In the White House coronavirus updates, President Trump has commended FDA for working “around the clock” to expedite the review of new medical products to help with the testing and treatment of COVID-19. This is not puffery, as we at HP&M have experienced lightning fast feedback from FDA staff on Emergency Use Authorizations and expanded access and research protocols (for more information on EUAs in response to COVID-19, see recent posts here and here).
At the same time as conducting this important review work, FDA must also manage the challenges that the COVID-19 pandemic presents to the conduct of clinical trials for every other disease and condition. Just 8 business days after releasing the original guidance on this, FDA provided an update by adding a Q&A section as an appendix. In these 10 responses to commonly asked questions, FDA builds on the core set of considerations and recommended actions that the Agency provided in the body of the original guidance. In this post, we summarize this new Appendix. We recommend first reading our summary the original guidance, which remains unchanged (available here).
The new Q&A portion covers a number of topics important to many sponsors. It first lays out decision-making considerations for two of the largest decisions sponsors must make as a result of this pandemic: (1) whether to continue the study and (2) whether continue administering the investigational product. Other Q&A’s address managing protocol deviations and amendments, helping navigate a number of contingency measures (e.g., initiating virtual visits, switching to home delivery or infusion of the investigational product, alternative monitoring), and documenting informed consent from a patient in isolation.
Deciding Whether to Suspend or Continue an Ongoing Study (or Initiate a New One)
Every clinical trial depends upon an assessment of the participants’ safety and welfare. In the updated guidance, FDA discusses specific factors for sponsors to consider when deciding how or whether to proceed with a trial during the COVID-19 pandemic:
- Limitations on the protocol that pose new safety risks on participants, feasibility of risk mitigation
- Availability of clinical investigators to provide oversight and assess/manage safety issues
- Sufficiency of clinical trial support staff; adequacy of equipment and materials
- Ability to conduct assessments (in-person at site or alternative site or virtually)
- Availability of clinical trial supplies and continued operation of vendors, especially related to the investigational product (and whether product stability will accommodate revised schedules)
- Availability of, and support for, IT systems and other technology needed, feasibility of contingency to minimize potential disruptions
- Continued operations of IRB/IEC and DMC staff, if applicable
- Feasibility given Federal and State public health measures/controls
FDA recommends involvement of the study’s safety monitoring committee, if established, to aid in supporting these assessments given their responsibility to assure the safety of participants.
FDA notes that the decision to start a trial presents different risks and benefits than continuing one, stating that (other than trials of products intended for COVID-19-related uses) sponsors of new studies need to be able to assure patient safety and trial integrity. Furthermore, sponsors of new studies should consider whether the trial could interfere with public health measure (e.g., social distancing) implemented by Federal and State authorities to control the virus.
Deciding Whether to Continue Administering the Investigational Product (to All or Some Participants)
In the decision to continue administering or using the product, assuming availability of the product and ability to administer and assure safe use, FDA recommends that sponsors consider the following:
- Participant benefit from treatment
- Availability of reasonable alternative treatments
- Seriousness of the disease being treated
- Risks involved in switching to an alternative treatment if necessary
A decision to discontinue administer need not be universal to all study participants. Where discontinuation would present substantial risk to certain participants, including because the investigator perceives them as benefitting clinically, then the sponsor can consider amending the protocol to include only those patients with apparent benefit and discontinue the others. Before doing so, the guidance states that sponsors should discuss this with the relevant review division.
FDA acknowledges there are situations where discontinuation of product may be necessary, including due to lack of product supply or inability to administer or ensure safe use. In any case where administration is discontinued, it is important to provide appropriate management after.
Capturing Protocol Deviations
As discussed in the main body of the guidance (and discussed in our previous post), sponsors should be documenting the specific deviations and reasons that result from the impacts of the COVID-19 pandemic. While typically deviations are captured individually, when large numbers of deviations are systematically experienced (e.g., all visits are being conducted remotely rather than at the site), these can be documented collectively with a listing of all study visits that experienced that deviation.
As noted in the main body of the guidance, it is important to capture specific information for individual participants that explains the basis for missing protocol-specified information, including the relationship to COVID-19 (e.g., missed study visits or discontinuations due to COVID-19-related closure of a clinical study site). This information should be captured in the case report form, or similar systematic process. Processes should be developed to capture site-level status, site- or vendor-level protocol deviations, and process deviations. COVID-19-related deviations should be summarized in the clinical study report.
Managing Protocol Amendments
FDA reminds sponsors of the regulatory threshold for when a particular decision necessitates a protocol amendment (21 CFR 312.30(b)), which is:
- For a change that significantly affects the safety of subjects
- For Phase 2 and 3 studies only, a change that significantly affects the scope of the investigation or the scientific quality of the study
To help interpret this regulation, FDA notes that protocol amendments are not required for when pausing enrollment to decrease potential exposure to COVID-19. In addition, a protocol amendment is not required for every individual modification unless required to prevent imminent safety risk to patients; instead, several protocol modifications can be consolidated. However, any modifications to protocol-specified procedures that occur prior to an amendment implementing that modification must be documented as a protocol deviation
For studies under an IDE, FDA recognizes that given the unique and evolving circumstances surrounding the impact of COVID-19, it may be challenging to submit 5-day Notices when implementing changes that are exempt from prior FDA approval (21 CFR 812.35(a)(3)). The guidance allows sponsors to instead consolidate implemented changes as long as the IDE is updated as soon as possible.
The guidance also recommends clearly identifying cover letters to accompany COVID-19-related protocol amendments under INDs and IDEs by adding to the subject line: PROTOCOL AMENDMENT – COVID-19.
Evaluating Contingency Measures: Virtual Visits & Home Delivery/Infusion & Off-Site Monitoring
All protocols should be evaluated periodically to consider whether modifications to the protocol could help ensure the safety of participants. The guidance provides greater granularity into FDA’s current thinking about contingency measures specific to avoiding the risk of exposure to COVID-19.
- Virtual Visits. Conducting telephone or video contact visits for safety monitoring rather than on-site visits can be immediately implemented with subsequent review by the IRB and notification to FDA. These reflect protocol deviations (until the amendment is approved), so need to be documented as previously described. Since this change would likely result in some protocol-required procedures not being conducted (e.g., vital signs, blood samples for safety laboratory values), the sponsor must assess the potential impact on patient safety, considering how to mitigate risks or even the need to discontinue the investigational product.
- Home Delivery. For products that are self-administered at home, home delivery, if it does not raise any new safety risks, may be implemented to protect patients from coming to clinical trial sites. Applicable FDA regulations for maintaining required storage conditions and product accountability remain. If the protocol indicates pharmacy dispensing, then a protocol amendment is required to change to direct-to-patient shipments.
- Home Infusion. For products infused at the clinical trial site, alternative sites for administration (e.g., home nursing or alternative sites by trained by non-study personnel) should be considered and discussed with the appropriate FDA review division, particularly where altered storage or handling conditions could adversely affect product stability (e.g., cell and gene therapies). Applicable FDA regulations for maintaining required storage conditions and product accountability remain. If suitable alternative arrangements cannot be made, sponsors should define circumstances when discontinuing product treatment, while continuing study participation even if with delayed assessments.
- Off-Site Monitoring. Recognizing that monitors may not be able to access trial sites for on-site visits in a timely manner during the pandemic, sponsors should work to find alternative approaches (e.g., enhanced central monitoring; telephone contact with sites to review study procedures, participant status, and study progress; or remote monitoring of individual participants). Sponsors should carefully document situations where monitors were unable to access, or had to delay, monitoring of a site. Sponsors should also document whether protocol deviations or other GCP non-compliance issues were delayed in being identified due to this. FDA recognizes the unique situations will occur at sites due to COVID-19 control measures and states it will consider these when evaluating inspection observations.
Obtaining Informed Consent from a Patient is in Isolation from COVID-19 Infection
While FDA regulations generally require that informed consent of a participant be document by use of a written form approved by the IRB and signed and dated by the subject (or their legally authorized representative) at the time of consent, the guidance identifies alternative ways to satisfy the documentation requirement if the patient is in COVID-19 isolation. First, if technology is available, electronic methods should be considered. When not possible to obtain it electronically, the guidance details a procedure where an unsigned consent form is provided to patients and, by direct communication or telephone/videoconference, verbal confirmation of consent is obtained and that the form in their possession is signed and dated. Documentation procedures are provided as well.