While much of drug repurposing is physician-initiated and occurs as part of innovative clinical care, clinical research is an important tool to objectively and systematically evaluate the safety and efficacy of an old drug for new uses. Before a clinical trial can begin, an Institutional Review Board (IRB) reviews and approves a proposed study; its goal is to protect human subjects and to support Good Clinical Practice. As such, IRB approval is a regulatory hurdle in repurposing research - but there may be another, like the Food and Drug Administration (FDA) or other regulatory agencies worldwide.
Repurposed drug studies can differ in many ways from the FDA-approved, “on-label” use of that drug. Examples of these differences can include a new patient population (gender, age, concurrent disease) and drug dosing and schedule (frequency, duration), among other changes. If the changes from on-label use of the drug can elevate study subject risk, the FDA expects that IRBs will require the investigator to submit an Investigational New Drug (IND) Exemption Request, or a full IND application, to the FDA.
In my work with academic medical centers and repurposing research, I can attest that many clinical investigators are surprised that their study might need an IND. Unpleasantly surprised. A common, exasperated response is “…but I use this all the time in clinic!” The distinctions of innovation clinical care and clinical research can be misunderstood, as I discussed in a previous Regulatory Roundup blog post. Regulatory bodies like IRBs and FDA can help us navigate these confusing waters.
If you are required to submit to FDA for your repurposing study, a few key elements will be needed whether you are asking for an IND Exemption or a full IND. At the very least, elements always needed include the clinical protocol and a copy of the latest FDA-approved drug label, in addition to the standard FDA administrative forms and a cover letter. The content of the protocol should ideally comply to the International Conference on Harmonization guidelines, as this approach provides information needed by IRBs and by FDA. In an IND Exemption Request, the cover letter should include a strong justification of why you feel that the proposed study meets FDA criteria for exemption.
There are numerous guidances to the contents of a full IND, but they can be modified for repurposed drugs. For example, the Chemistry, Manufacturing, and Controls section can be replaced with a drug maker-provided permission for FDA to reference their drug’s Drug Master File (on file with FDA). The Preclinical and Toxicology discussions and data can often be replaced with the drug maker’s Investigator’s Brochure (IB) for the approved drug. Even though a FDA-approved drug has already undergone animal testing, FDA may still require new animal studies to supplement what is already known about the drug before your repurposing trial. For example, the IB may only describe industry-sponsored studies in adult animals, though your trial is will use the drug in a pediatric population. A Pre-IND meeting with FDA is an excellent opportunity to clarify their expectations related to further testing needs for your IND submission.
Both local IRB and federal regulatory agencies may be on your repurposing path, and an IND submission may seem like a daunting task. However, FDA feedback can improve study design and enhance patient safety. As such, the outcomes of a repurposing study under an IND may more readily translate into clinical adoption – a foundational and driving goal Cures Within Reach.