On May 14, 2020, the U.S. Food and Drug Administration (FDA) updated its FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency – Guidance for Industry, Investigators, and Institutional Review Boards to both strengthen and expand previous guidance on, among other items, ongoing reporting and subject participation challenges due to COVID-19. The guidance was initially issued on March 18, 2020, and previously updated on March 27, 2020, and April 16, 2020.
The FDA continues to provide flexibility for clinical trials due to the reality of local shelter-in-place rules, uncoordinated phased openings throughout the country and other travel limitations. Specifically, the May 14 guidance added new Q&As addressing:
- The use of alternative laboratories and imaging centers for protocol-specified assessments.
- The use of videoconferencing in lieu of in-person clinical trial visits.
- Steps applicants must take if the public health emergency impacts their ability to meet the timetable for required postmarketing clinical trials.
- How New Drug Application (NDA) holders of an FDA-approved drug for a non-COVID-19 indication – that is also being investigated under an Investigational New Drug (IND) application to treat COVID-19 – should treat spontaneous reports of serious adverse events (SAEs).
- How sponsors of clinical trials unrelated to COVID-19 should treat SAEs associated with COVID-19.
Below we recap the previously issued guidance, summarize the new Q&As and highlight the differences.
I. Recap of Prior Guidance
In mid-March, the FDA issued the first version of guidance on the conduct of clinical trials during the COVID-19 public health emergency. That first version outlined a core set of considerations to assist sponsors, investigators and Institutional Review Boards (IRBs) to ensure the safety of trial participants, maintain compliance with good clinical practice, and minimize risks to trial integrity. Amongst other things, the guidance addressed:
- Factors to be considered when deciding whether to continue ongoing clinical trials, as well as whether to initiate new trials, in light of the public health emergency. The guidance emphasized that the safety of trial participants is paramount. With respect to ongoing trials, for example, the guidance suggested the need for an assessment of the nature of the investigational product, the ability to conduct safety monitoring, the potential impact on the investigational product supply chain, and the nature of the disease under study in the trial.
- When changes to the protocol or investigational plan in light of the public health emergency require notice and/or approval by the IRB or FDA. The guidance stated that such changes that are necessary to minimize or eliminate an immediate hazard or to protect the life and well-being of participants can be implemented without IRB approval or before filing an amendment to the IND or Investigational Device Exemption (IDE), but they must be reported afterward.
- When COVID-19 screening procedures need to be reported as an amendment to the protocol. In particular, the guidance stated that COVID-19 screening mandated by a health care system in which a trial is being conducted do not need to be reported as an amendment unless the sponsor is incorporating the data collected as part of a new research objective.
- The need to document the specific reason(s) for all protocol deviations.
- Alternative methods for sponsors to meet their safety monitoring obligations. The guidance noted that phone contacts, virtual visits, and alternative locations for conducting the safety assessments all present possible options, but the sponsor would need to determine whether in-person visits are necessary to fully assure the safety of participants.
- How sponsors can meet their obligation to maintain oversight of clinical sites when on-site monitoring visits are no longer possible. The guidance suggested that sponsors consider enhanced use of central and remote monitoring approaches.
- How to approach protocol modifications for the collection of efficacy endpoints or other changes that would require changes to the statistical analysis plan. The FDA recommended that sponsors consult with the appropriate review division on the acceptability of virtual assessments, alternative methods for collection of research specimens, and delays in conducting assessments.
After its release of the first version of the guidance, the FDA released updates in March and April containing its responses to commonly asked questions. In these Q&As, the FDA further elaborated on the core set of considerations described above:
- When deciding whether to continue or suspend an ongoing study, sponsors should consider, inter alia, the availability of clinical investigators and clinical trial support staff to provide oversight and complete required tasks; the ability to conduct necessary trial assessments; the availability of the investigational product, as well as other clinical trial supplies; and whether there will be continued operations of the IRB and Data Monitoring Committee (DMC).
- For studies under an IND, a protocol amendment is necessary for any study-wide change that significantly affects the safety of subjects. Further, a protocol amendment is necessary for any study-wide change in a phase 2 or 3 study that significantly affects the scope of the investigation or scientific quality of the study. However, pausing enrollment to decrease potential exposure to COVID-19 does not trigger these criteria.
- If obtaining signed informed consent is impossible due to a patient being in COVID-19 isolation, alternative electronic consent methods should be considered. When electronic methods are not possible, a process can be implemented to obtain the patient’s consent via phone or video with the participation of an impartial witness. The Q&As also address how to obtain informed consent from individuals unable to travel to the trial site for other COVID-19 related reasons (e.g., travel restrictions).
- Access to clinical site records for purposes of remote monitoring can possibly be achieved through a secure remote viewing portal that allows for the study monitor’s review. Alternatively, sites could upload certified copies of source records to a sponsor-controlled electronic system or cloud-based repository, provided appropriate security controls are established. If the study is blinded, controls are necessary to protect the integrity of the study blind. In any event, the site must maintain control of the original source records.
- For investigational products administered via infusion, it is acceptable to ship the product to locations other than clinical trial sites for administration, provided such sites have appropriately trained personnel with experience in the class of products involved. Local health care providers (HCPs) who are administering drugs in a manner that does not differ from their normal clinical practices would not be considered sub-investigators required to be listed on Form FDA 1572 (the Statement of Investigator). However, when a local HCP will be performing study-specific research procedures or assessments, these HCPs would be considered sub-investigators.
II. New Guidance in May 14 Version
1. Use of Alternate Labs/Imaging Centers
The FDA addressed the reality that trial participants may not be able to travel to the investigational site during the COVID-19 pandemic, resulting in the need to consider protocol-visit options elsewhere. The FDA confirmed its support for the use of alternative sites for laboratory tests and imaging centers that routinely provide the applicable tests and/or assessments – noting that the safety of trial participants remains paramount. Form FDA 1572 need only be updated if the alternative laboratories or imaging centers will be used by all patients in the study.
Sponsors must delineate the need for routine testing versus use for formal hypothesis testing. The FDA cautions that disparities in how different laboratories and imaging centers perform studies could result in avoidable error rates. The FDA encourages conversations with their review division to ensure that the alternate use does not unknowingly thwart the trial’s data collection efforts in circumstances where a shift for all patients is contemplated.
2. Remote Trial Participant Visits
It was inevitable that the increasing use of telemedicine in clinical practice would eventually reach the universe of clinical trials. In this iteration, the FDA attempts to provide guidance on what is considered best practice for the use of videoconferencing for trial participant visits but is quick to note that the Agency does not endorse any particular best practices for telemedicine. Recommendations include training on the use of telemedicine technology, procedures to maintain the trial participant’s privacy, and that the investigator and trial participant should confirm their identities prior to the real-time visit. Sponsors are encouraged to research other best practices that may be relevant outside of the FDA’s guidance. Notably, in March, the Office for Civil Rights (OCR) at the U.S. Department of Health and Human Services (HHS) announced that it would exercise enforcement discretion for Health Insurance Portability and Accountability Act (HIPAA) violations “against health care providers that serve patients through everyday communications technologies during the public health emergency.” The announcement recommends health care providers that seek additional privacy protections for telehealth “should use such services through technology vendors that are HIPAA compliant and will enter into HIPAA business associate agreements (BAAs) in connection with the provision of their video communication products.”
Regardless of the approach or technology used, the FDA notes that the interaction should be documented in the case report form, similar to the expectations for face-to-face interactions. Last, the FDA notes that real-time video interactions are not considered electronic records subject to 21 CFR Part 11.
3. Impact to Drug and Biological Product Trials Required as Postmarketing Requirements (PMRs)
Anyone who is required to complete postmarketing clinical trials pursuant to existing due dates should inform the FDA as soon as possible if there are any COVID-19-related delays that may impact the ability to meet the interim, trial completion and/or final report submissions. In the notification, applicants should propose alternative dates that the applicant intends to complete any missed milestones. This also applies to any post-market device studies or applicants with PMRs that may miss certain milestones, with a requirement that notice to the FDA should include an explanation of the COVID-19 impact in meeting the original timeframe. The explanation should be complete, as the FDA will use it (as well as conduct of the applicant) to determine ongoing compliance. Additional PMR guidance is also included in the FDA’s May 14 updates.
4. Reporting of SAEs
Reports of SAEs that occur in clinical practice with the use of an approved drug or biological product should continue to be reported under the postmarketing reporting requirements currently in use. SAEs that occur during a clinical trial under an IND for an approved drug or biological product being investigated for a possible COVID-19 treatment should be reported as an IND safety report pursuant to existing FDA regulations.
Regardless of the setting for the SAE or where it is initially reported, NDA holders of the FDA-approved drug who are also sponsors of an IND for the same drug being investigated for COVID-19 treatment purposes must monitor the accumulated safety data between the two mechanisms to identify any potential new serious risk associated with the drug. It may be that the sponsor will need to file an IND safety report or update its investigator brochure/informed consent depending on what the accumulated data shows on drug safety.
Trial participants may be diagnosed with COVID-19 and experience an SAE associated with COVID-19 and unrelated to the investigational drug. Equally possible is that the investigational drug causally related to an SAE could make COVID-19 patients more susceptible to COVID-19 complications. To assist in the determination of whether or not to report, the FDA recommends a “comparison between the rate of observed SAEs among COVID-19 infected trial participants in the investigational drug arm to COVID-19 infected trial participants in the control arm.” Alternatively, “determine whether there is an excess of SAEs in trial participants diagnosed with COVID-19 by comparing the rate of such events to an external similar population diagnosed with COVID-19.” If one or both of these methodologies suggests a causal relationship between the investigational product and the SAE, the SAE must be submitted as an IND safety report in accordance with existing guidance.
III. Updates to Previous Guidance
1. Protocol/Investigational Plan Changes
Additionally, the May 14 publication provided several important updates to previous guidance. Specifically, the update confirmed that protocol deviations should be included in final study reports and included in annual reports if appropriate. Previous guidance suggested that documenting deviations should occur locally using the sponsor’s standard processes only versus the clarification that such deviations should at least be included in the final study reports. Further, study-wide protocol changes made to prevent imminent hazards to trial participants must be done via notification to the FDA as an IND amendment. Any IND protocol amendments that are not required to prevent imminent safety risks can be implemented after FDA and IRB approval has been obtained.
Contrast the IND protocol updates with those for IDE: Here, the FDA has clarified that IDE changes to an investigational plan done to protect the life or physical well-being of a subject (individually or study-wide) in an emergency must, under its regulations, be reported to the FDA within five (5) working days. FDA continues in this version of the guidance to recognize, however, that it may be challenging for IDE sponsors to meet the five-day reporting requirement, and, therefore, sponsors are permitted to consolidate implemented changes when submitting five-day reports, as long as the IDE is updated as soon as possible.
2. Change to Home Infusion
Building on the theme of providing more flexible options to study participants, the FDA updated its requirements for patients receiving investigational products via infusion at the clinical trial site who wish to switch to home infusion. In those cases, the FDA expects the sponsor to perform a risk assessment that, at a minimum, considers the product type, risks to the participant receiving the product as well as risks to the health care providers administering the product, and consideration of any risk mitigation strategies. After completion of the risk assessment, the FDA welcomes sponsors to discuss with the Agency any plans to administer investigational products outside of a health care setting. Note that consultation with the FDA is strongly advised for complex investigational products prior to moving to an alternative site.
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