BY: MARK MATHIEU, DIRECTOR OF STRATEGIC RESEARCH, PARTHA ROY, PH.D., VP - TECHNICAL, SUGATO DE, M.S., VP - TECHNICAL, ROBERT ISER, VP REGULATORY CONSULTING
To provide structure and context to the measures the Food and Drug Administration (FDA) is taking to accelerate the review and availability of treatments for COVID-19, the Agency announced a special emergency program called the Coronavirus Treatment Acceleration Program, or CTAP (https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-accelerate-development-novel-therapies-covid-19). While the Agency has been working under the overarching principles of CTAP for some days now, the FDA has now taken concrete steps to announce an all-hands-on-deck approach to ensure that promising COVID-19 therapies reach patients as quickly as possible with an initial assessment of safety, while supporting further real-world evidence approaches to evaluate whether these medical countermeasures demonstrate continued safety and effectiveness.
Under CTAP, the FDA has implemented streamlined processes for developers and scientists to submit inquires and requests, and asks that “requests for product development for proposed COVID-19 uses and drug development” be sent to: COVID19email@example.com (mailto: firstname.lastname@example.org).” Upon receipt, the Agency says, the development requests will be immediately triaged and assigned to new COVID-19-dedicated review teams that may be supported by “redeployed medical and regulatory staff.”
Although earlier FDA releases have provided advice on submissions for COVID-19 research and established that subsequent agency advice would be “expedited and prioritized,” the CTAP release is the first to provide specific timelines—or at least to use actual turn-around times for previous COVID-19 proposals to set expectations going forward:
- Now that it has weathered that first wave of COVID-19-related requests, the agency notes that it will “generally respond [to requests] within a day.”
- While the agency notes that it has provided “ultra-rapid, interactive input on most development plans,” it adds that “interactions are generally prioritized based on a product’s scientific merits, stage of development, and identification as a possible priority product in consensus [U.S. Government] documents.”
- In many cases under CTAP, the FDA says that it has provided protocol reviews within 24 hours of their submission.
- Further, the Agency says that it has provided “around-the-clock” reviews of “single-patient expanded access requests.” These reviews were generally completed within three hours.
To meet these expedited timelines, the FDA notes that the review of submissions may involve both redeployed medical and regulatory staff and senior management. Although almost all CDER-related inquiries are channeled through CDER’s Division of Antivirals, other divisions--such as the Division of Pulmonary, Allergy and Critical Care and the Division of Rheumatology and Transplant Medicine--are brought in as consulting divisions as appropriate based on product/mechanism of action experience. Internally, the Agency has created dedicated review teams with around-the-clock availability for the accelerated review of COVID-19 therapies to ensure that input is provided as quickly as possible. “Under the FDA’s accelerator program, staff from the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research are providing regulatory advice, guidance and technical assistance as quickly as possible,” the Agency says.
Through the CTAP announcement, the FDA also acknowledges the potential for leveraging real-world data sources to complement traditional clinical studies, and thus speed the overall review process. As demonstrated by the recent emergency use authorization for the use of chloroquine phosphate or hydroxychloroquine sulfate for the treatment of COVID-19, the FDA is emphasizing a demonstration of safety in their initial assessments, while prioritizing a demonstration of effectiveness and continued safety in real-world clinical programs. Although this approach is novel and is certainly intended to meet the critical need for therapies in the midst of the current crisis, the FDA cannot use CTAP to perform incomplete safety reviews. While the benefit-risk calculus is skewed in the current environment characterized by an immediate global need for effective therapies, the FDA, as a body dedicated to promoting and protecting public health, must ensure that safety is well-characterized before allowing untested drugs to be used in patients.
What to submit in product development requests
Although the FDA’s CTAP launch announcement does not address Agency expectations for COVID-19 product development proposals, CDER’s Division of Antivirals has done so both publicly (https:www.fda.gov/emergency-preparedness-and-response/mcm-issues/covid-19/-therapeutics-general-information-interested-stakeholders) and also individually with companies seeking guidance.
In a recent document entitled, COVID-19 Therapeutics: General Information for Interested Stakeholders, the Division offered general tips “that may be useful to sponsors wishing to rapidly initiate interactions with the FDA regarding potential development of therapeutics for the COVID-19 virus.” In the document, the Division recommends the following, based on the nature of information available on a specific therapy:
- “If you feel your investigational product may have activity against the COVID-19 virus and have relevant cell culture and/or animal model data, you may submit a Pre-IND (PIND) application to the Agency as a “general correspondence.”
- “If you feel your product’s stage of development warrants a formal Pre-IND meeting, please refer to the Division of Antivirals Pre-IND letter of instruction...website for details.”
- “If you don’t have any activity information, but believe your product may have potential against the COVID-19 virus, you may find it useful to consult the National Institutes of Health, Division of Microbiology and Infectious Diseases website [www.niaid.NIHgov/about/dmid]..., which contains information about preliminary screening activities that may be available to potential sponsors of antiviral products.”
- “If you do not have specific information related to the COVID-19 virus, but still feel that your product warrants a PIND, then please include as much information as you can and a rationale for review.”
Although the Division of Anti-Viral Pre-IND Letter of Instruction provides considerable detail on the information that should be included in routine pre-IND requests for advice, it also offers additional thoughts regarding COVID-19 requests.
“So that we may give you the best assistance, we suggest that you provide us with as much information as possible about your new drug and your plans for its development...together with a list of specific questions you wish us to address,” the division’s letter of instruction notes. The letter of instruction recommends that a company submit information on chemistry, manufacturing and controls (“enough information to assure us that the identity, strength, quality and purity of the new drug are adequately characterized to assess its safety and to allow interpretability of preclinical studies and clinical investigations”), pharmacology/toxicology, microbiology (virology), proposed animal studies, and the clinical development plan (“we find that we can offer better guidance to those sponsors who are also able to provide us with information about their plans for initial clinical development (i.e., phase 1 or 2 studies), as the latter will impact on the selection and design of nonclinical studies”).
More recently, the Division has made several other recommendations on what COVID-19-related pre-IND information packages should contain:
- A draft protocol synopsis. This draft protocol, advises the division, should include “intensive safety monitoring and a DSMB. This recommendation is based upon the significant safety concerns in this patient population, because of risks associated with the [COVID-19] disease and because of the potential for adverse effects from the treatment that might be difficult to recognize.”
- Any data supporting the proposed use of the product in COVID-19.
- A “detailed justification of the proposed use.”
- Since it is difficult to know how potential endpoints intended to demonstrate clinical benefit will “perform,” the division says “a reasonable approach” might involve identifying “a number of potential endpoints to be studied in either a phase 2 or pilot phase of a proposed larger trial...until more information is available to support specific endpoints.”
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