Drug Digest: Expedited Regulatory Pathways for Biologics

Expedited regulatory pathways can give developers opportunities for more frequent interaction with the US Food and Drug Administration (FDA), rolling review, and potentially faster regulatory decisions. But these mechanisms do not eliminate the need for rigorous clinical, nonclinical, or chemistry, manufacturing, and controls (CMC) development.

In this episode of Drug Digest: Expedited Regulatory Pathways for Biologics, Harpreet Singh, MD, chief medical officer at Precision for Medicine and former FDA oncology division director, and Steven Quay, MD, PhD, founder, president, CEO, and chairman of Atossa Therapeutics, discuss how developers can determine whether a program may benefit from an expedited pathway and where these approaches fit within the broader drug development process.

Singh explains that expedited pathways are not necessarily about shortening the entire development timeline. Some, such as Priority Review, primarily accelerate the review period after an application has been submitted, while others can affect the development process earlier by creating additional opportunities for interaction between developers and FDA.

What do FDA’s expedited pathways actually change?

The experts discuss several mechanisms, including Fast Track, Breakthrough Therapy designation, Regenerative Medicine Advanced Therapy (RMAT) designation, Priority Review, Real-Time Oncology Review (RTOR), and the Commissioner's National Priority Voucher Pilot Program.

Singh describes Fast Track as an earlier-stage mechanism that can be granted based on preclinical evidence and provides more frequent interaction with FDA, as well as the possibility of rolling review once an application is submitted.

Breakthrough Therapy designation comes later in development and requires preliminary clinical evidence indicating that a therapy may provide a substantial improvement over available therapies for patients with a serious or life-threatening disease. Singh says one of its distinguishing features is the level of interaction between the FDA review division and the development team.

"How are you going to develop this asset, and how can we, as regulators and clinicians, help expedite this development in a safe manner?" Singh says of the discussions that can follow a Breakthrough Therapy designation.

RMAT provides a similar development-focused interaction for qualifying regenerative medicine therapies, including cell and gene therapies. Singh notes that RMAT can place greater consideration on translational or biomarker data when evaluating a promising program.

For products that reach the application stage, Priority Review can shorten the FDA review goal, while RTOR allows the agency to begin reviewing certain critical clinical data before the complete application is assembled.

The newer National Priority Voucher Pilot Program adds another potential mechanism for accelerating review of products addressing specified national health priorities. Singh notes that the program remains a pilot, while Quay views the voucher as a potential incentive for developers to think strategically about regulatory timing.

How should developers determine whether an expedited pathway is appropriate?

For Singh, the first consideration is unmet need. That does not necessarily mean a disease has no available treatment. A therapy could warrant consideration if it offers a meaningful advantage over existing options, such as improved central nervous system penetration or a more favorable safety profile.

Once a program enters clinical development, early evidence becomes increasingly important. Singh says regulators will consider safety, efficacy, and whether the endpoints provide a meaningful picture of the therapy's potential.

The appropriate evidence can also depend heavily on the disease and modality. Response rates may provide useful early evidence in oncology, for example, while other diseases may require different measures of clinical activity or biomarkers.

Singh recommends that developers begin discussions with FDA as early as possible, including before a therapy enters clinical trials.

An expedited designation also should not be viewed as a guarantee of eventual success. Early clinical data may not immediately meet the threshold for a particular designation, even when a program ultimately proves successful.

Does expedited development mean less evidence is required?

No. Both experts emphasize that faster regulatory interaction or review does not reduce the fundamental requirements for demonstrating that a therapy is safe, effective, and consistently manufactured.

Quay cautions developers against assuming that an expedited pathway means they can do less work. He points to the three fundamental components of a drug application: nonclinical development, clinical development, and manufacturing.

"You don't think that an expedited pathway that can get you an approval faster allows you to do less work," Quay says.

Instead, he recommends designing early clinical trials to generate as much informative data as possible. That can include multiple efficacy endpoints and biomarkers that help developers determine whether a therapy is producing the expected effect and has a potential role in treatment.

Where are the biggest challenges for newer biologic modalities?

Cell and gene therapies illustrate why expedited regulatory development can be particularly complicated. Singh notes that the rate-limiting step for complex therapies is not necessarily FDA's review of clinical data. Instead, challenges can arise much earlier in development, particularly around CMC, manufacturing, and nonclinical requirements.

Quay similarly points to the novelty of many advanced therapies. Developers may be working with manufacturing processes FDA has not previously evaluated, while traditional approaches to nonclinical testing and efficacy measurement may not always translate cleanly to new modalities.

For these programs, both experts emphasize the importance of engaging FDA early and frequently.

Singh also points to Operation Trailblazer as an example of the agency's effort to address development bottlenecks that occur before an investigational new drug application is submitted. She notes that the challenge for some programs is not the FDA's 30-day IND review itself, but the work required beforehand to establish appropriate CMC, pharmacology, toxicology, and other nonclinical packages.

How can developers balance speed with patient safety?

Expedited development ultimately requires a balance between faster access and sufficient evidence to protect patients.

"FDA's really primary responsibility is patient safety," Singh says. Moving too slowly can delay access to potentially beneficial therapies, while moving too quickly can create risks of missing safety signals that only become apparent with longer follow-up.

The experts point to cell therapies and radiopharmaceuticals as examples of modalities in which long-term safety monitoring remains important even after approval. Singh notes that CAR-T therapies can require five-year or longer follow-up, particularly as these treatments move into new patient populations.

The result is that regulatory acceleration does not end when a product is approved. Safety considerations continue throughout the product's life cycle.

For developers working with newer and more complex biologics, the message from both experts is straightforward: expedited pathways can create opportunities to work more efficiently with FDA, but they do not replace rigorous development.

Interview featuring

Harpreet Singh, MD
Chief Medical Officer, Precision for Medicine, Biotech Executive

Dr. Singh is chief medical officer at Precision for Medicine, where she leads medical and scientific strategy for biomarker-driven clinical development in oncology and rare diseases. Previously, she served at the US Food and Drug Administration, most recently as director of the Division of Oncology, overseeing regulatory review of oncology drugs and biologics. A medical oncologist, Dr. Singh is recognized for advancing precision medicine, innovative clinical trial design, and oncology regulatory science.

Steven Quay, MD, PhD, CEO at Atossa Therapeutics

Dr. Quay has served as chief executive officer, president, and chairman since founding the company in 2009. A specialist in Anatomic Pathology, he completed his residency at Massachusetts General Hospital (Harvard) and served on the faculty at Stanford University School of Medicine. An accomplished innovator, he holds 96 U.S. patents and developed seven FDA-approved pharmaceuticals. He earned an M.D. and Ph.D. from the University of Michigan. His board leadership is rooted in his status as a founder and his role as the principal researcher directing the clinical and regulatory advancement of the company’s pharmaceutical programs.

Sponsors

This episode of Drug Digest is sponsored by:

• Cygnus Technologies
• LabVantage
• Parenteral Drug Association

About BioPharm Drug Digest

Drug Digest is a video series with the BioPharm International® editors, who conduct in-depth interviews with industry experts around the latest research and pipeline developments as well as emerging opportunities, obstacles, and advances in the biopharmaceutical industry related to the manufacturing, distribution, supply, and regulatory compliance of bio/pharmaceutical products.

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