New global frameworks for managing clinical trials during COVID-19 emergency

March 31, 2020

By Phil Crooker, VP - Technical 

As global health authorities react and adjust to responding to the emerging COVID-19 threat to public health, one of the results has been more guidance, published much more often and without going through the typical comment, consultation and clearance processes. On March 18, all three major review centers (drugs, biologics and devices) at the U.S. Food and Drug Administration (FDA) published a final Guidance for Industry, Investigators, and Institutional Review Boards – FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic. A copy of the guidance can be found here – https://www.fda.gov/media/136238/download. This is an example of the “bulleted guidance” that FDA began to pilot in late 2017 in the Center for Drug Evaluation and Research (CDER). Shortly after that, on March 20, the European Medicines Agency (EMA) published a similar Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic. A copy of the guidance can be found here – https://www.ema.europa.eu/en/documents/press-release/guidance-sponsors-how-manage-clinical-trials-during-covid-19-pandemic_en.pdf

Global health authorities recognize that the COVID-19 pandemic may impact the conduct of clinical trials of medical products, including drugs, devices and biological products. These challenges may lead to difficulties in conducting the clinical trials. The FDA and EMA are aware that protocol modifications may be needed, and that there may be unavoidable protocol deviations due to COVID-19. In recent guidance documents, both the FDA and EMA outlined considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice and minimizing risks to trial integrity. The guidance also includes a harmonized set of recommendations to ensure the safety of trial participants across the European Union (E.U.) while preserving the quality of the data generated by the trials. The guidance include advice on how these changes should be communicated to health authorities.

For convenience, here is a rapid comparison of the major points and recommendations made by both FDA and EMA in their guidance documents.

FDA Guidance

EMA Guidance

Ensuring the safety of trial participants is paramount.

The safety of the participant is of primary importance.

Sponsors, investigators and institutional review boards (IRB) should consider  establishing and implementing policies and procedures or revising them to describe approaches to be used to protect trial participants and manage study conduct

All decisions to adjust clinical trial conduct should be based on a risk assessment by the sponsor. The sponsor should re-assess risk as the situation develops.

If a sponsor plans to initiate a new trial for new treatments for COVID-19 and related illnesses, advice should be sought on alternative procedures to obtain informed consent.

There may be a need to re-consent to already included trial participants.

There are several ways that a participant’s safety, welfare and rights could be best served such as – continuing in a study, discontinuing administration of the investigational drug or participation in the trial.

Risks of involvement in the trial should be weighed against anticipated benefit for the participant. All decisions to adjust clinical trial conduct should be based on a risk assessment.

Investigators should implement measures that prioritize subject safety and data validity.

Sponsors should consider in their risk assessments whether a temporary halt of the trial at some or all sites, a suspension of recruiting of new participants, an extension of the duration of the trial or postponement of trials or activation of sites not yet initiated are appropriate.

If it is not feasible for a site to continue participation at all, the sponsor should consider if the trial site should be closed.

If it is unavoidable and an exceptional circumstance, transfer of participants to investigational sites away from risk zones or closer to home to other participating sites could occur.

Alternative methods for safety assessments should be evaluated, including phone calls, virtual visits and alternative locations.

Sponsors should consider in their risk assessments, whether conversion of physical visits into phone or video visits are appropriate.

Possible temporary measures could include cancelling on-site monitoring visits and extending the period between visits; implementing phone and video visits; and adapting the on-site monitoring plan supplementing it with centralized monitoring and central review of data.

Additional safety monitoring may be needed even if a participant no longer has access to an investigational product.  
The need for new processes or modification of existing processes will vary by protocol and location.  
COVID-19 screening procedures that are necessary to meet local health system requirements do not need to be reported as an amendment to a protocol. It is expected that the sponsor will escalate and manage protocol deviations in accordance with their standard procedures.

Changes to protocols or investigational plans to minimize or eliminate immediate hazards or protect the life and well-being of trial participants may be implemented without IRB approval or before filing an amendment to an IND or IDE.

If there is an urgent need to open a new site for critical trial visits, this may be implemented as an urgent safety measure first followed by a substantial amendment later for the approval and initiation of the site.

Urgent safety measures may be taken without prior notification, but the information needs to be later provided to the national competent authority and ethics committee as soon as possible.

If changes do not require immediate action, it should be possible to submit them as substantial amendment applications. Over-reporting should be avoided.

Alternative processes should be consistent with the protocol as reasonably practical as possible and the reasons should be documented.

 
It is critical to capture specific information in the case report form that explains the basis for missing data, including its relationship with COVID-19.  
Alternative secure mechanisms for delivery of investigational drug products designed for self-administration may be possible.

Sponsors should check the NCA guidance regarding the possibility of direct sponsor to trial participant shipment of investigational products.

Direct delivery – if permissible – is expected to flow from investigator sites (such as hospital pharmacies) to trial participants.

Consult the assigned FDA review division before implementing plans for alternative administration of investigational products that are normally dispensed and administered in a health care setting.

Sponsors must assess the risks related to the investigational product and consider alternative shipping and storage arrangements, including whether the product is appropriate for storage and administration at different trial participant sites, stability of the product maintained during transport, safe custody and accountability.

Transfer and re-distribution of investigational product between sites may be performed in accordance with CGMP in situations where direct distribution is not possible and there are established written procedures involving the qualified person (QP).  Sponsors should assess whether a site is capable of handling and controlling the re-distribution, particularly for conditions other than controlled room temperature.

Consult the assigned FDA review division regarding protocol modifications for the collection of efficacy endpoints.  
Reasons for failing to obtain the efficacy assessment should be documented.  
Consult with the assigned FDA review division if changes in the protocol will lead to amending data management and/or statistical analysis plans. The impact of protocol changes on clinical data interpretability needs to be properly assessed by the sponsor and the overall evidence package later discussed within scientific advice with regulatory authorities.
Sponsors should consider optimizing the use of central and remote monitoring programs to maintain oversight of clinical sites.

It is acceptable that laboratory, imaging or other diagnostic tests are done at a local laboratory or relevant clinical facility authorized or certified to perform the tests routinely.

Certain oversight responsibilities such as monitoring and quality assurance activities may need to be re-assessed and alternative proportionate oversight mechanisms required.

For all trials impacted by the COVID-19 pandemic, sponsors should describe the following information in the clinical study report or a separate study-specific document: (1) contingency measures; (2) all participants affected by the study disruption; and (3) analysis that addresses the impact of the contingency measures. Protocol deviations will need to be assessed and reported in the clinical study report.

 

 

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