Introduction
Many sectors of the economy have ground to a halt in the effort to curtail the COVID-19 pandemic (the “Pandemic”), and the clinical research industry is not immune to the effects of these business shutdowns. While the Pandemic has suspended more than 440 clinical trials, affecting as many as 200,000 people, many clinical trial sponsors, investigators and institutional review boards ("IRBs") are left with tough questions and decisions regarding the continuity or adaptation of the investigations they are funding and/or overseeing. As citizens move through the most restrictive phase of stay-at-home orders towards “safer at home” guidelines and “soft re-openings” of businesses and cities, the long-term effects of the Pandemic on clinical trials are not yet fully understood.
Acknowledging this reality, the Food and Drug Administration (“FDA”) released a guidance document entitled, “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency” (the “Guidance”) for the clinical research industry, investigators, and IRBs, and continues to provide regular updates. The Guidance aims to assist sponsors in making decisions that assure the safety of trial participants, maintain compliance with good clinical practice (“GCP”), and minimize risks to trial integrity during the Pandemic. While the Guidance contains non-binding recommendations only, it presents considerations for sponsors, investigators, and IRBs in deciding whether and how to move clinical trials forward, including amending protocols to permit remote or decentralized conduct, and creating or amending existing policies to address social distancing guidelines and state and local stay-at-home orders. Many in the industry are seeking to implement sustainable alternatives to in-person visits and administration of clinical protocols. As of the date of this writing, the Guidance was most recently updated on Thursday, April 16, 2020, to answer new frequently asked questions (“FAQs”) from sponsors and investigators, discussed below.
Discussion
The Guidance contains many insightful questions and potentially helpful recommendations. While a full read-through is encouraged to help understand if any such recommendations apply to a particular scenario, a sampling of relevant FAQs presented to FDA, and its resulting recommendations, are summarized below:
What key factors should sponsors consider when deciding whether to continue administering or using an investigational product that appears to be providing benefit to the trial participant during the COVID-19 public health emergency?
Per the Guidance, a sponsor deciding whether to continue administering or using such a product during the Pandemic should carefully consider whether a trial participant appears to be benefitting from treatment with the investigational product, whether there are reasonable alternative treatments, the seriousness of the disease or condition being treated, and the risks involved in switching to an alternative treatment (if necessary). If there are individual trial participants for whom discontinuing the investigational product might present a substantial risk, then the sponsor should consider amending the protocol (after discussion with the relevant review division) to limit investigational product use to those trial participants with apparent benefit and discontinue investigational product use to other participants. In all cases, if a trial participant is discontinued from an investigational therapy, it is important that there be appropriate management of the trial participant after discontinuation.
Can a sponsor initiate virtual clinical trial visits for monitoring patients without contacting FDA if there is an assessment by the sponsor and investigator that these visits are necessary for the safety of the trial participant and it will not impact data integrity?
Per the Guidance, FDA regulations allow for changes to be made to the investigational plan or protocol without prior FDA review or approval, if the change is intended to eliminate an apparent immediate hazard or to protect the life and well-being of trial participants. Therefore, changes in the investigational plan or protocol conduct necessary to immediately assure trial participant and clinical investigator safety, such as 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. Since this reflects a protocol deviation (until the amendment is approved), documentation of the required deviations, as described above, would generally be acceptable (i.e., a document that lists each deviation, study reference ID, patient ID, and date). For example, documenting that all protocol-specified visits will be done by telephone contact rather than on-site visits, and that procedures requiring in-person visits will either not be conducted, or performed by other means (specified, as appropriate). Since the change to telephone or video contact visits would likely result in some protocol-required procedures not being conducted, the sponsor must evaluate the potential impact on trial participant safety and consider how to mitigate risks to trial participants and clinical investigators, including the need to discontinue the investigational product.
How do I obtain informed consent from a patient unable to travel to a clinical trial site where electronic informed consent is not an option?
Per the Guidance, when investigators do not have electronic informed consent capabilities, methods of obtaining informed consent other than a face-to-face consent interview may still be acceptable if those methods allow for an adequate exchange of information and documentation, and a method to ensure that the signer of the consent form is the person who plans to enroll as a subject in the clinical investigation or is the legally authorized representative of the subject. For example, the consent form may be sent to the trial participant or the trial participant’s legally authorized representative by facsimile or e-mail, and the consent interview may then be conducted by telephone when the trial participant or trial participant’s legally authorized representative can read the consent form during the discussion. Alternatively, the trial participant may bring the signed and dated consent form to his/her next visit to the clinical site, if restrictions on traveling to the clinical trial site are alleviated, or mail it to the clinical investigator.
I am a study monitor and am unable to conduct on-site monitoring visits due to the COVID-19 public health emergency. May I remotely perform the site monitoring visit? What recommendations does FDA have for how I can remotely perform source document review?
Per the Guidance, FDA regulations do not prescribe how sponsors must conduct clinical monitoring and are therefore compatible with a range of approaches to monitoring that may vary depending on multiple factors. Therefore, certain aspects of site monitoring visits may be done remotely if technically feasible. FDA understands that there may be deviations from the timing of on-site monitoring visits set forth in the trial monitoring plan and procedures, and that sponsors may consider ways to replace on-site monitoring visits with remote monitoring visits during the Pandemic. Further, there may be components of an on-site monitoring visit, as outlined in the trial monitoring plan, that cannot be completed remotely. The sponsor should therefore consider using a risk-based approach to prioritize sites for remote monitoring, including as many study sites as feasible (and with a frequency as close to that described in the site monitoring plan as feasible).
The decision regarding which sites to prioritize for remote monitoring should be guided by centralized monitoring or other information available about site performance (e.g., frequency and severity of protocol deviations previously identified during monitoring visits or currently identified by centralized monitoring, number of randomized active trial participants, experience of site staff, known history of prior major audit or inspection findings). During remote monitoring, the study monitor should focus on trial activities that are essential to the safety of trial participants, clinical investigators and data reliability. Remote monitoring activities, including remote review of source documents, should be documented in the same level of detail as on-site monitoring activities, and any resulting actions to address issues identified from the remote source document review should be consistent with procedures and processes described in the study monitoring plan.
Conclusion
Notwithstanding these challenging and uncertain times, clinical research stakeholders are collaborating and innovating to try to ensure new or improved therapeutics continue to be developed in areas of unmet need. In response, FDA is attempting to provide timely recommendations to sponsors, investigators and IRBs for the adaptation of clinical trials during the Pandemic on a regular basis. Ultimately, FDA remains interested in securing and maintaining (1) the safety of trial participants, and (2) the clinical and statistical integrity of the trial.
Not surprisingly, many of the recommendations are highly fact-specific and dependent upon the nature and context of a particular clinical trial. Accordingly, sponsors, investigators and IRBs that are facing these types of decisions regarding whether and how to continue or adapt a clinical trial should consider reading the Guidance fully and consulting with the overseeing IRB and/or FDA, or other clinical, regulatory, and legal advisors, as appropriate. We will continue to monitor FDA guidance as it becomes available, so please check back for future updates on this topic.
Footnotes:
- https://www.npr.org/sections/health-shots/2020/04/11/832210606/coronovirus-pandemic-brings-hundreds-of-u-s-clinical-trials-to-a-halt
- See 21 CFR 56.108(a)(4), 312.30(b)(2)(ii), and 812.35(a)(2)
- See 21 CFR 312.50, 312.53(d), 312.56(a), 812.40, 812.43(d), and 812.46
- “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency,” at 19-20
