Federal Agencies Provide Guidance on the Conduct and Oversight of Clinical Trials and Human Subject Research During COVID-19 Outbreak

April 20, 2020

By: Linda A. Malek, Nora Lawrence Schmitt, Jill E. Anderson, and Khaled Mowad

COVID-19 has had a significant impact on the conduct of clinical research across the country.  Sponsors, institutions, and institutional review boards (IRBs) are facing unprecedented challenges resulting from the COVID-19 outbreak, such as clinical trial site closures, travel restrictions, limitations in the availability of study product, and threats to the health and wellbeing of research personnel and study participants. Additionally, researchers are struggling to navigate the relationship between human subject protections and public health activities, including the release of identifiable health information to public health authorities.

As such, the US Food and Drug Administration (“FDA”) and the Office of Human Research Protections (“OHRP”) have each issued guidance documents that set forth key considerations to help sponsors, institutions, investigators, and IRBs navigate the conduct of clinical trials and assure the safety and wellbeing of study participants during the COVID-19 outbreak. 

Below are key highlights and considerations from the respective guidance documents.

OHRP Guidance on COVID-19

On April 8, 2020, OHRP issued a guidance document (available here) addressing the impact of COVID-19 on human subject research and the regulatory requirements contained at 45 CFR Part 46 (the “Common Rule”).  OHRP stressed the importance of prioritizing public health and safety, and took steps to reassure the research community that it will take into account the specific circumstances facing institutions and investigators as a result of the outbreak.  OHRP committed to exercising flexibility in its decision making as institutions and investigators implement actions necessary to protect public health and research subjects.

Highlights

  • Actions taken for public health or clinical purposes, rather than research purposes, are not research procedures and therefore do not require IRB approval before implementation.  For example, mandatory clinical screening procedures related to COVID-19 for all individuals entering an institution, including research subjects, would not require IRB review and approval before implementation.  Similarly, because such activities do not constitute research, the institution does not need IRB approval in order to share screening results with public health authorities or the research subjects (although other authorizations may be required under state law or institutional policy).

  • Although certain public health surveillance activities, including collection and testing of information or biospecimens, conducted, supported, requested, ordered, required or authorized by a public health authority are expressly excluded from the Revised Common Rule[1], FDA regulations may continue to apply if the activity involves the use of an investigational in vitro diagnostic device.

  • When required by law to provide information related to an individual’s COVID-19 status to a public health authority, including individually identifiable information about research subjects, the Common Rule does not prevent investigators or institutions from fulfilling this requirement even if the disclosure would be inconsistent with statements made in the study’s informed consent form. However, the investigator should inform study participants of any required reports. 

  • Investigators and institutions are entitled to implement changes to approved research prior to obtaining IRB review and approval to the extent necessary to eliminate apparent immediate hazards to the subject.  For instance, investigators are entitled to cancel or postpone non-essential study visits or conduct remote visits instead of in-person visits without prior IRB approval, provided such changes are reported to the applicable IRB as soon as possible.

  • Investigators may submit proposed changes relating to previous approved research to the applicable IRB at any time.  To the extent the proposed changes are minor, the IRB may use an expedited review process.

  • Decisions made by institutions or investigators regarding the suspension or termination of approved research need not be reported to OHRP.  Only suspensions or terminations of approved research that are mandated by an IRB must be reported to OHRP under 45 CFR 46.113.

FDA Guidance on the Conduct of Clinical Trials During the COVID-19 Outbreak

The FDA issued a guidance document entitled, “Guidance on Conduct of Clinical Trials of Medical Products during COVID-19," on March 25, 2020 (available here) to which it has made multiple subsequent updates, most recently on April 16, 2020.  The FDA Guidance document is effective immediately (without prior public comment) because of the emergency circumstances, though it remains subject to further comment.

Highlights

  • Sponsors, in consultation with IRBs and investigators, must determine whether the safety, welfare, and rights of study participants are best protected by continuing the study according to the existing protocol, revising the protocol or by discontinuing subject participation in the trial all together.  This is a fact-specific determination and may depend on the following conditions:

    • 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.

  • The inability of participants to make protocol required in-person visits at investigational sites (e.g. because of shelter in place orders, lack of transportation or because the study participant is at high risk with respect to COVID-19) must be specifically considered especially in the context of safety assessments.  Alternative communication methods, such as phone calls or virtual visits, must be carefully assessed to determine whether they will suffice to ensure the safety of participants. 

  • Clinical trials may require protocol and informed consent form modifications, which will necessitate IRB involvement and compliance with institutional policies.  The following deviations from the protocol may be particularly relevant:

    • Changes in subject screening, efficacy and safety assessment, and site monitoring such as the use of virtual technology to interact with study participants;

    • Use of alternative delivery methods or personnel for delivering and administering investigational drugs to subjects (in particular, for drugs typically administered in a healthcare setting);

    • Modifications to the collection of efficacy endpoint data;

    • Changes to statistical analysis or data management plans to account for the above modifications.

  • COVID-19 screening procedures mandated by the institution or other public health authorities need not be included as amendments to a protocol (even if done during a study visit) unless the sponsor intends to incorporate the COVID-19 data as part of its research objective.

  • Sponsors should carefully ensure proper documentation of modifications due to COVID-19 on case report forms and other study related documentation.  This includes documenting the duration of any modifications, the study participants affected, and the nature of the impact on such participants. 

  • Study participants must be informed of changes to the study and monitoring plans that may have an impact on them.  This may require amendments to informed consent forms made in conjunction with the IRB. 

  • Sponsors should account for missing information in case report forms resulting from changes in study visit schedules, missed visits or patient discontinuations  and explain the basis of the missing data, including the relationship to COVID-19 (e.g., from missed study visits or study discontinuations due to COVID-19).

  • Sponsors should consult with the applicable FDA review division (e.g. CDER, CBER) for modifications to investigational product administration and efficacy assessments. 

  • If planned on-site monitoring visits are no longer possible, sponsors and hosting institutions should consider optimizing the use of central and remote monitoring programs to maintain oversight of clinical sites.

Key Takeaways

Both the FDA and OHRP are primarily concerned with how the exigencies brought on by the COVID-19 pandemic affect patient safety.  The guidance documents are aimed at encouraging the research community to think broadly about how the immediate and long-term effects of the pandemic impact clinical trial recruitment, investigational product administration, and efficacy and safety monitoring. 

Sponsors, institutions, and investigators should consider all critical circumstances with a specific focus on the impact to study participants.  Accordingly, sponsors and investigators are encouraged to engage with their IRBs as early as possible when protocol or informed consent changes may be needed. If changes are needed to minimize or eliminate immediate hazards or to protect the safety and well-being of research subjects, they may be implemented without IRB approval or before filing an amendment with the FDA. Such changes, however, must be documented and thereafter be reported to the IRB and FDA.

Sponsors and institutions should consider revising existing human subject research policies and procedures to the extent they do not already address emergency situations, such as the COVID-19 pandemic.  Changes to policies and procedures may be needed to address the impact on the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting, and changes in investigator(s) and site staff.   Sponsors should also consider training study monitors to assist investigators in addressing the risks presented by COVID-19, as well as any necessary deviations in or adjustments to study protocols or practices.   

 

 

[1] 45 CFR 46.102(I)(2).