Emergency Use Authorization to Full Approval–Charting a Course in Unexplored Territory
Part 1: Pathway for a Novel Therapeutic
J. Shawn Roach
Halloran Consulting Group

he COVID-19 pandemic has put the FDA guidance on Emergency Use Authorization to a new test. Both sponsor companies developing new therapeutics and the FDA itself have had to find new and innovative ways to rapidly make therapeutics, vaccines, diagnostics, and devices available to combat the public health emergency. Even though speed has been of the essence, no sacrifices were made to maintain solid, data-based standards to ensure both the safety and efficacy of these novel treatments. This two-part series describes how therapeutics (drugs or biologics) have navigated this novel path to bring aid to respond to the current public health crisis.

FDA’s Emergency Use Authorization (EUA) Guidance

The US Food and Drug Administration’s (FDA) Guidance on Emergency Use Authorization (EUA) was finalized in 2017, but the COVID-19 pandemic has put guidance pathways to widespread test. To combat the public health emergency, the guidance provided procedures that allow the use of certain medical products (medical countermeasures, or MCMs) that either were not previously approved or were approved only for uses or indications different from the indication outlined in the emergency response declaration.

It is important to note that the EUA authority does not lower the bar for scientific rigor applied to approval of an MCM but instead allows for flexibility in execution of required tasks. Examples include, but are not limited to, an extension of expiration dates in the case of stockpiled MCMs, waiver of certain cGMP storage requirements to accommodate emergency response needs, and flexibility on clinical and nonclinical trial execution.

Potential Strategies for Bringing an EUA to Full Approval (FA)

When submitting an EUA request, the sponsor should have a strategy for how to proceed from EUA to FA. Since the current public health emergency was declared, multiple EUAs have been granted to sponsor companies to make more MCMs available to mitigate the risks of COVID-19. This article focuses on EUAs for therapeutics.

There are two pathways for therapeutic MCMs to be issued an EUA:

  • 505 (b)(1): New Chemical/Biological Entity (NCE/NBE) for initial approval by the FDA
  • 505(b)(2): An application that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. This is often seen as a previously FDA approved therapeutic being submitted for approval to treat a new indication

As of September 3, 2021, only one therapeutic, Veklury (remdesivir), has moved from EUA to FA. That product followed the 505(b)(1) pathway since the same sponsor obtained both the original and new approvals.

Speed to EUA vs. Regulatory Requirements

Having a clearly outlined strategy on how to proceed from discovery to submission is crucial for success. The key to this strategy is building a solid, scientifically sound body of evidence throughout the EUA to FA process which allows for adequate review by the FDA. The EUA process calls upon sponsors to engage with the FDA (and other health authorities) to begin a conversation early, focusing on how processes can achieve maximum efficiency while ensuring patient safety and therapeutic efficacy.

For an NBE, Lynne Krummen of Vir Biotechnology Inc. offered insights that are shared throughout this article, garnered from Vir’s recent experiences in obtaining an EUA for a monoclonal antibody therapeutic for the treatment of COVID-19.

Sotrovimab is a new biological entity (NBE) monoclonal antibody (mAb) for which Vir was granted an EUA on May 26, 2021, for the treatment of mild to moderate COVID-19 in adults and pediatric patients at high risk of progression to severe COVID-19. The amino acid sequence of the mAb was originally derived from a survivor of the 2013 SARS outbreak. Approximately nine months elapsed from initiation of clinical studies to the FDA EUA.

Key Components and Challenges Moving from an IND to EUA

Two key components in moving from an Investigational New Drug (IND) to an EUA are engaging the FDA early to establish a partnership throughout the development process and, where possible, using prior knowledge garnered from a history of platform (e.g., therapeutic monoclonal antibody) development.

Over the course of sotrovimab development, the company had multiple early meetings (Type B and C) with the FDA, addressing all segments of the development process, and continued to have discussions as milestones were achieved.

During development, some CMC considerations encountered were:

  • Assuring comparable product quality during rapid implementation of manufacturing process changes.
  • Establishing a practical shelf life for the drug substance and drug product based on limited lot history.
  • Compressed timelines between discovery, initial clinical entry, and need for a market-ready process.
  • Careful planning and rapid implementation of the transition to commercial standards to assure adequate supply of high-quality product for emergency authorization and to enable subsequent approval.

The level of manufacturing information provided to support the EUA resembled that of a late-stage IND. A fully validated process and commercial control strategy is expected for Biologics License Application (BLA) approval.

The nonclinical requirements for an EUA application are a molecule-specific discussion and require clear agreement early on with the FDA. As part of the EUA process, some permissions were granted by the FDA to begin clinical work while nonclinical reports were being finalized. For the trial to be initiated, data derived from in-life phases of the safety studies were required.

For clinical development, since knowledge of the populations most at risk was rapidly developing, key aspects of the dialogue between global health authorities and industry revolved around inclusion criteria and study endpoints. An FDA Guidance was published in May 2020 which provided a useful basic framework and insight into current FDA thinking on acceptable patient populations and relevant clinical endpoints in various disease settings. Due to the urgency of the situation, there was openness from regulators to enter into pivotal trials in patients already confirmed to be COVID-19 positive, while still requiring thoughtful study designs that allowed for incremental patient exposure to assure no untoward safety risks.

For sotrovimab, a single pivotal trial in high-risk subjects was conducted to support the EUA with clinical endpoints, such as prevention of hospitalization and death. Evidence of clinical benefit is central to the granting of full approval of COVID-19 therapies.

In summary, the benefit/risk of each molecule proposed to enter the clinic and the appropriate nonclinical and clinical study strategies were assessed on a molecule-by-molecule basis. This highlights the importance of establishing an ongoing, dynamic, open conversation with the FDA and other health authorities as early as possible.

Insight on Regulatory Efficiency

In general, the opportunities identified for streamlined and risk-based approaches to development of a treatment for COVID-19 in the context of an ongoing pandemic were accepted by numerous global health authorities. Individual global health authorities were also highly responsive and willing to accelerate their processes to enable rapid development of MCMs. However, since there is no global mechanism for emergency authorization, multiple parallel advice and submission procedures were required. This resulted in a significant amount of duplicative work to be managed in a compressed timeframe. This scenario highlights the general need for and value of harmonizing global processes and information sharing for regulatory efficiency.

The second installment of this two-part article series on “Emergency Use Authorization to Full Approval–Charting a Course in Unexplored Territory” will be published in October and will focus on the 505(b)(2) pathway.