An Update On Regulatory Guidance For U.S. Clinical Trials During COVID-19

By Madeleine Giaquinto and Sean Hilscher

A multitude of factors related to the global spread of the novel coronavirus (COVID-19), including social distancing strategies, have disrupted new drug development, as well as the development processes for other medical products. Public health regulators recognize that site closures, travel limitations, supply chain interruptions, and risk of exposure to, or infection of, COVID-19 may lead to difficulties in meeting protocol-specified procedures for clinical and human subject trials. Despite disruptions, the urgency of ensuring the integrity and safety of drug development has predictably not subsided.

To preserve integrity in clinical trials and mitigate the need to place clinical trials on hold indefinitely, the FDA issued guidance to support important research and exploration of new treatments. Additionally, the U.S. Department of Health and Human Services’ (HHS) Office of Human Research Protection (OHRP) issued guidance to assist researchers in applying human subject protection regulations. This article reviews public health regulators’ efforts to mitigate COVID-19-related disruptions as expressed in updated FDA guidance on conducting clinical trials and in new OHRP guidance on assisting the greater healthcare research community.

New Guidance Issued Amid COVID-19

Mitigating disruption of clinical trials requires meeting criteria for maintaining compliance with study protocols and social distancing requirements. To address these extraordinary circumstances, regulators have issued guidance to assist sponsors and researchers in ensuring the integrity of clinical trials and the safety of participants during the pandemic.

FDA Guidance on Conducting Clinical Trials

As part of this effort, on March 18, 2020, the FDA published FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency providing sponsors with specific recommendations on ensuring the safety of trial participants, maintaining compliance with good clinical practice, and minimizing risk to trial integrity during the COVID-19 pandemic.¹

Under the FDA guidance, sponsors are advised to consult with investigators and IRBs to determine whether a participant’s safety is best protected through continued participation in the trial. Because participants may not be able to come to the investigational site for protocol-specified visits, sponsors may consider alternative methods for safety visits (e.g., phone contact, virtual visits, etc.). COVID-19 screening procedures mandated by a healthcare system do not need to be reported in a protocol amendment unless the data is being collected as part of a new research objective.¹

Additionally, under the FDA guidance, in the event that a protocol change must be made to eliminate an immediate hazard or protect the life of a research participant, a sponsor can implement the change prior to IRB approval or before filing an amendment to an IND or IDE, but it must report such changes afterward. In case report forms, it is important for sponsors to explain the basis of the missing information, due to changes in study visits or patient discontinuation, and its relationship to the COVID-19 pandemic. Should changes in efficacy assessments be required, the FDA recommends consultation with the appropriate review divisions to discuss protocol modifications for the collection of efficacy endpoints (e.g., move to virtual assessments or delay the assessment).

Lastly, the FDA recommends sponsors establish policies and procedures to protect participants during the pandemic, if such policies and procedures are not already in place. For all trials impacted by COVID-19, the FDA requests sponsors describe in their clinical study reports the contingency measures implemented to manage the study during disruptions resulting from COVID-19 control measures, a list of all participants affected by COVID-19 study disruptions, and analyses and discussion of the impact of COVID-19 control measures on the safety and efficacy results reported from the study. Per 21 CFR 312.30(b) and 21 CFR 812.35(a), changes to the policies and procedures may require a protocol amendment.¹

Appendix Updates to the FDA Guidance

The FDA guidance was updated on March 27, 2020,² initially creating an appendix of 10 questions and answers with more specific information about challenges in conducting clinical trials due to COVID-19, such as ensuring patient safety and obtaining informed consent from quarantined patients. Three more updated iterations were published on April 16,³ May 11,⁴ and May 14, adding to the appendix and bringing the total number of questions and answers to 22.

Questions and answers added on April 16 were primarily dedicated to assisting sponsors in circumstances where electronic and remote capabilities are limited.⁵ For example, if investigators are unable to obtain electronic informed consent, they are given the opportunity to use other methods, including faxing or emailing documentation and performing consent interviews by phone. Remotely performed and interview-based outcome assessments, as well as site monitoring visits, may be appropriate as long as adequate consideration has been given. In the event sponsors experience technical difficulties, and the FDA’s electronic submission staff has been contacted, the updated guidance provides an opportunity to request a waiver from eCTD requirements for a limited duration. The updated appendix also allows for the use of commercially available treatments, where a subject is unable to receive the investigational drug from the trial site but where the product is FDA-approved for other uses. In such a case, the sponsor can reimburse the subject for their expenses in securing the commercially available drug.⁵

More recently, questions and answers added on May 11 focused on alternative laboratory or imaging centers, use of videoconferencing, and postmarketing requirements (PMRs). The suitability of alternative locations is dependent on whether the protocol-specified procedure is related to the eligibility criteria, safety evaluations, or endpoint assessments. That is, if laboratory tests or imaging are conducted to assess safety, alternative sites can be used as long as those sites routinely perform those procedures (e.g., blood counts, chest radiographs). However, if the results from laboratory tests or imaging assessments are used as the basis for formal hypothesis testing, the sponsor should consult the review division on whether the alternative site is suitable. Similarly, the use of an alternative laboratory or imaging center to perform baseline tests to characterize the study population should also be discussed with the review division. Any alternative laboratory used to conduct tests will be subject to certification and additional requirements under the Clinical Laboratory Improvement Amendments (CLIA).⁵

Additionally, when employing videoconferencing for remote visits, the FDA suggests that sponsors consider the training of investigators or study personnel, ensure procedures are in place to maintain trial participants’ privacy, and require confirmation of identification of both the investigator and trial participant before engaging in the video conference. The appendix notes that videoconference interactions are not considered electronic records and, thus, are not subject to 21 CFR Part 11.⁵

The updated appendix also notes that the FDA guidance applies to all clinical trials, including clinical trials required by the FDA as a PMR. If sponsors anticipate delays in completing any milestones or meeting any due dates in drug or biological product clinical trials due to COVID-19-related issues, the FDA encourages sponsors to inform the FDA immediately and propose feasible revised milestones for interim, trial completion, and/or final report submission milestones. Similarly, if delays are anticipated in fulfilling milestones for post-market device studies, applicants are also encouraged to contact the FDA with revised milestones. In communicating the likely occurrence of a delay, sponsors should provide an explanation as to how COVID-19 impacts their ability to meet the original milestones.⁵

Lastly, in the latest update published on May 14, the FDA provided recommendations on the reporting of serious adverse events (SAEs). The FDA emphasizes that an SAE should be reported if it is both unexpected and for which there is a reasonable possibility that the SAE is related to the investigational drug. If an unexpected SAE occurs during a clinical trial under an IND for an approved drug that is being investigated and the sponsor determines there is a possibility the SAE is related to the administration of the drug, the SAE must be reported in an IND safety report. If an SAE occurs in the course of clinical practice or during a clinical trial and indicates a new serious risk may be associated with it, then an IND safety report should be filed. To assess whether there is a causal relationship between COVID-19 complications and an investigational drug, the FDA recommends sponsors compare rates of observed SAEs of COVID-19-infected trial participants in the investigational drug arm to either the control arm or to an external population.

OHRP Guidance for the Research Community

Addressing the wider healthcare research community, the OHRP issued a guidance on April 8, 2020, OHRP Guidance on COVID-19 to assist researchers in applying human subject protection regulations (45 CFR Part 46) during the pandemic.⁶ The OHRP guidance differs from the FDA guidance in terms of the intended audience and focus, i.e., it is oriented toward all healthcare researchers and emphasizes the prioritization of public health and safety by underscoring human subject protections. This article only provides insights into the specific parts of the OHRP guidance that pertain to clinical trials and does not attempt to summarize the OHRP guidance in general.

Under the OHRP guidance, actions taken for clinical or public health reasons are not considered research procedures and do not require institutional review board (IRB) approval prior to implementation.⁶ For example, procedures for mandatory screening of patients for COVID-19 implemented by hospitals do not need IRB review. Similarly, institutions do not need IRB approval to share the screening results with a public health authority. OHRP notes that the human subject protection regulations in 45 CFR Part 46 provide flexibility for these situations, allowing investigators to incorporate some public health surveillance activities, such as the collection and testing of information or biospecimens as authorized by a public health authority, in a research study without prior IRB approval. Similarly, the regulations do not prevent researchers from reporting specific test results (e.g., COVID-19 test results) along with individually identifiable information to a public health authority if required by law.⁶

In alignment with OHRP’s commitment to public health and safety, the OHRP guidance notes that an investigator may implement changes to approved research prior to IRB review and approval in order to eliminate any apparent or immediate hazards to a subject. In light of current circumstances, OHRP notes that transitioning in-person visits to telephonic visits, or the cancellation of nonessential study visits to reduce the risk of COVID-19 transmission, is acceptable. These types of changes to previously approved research can be submitted to the IRB at any time. In addition, the IRB may use expedited review procedures to review and approve minor changes to the study.⁶

The OHRP guidance also discusses reporting requirements in the event research is suspended, in which case only IRB suspensions or terminations of approved research should be reported. Approved research that was suspended or terminated by an institutional office or an investigator does not need to be reported to the OHRP.

Conclusion

As discussed, the FDA is entrusted with ensuring the integrity of clinical trials during drug development, while OHRP instructs the wider healthcare research community on ensuring the safety and protection of human subjects. Through the issuance of guidances, public health regulators aim to keep clinical and human subject trials safe and in operation during the current public health crisis, albeit through lenses of their respective priorities.

References:

1. FDA Final Guidance, “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency,” (March 18, 2020), available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency.
2. Mezher, Michael, “Clinical trials during COVID-19; Updates from FDA, MHRA and TGA,” (April 1, 2020), available at https://www.raps.org/news-and-articles/news-articles/2020/4/clinical-trials-during-covid-19-updates-from-fda-m.
3. Mezher, Michael, “FDA, EU authorities update guidance on clinical trials during COVID-19,” (April 28, 2020), available at https://www.raps.org/news-and-articles/news-articles/2020/4/fda-eu-authorities-update-guidance-on-clinical-tri.
4. Mezher, Michael, “FDA updates guidance on clinical trials amid COVID-19,” (May 13, 2020), available at https://www.raps.org/news-and-articles/news-articles/2020/5/fda-updates-guidance-on-clinical-trials-amid-covid.
5. FDA Final Guidance, “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency,” (March 18, 2020), available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency.
6. HHS OHRP, “OHRP Guidance on COVID-19,” (April 8, 2020), available https://www.hhs.gov/ohrp/regulations-and-policy/guidance/ohrp-guidance-on-covid-19/index.html.

About The Authors:

Madeleine Giaquinto is manager of regulatory affairs at Greenleaf Health, Inc. She specializes in analyzing FDA regulations, policies, and guidances related to good practice standards for medical products, and in advising clients on strategic engagements with FDA concerning a range of compliance issues, including remediating deficiencies identified in FDA Form 483 observations and FDA warning letters and building cultures of quality within mature quality management systems. Previously, Giaquinto worked at 340B Health, a membership organization of public and private nonprofit hospitals and health systems in the federal 340B drug pricing program, where she researched and analyzed implications of 340B development and educated members on issues involving program compliance, implementation, and advocacy strategies. She earned a B.S. in biology from Georgetown University and a J.D. from George Mason University School of Law. You can connect with her on LinkedIn.

Sean Hilscher is associate VP of regulatory affairs with the Drugs and Biologics Team at Greenleaf Health. He has over 10 years of experience in healthcare and life sciences consulting with a specific focus on registry management and real world evidence. Hilscher has an M.B.A. from Georgetown University and an M.A. in politics, philosophy, and economics from the University of Oxford. You can connect with him on LinkedIn.