|Footnotes for this article are available at the end of this page.
Over the past few months, several clients have alerted us to the delayed or discontinued status of their clinical trials due to the COVID-19 pandemic. Studies typically conducted in physicians’ offices, clinics, or hospitals have been paused as in-person visits to such sites abruptly stopped. Patients are no longer visiting (or visiting in a limited capacity) brick and mortar physicians’ offices and clinics for treatment or follow-up, and visits to hospitals have been curbed due to the pandemic.
Clinical trial participants, including those battling advanced or terminal diseases in which a clinical trial may be a promising option, are being discontinued or delayed from needed trials. Sponsors are struggling with a number of issues, including how to determine which participants should be discontinued, addressing unexpected clinical trial site closures, and reporting clinical trial data for ongoing, but delayed, clinical trials.
In March 2020, the Food and Drug Administration issued a guidance document to provide some parameters on the conduct of clinical trials during the pandemic, including amendments to protocol-specified procedures and adhering to protocol-mandated visits and laboratory/diagnostic testing.1 Notably, FDA provided the following guidance regarding the conduct of clinical trials:
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.
Based on the foregoing, FDA guidance anticipates the possibility that sponsors may choose to work with entities that may be able to provide home nursing, such as home health agencies, or other alternative sites providing trained, but non-study, personnel. After consultation with the FDA review division, an investigator may be able to delegate the responsibility for administering the investigational product to a home health aide or other qualified individual.
From an FDA perspective, it would likely be optimal if the home nurse or other qualified personnel were a member of the existing clinical trial site or if the principal investigator could deliver or administer the medication or therapy directly in the home setting and perform necessary follow-up. However, it appears from the foregoing that FDA may be amenable, at least for some therapies and medications, for a third-party entity, such as a home health agency, to provide such services if the sponsor can ensure that existing regulatory requirements are in place, addressed, and documented. One potential issue to address is handling adverse reactions a patient might experience from the investigational product (e.g., a seizure). This may be a difficult challenge to overcome if the trial is conducted remotely.
In addition, the principal investigator will need to ensure that the individual providing the home services is trained on good clinical practices (GCPs), how to handle the investigational product, appropriate recordkeeping, and procedures to follow-up and monitor clinical trial participants. Again, these types of arrangements will need to be discussed with the appropriate FDA review division. The agency will need to review the arrangement to ensure that all regulatory requirements are met. If FDA approves of the arrangement, it may prove to be a useful means to help sponsors continue clinical trials as the United States continues to weather the COVID-19 pandemic.
The guidance document also includes a number of other considerations for ongoing trials during the COVID-19 pandemic. Some of these are included below:
- Sponsors should consider patient circumstances and the potential effect on the safety of participants to modify a study accordingly. A sponsor, in consultation with the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), may decide that a participant’s safety, welfare, and rights are best served by continuing (or discontinuing) participation in the trial per the protocol or by discontinuing use of the investigational product.
- Sponsors may evaluate whether alternative methods for assessments (e.g., phone contact or virtual visit) can be implemented when necessary and feasible to assure the safety of trial participants. Trial participants who do not have access to the investigational product or site may need additional safety monitoring.
- There may be a need to put new processes (e.g., clinical trial recruitment) in place or modify existing processes, depending on the protocol and local situation. COVID-19 screening procedures, which may be mandated by a health care system where a clinical trial is conducted, are not required 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.
- Sponsors and investigators are encouraged to engage with the IRB/IEC as early as possible when an urgent or emergent change to a protocol or informed consent process is anticipated due to COVID-19. To the extent possible, alternative processes should be consistent with the protocol, and sponsors and investigators should document the reason for any contingency measures implemented.
- Sponsor and investigators should document how restrictions related to COVID-19 led to the changes in study conduct and duration of those changes. Furthermore, the review and documentation should indicate which trial participants were effected and how. FDA cautions that it will be important to capture specific information to explain the basis of missing data (i.e., if there are missed visits or patient discontinuations). With respect to efficacy assessments, the agency recommends consultation with the review division regarding protocol modifications for the collection of efficacy endpoints. If efficacy endpoints are not collected, the sponsor should document the reason for failing to obtain an efficacy assessment.
- If there is a need to amend data management or statistical analysis plans (or both), the sponsor should consider doing so in consultation with the FDA review division. If on-site monitoring visits are no longer possible, sponsors should evaluate optimizing use of central and remote monitoring programs for oversight of clinical sites.
- Sponsors should consult appropriate parties (e.g., the IRB and FDA review division) when making amendments or changes to clinical trials.
- As the COVID-19 pandemic continues to alter the current health care landscape, sponsors have the opportunity to look to alternative methods for delivering investigational products and therapies. As noted, sponsors should discuss any alternatives with the appropriate FDA review division first.
- Sponsors may have the ability to work with a current member of a clinical trial site to deliver investigational products at home or, with appropriate FDA review, training, and oversight, it may also be possible to outsource some responsibilities for administering investigational products to other applicable entities with appropriate state licensure and personnel, depending on the particular circumstances.
- We are living in interesting times. FDA and state regulatory agencies are aware of the challenges with clinical trial continuation and enrollment. Proactive planning, communication and (lawful) creativity may help alleviate these challenges.
- We can assist in crafting compliant arrangements with home health companies and other alternative providers to meet these goals. Please let us know if we can help.
 The guidance document, which was updated on July 2, 2020, is available at the following: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency.