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Regulatory Focus™ > News Articles > 2020 > 6 > How regulators have adapted globally to clinical trials for drugs and biologics during the COVID-19

How regulators have adapted globally to clinical trials for drugs and biologics during the COVID-19 crisis

Posted 15 June 2020 | By Nimita Limaye 

How regulators have adapted globally to clinical trials for drugs and biologics during the COVID-19 crisis

The COVID-19 pandemic has disrupted clinical trials globally and has resulted in a 65% worldwide decrease in new patient enrollment year-over-year during March 2020. As a result, regulators across the globe have issued new guidances to support the industry in their hour of need.

The US Food and Drug Administration (FDA) has launched a special emergency program for possible therapies for COVID-19 – the Coronavirus Treatment Acceleration Program (CTAP), which combines elements of multiple existing review pathways. It was under CTAP, for example, that the FDA issued the emergency use authorization (EUA) for remdesivir. While there are over 50 regulatory pathways available for sponsors to get their drugs or biologics approved, there are 22 pathways that the FDA would be most likely to leverage under CTAP. Under CTAP, FDA will be providing “ultra-rapid, interactive input”, completing protocol reviews within one day, and “round-the-clock” single patient expanded access request review within three hours. This is a striking reduction in the standard protocol review timelines of 30 days for a Phase 1 protocol, to up to 90 days for a Phase 3 protocol, the four days response time for non-emergency requests and less than one day for emergency requests for expanded access.

The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) consortium launched by the National Institutes of Health (NIH), in collaboration with 16 biopharma companies, FDA, Centers for Disease Control and Prevention (CDC), Health and Human Services (HHS) and European Medicines Agency (EMA) represents an unprecedented collaborative framework between industry and regulators to support and  prioritize the global development of therapeutics and vaccine for COVID-19. Of 39 prioritized agents, ACTIV has chosen six agents to be moved ahead into the master protocol clinical trial(s) and has supported the use of platform trials and master protocols to enable the simultaneous testing of multiple therapies. Sponsors planning on implementing platform and adaptive designs should discuss their trial’s plans in advance with the agency.
FDA published a guidance for the conduct of clinical trials during the COVID-19 pandemic in March 2020 and updated it in May 2020. While FDA recognizes that protocol deviations may occur, it recommends that changes should not be implemented before review and approval by an Institutional Review Board (IRB). Changes resulting from protocol deviations arising from medical emergencies may be implemented without IRB approval or before filing an investigational new drug (IND) amendment but must be reported afterwards. Changes in study conduct related to COVID-19 as a result of contingency measures taken, the duration of those changes, their impact on safety and efficacy measures and the list of trial participants that were impacted as a result of the same and how they were impacted should be documented by sponsors and investigators and presented in the clinical study report. Participants need to be informed of all changes to the study and monitoring plans that could impact them. FDA has noted that COVID-19 screening procedures mandated by the healthcare system need not be reported as amendments unless the sponsor is incorporating the data collected as part of a new research objective. The statistical analysis plan (SAP) should be updated prior to database lock to record how protocol deviations will be handled. The reason for missing visits and study discontinuations and any association of the same with COVID-19 should be noted on the case report form (CRF) and should also be explained in the clinical study report (CSR).
Both FDA and EMA have published guidance documents that have called out the use of telemedicine and virtual visits as vital tools to ensure patient safety. In the case of protocol modifications for the collection of efficacy endpoints, such as the use of virtual assessments, which may be impacting data management plans (DMPs) or SAPs, FDA recommends consultation with the appropriate review division. FDA has also recommended the use of remote monitoring and the centralized monitoring approach for providing trial oversight. FDA has also indicated that sponsors may qualify for a short-term waiver from electronic common technical document (eCTD) requirements in case of technical difficulties, but should contact FDA’s electronic submission staff prior to applying for a waiver. FDA has indicated that if investigators do not have electronic informed consent capabilities, they may use other methods such as fax or email, with consent interviews taking place by phone, while ensuring the authenticity of the subject or the legally authorized representative (LAR). FDA has recommended testing the drug on elderly patients as COVID-19 disproportionately affects adults, as well as patients at high risk of complications, such as the elderly, those who are immunocompromised, as well as racial and ethnic minorities.
While the Center for Drug Evaluation and Research’s (CDER) final guidance focuses on drugs with antiviral or immunomodulatory activity, the Center for Biologics Evaluation and Research (CBER) issued a guidance on the development of therapies using convalescent plasma on 8 April 2020. COVID-19 convalescent plasma has not been approved for use by FDA and is regulated as an investigational product.  Healthcare providers or acute care facilities need to obtain COVID-19 convalescent plasma from an FDA-registered blood establishment.
EMA has stressed that sponsors need to carry out a risk assessment of each trial and each trial participant, and implement changes accordingly, prioritizing patient safety. Evaluation of whether a protocol amendment is “substantial” or not is for the sponsor to determine, and only these need to be submitted to the authorities. While study visits may be converted to phone or video visits, a transition to remote source data verification (SDV) will be considered to be a substantial amendment. Electronic consent may continue to be used if it was already being implemented; otherwise, standard consenting procedures should be followed. If re-consent needs to be obtained, phone or videocalls may be used and needs to be documented in the trial participants' medical records, supplemented with e-mail confirmation.
Medicines and Healthcare products Regulatory Agency (MHRA) issued a guidance in March 2020, updated April 2020, indicating that protocol deviations (PDs) such as phone calls instead of in-person study visits are acceptable, would not be treated as a serious breach of protocol and should not be reported to the agency unless there is a risk to the patients. Both FDA and MHRA have stressed the need for the documentation of the reasons for these PDs. MHRA also recommends performing a risk/benefit assessment to evaluate whether ongoing trials should be discontinued.
Central Drugs Standard Control Organization (CDSCO) has declared that no fresh approvals for clinical trials would be provided in India, except for those related to COVID-19, and recognized that under the extenuating circumstances, relaxations are required for the ongoing clinical trials on COVID-19. The draft Indian Council of Medical Research (ICMR) guidelines have indicated that patients can consent via WhatsApp, text messaging or email. It has also provided the provision for ethics committees to meet virtually. It is possible that online ethics meetings may become a permanent feature even after the COVID-19 pandemic ends. Further, if members of an ethics panel are not available for any reason, a researcher can approach another ethics committee to seek its consent.
CSOFT Health Sciences provides expert medical writing and consulting for regulatory submissions, in addition to medical translation services. Learn more about our services here.
Nimita Limaye is SVP, Strategic Partnerships & Medical Writing at CSOFT Health Sciences
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