FDA’s COVID-19 Pandemic Plan Calls For Ongoing Clinical Trial Innovation

Source : 'The Pink Sheet'

A continued focus on innovation in clinical trials is among the steps the US Food and Drug Administration could take to improve its response to the COVID-19 pandemic and future public health emergencies, a report commissioned by the agency concludes.

The recommendations are included in FDA’s COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) summary report, which notes that trial sponsors are eager to understand how FDA will guide clinical trial conduct through the remainder of the pandemic and beyond. It says FDA could communicate what elements of the current guidance on clinical trial conduct will remain in effect following the public health emergency.

FDA issued the guidance in March and has updated it several times since then. ()

“Continuing to add to the Q&A section content that clarifies how FDA will treat data that suffered a measure of ‘interruption’ during the pandemic would also provide welcome clarity while sponsors await publication of formal guidance on the topic,” the report says.

“Interrupted” trials are a large worry for the agency, with CBER Director Peter Marks comparing the scope of the disruption to a hurricane. ()

FDA has emphasized it will be flexible in handling the disjointed data that has been collected during the pandemic. However, the techniques that the agency will likely employ have already been met with a far bit of skepticism from outside experts, suggesting products that experienced such clinical troubles could face reimbursement challenges even if they make it through FDA on the first round. ()

Another worry for industry is that FDA may respond to the pandemic by encouraging a more top-down approach to trial design that could use master protocols to generate faster results – just not necessarily to the clinical questions that sponsors wanted answered. ()

The report suggests that FDA conduct a pilot study after the public health emergency to measure whether innovations and flexibilities used during the pandemic increased patient enrollment, diversity of patient populations, and patient retention. It also suggests that FDA publish a specific plan that covers a range of activities FDA will undertake at the end of the public health emergency, to foster continued innovation in clinical trial conduct and specifying a measure that captures the extent of adoption of new trial execution approaches, such as the percentage of protocols that incorporate novel elements.

As a longer-term priority, the report says, “FDA could use the COVID-19 experience as a catalyst to define a broader agency-wide approach to encouraging sustained innovation in clinical trial conduct.” To achieve this, the report says FDA could focus sponsor engagement activities (either through public meetings or a dedicated consortium-driven approach) to better understand barriers to adoption of innovative trial approaches and identify “next-horizon” innovations, some of which will likely be therapeutic area-specific.

During the pandemic, FDA has evaluated nearly 400 COVID-19 therapeutic candidates, published more than 65 industry guidance documents, reviewed more than 2,300 emergency use authorization requests and issued over 600 EUAs for medical countermeasures to combat COVID-19, including EUAs for eight therapeutics and two vaccines, and approved one drug, Gilead Sciences, Inc.’s Veklury (remdesivir), the report noted.

The Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research are working individually with sponsors to determine appropriate review approaches. CDER has established checklists for sponsors to indicate critical application components to prioritize for preparation, and implemented cross-functional task forces to address key review issues, such as those related to technology transfers.

The report says external stakeholders who participated in the PREPP listening sessions asked that the agency continue to clarify the review approaches it intends to use for vaccines, therapeutics, diagnostics and devices. In particular they want clarity on whether and where the agency plans to use formal expedited review programs, rolling and real-time review approaches, and the range of potential review timelines. FDA could continue to communicate these review plans to sponsors individually on a case-by-case or product class basis and/or through policy guidances, the report says.

Stakeholders also expressed appreciation for FDA’s interactive engagement with innovators and industry, as it has  allowed industry to accelerate product development timelines. The report says FDA could consider strengthening ties with external stakeholder groups and designate FDA points of contact to improve rapid two-way coordination and build pandemic preparedness.

Another area of focus in the report is real-world monitoring of COVID-19 products. It notes that FDA’s Sentinel initiative has carried out 20 discrete COVID-19 studies to date, including an analysis of the disease’s natural history. It also aims to address the critical evidence gap in the use of anticoagulant therapy during in-patient treatment of COVID-19.

The report recommends that FDA define a framework for post-authorization and post-market surveillance and monitoring of COVID-19 vaccines and therapeutics “to articulate specific cases for application of RWD [real-world data] in assessing questions related to the real-world use, safety and efficacy of these products.”

The framework could also define opportunities to incorporate extramural research, possibly in coordination with other agencies, to study the long-term health effects of COVID-19, the report says.

The agency began the PREPP initiative in April 2020, with a formal launch in August, to evaluate its regulatory actions, operations, crisis communications and inter-agency partnerships and identify ways to optimize its response to the pandemic. 

“The potential actions reflect lessons learned from the response so far and serve as a basis for continued learning and progress through and beyond the current pandemic,” FDA Commissioner Stephen Hahn and Deputy Commissioner for Medical and Scientific Affairs Anand Shah write in the forward to the report.

They note that the ideas in the report are not exhaustive or binding. The next step is for agency leadership to deliberate whether and how FDA will proceed with the potential actions or other alternative approaches.

A retrospective assessment of the agency’s response to the pandemic is ongoing and not part of this report.

Issued on 13 January, the report was based on interviews with more than 70 FDA leaders and more than 50 FDA subject-matter experts, as well as listening sessions with seven external stakeholder groups, including the Pharmaceutical Research and Manufacturers of America, Biotechnology Innovation Organization, and the American Association of Medical Colleges.

The report was released ahead of Shah's departure from the agency. The head of the PREPP initiative, he tendered his resignation on 11 January and will depart  around the time of President-elect Biden's inauguration next week. ()

The report notes that implementation of these recommendations may require changes to FDA’s statutory authorities, increased personnel capacity, new funding, and mutual prioritization by other US government agencies.

The report also cites the risks and feasibility of implementing these proposed actions, noting the demands the pandemic has placed on the FDA workforce. For example, CDER and CBER have managed a 33% increase in the volume of commercial IND applications in 2020 compared to the previous year.

“In this context, the agency should carefully consider the implications of any potential actions on personnel well-being, workload, and resilience,” the report states. FDA could continue policies encouraging telework and caregiver flexibility, and address capacity shortages through temporary personnel details, it concludes.

By Brenda Sandburg