The race to develop new therapies and test existing products for activity against COVID-19 is all encompassing. In the US, the National Institutes of Health and the FDA have assembled teams to rapidly test promising drug candidates, and to ensure expedited reviews, respectively. FDA officials have described “around the clock” working hours dedicated to helping trial sponsors navigate a clinical landscape pockmarked with procedural challenges.
Basic trial processes, such as informed consent, trial monitoring, product availability and IRB review, for example, are hindered by social distancing and exposure risks. For regulators, the overwhelming priority is COVID-19, and many large biopharmaceutical companies – including Eli Lilly & Co., Amgen Inc., Bristol-Myers Squibb Co. and Pfizer Inc. – announced plans to delay or halt trial enrollment for patients without life-threatening conditions, or in geographies where trial disruptions are likely to jeopardize clinical results.
Despite the urgency behind potential treatments for COVID-19, it is of course not the only deadly or debilitating disease in circulation. While it may not be the wisest of times to kick off new patient enrollment into large multi-site trials for type 2 diabetes or rheumatoid arthritis, biopharmaceutical companies with new or ongoing studies targeting rare or critical unmet needs risk leaving patients (and investors) in the lurch by ending trials unnecessarily. To that end, the FDA published updated guidance on 16 April for conducting clinical trials during the COVID-19 public health emergency. Protecting patient safety is the agency’s chief concern, according to the guidance, which includes several provisions that trial sponsors can use to support good clinical practices, even when clinicians, investigators and patients cannot meet face to face.
Impact On Cell And Gene Therapy Trials
Tejashri Purohit-Sheth, director, Division of Clinical Evaluation and Pharmacology/Toxicology at the FDA’s Office of Tissue and Advanced Therapies, discussed several important considerations for sponsors conducting gene and cell therapy trials during a webcast hosted by the Alliance for Regenerative Medicine, an international advocacy organization focused on tissue engineering. Unlike orally formulated products that can be mailed directly to the homes of trial participants, gene and cell therapies require hands-on administration, often including apheresis – a process that cannot be completed by an offsite physician with videoconferencing. “For efficacy assessments, adhering to strict time periods are necessary, especially for our products,” said Purohit-Sheth. “Laboratory and diagnostic products will be impacted as well, and it may be challenging for staff to conduct monitoring.” Additionally, altered storage and handling could impact gene and cell therapy product stability, Purohit-Sheth said.
Before commencing a new cell or gene therapy trial, or continuing an ongoing trial, sponsors should ask themselves three key questions, according to Purohit-Sheth:
Will you be able to adhere to the trial protocols?
Will you be able to administer the investigational product?
Will patients be able to come to the trial site?
Purohit-Sheth noted the FDA’s creation of a Coronavirus Treatment Acceleration Program (CTAP), a team capable of providing 24-hour review of trial protocol and other expedited services for COVID-19 drug sponsors, but said that the FDA’s Office of Tissue and Advanced Therapies had not be granted any additional resources.
Asked about timelines for gene and cell therapy protocol reviews, Purohit-Sheth said that for non-COVID-19 products, the FDA is reviewing them in accordance with PDUFA timelines. Product reviews without PDUFA deadlines may be delayed due to the focus on COVID-19 products. “We are trying our best to juggle numerous competing priorities, and are meeting every day to address inquiries as fast as possible for pre-INDs and INDs,” she said
FDA Flexibility During Pandemic
The FDA’s updated guidance provides a number of options for trial sponsors that deviate from standard compliance practices, with the goal of moving research forward while also protecting patients and medical staff. While the agency encourages sponsors to implement alternative processes when necessary, it recommends consistency with the original protocol whenever possible. Overall, the FDA aims to avoid penalizing companies for modifying protocols on the basis of protecting patients. To that end, sponsors may use alternative communication channels, such virtual visits, or alternative locations for assessment, such as local labs or imaging centers not previously affiliated with a trial.
Typically, changes to a trial protocol cannot be implemented until an institutional review board (IRB) or institutional ethics committee (IEC), or the FDA, approves the changes. During the pandemic, however, protocol changes aimed at protecting the life and well-being of research participants – such as limiting exposure to the virus, for example – can proceed without IRB approval or study amendment, as long as the changes are reported afterward. Sponsors are encouraged to document how COVID-19 created a need for protocol changes, what changes occurred, and how trial participants were impacted, according to the guidance. Study amendments dealing only with COVID-19 protective measures are not required.
With respect to monitoring, a similar process is acceptable. For example, sponsors wishing to use virtual trial visits in lieu of on-site visits to avoid potential coronavirus infection risks may do so, with the requirement that IRB review and FDA notification proceed afterward. Informed consent, too, received additional flexibility as described in the FDA guidance. For patients in COVID-19 isolation, electronic signatures are permissible. Investigators have the option of using a three-way telephone call or video conference to communicate with a patient, and an impartial witness, in order to secure informed consent. With respect to documenting informed consent in such situations, the FDA will allow a dated attestation by the witness and investigator confirming that the patient agree to participate in a study and signed the informed consent. A photograph of the informed consent document, with attestation from the individual entering the photograph into the study record is also acceptable.
In the case of site closures, patients may receive an infused product at an alternative location, as long as the local health care provider has the appropriate training, and is administering a drug in a way that mirrors his or her normal clinical practice. However, if a local provider is performing study-specific research procedures or assessments that contribute to the study’s clinical data set, the provider would need to be classified as a sub-investigator in relevant submission materials.
Document And Communicate
The importance of documenting protocol changes, and communicating as often as possible with FDA officials, is emphasized throughout the FDA’s guidance document. Sponsors developing new gene and cell therapies in particular are encouraged to engage with FDA’s regulatory project management staff often. That may require additional persistence: the FDA’s Office of Tissue and Advanced Therapies is reviewing over 800 active INDs, and may face additional inquiries as parts of the US begin to relax coronavirus precautions. For now, the division has currently “paused almost all of our inspections … and we are taking things as they evolve to see what we can resume, or not, and we are considering other approaches,” said Purohit-Sheth. “Once something has been determined, FDA will communicate that.”
As coronavirus infections lessen, clinical trial sponsors will need to maintain meticulous records of changes initiated during a constantly changing period. “At the end of the day, if a trial is going to be completed, in part during the pandemic, we really need to be able to evaluate how these protocol modifications and deviations impact the ability to analyze the data collected, and to support safety and efficacy,” Purohit-Sheth said.
Additional reporting by Maire Gerrard