As the coronavirus (COVID-19) pandemic continues to grow, the US Food and Drug Administration (FDA) on March 18 issued a guidance document titled FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic. The guidance provides general considerations to “assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity . . . .”
- Some clinical trials may need to be deferred or modified to address patient safety and access issues. Real-time communications with subjects and sites will be critical.
- Clinical trials that proceed may require protocol and informed consent form (ICF) modifications. Close contact with Institutional Review Boards (IRBs) is essential. Changes may include the following:
- Changes in subject screening, assessment, and site monitoring to use virtual technology
- Use of alternative delivery approaches for getting investigational drug to subjects
- Changes to efficacy endpoints to account for delayed subject assessments or other issues
- Changes to the statistical analysis or data management plans to account for the above modifications
- Changes for screening of subjects for COVID-19 generally do not require FDA protocol amendments. Additionally, preapproval by IRBs and FDA is not needed for protocol changes to minimize or eliminate immediate hazards or protect research subject life and well-being, but post change notice is required.
- Sponsors should ensure sites are properly documenting modifications due to COVID-19 carefully on case report forms and other trial related documentation; monitors should be trained to recognize these deviations.
- Sponsors should also be in dialogue with clinical suppliers and their suppliers to ensure there is an understanding of potential disruptions to the supply chain for investigational products and to confer with FDA about approaches to mitigate any disruption.
FDA recognizes that COVID-19 may impact clinical trials and that sponsors may face a number of challenges, including quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, and potential site personnel and trial subject infection. FDA also recognizes that protocol modifications and deviations may be required or unavoidable, and outlined the below general considerations for sponsors, investigators, and IRBs:
- As always, clinical trial subject safety is the priority. FDA states that sponsors should consider each circumstance, with a focus on potential participant impact. Sponsors may need to make decisions regarding “continuing trial recruitment, continuing use of the investigational product . . ., and the need to change patient monitoring . . . .” Sponsors should also consider whether it is appropriate to delay certain trial assessments for ongoing studies. Subjects must be kept informed of any applicable changes to the study and monitoring plans. ICF modifications may be needed to account for study changes.
- Decisions regarding continuation of the trial, discontinuation of investigational product administration or use, or discontinuation of trial participation will depend on the specific circumstances of the trial and should be made in consultation with IRBs. Considerations may include the nature of the investigational product, the ability of the sponsor to continue appropriate safety monitoring, the potential impact of the investigational product on the supply chain, and the specific disease being studied. Protocol amendments may be necessary.
- As we discussed in our Law Flash titled Potential Impact of Coronavirus (COVID-19) on the Pharmaceutical and Biotech Industries, sponsors should assess whether alternative methods, such as phone contacts, virtual visits, or alternative assessment location sites, can be used for safety monitoring.
- Additional safety monitoring may be needed if trial participants need to be withdrawn from the investigational treatment.
- Healthcare systems may mandate COVID-19 screening procedures. These screenings do not need to be reported to FDA as a protocol amendment, even if they are done during a clinical study visit, unless the sponsor will incorporate the data into the study as a new objective.
- Sponsors and investigators should engage with their IRBs as early as possible when protocol or informed consent changes may be needed as, typically, protocol changes must be preapproved by the IRB and sometimes FDA. However, if changes are needed to minimize or eliminate immediate hazards or protect research subject life and well-being (e.g., to limit COVID-19 exposure), these may be implemented without IRB approval and before filing the amendment with FDA. Such changes, however, must be reported to the IRB and FDA after they have been put in place. Sponsors and investigators are encouraged to work with their IRBs ahead of time to define procedures and prioritize deviation reporting.
- If alternative trial procedure are needed, to the extent possible, they should be consistent with the protocol and the reason for the changes, as well as information about the change and its impact, should be documented.
- Sponsors and investigators should capture specific information in case report forms regarding missing information (e.g., missed visits, discontinuations, and changes to the study). This information should include the relationship of the missing information to COVID-19 and should be summarized in the ultimate clinical study report.
- If site visits for investigational product administration will be significantly impacted, certain products (e.g., those typically distributed for self-administration) may be able to be distributed to patients through secure delivery methods. FDA also recommends consulting with the applicable review division for investigational products that are administered in healthcare settings regarding alternative administration arrangements. Sponsors and investigators must continue to maintain investigational product accountability.
- FDA also recommends consulting with the review division regarding potential protocol modifications related to efficacy endpoints (e.g., to discuss virtual assessments, delayed assessments, and alternative arrangements for specimen collection). If efficacy endpoint measures are not collected, the reason for the deviation should be documented.
- If protocol changes lead to amended data management or statistical analysis plans, FDA recommends consulting the applicable review division. Sponsors should also address how COVID-19 protocol deviations should be handled in the statistical analysis plan prior to database lock.
- If on-site monitoring is not possible, FDA recommends considering central and remote monitoring programs to maintain site oversight.
Overall, and to the extent policies and procedures are not already in place, FDA recommends that sponsors, investigators, and IRBs establish and implement procedures or revise existing ones to describe how study participants will be protected and how trials will be managed during possible COVID-19 disruptions. Consideration should be given to the impact of the pandemic on informed consent processes, study visits and procedures, study monitoring and data collection, adverse event reporting, and changes in investigators, site staff and monitors. All policies and procedures will need to continue to be compliant with regional or national policies regarding COVID-19.
Finally, to the extent that a study is impacted, in the clinical study report or a separate study specific document, sponsors should describe the implemented contingency measures, include a list of impacted subjects by subject number and site (including how the individual’s participation was affected), and provide an analysis and discussion regarding the impact of the contingency actions on safety and efficacy results.
Right to Try and Expanded Access Considerations
Although not addressed by the FDA guidance, sponsors, especially those with clinical trials involving investigational products that are anti-virals and other potential treatments for COVID-19 and related conditions like pneumonia may see increased requests for expanded access to these products outside of clinical trials or through right-to-try statutes. It is important for companies to be ready to respond to such requests and to ensure that such demands are not jeopardizing ongoing clinical trials. Reviewing company policies around patient access outside of clinical trials is prudent, and ensuring personnel are trained to properly respond to such requests could avoid disruption and inconsistent decisionmaking.
If you have any questions on the issues discussed in this Law Flash, please contact Kathleen Sanzo or Jacqueline Berman.