Revising Our Regulatory Approach To Oral Antivirals For COVID-19

The Food and Drug Administration (FDA) continues to face scrutiny over the timeline for an emergency use authorization for both a COVID-19 vaccine for children younger than age 12, and a vaccine booster for certain members of the population, such as the elderly and immunocompromised. Furthermore, regulatory uncertainty has been compounded by the challenge of ensuring and distributing an adequate supply of vaccines to the rest of the world. While wealthy nations have seen disproportionate access to vaccine stocks, many other countries have seen less than 5 percent of their populations vaccinated. Although monoclonal antibodies have been available as an intravenous treatment for symptomatic infection, accessibility to date has been limited.

In the interim, oral antivirals could serve as an outpatient treatment for symptomatic COVID-19 infection, post-exposure prophylaxis, and as a therapeutic alternative for individuals unable to receive the vaccine due to medical comorbidities. More than 50 COVID-19 antivirals are under development or in clinical trials. On October 1, Merck reports that its oral antiviral halved the risk of hospitalization among unvaccinated patients with COVID-19; Pfizer initiated pivotal trials of its own oral antiviral in September 2021. However, trials largely have been running at a glacial pace, and it is likely that the traditional FDA review timeline, including emergency use authorization, will further delay commercialization of these therapeutics. Furthermore, demand for outpatient oral antivirals has also led to widespread off-label—and potentially dangerous—use of therapeutics that haven’t been adequately tested in the context of COVID-19, including hydroxychloroquine and ivermectin. Given the pace of new infections, the concern for future COVID-19 variants, and the relative ease of both production and distribution of oral antiviral drugs relative to vaccines, revising the FDA review process for oral antivirals may improve our pharmaceutical approach against COVID-19.

Here, we review the current accelerated regulatory review programs available for COVID-19 drug development, including the Coronavirus Treatment Acceleration Program (CTAP). We propose adapting two elements of the Real-Time Oncology Review (RTOR) pilot program—established by the FDA’s Oncology Center of Excellence (OCE) in 2018 to accelerate the review of supplemental applications for cancer therapeutics—to CTAP. The adoption of these proposed elements can be achieved with the publication of additional guidance by the FDA without requiring additional legislative approval by other federal government agencies. We also highlight the regulatory requirements that drug sponsors should be aware of for rapid review and scale-up of COVID-19 treatments without compromising standards for approval.

Accelerated Regulatory Review Programs

There are more than 50 ways for a drug or biological product to obtain regulatory approval and market access in the U.S. The primary vehicle for FDA review of new molecular entities or indications (non-biologics) involves the submission of a New Drug Application (NDA), which follows clinical trial testing in humans that typically involves three main phases: Phase 1 to assess safety and establish acceptable drug dosing values, Phase 2 to further assess safety and preliminary efficacy, and Phase 3 to establish efficacy and safety in larger patient populations. For biological products regulated under 21 CFR 601 (for example, virus, serum, antibodies), the primary vehicle of FDA review involves the submission of a Biologics License Application (BLA), which proceeds pre-marketing clinical trials in humans that also typically involve three phases: Phase 1 to assess safety and immunogenicity, Phase 2 for dose-ranging, and Phase 3 for large-scale safety and efficacy studies. The use of an NDA or BLA to request FDA approval is expensive and time consuming, requiring a median total review time of 8–10 months. In addition, numerous expedited regulatory programs and emergency methods exist to accelerate the drug approval process for serious diseases or public health emergencies such as COVID-19.

The development or review acceleration mechanisms that companies and sponsors have primarily considered to date for COVID-19 therapeutic development are outlined in exhibit 1. Importantly, these programs, including RTOR, only change the timeline for development and FDA review, and are distinct from programs that change standards for approval, such as the Accelerated Approval program.

In April 2020, the FDA launched a new accelerated regulatory measure entitled the Coronavirus Treatment Acceleration Program (CTAP) that uses “every available method” to accelerate COVID-19-related therapy review, borrowing elements from a number of the expedited programs described in exhibit 1 (for example, Fast-Track Designation’s rolling review). At a high level, the FDA promises response and review of protocols within one day, “ultra-rapid, interactive input” on sponsors’ development plans and completed review of single patient expanded access requests within three hours, at any time of day.

Exhibit 1: Expedited review pathways and review acceleration mechanisms

Name	Nature of Pathway	Effect	Qualification Criteria	Application to COVID-19
Breakthrough Therapy Designation (BTD)	Review designation	Allows for rolling review (submission of NDA section by section rather than after final completion), FDA guidance and coordination, and all benefits of Fast-Track Designation.	Medical products intended to treat a serious condition with evidence for substantial improvement over existing therapies.	All COVID-19 therapeutics are expected to receive BTD.
Fast-Track Designation (FTD)	Review designation	Allows for rolling review, more frequent meetings with FDA.	Drugs that treat a serious condition and demonstrate potential to address unmet medical need OR designated qualified infectious disease products.	All COVID-19 therapeutics are expected to receive FTD.
Priority Review Designation (PRD)	Review designation	Acceleration mechanism that generally shortens review time from 10-12 months to 6-8 months	Medical products that treat a serious condition, provide significant improvement in safety or efficacy, and have supporting data to justify a priority review OR designated qualified infectious disease products.	Many COVID-19 therapeutics will likely receive PRD, which is commonly used with FTD.
Coronavirus Treatment Acceleration Program (CTAP)	Expedited approval pathway	Allows accelerated review via rolling review, frequent FDA input, review of clinical protocols within 24 hours, review of single patient expanded access requests within 3 hours.	All therapies intended to treat, cure, or prevent COVID-19.	All COVID-19 therapeutics are expected to enter CTAP.
Real-Time Oncology Review Program (RTOR)	Expedited approval pathway	Allows accelerated review via real-time pre-submission (raw) data review and continuous (non-scheduled) conversational feedback between FDA and sponsor.	New molecular entities or supplemental applications for drugs with straightforward trial designs and easily interpretable endpoints.	Features of RTOR, including real-time pre-submission review and non-scheduled FDA-sponsor communication, may be adapted into CTAP.

Source: Food and Drug Administration. Home page on the Internet. Silver Spring (MD): FDA; [cited 2021 Oct 13].

The Real-Time Oncology Review Program

RTOR was initially established by the FDA’s OCE in 2018 to accelerate the review of supplemental applications for cancer therapeutics; however, its scope has since expanded to include new drug candidates. Akin to the rolling review process in the Fast-Track and Breakthrough Therapy pathways, RTOR allows the FDA to review portions of NDA and BLA data before an applicant submits a complete application. However, for RTOR applications, the agency may additionally offer immediate, ad hoc feedback to the sponsor on data quality and regulatory issues, pinpointing areas for focused review and improvement early. Importantly, the RTOR program offers expedited review of applications but does not modify the standard for approval of drug candidates.

Both the real-time review process and nature of continuous communication built into the RTOR pilot program may prove to be useful additions to CTAP for faster review of COVID-19 therapeutic candidates approaching pivotal trials. This will require trial sponsors to understand the RTOR submission timeline, package clinical study reports for early submission, and be wary of the need to respond to FDA correspondence immediately.

1. Real-Time Review Process

First, the FDA adjudicates top-line data from the applicant to determine whether RTOR is the appropriate review process for the submission. If RTOR is deemed appropriate, the applicant may request FDA approval and begin sending pre-submission data to the agency between two and four weeks after all patient data has been entered and locked in the applicant’s database. The FDA will start evaluating pre-submitted data for sufficiency and integrity, offering the possibility for the agency to propose a pre-submission timeline (exhibit 2) and communicate key needs or concerns early in the review process. The FDA typically evaluates an NDA or BLA for 60 days prior to accepting it for review; the real-time review and iterative back and forth between sponsor and the agency minimizes this period.

Exhibit 2: Current FDA Real-Time Oncology Review program timeline

Source: Food and Drug Administration. Home page on the Internet. Silver Spring (MD): FDA; [cited 2021 Oct 13].

Notes: OCE is Oncology Center of Excellence. NDA is New Drug Application. BLA is Biologics License Application. SAP is Statistical Analysis Plan.

Current submission criteria for RTOR include oncology drugs likely to demonstrate substantial improvements over currently available therapies undergoing a straightforward study design with an easily interpretable endpoint, such as overall survival or progression-free survival. More complex submissions will be considered for RTOR on a case-by-case basis at the discretion of the OCE. In July 2018, a supplemental NDA for the drug ribociclib (Kisqali) was completed in 20 days following formal submission. Similarly, in early May 2019, a supplemental BLA for Kadcyla (trastuzumab emtansine) was approved 12 weeks after submission. Later that month, the first new molecular entity to go through RTOR, alpelisib (Piqray), was approved in combination with fulvestrant to treat men and post-menopausal women with a certain type of advanced or metastatic breast cancer (as detected by an FDA-approved test) following progression on or after an endocrine-based regimen. The companion diagnostic was approved in tandem. These early examples of the RTOR program highlight the scope of drug application approvals and their fast review timelines. As such, incorporating this rolling real-time review process into CTAP may further reduce the time needed to evaluate novel COVID-19 therapeutics at a time where speed is critical.

This rolling, real-time review process from RTOR can be directly incorporated into updated FDA guidance for CTAP. The discretion to make these updates lies with the FDA and does not require issuance of additional regulations per the rulemaking process to the Federal Register for review by the Department of Health and Human Services or other governmental agencies.

2. Continuous Communication

RTOR was initially designed for the rapid review of supplemental filings with straightforward trial designs for supplemental NDAs. By contrast, although many COVID-19 therapeutics under investigation are repurposed drugs, novel therapeutics will require new filings. Furthermore, given the range of disease severity, many COVID-19 therapeutics may have complex trial designs with surrogate endpoints, as well as new chemistry, manufacturing, and controls information, which traditionally would disqualify an application from RTOR. These differences between prior RTOR drugs and COVID-19 treatments may lengthen the typical RTOR timeline experienced by oncology therapeutics sponsors. Additionally, sponsors will need to account for the timeline required to rapidly establish scalable manufacturing processes, which presents additional financial and regulatory challenges. These challenges to rapid review would benefit from the second key element of RTOR, the continuous communication protocol between the FDA and drug sponsors throughout the pre-submission process.

Given the uncertainty in development of future variants and subsequent COVID-19 infection rate, companies that receive FDA approval for COVID-19 therapeutics may need to expand their production capacity, produce treatments in a new manufacturing facility, or change their production process altogether to improve yield. This may take the form of internal changes in manufacturing or partnerships with pharmaceutical firms with regional, specialized, or larger manufacturing and distribution capacity. All scale-up and post-approval changes require the sponsor to notify the FDA; some changes require deliberate FDA review and approval.

Fortunately, production scale and manufacturing process changes that do require FDA approval either involve rapid review or can be expedited in the event of a public health emergency. This makes the RTOR model both useful for COVID-19 drug development and in future FDA programs designed for pandemic preparedness and response.

Within this early, iterative communication, the FDA and drug sponsor can establish a timeline and discuss flexible approaches to the submission of chemistry, manufacturing, controls, and facility data, which would both help with the scheduling of timely pre-approval inspections and highlight any changes that could be addressed in post-approval commitments.

Conclusion

The emergence of COVID-19 variants, concern of waning immunity from vaccination, and geopolitical barriers to vaccine distribution have changed the nature of the pandemic. Oral antivirals may serve as a therapeutic bridge as we address challenges with vaccine access and durability. Adapting the RTOR model for evaluation of COVID-19 therapeutics, including RTOR’s real-time review process and continuous communication, would accelerate review and distribution of novel COVID-19 antivirals without compromising regulatory standards for approval. The adoption of these proposed elements can be achieved with the publication of additional guidance by the FDA without requiring additional legislative approval by other federal government agencies. Finally, adoption of RTOR elements to CTAP may serve as a test case for quickly establishing a rapid therapeutic response to future national health emergencies.

Authors’ Note

Nisarg Patel is employed by Bessemer Venture Partners, which invests in health care companies. The authors’ employers had no role in the preparation, review, or approval of this work and the decision to submit this work for publication. Thanks to Aaron S. Kesselheim, MD, JD, Brigham and Women’s Hospital/Harvard Medical School for his comments on earlier drafts.