresee that this agreement cannot be ensured during the COVID-19 pandemic with proper contingency and it is therefore our general expectation that all FiH trials will be put on hold.

Specifically, this means that recruitment for FiH trials should be halted. Thus, new trials should not be initiated and, for ongoing trials, higher dose levels than already initiated should not be started. This means that ongoing treatment can continue if it is in the interest of the trial participant.

We are aware that some FiH trials involve treatment of critically ill patients without other treatment options. In those cases, the trial may continue recruitment and dose escalation. This is conditioned that acceptance must be obtained from the intensive care unit that also state how it is ensured that the intensive care unit have the re-sources to receive and treat trial participants under COVID-19. This can be documented by, for example, mail correspondence. The intensive care unit must be advised and accept that a new trial participant is dosed or dose-escalated one day in advance. In addition, recruited trial participants under the COVID-19 pandemic are expected to be properly informed of the risk that they will not receive IMP administration, due to a lack of resources at the intensive care unit.

Communication should be strengthened to the trial subjects during the COVID-19 pandemic
During the COVID-19 pandemic we might experience increased levels of anxiety and concern among some trial subjects. This is expected due to, among other things, the procedural changes that might affect the trial subject’s participation in the trial and the associated uncertainty as to whether treatment is discontinued or how/when the treatment is continued. We therefore encourage sponsors to develop a specific COVID-19 communication plan, that clarifies whom is responsible for the needed strengthened communication together with how and when information should be given to the trial subjects. This will also allow trial subjects to ask questions and share their concerns »
(Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

us Etats-Unis « Q8. If patients are currently receiving an investigational product infusion at the clinical trial site, can a sponsor switch to home infusion?

Sponsors should consider the safety risk to trial participants who would miss an investigational product infusion because of the inability to come to the clinical trial site. In general, for investigational product that is usually administered in a health care setting, consulting the appropriateFDA review divisions is recommended regarding plans for alternative sites for administration (e.g., home nursing or alternative sites by trained but non-study personnel). For example, consulting FDA would be strongly advised for complex investigational products (e.g. cellular therapy and gene therapy products) where potentially altered storage and handling conditions could adversely affect product stability. In all cases, applicable requirements for maintaining required investigational product storage conditions (prior and after reconstitution), investigational product reconstitution specifications per the Investigational Brochure, and investigational product accountability remain and must be addressed and documented. Storage conditions and investigational productaccountability should be considered if the protocol is amended to permit alternative site infusions. Defining circumstances when discontinuing investigational product treatment, while continuing study participation albeit with potentially delayed assessments, may be an appropriate option when suitable alternative arrangements cannot be made. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

Vigilance des essais cliniques

Les événements indésirables graves et les SUSARs doivent toujours être déclarés à l’Autorité Compétente
selon les modalités habituelles

fr France « L’investigateur doit-il déclarer les événements indésirables graves au promoteur ?
Oui
L’investigateur doit déclarer immédiatement les événements indésirables graves au promoteur selon les dispositions réglementaires en vigueur excepté ceux mentionnés dans le protocole ou dans la brochure pour l’investigateur comme ne nécessitant pas une notification immédiate

Si le promoteur est dans l’incapacité d’évaluer les événements déclarés, peut-il reporter sa déclaration de SUSARs ?
Non
Il est demandé au promoteur de continuer à déclarer les SUSARs ainsi que toutes les déclarations immédiates de vigilance conformément aux dispositions en vigueur.

Peut-on considérer les cas de COVID 19 confirmés comme « attendus » si les infections virales sont décrites dans les Informations de Référence sur la Sécurité (IRS) des médicaments expérimentaux ?
Non
Les effets indésirables graves attendus mentionnés dans le RSI doivent correspondre à un terme préférentiel (PT) spécifique de la classification MedDRA en vigueur. »
(FAQ – Covid 19 – Essais cliniques en cours, ANSM, France, 20 mars 2020, Updated 27 mars 2020)

fr France « Should the investigator report serious adverse events to the sponsor?
Yes
The investigator must immediately report serious adverse events to the sponsor according to the current regulation except those mentioned in the protocol or in the brochure for the investigator as not requiring immediate notification.

If the sponsor is unable to assess the events declared, may he postpone his declaration to SUSARs?
No
The sponsor is requested to continue to declare the SUSARs as well as all the immediate vigilance notifications in accordance with the French regulation in force.

May confirmed cases of COVID 19 be considered « expected » if viral infections are described in the Reference Safety Information (RSI) of the investigational medicinal products?
No
The expected serious undesirable effects mentioned in the RSI should correspond to a specific preferential term (PT) of the MedDRA classification in force. »
(QnA – Covid 19 – Ongoing clinical, ANSM, France, 20 March 2020, Updated 27 mars 2020)

eu Europe « 4. Safety Reporting
Sponsors are expected to continue safety reporting in adherence to EU and national legal frameworks (Directive 2001/20; CT-3). When per protocol physical visits are reduced or postponed, it is important that the investigator continue collecting adverse events from the participant through alternative means , e.g. by phone.
 » (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 27 March 2020)

UK Royaume-Uni « Reporting of serious adverse events (SAEs), suspected unexpected serious adverse reactions (SUSARs), and submission of annual safety reports (DSURs)

Timely reporting of SAEs from investigators to sponsors and of SUSARs from sponsors to the competent authority is paramount in protecting the safety of participants.

We expect regulatory timelines for reporting to continue to be met. Sponsors who plan to introduce changes to safety recording and reporting procedures are invited to contact us.

They should do this by email to clintrialhelpline@mhra.gov.uk with the subject ‘Safety recording/reporting’. The email should discuss the impact of the changes on the benefit-risk balance of the trial as well as the strategies to mitigate the potential risks introduced by the changes.

Provision of the annual list of suspected serious adverse reactions and safety report (DSUR) is expected as soon as practicable after the end of the reporting year, as per current legislation. If the DSUR is to be delayed, you do not need to inform us, but please provide a rationale in the covering letter once the DSUR is submitted.

For lower-risk trials, sponsors are encouraged to use a risk adapted approach to trial management. If your trial fits into a ‘Type A’ category trial, then you may wish to consider submitting a substantial amendment to address risk adaptions, if appropriate. Please refer to existing guidance .

Risk adaption of safety reporting is acceptable, and MHRA have produced guidance on this along with some examples of real-life risk assessments:

Where adverse event expectedness assessments have been delegated to investigators at clinical sites, this should be reconsidered where possible to alleviate the burden on front line staff. It should be determined if this assessment can be made by the sponsor upon receipt of the SAE. Expectedness is not a medical decision and should be based on the approved Reference Safety Information (RSI) for the trial. This change would not require prior authorisation by the MHRA.

SAEs can be reported to the sponsor initially via a telephone call, followed by a written report at a later date. Therefore the sponsor may consider alternative mechanisms for investigators onwards reporting of SAEs, such as email or telephone calls in order to reduce administrative burden on sites. However, it is important that the sponsor ensures the minimum reportable information has been provided. sponsors should ensure they have processes in place to receive this information in alternative formats to those agreed for the trial (e.g. eCRF or fax) and communicate this to the investigator sites.

In order to ensure that sites are not put under undue pressure, the sponsor should consider processes to integrate data received from emails into the clinical and safety database, whilst ensuring data integrity. The sponsor should not require the site staff to perform data entry of information that has previously been reported to the sponsor in a different format.

Changes to the way SAEs are reported to the sponsor and to data entry do not require submission of a substantial amendment. »(Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 22 avril 2020)

DE Allemagne « 4. Safety Reporting in connection with clinical trials related to COVID-19
The regulations in accordance with Sections 12 and 13 GCP-V concerning safety reporting in clinical trials continue to apply during this pandemic. This concerns both the reporting of serious adverse events (SAE) to be reported immediately by the investigator to the sponsor unless the licensed trial protocol provides otherwise, as well as the sponsor’s reporting obligations towards federal higher authorities, other authorities, and Ethics Committees. If, in connection with an SAE report, a trial participant is unable to visit the trial centre in person, initial communication with the investigator can also take place by telephone. In such cases, a decision must be made as to whether the participant’s appearance in person, e.g. for further testing, is necessary based on safety considerations. If it is intended to convert regular visits in in part or completely to telephone contact or telemedical visits, this is to be submitted to the competent federal higher authority and competent Ethics Committee as a notification of variation subject to approval. In the case of notifications of variation that affect safety reporting, the sponsor is requested to include a risk analysis of the effects of these changes on the safety of trial participants and the validity of the data collected. »
(Clinical Trials during the COVID-19 Pandemic – Information on the authorisation and conduct of clinical trials of medicinal products during the COVID-19 pandemic (Version 2.1), BFarm, Allemagne, 30 March 2020)

AU Australie « Researchers, sponsors, institutions, and HRECs should consult and adhere to existing guidance for safety monitoring and reporting published by NHMRC and the TGA (see https://www.nhmrc.gov.au/about-us/publications/safety-monitoring-and-reporting-clinical-trials-involving-therapeutic-goods). Any proposed modifications to standard practice should be discussed between the relevant parties and authorised, if appropriate, by the responsible party.
Any incidents associated with the attendance at a clinic (or other relevant context) of a participant known, or later discovered, to be symptomatic should be promptly reported as an adverse event or safety issue, as relevant, in accordance with existing guidance »
(COVID-19 : Guidance on clinical trials for institutions, HRECs, researchers and sponsors, CTPRG, Australia, 24 mars 2020)

PE Perou « Finalmente, toda notificación estipulada enel REC, Eventos adversos serios, deberá seguir siendo notificada por el REAS_NET y posteriormente regularizado, por mesa de partes. La informaciónde seguridad del producto de investigación, notificación de mujer gestante y recién nacido en ensayos clínicos, deberá ser notificada a través del correoconsultaensayos@ins.gob.pe«  (Covid-19 – Comunicado n° 001-2020-OGITT/INS, Ministerio de Salud, Pérou, 18 mars 2020)

Les mesures urgentes de sécurité prises dans le contexte du Covid-19 doit être notifiées le plus rapidement possible (et non plus préalablement) à l’Autorité Compétente et au Comité d’Ethique

eu Europe « In case the risk assessment leads to actions that affect the trial as described below in a), b), and c), the relevant NCA and/or Ethics Committees must be informed in accordance with Directive 2001/20/EC and national laws:

  • It is possible that urgent actions are required by the sponsor and investigator to protect the trial participants against immediate hazard. These urgent safety measures do not need prior notification. Due to specific local or national circumstances related to the COVID-19 Pandemic, submission to the relevant authorities could take longer than usual, but the information needs to be provided to the NCA and the Ethics Committee as soon as possible (CT-1, Art 3.9). The sponsor needs to document the justification for this delay in the trial master file. In communication with authorities, the sponsor is expected to provide adequate information on the cause, measures taken and the plan for further actions.
  • If changes, which are substantial amendments, do not require immediate action from the sponsor or investigator, these should be submitted as substantial amendment applications. Sponsors are encouraged to take into account the limited capacity of regulatory authority assessors and Ethics Committees, and submit only high quality, complete applications containing only the necessary changes. Over-reporting should be avoided (Art. 11b of Directive 2001/20/EC; CT-1 article 3.9).
  • Certain procedural or other changes might become necessary to address global or local consequences of the pandemic (e.g. related to social distancing or to avoid unnecessary strain on health care professionals). If these changes are justifiable, COVID-19 related changes, not related to trial participants’ safety and do not have a serious effect on the benefit-risk balance for the trial participants and the scientific value of the trial, they can be notified as soon as possible taking into account national and local circumstances. In these cases, sponsors are expected to submit to the relevant NCA and Ethics Committee the list of all changes with appropriate risk assessment and justification as well as follow-up actions when necessary. Cumulative changes must not have a negative impact on trial participants’ safety and/or on the integrity of the trial. Relevant protocol deviations are sufficient to be recorded according to chapter 13.

The sponsor is expected to maintain appropriate records, in a timely manner, of all changes described in the chapter above in the trial master file.

Communication should be clearly marked with ’COVID-19’ in the subject field. »(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 28 April 2020)

BE Belgique « Urgent safety measures taken in the context of coronavirus may be taken without prior notification to FAMHP and the EC. However, the sponsor must inform as soon as possiblethe FAMHP and the EC of the measures taken and the plan for further action. This should be reported to the FAMHP via CESP or ct.rd@fagg-afmps.be (or CTRPilot@fagg-afmps.be for Pilot Projects). A substantial amendment must be submitted afterwards. » (Addendum to the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, v1, AFMPS, Belgique 25 March 2020)

Le rapport annuel de sécurité peut être soumis sans signature manuscrite et avec un délai de 2 mois supplémentaires (après information de l’ANSM)

fr France « Est-il possible de soumettre les rapports annuels de sécurité (RAS) sans signature manuscrite ?
Oui
Il est possible d’adresser les RAS (appelés DSURs ou ASR pour les médicaments) avec une signature scannée ou une simple mention dans le mail précisant le nom de la personne qui a validé le document.

Est-ce que le délai de soumission du rapport annuel de sécurité (RAS) peut être rallongé ?
Oui
Un délai supplémentaire maximal de 2 mois peut être accordé après information de l’ANSM par mail aux adresses habituelles.
Il est rappelé que le promoteur dispose déjà d’un délai de 2 mois après la fin de la période couverte par le RAS pour le soumettre. »
(FAQ – Covid 19 – Essais cliniques en cours, ANSM, France, 20 mars 2020, Updated 27 mars 2020)

fr France « Is it possible to submit annual safety reports (ASR/DSUR) without a handwritten signature?
Yes
It is possible to send annual safety reports (also named DSUR for drugs) with a scanned signature or a simple mention in the email specifying the name of the person who validated the document.

May the deadline for submitting annual safety report (ASR) be extended?
Yes
A maximum period of 2 additional months may be granted after informing the ANSM by email on its usual mail boxes. Note that the sponsor already has 2 months to submit the report after the end of the period covered by the ASR . »
(QnA – Covid 19 – Ongoing clinical, ANSM, France, 20 March 2020, Updated 27 mars 2020)

Les décisions de report des réunions des comités de surveillance doivent être documentées et communiquées aux personnes concernées (dont ANSM et CPP)

fr France « Les réunions des comités de surveillance des essais peuvent-elles être décalées en raison de l’absence de monitoring et/ou de la non disponibilité des membres ?
Oui
S’il n’est pas possible de mettre en place les réunions prévues du comité de surveillance d’un essai, le promoteur peut envisager un report après évaluation des conséquences sur la sécurité des participants. Selon les cas, le promoteur peut également être amené à prendre des mesures, par exemple la suspension des inclusions dans l’attente de la tenue de la réunion
Documentation

  • Décision de report : communication aux membres du comité de surveillance et aux investigateurs ainsi qu’à l’ANSM et au CPP (MSI)
  • Autres mesures : documentation et transmission à l’ANSM et au CPP en fonction de leur nature selon les modalités précisées auparavant par exemples MSI en cas de suspension des inclusions et MSA si mesures urgentes de sécurité. » (FAQ – Covid 19 – Essais cliniques en cours, ANSM, France, 20 mars 2020, Updated 27 mars 2020)

fr France « May the meetings of the safety committees be postponed due to the lack of monitoring and / or the non-availability of members?
Yes
If it is impossible to set up the planned meetings of the safety committee, the sponsor may consider postponing after assessing the consequences for the safety of participants. As appropriate, the sponsor may also take measures, for example the suspension of inclusions pending the next meeting.
Documentation

  • Postponement decision : communication to the members of the supervisory committee and to the investigators as well as to the ANSM and the CPP (substantial amendment for information)
  • Other measures: documentation and transmission to the ANSM and the CPP according to their nature as previously detailed : i.e. substantial amendment for information in case of suspension of inclusions and substantial amendment for authorization if urgent safety measures are taken. » (QnA – Covid 19 – Ongoing clinical, ANSM, France, 20 March 2020, Updated 27 mars 2020)

Data Management

Approbation et modification des documents de l’essai

fr France « Est-il possible de soumettre les rapports annuels de sécurité (RAS) sans signature manuscrite ?
Oui
Il est possible d’adresser les RAS (appelés DSURs ou ASR pour les médicaments) avec une signature scannée ou une simple mention dans le mail précisant le nom de la personne qui a validé le document.

UK Royaume-Uni « Signatures

A request for a clinical trial authorisation (“Annex 1” form) is required to be signed by or on behalf of the sponsor. This signature does not need to be wet-ink and an electronic signature is acceptable. This can be a scanned electronic signature.

Alternatively, the CESP User ID can be used in the ‘signature’ field of the application form if the ID is issued to an individual person and this person is authorised by the sponsor to sign the application on their behalf.

If your processes require wet-ink signatures, consider alternative methods of demonstrating approvals, such as email confirmation.

Inspectors will take a pragmatic approach to this, but you may want to consider an SOP deviation to cover this in the interim. » (Guidance – Managing clinical trials during Coronavirus (COVID-19), MHRA, Royaume-Uni, 19 March 2020, Updated on 22 avril 2020)

UK Royaume-Uni « Paper documents that were approved with wet ink signature

These are documents that have traditionally been printed on paper, physically handed to each reviewer in an office and approved using wet ink signatures.
Examples may include, but are not limited to:

  • Validation protocols and reports
  • Risk assessments
  • Technical reports
  • Quality management system documents that are paper-based such as SOPs, investigations and change requests.

These can be shared with remote workers, but they have no formal system describing how the review and approval can be recorded.

Alternative methods

The solution will vary between organisations depending on the type of document and the tools available to the person performing the approval e.g. printer, scanner/smartphone, secure email, third party software or existing systems that have tools to capture electronic signatures.

Principles to maintain control

Regardless of what system or process is used, the following principles apply:

  • Controls should be proportionate to the risk considering the type of document and the methods used for distribution and approval
  • A signature performed remotely should be equivalent to the handwritten signature of the signatory
  • The method of document distribution and approval should be defined to minimise the risk of error due to misunderstanding of what is being reviewed/approved

Risks with remote approval

Aspects to consider when assessing risk include:

  • How the approval signature is attributable to an individual
  • Whether there is a legislative requirement or GxP guidance for a signature. If there is, then the signature should be considered more critical and have proportionately greater control – for example when a QP certifies a batch of finished product to enable release for sale
  • The security of the electronic signature i.e. so that it can only be applied by the ‘owner’ of that signature
  • How the act of ‘signing’ is recorded so that the document cannot be altered or manipulated without invalidating the signature or status of the entry
  • Ensuring that all required associated data is available to a remote reviewer that would have been available to them if they were performing the review at a site » (Approval of GxP documents when working from home during the coronavirus (COVID-19) outbreak, MHRA, Royaume-Uni, 9 April 2020)

BE Belgique « 7.Electronic way of working and accepting possible electronic signatures

DK Danemark « 6. Changes in documentation practice
As stated above, it is expected that the sponsors perform a thorough risk assess-ment of each individual ongoing trial and implement measures which priorities pa-tient safety and data validity. In case these two conflicts, patient safety should take priority.

These risk assessments should be based on relevant parties’ input and should be documented on an ongoing basis. In case this risk assessment affects trial conduct, the Danish Medicines Agency should be notified.

The sponsors should reassess risk as the situation develops. This reassessment should also be documented.

With regards to the need for wet ink signatures e.g. from investigator sites, alterna-tive means of documentation (e.g. emails) should be considered. «  (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)

us Etats-Unis « If changes in the protocol will lead to amending data management and/or statistical analysis plans, the sponsor should consider doing so in consultation with the applicable FDA review division. Prior to locking the database, sponsors should address in the statistical analysis plan how protocol deviations related to COVID-19 will be handled for the prespecified analyses. » (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic – Guidance for Industry, Investigators, and Institutional Review Boards, FDA, Etats-Unis, 18 March 2020, Updated on 2 April 2020)

Afrique du Sud « Impact of in-study protocol deviations on data management: If changes in the protocol will lead to amending data management and/or statistical analysis plans, the sponsor should consider doing so in consultation with the Clinical Trials Unit. Prior to locking the database, sponsors should address in the statistical analysis plan how protocol deviations related to COVID-19 will be handled for the pre-specified analyses. » (SAHPRA Policy on Conduct of Clinical Trials of Health Product during the current COVID-19 pandemic, SAHPRA, 25 mars 2020)

Protection des données personnelles

L’intérêt scientifique des recherches portant sur le Covid-19 ne doit pas se faire au détriment du RGPD et des droits des individus

eu Europe « The GDPR provides special rules for the processing of health data for the purpose of scientific research that are also applicable in the context of the COVID-19 pandemic » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

eu Europe « 2. APPLICATION OF THE GDPR

4. Data protection rules (such as the GDPR) do not hinder measures taken in the fight against the COVID-19 pandemic.The GDPR is a broad piece of legislation and provides for several provisions that allow to handle the processing of personal data for the purpose of scientific research connected to the COVID-19 pandemic in compliance with the fundamental rights to privacy and personal data protection. The GDPR also foresees a specific derogation to the prohibition of processing of certain special categories of personal data, such as health data, where it is necessary for these purposes of scientific research.

5. Fundamental Rights of the EU must be applied when processing health data for the purpose of scientific research connected to the COVID-19 pandemic. Neither the Data Protection Rules nor the Freedom of Science pursuant to Article 13 of the Charter of Fundamental Rights of the EU have precedence over the other. Rather, these rights and freedoms must be carefully assessed and balanced, resulting in an outcome which respects the essence of both. » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

Les traitements de données de santé doivent correspondre à une des bases
légales prévues et chaque pays peut adopter des lois spécifiques pour permettre
le traitement des données relatives à la santé à des fins de recherches
scientifique

eu Europe « The national legislator of each Member State may enact specific laws pursuant to Article (9) (2) (i) and (j) GDPR to enable the processing of health data for scientific research purposes. The processing of health data for the purpose of scientific research must also be covered by one of the legal bases in Article 6 (1) GDPR. Therefore, the conditions and the extent for such processing varies depending on the enacted laws of the particular member state » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

eu Europe « 4. LEGAL BASIS FOR THE PROCESSING

15. All processing of personal data concerning health must comply with the principles relating to processing set out in Article 5 GDPR and with one of the legal grounds and the specific derogations listed respectively in Article 6 and Article 9 GDPR for the lawful processing of this special category of personal data.

16. Legal bases and applicable derogations for processing health data for the purpose of scientific research are provided for respectively in Article 6 and Article 9. In the following section, the rules concerning consent and respective national legislation are addressed. It has to be noted that there is no ranking between the legal bases stipulated in the GDPR.

4.1 Consent

17. The consent of the data subject, collected pursuant to Article 6 (1) (a) and Article 9 (2) (a) GDPR, may provide a legal basis for the processing of data concerning health in the COVID-19 context.

18. However, it has to be noted that all the conditions for explicit consent, particularly those found in Article 4 (11), Article 6 (1) (a), Article 7 and Article 9 (2) (a) GDPR, must be fulfilled. Notably, consent must be freely given, specific, informed, and unambiguous, and it must be made by way of a statement or “clear affirmative action”.

19. As stated in Recital 43, consent cannot be considered freely given if there is a clear imbalance between the data subject and the controller.It is therefore important that a data subject is not pressured and does not suffer from disadvantages if they decide not to give consent. The EDPB has already addressed consent in the context of clinical trials.7Further guidance, particularly on the topic of explicit consent, can be found in the consent guidelines of the former Article 29-Working-Party.

20. Example: A survey is conducted as part of a non-interventional study on a given population, researching symptoms and the progress of a disease. For theprocessing of such health data, the researchers may seek the consent of the data subject under the conditions as stipulated in Article 7 GDPR.

21. In the view of the EDPB, the example above is notconsidered a case of “clear imbalance of power” as mentioned in Recital 43 and the data subject should be able to give the consent to the researchers. In the example, the data subjects are not in a situation of whatsoever dependency with the researchers that could inappropriately influence the exercise of their freewill and it is also clear that it will have no adverse consequences if they refuse to give their consent.

22. However, researchers should be aware that if consent is used as the lawful basis for processing, there must be a possibility for individuals to withdraw that consent at any time pursuant to Article 7 (3) GDPR. If consent is withdrawn, all data processing operations that were based on consent remain lawful in accordance with the GDPR, but the controller shall stop the processing actions concerned and ifthere is no other lawful basis justifying the retention for further processing, the data should be deleted by the controller.

4.2 National legislations

23. Article 6 (1) e or 6 (1) f GDPR in combination with the enacted derogations under Article 9 (2) (j) or Article 9 (2) (i) GDPR can provide a legal basis for the processing of personal (health) data for scientific research. In the context of clinical trial this has already been clarified by the Board.

24. Example: A large population based study conducted on medical charts of COVID-19 patients.

25. As outlined above, the EU as well as the national legislator of each Member State may enact specific laws pursuant to Article 9 (2) (j) or Article 9 (2) (i) GDPR to provide a legal basis for the processing of health data for the purpose of scientific research. Therefore, the conditions and the extent for such processing vary depending on the enacted laws of the particular Member State.

26.As stipulated in Article 9 (2) (i) GDPR, such laws shall provide “for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular professional secrecy”. As similarly stipulated in Article 9 (2) (j) GDPR, such enacted laws “shall be proportionate to theaim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject”.

27. Furthermore, such enacted laws must be interpreted in the light ofthe principles pursuant to Article 5 GDPR and in consideration of the jurisprudence of the ECJ. In particular, derogations and limitations in relation to the protection of data provided in Article 9 (2) (j) and Article 89 GDPR must apply only in so far asis strictly necessary. » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

Un projet de recherche conforme aux Méthodologies de Référence peut être mis en oeuvre dès que l’engagement de conformité est effectué par le Responsable de Traitement

fr France « Si votre projet de recherche est conforme aux dispositions d’une méthodologie de référence
Vous devez réaliser (si cela n’a pas déjà été fait) une déclaration de conformité à la méthodologie de référence correspondante. Votre projet de recherche peut être mis en œuvre dès que cette formalité est effectuée. »
(Recherches sur le COVID-19 : la CNIL se mobilise, CNIL, France, 26 mars 2020)

Possibilité d’instruire le dossier en urgence auprès de la CNIL pour une demande d’autorisation « recherche »

fr France « Si votre projet de recherche n’est pas conforme aux dispositions d’une méthodologie de référence
Vous devez déposer une demande d’autorisation « recherche ». En plus des éléments habituellement requis (avis du comité compétent, protocole de recherche et son résumé, document d’information destiné aux patients, etc.), vous êtes invités, afin de faciliter l’instruction en urgence de votre demande :

  • à détailler les points de non-conformité du projet de traitement à la méthodologie de référence (ex : impossibilité d’informer les personnes concernées, accès du responsable de traitement à des données directement identifiantes) ;
  • vérifier que le protocole ou tout document présentant l’étude précise clairement :
    • les destinataires des données directement identifiantes ;
    • la durée de conservation des données et, le cas échéant, des échantillons biologiques, exprimée en années (en base active et en archivage) ;
  • transmettre, en cas d’inclusion en situation d’urgence et en situation d’urgence vitale immédiate
    • la note d’information à destination du proche ou de la personne de confiance (patient hors d’état d’exprimer sa volonté) ;
    • la note d’information de poursuite à destination du patient ;
    • la note d’information de poursuite à destination du proche ou de la personne de confiance (inclusion en situation d’urgence vitale immédiate).

Comment effectuer une demande d’autorisation « recherche » ?

  • Le dépôt d’un dossier de demande d’autorisation recherche « impliquant la personne humaine (RIPH) » s’effectue via le formulaire disponible sur le site web de la CNIL.
  • Le dépôt d’un dossier de demande d’autorisation recherche « n’impliquant pas la personne humaine (RNIPH) » s’effectue via le formulaire disponible sur le site web de la plateforme des données de santé.

Faites figurer les termes « COVID-19 » dans la partie « finalité » ou « dénomination » du formulaire afin de permettre aux services de la CNIL d’identifier votre dossier comme prioritaire.

Que faire si votre dossier est incomplet ?
S’il vous manque encore certaines pièces, par exemple l’avis d’un CPP, votre demande et les éléments d’ores et déjà finalisés peuvent être adressés aux services de la CNIL en vue de leur pré-instruction, à l’adresse suivante : recherchecovid19[@]cnil.fr
Cette adresse est strictement réservée à la transmission d’informations et de pièces préalablement à une demande d’autorisation portant sur des traitements contenant des données de santé et relatifs au COVID-19, en vue de leur pré-instruction.
L’envoi d’éléments via cette messagerie ne dispense pas le responsable de traitement du dépôt ultérieur d’une demande d’autorisation (cf. Comment effectuer une demande d’autorisation « recherche » ?).
Toute modification apportée aux éléments déjà transmis devra nous être signalée lors du dépôt de la demande d’autorisation. »
(Recherches sur le COVID-19 : la CNIL se mobilise, CNIL, France, 26 mars 2020)

Les Etats peuvent  restreindre l’exercice de certains droits des personnes concernées par les traitements de données

eu Europe « 2. In principle, situations as the current COVID-19 outbreak do not suspend or restrict the possibility of data subjects to exercise their rights pursuant to Article 12 to 22 GDPR. However, Article 89 (2) GDPR allows the national legislator to restrict (some)of the data subject’s rights as set in Chapter 3 of the GDPR. Because of this, the restrictions of the rights of data subjects may varydepending on the enacted laws of the particular Member State.

3. All enacted laws based on Article (9) (2) (i) and (j) GDPR must be interpreted in the light of the principles pursuant to Article 5 GDPR and in consideration of the jurisprudence of the ECJ. In particular, derogations and limitations in relation to the protection of data provided in Article 9 (2) (j) and Article 89 (2) GDPR must apply only in so far as is strictly necessary. » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

eu Europe « 6. EXERCISE OF THE RIGHTS OF DATA SUBJECTS

55. In principle, situations as the current COVID-19 outbreak do not suspend or restrict the possibility of data subjects to exercise their rights pursuant to Article 12 to 22 GDPR. However, Article 89 (2) GDPR allows the national legislator to restrict (some) of the data subject’s rights as set in Chapter 3 of the regulation. Because of this, the restrictions of the rights of data subjects may vary depending on the enacted laws of the particular Member State.

56. Furthermore, some restrictions of the rights of data subjects can be based directly on the Regulation, such as the access right restriction pursuant to Article 15 (4) GDPR and the restriction of the right to erasure pursuant to Article 17 (3) (d) GDPR. The information obligation exemptions pursuant to Article 14 (5) GDPR have already been addressed above.

57. It has to be noted that, in the light of the jurisprudence of the ECJ, all restrictions of the rights of data subjects must apply only in so far as it is strictly necessary. » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

Les violations de données doivent toujours être soumises dans les 72h (une tolérance est néanmoins appliquée)

UK Royaume-Uni « 1. Organisations should continue to report personal data breaches to us, without undue delay. This should be within 72 hours of the organisation becoming aware of the breach, though we acknowledge that the current crisis may impact this. We will assess these reports, taking an appropriately empathetic and proportionate approach.
2.When we conduct investigations, we will act knowing there is a public health emergency and seek to understand the individual challenges faced by organisations. We will take into account the particular impact of the crisis on that organisation. This may mean less use of formal powers that require organisations to provide us with evidence,and allowing longer periods to respond. We also expect to conduct fewer investigations, focussing our attention on those circumstances which suggest serious non-compliance. »
(The ICO’s regulatory approachduring the coronavirus public health emergency, ICO, Royaume-Uni, 15 April 2020)

Pour les transferts internationaux de données, en l’absence de décisions d’adéquations, les dérogations prévues à l’article 49 du RGPD ont lieu à s’appliquer de manière exceptionnelle
(consentement explicite au transfert, motifs importants d’intérêt public…)

eu Europe « With respect to international transfers,in the absence of an adequacy decision pursuant to Article 45 (3) GDPR or appropriate safeguards pursuant to Article 46 GDPR, public authorities and private entities may rely upon the applicable derogations pursuant to Article 49 GDPR. However, the derogations of Article49 GDPR do have exceptional character only » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

eu Europe « 7. INTERNATIONAL DATA TRANSFERS FOR SCIENTIFIC RESEARCH PURPOSES

58. Within the context of research and specifically in the context of the COVID-19 pandemic, there will probably be a need for international cooperation that may also imply international transfers of health data for the purpose of scientific research outside of the EEA.

59. When personal data is transferred to a non-EEA country or international organisation, in addition to complying witht he rules set out in GDPR,especially its Articles 5 (data protection principles), Article 6 (lawfulness) and Article 9 (special categories of data),
the data exporter shall also comply with Chapter V (data transfers).

60. In addition to the regular transparency requirement as mentioned on page 7 of the present guidelines, a duty rests on the data exporter to inform data subjects that it intends to transfer personal data to a third country or international organisation. This includes information about the existence or absence of an adequacy decision by the European Commission, or whether the transfer is based on a suitable safeguard from Article 46 or on a derogation of Article 49 (1). This duty exists irrespective of whether the personal data was obtained directly from the data subject or not.

61. In general, when considering how to address such conditions for transfers of personal data to third countries or international organisations, data exporters should assess the risks to the rights and the freedoms of data subjects of each transfer and favour solutions that guarantee data subjects the continuous protection of their fundamental rights and safeguards as regards the processing of their data, even after it has been transferred. This will be the case for transfers to countries having an adequate level of protection, or in case of use of one of the appropriate safeguards included in Article 46 GDPR, ensuring that enforceable rights and effective legal remedies are available for data subjects.

62. In the absence of an adequacy decision pursuant to Article 45 (3) GDPR or appropriate safeguards pursuant to Article 46 GDPR, Article 49 GDPR envisages certain specific situations under which transfers of personal data can take place as an exception. The derogations enshrined in Article 49 GDPR are thus exemptions from the general rule and, therefore, must be interpreted restrictively, and on a case-by-case basis. Applied to the current COVID-19 crisis, those addressed in Article 49 (1) (d) (“transfer necessary for important reasons of public interest”) and (a) (“explicit consent”) may apply.

63. The COVID-19 pandemic causes an exceptional sanitary crisis of an unprecedented nature and scale. In this context, the EDPB considers that the fight against COVID-19 has been recognised by the EU and most of its Member States as an important public interest,which may require urgent action in the field of scientific research (for example to identify treatments and/or develop vaccines), and may also involve transfers to third countries or international organisations.

64. Not only public authorities, but also private entities playing a role in pursuing such public interest (for example,a university’s research institute cooperating on the development of a vaccine in the context of an international partnership) could, under the current pandemic context, rely upon the derogation mentioned above.

65. In addition, in certain situations, in particular where transfers are performed by private entities for the purpose of medical research aiming at fighting the COVID-19 pandemic, such transfers of personal data could alternatively take place on the basis of the explicit consent of the data subjects.

66. Public authorities and private entities may, under the current pandemic context, when it is not possible to rely on an adequacy decision pursuant to Article 45(3) or on appropriate safeguards pursuant to Article 46, rely upon the applicable derogations mentioned above, mainly as a temporary measure due to the urgency of the medical situation globally.

67. Indeed, if the nature of the COVID-19 crisis may justify the use of the applicable derogations for initial transfers carried out for the purpose of research in this context, repetitive transfers of data to third countries part of a long lasting research project in this regard would need to be framed with appropriate safeguards in accordance with Article 46 GDPR.

68. Finally, it has to be noted that any such transfers will need to take into consideration on a case-by-case basis the respective roles (controller, processor, joint controller)and related obligations of the actors involved (sponsor, investigator) in order to identify the appropriate measures for framing the transfer. » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

Le Health Data Hub et la CNAM sont autorisés à traiter et stocker des données de santé en lien avec l’épidémie actuelle de Covid-19

fr France « Art. 1er. – Après l’article 10-6 de l’arrêté du 23 mars 2020 susvisé, il est inséré un chapitre 10 ainsi rédigé :

CHAPITRE 10 – MESURES CONCERNANT LE TRAITEMENT DES DONNÉES À CARACTÈRE PERSONNEL DU SYSTÈME DE SANTÉ

Art. 10-7. – I. – Aux seules fins de faciliter l’utilisation des données de santé pour les besoins de la gestion de l’urgence sanitaire et de l’amélioration des connaissances sur le virus covid-19, le groupement d’intérêt public mentionné à l’article L. 1462-1 du code de la santé publique et la Caisse nationale de l’assurance maladie sont autorisés à recevoir les catégories de données à caractère personnel suivantes:

  • les données issues du système national des données de santé mentionné à l’article L. 1461-1 du même code;
  • des données de pharmacie;
  • des données de prise en charge en ville telles que des diagnostics ou des données déclaratives de symptômes issues d’applications mobiles de santé et d’outils de télésuivi, télésurveillance ou télémédecine;
  • des résultats d’examens biologiques réalisés par les laboratoires hospitaliers et les laboratoires de biologie médicale de ville;
  • des données relatives aux urgences collectées par l’Agence nationale de santé publique dans le cadre du réseau de surveillance coordonnée des urgences;
  • des données relatives aux appels recueillis au niveau des services d’aide médicale urgente et des services concourant à l’aide médicale urgente;
  • des données relatives à l’activité et à la consommation de soins dans les établissements ou services médico- sociaux, notamment dans les établissements d’hébergement pour personnes âgées dépendantes;
  • des enquêtes réalisées auprès des personnes pour évaluer leur vécu;
  • des données non directement identifiantes issues du système d’identification unique des victimes mentionné à l’article L. 3131-9-1 du code de la santé publique;
  • des données cliniques telles que d’imagerie, de pharmacie, de biologie, de virologie, de comptes rendus médicaux de cohortes de patients pris en charge dans des centres de santé en vue de leur agrégation.

II. – Le groupement d’intérêt public et la Caisse nationale de l’assurance maladie ne peuvent collecter que les données nécessaires à la poursuite d’une finalité d’intérêt public en lien avec l’épidémie actuelle de covid-19. Ils sont responsables du stockage et de la mise à disposition des données. Ils sont autorisés à croiser les données mentionnées au I.

La Caisse nationale de l’assurance maladie est responsable des opérations de pseudonymisation dans le cadre du croisement des données et peut traiter le numéro d’inscription au répertoire national d’identification des personnes physiques à cette fin.

Seuls des responsables de traitement autorisés dans les conditions prévues aux articles 66 et 76 de la loi no 78-17 du 6 janvier 1978 relative à l’informatique, aux fichiers et aux libertés, l’Etat mettant en oeuvre des traitements mentionnés au 6° de l’article 65 de cette même loi, la Caisse nationale de l’assurance maladie mettant en oeuvre des traitements mentionnés au 3° de l’article 65 de cette même loi, ou les organismes et les services chargés d’une mission de service public mentionnés à l’article 67 de cette même loi, peuvent traiter les données ainsi rassemblées par le groupement d’intérêt public.

III. – Les données ne peuvent être traitées que pour des projets poursuivant une finalité d’intérêt public en lien avec l’épidémie actuelle de covid-19 et pour la durée de l’état d’urgence sanitaire institué pour faire face à cette épidémie.

Les données ne peuvent être traitées que sur la plateforme technologique du groupement d’intérêt public et sur la plateforme de la Caisse nationale de l’assurance maladie, et ne peuvent pas en être extraites. Au sein de ces plateformes, les données ci-dessus mentionnées ne peuvent contenir ni les noms et prénoms des personnes, ni leur numéro d’inscription au répertoire national d’identification des personnes physiques, ni leur adresse.

Le groupement d’intérêt public établit et met à disposition sur son site internet un répertoire public qui recense la liste et les caractéristiques de tous les projets portant sur ces données.

IV. – Sans préjudice des dispositions de l’article 6 de l’arrêté du 23 décembre 2016 relatif au recueil et au traitement des données d’activité médicale et des données de facturation correspondantes, produites par les établissements de santé publics ou privés ayant une activité en médecine, chirurgie, obstétrique et odontologie, et à la transmission d’informations issues de ce traitement dans les conditions définies à l’article L. 6113-8 du code de la santé publique, les établissements de santé mentionnés à l’article 1er du même arrêté transmettent, selon une périodicité hebdomadaire, les fichiers mentionnés au I de l’article 5 du même arrêté directement à l’Agence technique de l’information sur l’hospitalisation.

Cette agence traite les données et transmet sans délai à la Caisse nationale de l’assurance maladie les données ayant vocation à alimenter le système national des données de santé.

Les données ainsi transmises ne peuvent être traitées pour les finalités mentionnées au premier alinéa de l’article L. 6113-8 du code de la santé publique, à l’exception de la veille et la vigilance sanitaires. » (Arrêté du 21 avril 2020 complétant l’arrêté du 23 mars 2020 prescrivant les mesures d’organisation et de fonctionnement du système de santé nécessaires pour faire face à l’épidémie de covid-19 dans le cadre de l’état d’urgence sanitaire)

fr France « Un arrêté encadrant les mesures d’organisation et de fonctionnement du système de santé nécessaires pour faire face à l’épidémie de COVID-19 dans le cadre de l’état d’urgence sanitaire a été publié le 21 avril 2020. Ce texte précise notamment à quelles données peuvent accéder, sous certaines conditions, la « Plateforme des données de santé » de l’État ainsi que la Caisse nationale de l’assurance maladie (CNAM). La CNIL, qui a donné son avis sur ce texte, procèdera ultérieurement à une analyse plus poussée de cette Plateforme dans le cadre des usages envisagés ne relevant pas de la gestion de crise sanitaire. » (Organisation et fonctionnement du système de santé dans le contexte du COVID-19 : publication d’un arrêté après avis de la CNIL, CNIL, France, 22 avril 2020)

Information des personnes concernées

eu Europe « 5.1 Transparency and information to data subjects

29. The principle of transparency means that personal data shall be processed fairly and in a transparent manner in relation to the data subject. This principle is strongly connected with the information obligations pursuant to Article 13 or Article 14 GDPR.

30. In general, a data subject must be individually informed of the existence of the processing operation and that personal (health) data is being processed for scientific purposes. The information delivered should contain all the elements stated in Article 13 or Article14 GDPR.

31. It has to be noted that researchers often process health data that they have not obtained directly from the data subject, for instance using data from patient records or data from patients in other countries. Therefore, Article 14 GDPR, which covers information obligations where personal data is not collected directly from the data subject, will be the focus of this section.

5.1.1 When must the data subject be informed?

32.When personal data have not been obtained from the data subject, Article 14 (3) (a) GDPR stipulates that the controller shall provide the information “within a reasonable period after obtaining the personal data, but at the latest within one month, having regard to the specific circumstances in which the personal data are processed”.

33. In the current context, it has to be particularly noted that according to Article 14 (4) GDPR, where “the controller intends to further process the personal data for a purpose other than that for which the personal data were obtained, the controller shall provide the data subjectprior to that further processing with information on that other purpose”.

34. In the case of the further processing of data for scientific purposes and taking into account the sensitivity of the data processed, an appropriate safeguard according to Article 89(1) is to deliver the information to the data subject within a reasonable period of time beforethe implementation of the new research project. This allows the data subject to become aware of the research project and enables the possibility to exercise his/her rights beforehand.

5.1.2 Exemptions

35. However, Article (14) (5) GDPR stipulates four exemptions of the information obligation. In the current context, the exemption pursuant to Article (14) (5) (b) (“proves impossible or would involve a disproportionate effort”) and (c) (“obtaining or disclosure is expressly laid down by Union or Member. State law“) GDPR are of particular relevance, especially for the information obligation pursuant to Article 14 (4) GDPR.5.1.2.1Proves impossible

36. In its Guidelines regarding the principle of Transparency, the former Article 29-Working-Party has already pointed out that “the situation where it “proves impossible” under Article 14 (5) (b) to provide the information is an all or nothing situation because something is either impossible or it is not; there are no degrees of impossibility. Thus, if a data controller seeks to rely on this exemption it must demonstrate the factors that actually prevent it from providing the information in question to data subjects. If, after a certain period of time, the factors that caused the “impossibility” no longer exist and it becomes possible to provide the information to data subjects then the data controller should immediately do so. In practice, there will be very few situations in which a data controller can demonstrate that it is actually impossible to provide the information to data subjects.”

5.1.2.2 Disproportionate effort

37. In determining what constitutes disproportionate effort, Recital 62 refers to the number of data subjects, the age of the data and appropriate safeguards in place as possible indicative factors. In the Transparency Guidelines mentioned above,it is recommended that the controller should therefore carry out a balancing exercise to assess the effort involved to provide the information to data subjects against the impact and effects on the data subject if they are not provided with the information.

38. Example: A large number of data subjects where there is no available contact information could be considered as a disproportionate effort to provide the information.

5.1.2.3 Serious impairment of objectives

39. To rely on this exception, data controllers must demonstrate that the provision of the information set out in Article 14(1) per sewould render impossible orseriously impair the achievement of theobjectives of the processing.

40. In a case where the exemption of Article (14) (5) (b) GDPR applies, “the controller shall take appropriate measures to protect the data subject’s rights and freedoms and legitimate interests, including making the information publicly available”.

5.1.2.4 Obtaining or disclosure is expressly laid down by Union or Member State law

41. Article 14 (5) (c) GDPR allows for a derogation of the information requirements in Articles 14 (1), (2) and (4) insofar as the obtaining or disclosure of personal data “is expressly laid down by Union or Member State law to which the controller is subject”. This exemption is conditional upon the law in question providing “appropriate measures to protect the data subject’s legitimate interests”. As stated in the above mentioned Transparency Guidelines,such law must directly address the data controller and the obtaining or disclosure in question should be mandatory upon the data. When relying on this exemption, the EDPB recalls that the data controller must be able to demonstrate how the law in question applies to them and requires them to either obtain or disclose the personal data in question » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

Limitation du traitement et durée de conservation

eu Europe « Storage periods (timelines) shall be set and must be proportionate.In order to define such storage periods, criteria such as the length and the purpose of the research shouldbe taken into account. National provisions may stipulate rules concerning the storage period as well and must therefore be considered. » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

eu Europe « 5.3 Data minimisation and storage limitation

46. In scientific research, data minimisation can be achieved through the requirement of specifying the research questions and assessing the type and amount of data necessary to properly answer these research questions. Which data is needed depends on the purpose of the research even when the research has an explorative nature and should always comply with the purpose limitation principle pursuant to Article 5 (1) (b) GDPR. It has to be noted that the data has to be anonymised where it is possible to perform the scientific research with anonymised data.

47. In addition, proportionate storage periods shall be set. As stipulated by Article 5 (1) (e) GDPR “personal data may be stored for longer periods insofar as the personal data will be processed solely for archiving […] scientific purposes […] in accordance with Article 89 (1) subject to implementation of the appropriate technical and organisational measures required by this Regulation in order to safeguard the rights and freedoms of the data subject”

48. In order to define storage periods (timelines), criteria such as the length and the purpose of the research should be taken into account. It has to be noted that national provisions may stipulate rules concerning the storage period as well. » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

L’intégrité et la confidentialité des données doivent être garanties

eu Europe « 5.4 Integrity and confidentiality

49. As mentioned above, sensitive data such as health data merit higher protection as their processing is likelier to lead to negative impacts for data subjects. This consideration especially applies in the COVID-19 outbreak as the foreseeable re-use of health data for scientific purposes leads to an increase in the number and type of entities processing such data.

50. It has to be noted that the principle of integrity and confidentiality must be read in conjunction with the requirements of Article 32 (1) GDPR and Article 89 (1) GDPR. The cited provisions must be fully complied with. Therefore, considering the high risks as outlined above, appropriate technical and organisational up-to-date measures must be implemented to ensure a sufficient level of security.

51. Such measures should at leastconsist of pseudonymisation,encryption, non-disclosure agreements and strict access role distribution, restrictions as well as logs. It has to be noted that national provisionsmay stipulate concrete technical requirements or other safeguards such as adherence to professional secrecy rules.

52. Furthermore, a data protection impact assessment pursuant to Article 35 GDPR must be carried out when such processing is “likely to result in a high risk to the rights and freedoms of natural persons »pursuant to Article 35 (1) GDPR. The lists pursuant to Article 35 (4) and (5) GDPR shall be taken into account.

53. At this point, the EDPB emphasises the importance of data protection officers.Where applicable, data protection officers should be consulted on processing of health data for the purpose of scientific research in the context of the COVID-19 outbreak.

54. Finally, the adopted measures to protect data (including during transfers) should be properly documented in the record of processing activities. » (Guidelines 03/2020 on the processing of data concerning health for the purpose of scientific research in the context of the COVID-19 outbreak, EDPB, Europe, 21 April 2020)

Recherches sur des données anonymisées de patients

UK Royaume-Uni « Research using anonymous health information

A member of a patient’s or service user’s care team may render confidential patient information anonymous without breaching the duty of confidentiality. The care team includes registered health and social care professionals and other staff that directly provide or support care to patients.

Anonymised information can then be used in health and care research. There are two main scenarios that are likely to apply to health and care research:

  • A member of the care team enters information about patients into a database (for example, using a secure web-based system) without any identifiers, where the primary purpose of the database is to support public health surveillance and wider clinical decision-making. That database would then hold information that would be anonymous to the researcher (where appropriate controls about linking that data to other data are put in place). The establishment of a database for public health or clinical purposes does not require review by a REC and should be managed under clinical governance arrangements. This anonymous data may then be used for research without REC approval
  • A member of the care team enters information about patients into a study-specific database (for example, using a secure web-based system) without any identifiers, where the primary purpose of the database is to support an individual research project. Where the purpose of new data collection is for research, it requires review by a REC, even if the data analysed by researchers will be anonymous to the researcher. Where such research involves NHS Trusts, GP Practices or Health Boards in England and Wales, it requires HRA or HCRW approval.

In either scenario, a member of the care team does not need to have consent to enter de-identified data into the database » (Covid-19 research – Guidance for using patient data, NHS, Royaume-Uni, Last updated on 6 April 2020)

UK Royaume-Uni « Guidance for using patient data without consent

Ordinarily, applications are made for support from the Confidentiality Advisory Group (CAG) where confidential patient information is to be processed in England and Wales without consent for research and non-research activities. A temporary arrangement has been made for COVID-19 studies going through the fast-track review process, in which support from CAG is not required. However, CAG is providing advice as part of the fast-track process. Secretary of State for Health and Social Care has issued a general notice under the Health Service Control of Patient Information Regulations 2002 to support the response to COVID-19. This notice requires NHS Trusts, Local Authorities and others to process confidential patient information (CPI) without consent for COVID-19 public health, surveillance and research. The notice is in force until 30 September 2020.

This means that research activities (and non-research activities) that normally require CAG support for processing CPI without consent do not require CAG support where they relate to a ‘COVID purpose’.

How to use patient data without consent

NHSX has created a process for capturing and using COVID-19 data without consent under the terms of the notice. If you plan to use such data without consent contact covid-19datasharing@nhsx.nhs.uk, instead of applying to the CAG.

Your study will still need a research ethics review, so you should apply for fast-track review in the same way as other COVID-19 studies. Though formal CAG support is not required NHSX has asked that CAG provides advice to the researcher about the use of confidential patient information in the study. CAG will receive information it needs on your study from NHSX or from your application for fast-track ethics review, so you do not need to contact CAG separately.

Data protection legislation

In addition to the common law relating to confidential patient information, you also need to meet data protection requirements, even where data is anonymised.

Patient information is personal data under data protection legislation if it is identifiable, or has the potential to be identifiable, on the basis of the information held by the organisation holding the data. So, patient information may be de-identified to a researcher but still be classed as personal data as far as the organisation holding the data is concerned.

In order to process personal data, the GDPR and the Data Protection Act 2018 require that you have a legal basis. Our GDPR guidance recommends that research organisations that are public authorities rely on public interest and commercial research partners should use legitimate interests as their legal basis. Explicit consent under the GDPR is not necessary for health and care research.

Transparency about use of patient data

Where patient information is being used for research, there should be as much openness and transparency about that use as possible. This may be through a mix of leaflets, posters, verbal information or information on websites. This should be proportionate and appropriate to the circumstances. »(Covid-19 research – Guidance for using patient data, NHS, Royaume-Uni, Last updated on 27 April 2020)

Inspections et Audit

Possibilité d’inspection par voie électronique

UK Royaume-Uni « On 20th March 2020 MHRA announced a risk-based prioritisation of Good Practice inspections due to the COVID19 outbreak. Until further notice, MHRA will only conduct on-site inspections linked to the UK Government’s COVID19 response or any other potential serious public health risk, and where remote assessment is not possible. Other inspections will be temporarily replaced with alternative regulatory supervision approaches such as office-based assessment. This will support the industry and NHS to focus on service continuity, and essential clinical trial authorisation applications will not be affected.
During this period of disruption, MHRA’s remote assessment procedures and our communication with the international regulatory network will maintain protection of public health.

  • Office based inspections will involve organisations being asked to provide electronic copies of documents and other information for review off-site, with teleconferences and email to follow up. Where necessary, the on-site portion of routine surveillance such as manufacturing plant tours and oversight of clinical trials facilities will be re-scheduled when travel restrictions are lifted
  • Our confidentiality arrangements with the 53 global inspectorates in the Pharmaceutical Inspection Cooperation Scheme (PIC/S), mutual recognition partners and other collaborating regulators ensures that we have access to GxP information on international organisations and supply chains involved in the development, manufacture and supply of medicines. The PIC/S Inspection reliance procedure is particularly important, as it sets out a framework for participating authorities to rely on the inspection information provided by the network.

If on-site inspection is required, we will continue to operate to normal procedures, including the possibility of an unannounced visit if considered necessary to protect public health. Our inspectors will take all possible steps to protect the inspected organisation and themselves from COVID19 transmission risks, including strict hygiene measures in line with UK Government advice » (MHRA Good Practice (GxP) inspections during the COVID19 outbreak, MHRA, Great-Britain, 23 March 2020)

UK Royaume-Uni « Inspections

  • Routine inspections approach – we are no longer routinely undertaking onsite inspections which are being replaced with desk-based inspections in most cases
  • Specials’ licence holders – We are permitting the ‘pack down’ of large packs of licenced medicinal products into smaller quantities for retail sale by pharmacies
  • Imported products (3rd countries) – We may implement reduced re-testing where this will significantly delay Qualified Person (QP) certification and batch release (e.g. sterility tests)
  • Analytical tests for active substance identification and assay should be retained, unless manufactured in the territory of a PIC/S participating authority. The MHRA will not object to such importation re-testing being omitted where:
    • Reliance can be placed on measures such as previous testing history and full testing of each batch at the third country manufacturing site
    • A retrospective, risk-based, skip lot approach for testing imported batches is undertaken with full testing performed to inform the QP of the continued quality
    • Quality attributes that have failed import re-testing should continue to be tested unless robust preventative actions have been implemented and confirmed by the QP
    • Documentation of the justification and details of omission of tests is retained within the Pharmaceutical Quality System
    • Specialist analysis for certain biological products (e.g. vaccine inactivation tests) should continue to be performed on importation
  • QP certification – We will prioritise variations to add replacement QPs to MIA/MIA(IMP), including non-practising or retired QP. QP remote working arrangements will be permitted, where procedures facilitate this approach
  • Dedicated email address for MIA and MIA(IMP)s to notify the MHRA of use of flexibilities – MIA and MIA(IMP) holders making use of this flexibility should notify the MHRA with product name and marketing authorisation number to Covid19.GMDP@mhra.gov.uk on a ‘do and tell’ basis. No prospective MHRA approval is necessary » (Guidance – MHRA regulatory flexibilities resulting from coronavirus (COVID-19), MHRA, Royaume-Uni, 1 April 2020, Updated 2 April 2020)

DK Danemark « Due to the COVID-19 pandemic, the Danish Medicines Agency is putting all on-site inspections and laboratory controls on hold until further notice. The Danish Medicines Agency will, however, continue with office-based assessments and controls, and, if needed, also on-site inspections.

The Danish Medicines Agency will only conduct on-site inspections if there is a potential risk to patient safety. All other on-site inspections and laboratory controls are put on hold until further notice. We will, however, carry on with some inspections in the form of office-based assessments. (…)

This has changed with the present measures to contain the spread of coronavirus, which obviously also apply to the authorities and the pharmaceutical industry.

The Danish Medicines Agency is therefore working with the European Medicines Agency to find common control methods and guidance for the industry to be used under the current COVID-19 breakout. The common agreement is to ensure that both inspections and controls can be conducted in compliance with the preventive measures to contain the spread of the virus, while safeguarding patient safety and ensuring that critical clinical trial applications are not affected. » (COVID-19: Danish Medicines Agency puts inspection and control tasks on hold, DMA, Danemark, 26 March 2020)

Les audits devraient être annulés ou repoussés s’ils ne peuvent être réalisés dans le respect des mesures de distanciation sociale

eu Europe « 12. Changes to auditing
In the current situation, audits should in general be avoided or postponed. Audits should only be conducted if permitted under national, local and/or organizational social distancing restrictions. For critical trials, on-site visits as well as remote audits can be considered, after agreement with the investigator and if the audits are assessed as essential, e.g. triggered audits with the purpose of investigating serious non-compliance. »
(Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, EMA, 20 March 2020, Updated on 27 March 2020)

DK Danemark « Onsite audits should currently be avoided/postponed in order not to visit investiga-tor sites unnecessarily. The sponsors should consider in their risk assessment whether remote audits or postponing of audits is the preferred option. On-site as well as remote audits should only be conducted after agreement with the investiga-tor and if the audits are assessed as critical, e.g. triggered audits with the purpose of investigating serious non-compliance.

Audit of the areas under sponsor responsibility, including audits of contracted par-ties should only be conducted with appropriate consideration for the sponsor’s, contracted party’s and authorities’ implemented restrictions and in accordance with the sponsor’s assessment of criticality. » (Extraordinary measures for clinical trials due to COVID-19 – V4.0, Danish Medical Agency, 13 March 2020, Updated 1 avril 2020)