Enabling rapid response drug development

In an age where new chemical entity drug development can average 15 years to complete and only 0.1% of drugs advance from early drug discovery to approval, a different approach is needed to address a pandemic like COVID-19.

“Drug repurposing” and the request of an Emergency Use Authorization (EUA) are two approaches that can address the speed of development during emergency situations.

With a drug repurposing strategy, compounds with at a minimum, partial nonclinical and clinical datasets are analyzed for utility against new therapeutic targets. Some of these compounds may have achieved marketing authorization; others may not have met their original efficacy benchmarks and their development was discontinued. In either event, choosing the right compound to repurpose for a new route of administration and/or indication can significantly decrease cost of development and increase speed to market.

While drug repurposing can shorten the development timeline, it is still incumbent upon the sponsor to determine if the efficacy and safety profile of the candidate drug supports the new route of administration and indication before filing their IND or EUA request. The FDA’s guidance entitled “Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route” (2015), provides specific recommendations.

The concept of an EUA is described in “Emergency Use Authorizations of Medical Products and Related Authorities; Guidance for Industry and other Stakeholders” (2017). The therapies for which an EUA can be requested include drugs (e.g., antivirals and antidotes), biological products (e.g., vaccines, blood products, and biological therapeutics), and devices (e.g., in vitro diagnostics and personal protective equipment) when there are no adequate, approved and available alternatives to address the subject unmet medical need. If granted, the EUA is a temporary measure put in place for national safety; an EUA does not circumvent the need to complete the standard IND and NDA/BLA or other processes to maintain long-term patient access to the product.

Incorporating scientific considerations for an EUA request

The EUA process lays out the FDA’s framework for altering the standard review and approval process for bringing drugs forward for unmet medical needs involving chemical, biological, radiological and nuclear (CBRN) agents, including emerging infectious disease threats such as the COVID-19 pandemic. It also lays out a number of scientific considerations for assessing the applicability of these drugs for accelerated progression into human trials. Sponsors should consider the following scientific questions when contemplating repurposing a drug and requesting an EUA, as noted in the FDA’s Emergency Use Authorization of Medical Products and Related Authorities:

Has the drug already achieved marketing approval?
If not already approved, how much nonclinical and clinical data are available to support the safety and mechanism of action of the drug?
- Any information on safety associated with use in humans of this or related compounds should be submitted, including that from other than well-controlled clinical trials.
Can the new therapeutic indication be effectively treated with the route of administration and dose/formulation for which safety and efficacy data were previously collected?
Is robust data concerning the product’s mechanism of action and applicability to the subject disease available?
- It is unlikely that comprehensive effectiveness data would be available for every EUA candidate. Therefore, authorization of an EUA will also depend on the circumstances of the CBRN emergency, as well as available knowledge about the product’s safety profile.
Is data on the pharmacology/effectiveness, pharmacokinetics or toxicity of the drug in animals available which would contribute to understanding potential effects in humans?
Is data from animal efficacy studies available for products which were, or are, being developed under the “Product Development Under the Animal Rule; Guidance for Industry” (2015)?
Is the risk benefit profile of the drug for the new indication the same or better than it was for the originally developed indication?
- FDA expects to interpret safety information in light of the seriousness of the clinical condition, alternative diagnostics, prophylaxis or alternative therapies (if any), and the specific circumstances of the emergency or threat of emergency.
Is evidence available from human experience relevant to assessing activity, effectiveness and dosing (e.g., in published case reports, uncontrolled trials, controlled trials and any other relevant human use experience)?
For drugs, is data available to support the proposed dosage for the intended use (including pharmacokinetics and pharmacodynamics data, and for vaccines or antibody therapies, immunogenicity and/or achievement of protective levels of relevant parameters of immunity)?

Preparing an integrated assessment for an EUA

The generation of a well-developed integrated assessment of the available data will be a key stepping stone in the pursuit of an EUA request. The content and format of the assessment will include many of the elements of a traditional IND application, including the submission of comprehensive study reports, tabulated group and individual data for both nonclinical and clinical studies with regulatory compliance status duly noted (GLP or GCP, respectively). The dossier will also include a comprehensive description of the available Chemistry Manufacturing and Control (CMC) data for the candidate drug.

If the assessment demonstrates that the existing dataset is fully supportive of the new indication, then it may be feasible to request an EUA based solely on the integrated assessment described above and a letter of cross reference granted by the holder of the previously approved marketing authorization.

If the new use of a previously approved drug poses a unique risk to the targeted patient population (e.g., inconsistent with the originator product), then information from additional in vitro studies, animal studies and clinical studies would be required before an EUA could be granted.

For repurposed drugs which did not achieve a prior marketing authorization, the FDA’s expectations for consideration of an EUA request will include submission of available in vitro and in vivo safety pharmacology, pharmacokinetic and toxicology data. As available, human safety information from clinical trials and individual patient experience must be provided. A comprehensive assessment of correlation between exposure and toxicity should be conducted for any nonclinical data submitted and use of modeling and simulation approaches to estimating human exposure are encouraged.

Regardless of the prior approval status of the drug, the FDA’s expectations for an EUA include the following, again from the document Emergency Use Authorization of Medical Products and Related Authorities:

A discussion of the candidate product’s known and potential risks and benefits based upon the integrated data assessment described above;
A plan for measures planned to mitigate risk or optimize benefit of the therapy;
A description of limitations, uncertainty and data gaps;
A description of circumstances, if any, under which the product should not be used (e.g., contraindications);
To the extent known, information concerning the threats posed by the CBRN agent(s) (actually or potentially) involved and anticipated response and operational considerations that may be relevant to an assessment of risks and benefits.

Finding a drug development partner

If collaborating with a CRO, sponsors should consider a partner with end-to-end scientific and strategic tools and capabilities to provide guidance through the entire duration of the drug development process. Whether developing an NME or repurposing a previously evaluated drug, a partner should offer comprehensive services ranging from in vitro and animal efficacy models in which to evaluate candidates against corona viruses, the nonclinical development capabilities to conduct any necessary nonclinical bridging studies and the support of swift progression through the regulatory process to advance efficiently into the clinical investigations around your new therapy. With a goal in support of your drug repurposing efforts, a CRO should ultimately identify a scientifically sound yet time and resource efficient plan to progress your program into clinical trials.

Learn how we can accelerate your drug repurposing efforts during COVID-19.

Incorporating scientific considerations for an EUA request

Preparing an integrated assessment for an EUA

Finding a drug development partner

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