More than 750,000 deaths have occurred worldwide as a result of the novel coronavirus as of August 2020. Clinicians have reported a range of physiological abnormalities in severely ill COVID-19 patients, including respiratory distress, severe immune reactions, and cardiac and vascular complications. Research also suggests that death rates are alarmingly high for patients requiring ventilator support, demonstrating the need for therapeutic interventions that can prevent the escalation of disease severity.
The Food and Drug Administration (FDA) has taken a number of steps to accelerate the development of COVID-19 therapeutics, from issuing guidance documents for product developers, to creating initatives to facilitate regulatory review. We also continue to engage in public-private partnerships that prioritize evaluating potential therapeutics and vaccines in clinical trials and leveraging real-world data to better understand the natural history of COVID-19 infection. In this blog, we summarize the therapeutic landscape for COVID-19, describe the agency’s initiatives to support development, and outline lessons learned for modernizing the clinical research enterprise.
Therapeutic Landscape For COVID-19
While new research to continues to add to our clinical understanding of COVID-19, potential therapeutic agents include:
- Antivirals: Drugs that inhibit the virus’s replication machinery, which might help halt the spread of the virus within an individual’s body to prevent the escalation of illness. Examples include drugs that interfere with viral entry or viral synthesis.
- Immunomodulators: Drugs that work to dampen the body’s natural immune response to infection, which when uncontrolled can cause fever and multi-organ failure. Potential examples include drugs for the treatment of certain autoimmune diseases or select cancers.
- Neutralizing Antibodies: These are derived biological products that may have a role in the prevention of infection or in the treatment of infection. Examples include monoclonal antibodies designed to target the receptor-binding domain on the SARS-CoV-2 spike protein.
- Other: Drugs and biological products spanning an array of therapeutic modalities for treating the virus. Examples include convalescent plasma, hyperimmune globulins, and cell and gene therapies.
Regulatory Support for Therapeutic Innovation
Each of the therapeutic approaches described above, if shown to be safe and effective, may offer distinct clinical benefit to COVID-19 patients. FDA is committed to supporting the development of COVID-19 therapies, and took steps beginning in March 2020 to focus regulatory resources on therapeutic innovation for the pandemic, including:
1. Regulatory Support for New Therapeutics
FDA launched the Coronavirus Treatment Acceleration Program (CTAP) in March 2020 to provide start-to-finish regulatory support for innovators developing COVID-19 therapies. CTAP exists independently of other government initiatives like Operation Warp Speed and does not include vaccines or diagnostics. All decisions about CTAP’s work and priorities are made with the same focus on scientific rigor (e.g., disease-specific considerations, statistical considerations) and follow the agency’s established legal and regulatory standards, with the agency issuing a specific guidance document on best practices for COVID-19 therapeutic development.
CTAP organized a scientific technical team of subject matter experts within FDA to triage incoming inquiries about therapeutics to ensure the completeness and sufficiency of the information provided by developers for review. We also charged the team with identifying the appropriate experts to provide contextual and relevant scientific support to prospective sponsors – for example, reviewing study protocols or suggesting the most appropriate regulatory submission process. This intra-agency coordination and interactive regulatory support has enabled FDA to meet regulatory milestones on an accelerated timeline, ultimately expediting the initiation of clinical trials for COVID-19 therapeutics. Progress is publicly-reported on the CTAP dashboard, which provides monthly updates on the status of the COVID-19 pipeline.
As of July 31, 2020, FDA has supported the initiation of more than 270 clinical trials, with over 570 additional investigational programs currently under review by the agency. The agency has significantly accelerated timelines for pre-Investigational New Drug (IND) application meetings (where sponsors may consult with FDA about proposed development progams) and IND reviews (where FDA works to ensure that appropriate safeguards for patients are in place prior to the initiation of clinical trials) for CTAP applicants as compared with usual processes. However, this has nearly doubled staff’s workload at the same time they continue working to keep pace with user fee goals — performance targets for the timeline of FDA review and action on applications from sponsors — for the review of non-COVID medical products. Ensuring that the agency is sufficiently resourced will be important to avoid staff burnout and ensure program sustainability.
2. Facilitating Expanded Access to Potential Therapies
During the pandemic, FDA has provided guidance on the use of expanded access for COVID-19 investigational therapies. A prominent example is convalescent plasma (CP), which is a potential therapeutic intervention that uses antibodies derived from the blood donated by patients who have already recovered from COVID-19 to potentially help treat newly infected patients. Expanded access is an alternative for use of CP for patients with serious or immediately life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials. This therapeutic approach has been studied in previous pandemics, including for the 2003 SARS outbreak. To accelerate access to CP, FDA partnered with the Mayo Clinic to create an expanded access program that has enabled more than 60,000 patients to receive CP infusions as of August 2020. To increase awareness about CP, FDA also set up a consumer-facing website with information about eligibility, enrollment, and donations. Analyses of existing data and ongoing studies of CP will clarify whether this therapy is safe and effective and might also provide insights for the efforts to develop a COVID-19 vaccine.
3. Flexibilities For Trial Conduct
While conducting clinical trials under normal circumstances is already a challenging endeavor, operating large-scale studies during a pandemic introduces additional complexity for investigators and patients. For example, recruitment and enrollment may need to be conducted remotely and study clinic visits may need to transition to virtual interactions to reduce infection risk for participants and investigators. Likewise, investigators may have to explore alternative avenues to ensure patients can access investigational products, such as home-based delivery of self-administered medicines, or the identification of alternative sites for medicines which must be administered under trained supervision. These challenges are relevant not only for the hundreds of trials which have been initiated for COVID-19-specific therapies, but also for the thousands of studies which were already underway for indications ranging from oncology to cardiology.
FDA has issued guidance for investigators to provide regulatory clarity on the conduct of trials during the pandemic. For example, the agency recommends that sponsors use telehealth if in-person visits are not possible and also issued a separate guidance document to expand access to non-invasive medical devices for remote patient monitoring (e.g., blood pressure cuffs). Investigators will likely need to take additional steps to document potential modifications to study protocols and ensure the integrity of trial data. Lessons from this experience will inform FDA’s ongoing efforts to spur innovation in clinical trials, such as through the use of decentralized designs and digital health technologies.
Early Progress and Lessons Learned
Some emerging results from trials of COVID-19 therapies are promising. For example, a randomized trial led by the National Institutes of Health (NIH) demonstrated that the antiviral drug remdesivir shortened the time to recovery in adults hospitalized with COVID-19, leading FDA to issue an emergency use authorization within 48 hours. As data on other drugs continues to become available, FDA will continue to evaluate it and make decisions about potential therapeutics in accordance with established legal and regulatory standards.
By providing regulatory support for the development of COVID-19 therapeutics, we are also building on the agency’s existing efforts to improve the clinical research enterprise. For example, experience from CTAP can offer lessons on how FDA could expedite the development of guidance documents and streamline communications and review processes at the pre-IND and IND stage. Likewise, the demonstrated value of different trial designs during the pandemic – from decentralized trials, to adaptive trials, to trials with shared control arms – may help investigators make it easier for patients to participate in clinical trials and improve operational efficiency while still ensuring trial safety and data integrity. Furthermore, to help accelerate the development of therapeutics for other unmet medical needs, we can draw lessons from efforts such as the development of a COVID-19 Natural History Master Protocol through the Sentinel Initiative and the use of the CURE ID platform in partnership with the Critical Path Institute to aggregate real-world data to support further research.
As the medical and scientific community works to broaden the therapeutic toolkit for COVID-19, FDA is committed to reviewing investigational programs, policies, and partnerships with the aim of providing a clear path forward for the rigorous development of new therapies for the COVID-19 pandemic and possibly beyond.