FDA Special Designations and Programs for Pipeline Drugs: How They Impact Drug Development Deep Dive

Part 2 of 2: Special Designation Deep Dive
This is the second part of a two-part series from Two Labs Drug Pipeline Manager, Ryan Chandanais

In the first blog in this 2-part series, I provided an overview of FDA Special Designations and Programs and discussed how the FDA must strike a balance in approving drugs in a timely, but safe, fashion. Here, I will dive deeper into the nine special designations and programs that I mentioned.

1) Priority Review

After the FDA accepts an NDA or BLA, they will assign a PDUFA date (short for Prescription Drug User Fee Act). This is the FDA’s target goal date for deciding on approval or denial. Reviewing an NDA or BLA is a time-consuming task. With a standard review timeline, the PDUFA is set for 10 months after the NDA/BLA is accepted. A priority review cuts this time down to 6 months.

For example: NDA/BLA is accepted on January 1, the PDUFA with a standard review would be November 1 compared to July 1 with a priority review. Not just any old NDA/BLA can qualify for Priority Review, though. Eligible drugs represent “significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions.” Which drugs meet this definition is up to interpretation by the FDA.

2) Accelerated Approval

Most drugs are approved based on the results of clinical trial endpoints that prove efficacy such as overall survival (OS) or progression-free survival (PFS). These show if the drug has helped patients live longer (OS) or has stopped their disease from worsening (PFS) compared to placebo or possibly another currently available treatment, depending on the trial design.

These are great endpoints for determining efficacy, but it often takes a long time for them to mature to show results. The Accelerated Approval program reduces wait time for slow-developing trial endpoints by using a “surrogate endpoint” to predict clinical benefit. Examples of a surrogate endpoints include:

  • Lab values
  • Imaging
  • Physical signs
  • Other scientifically accepted measures

Approving a product via the Accelerated Approval program allows it to be an available treatment option for patients sooner. This can be valuable for patients with severe disease states (such as cancer) where limited treatment options may exist and/or where the effectiveness of currently available treatments leaves something to be desired. To confirm the results shown by the surrogate endpoints, the FDA requires additional studies to be completed after the drug reaches the market. If these post-marketing studies don’t verify the efficacy of the drug, approval can be revoked at the discretion of the FDA.

Certain manufacturers who have had products approved through the Accelerated Approval pathway haven’t always followed through on completing these confirmatory studies and there has been a movement in recent times for stricter enforcement of these requirements. The idea behind Accelerated Approval is to strike an appropriate balance between quickness in bringing new treatments to market and having an appropriate amount of supporting evidence in terms of safety and efficacy for the new drug.

Here’s an example scenario of where an Accelerated Approval might be used: A high prostate-specific antigen (PSA) value is associated with an increased risk of prostate cancer progression. A pipeline drug shows it controls PSA value in prostate cancer studies. The FDA allows the manufacturer to file for approval using the PSA value as a surrogate endpoint. The FDA grants Accelerated Approval and the drug is available for patients. The manufacturer runs additional studies to determine the overall survival or progression-free survival of the drug.

Over time, post-marketing trial results develop that either confirm the efficacy of the drug and the Accelerated Approval is converted to a “full approval” (more common) or the additional results do not support efficacy and the drug is removed from the market (less common).

3) Fast Track

There are multiple segments of each NDA or BLA that need to be reviewed such as clinical trial results and manufacturing information. In most cases, the FDA requires all segments of the NDA or BLA to be submitted before they begin their review. The Fast Track program allows for a manufacturer to submit segments of their NDA or BLA and the FDA will review them as they come in rather than waiting for all segments to arrive. Fast Track also allows for some additional communication between the manufacturer and the FDA.

The overall impact of this program is to improve the efficiency of the NDA/BLA submission and review process. In 2022, 32% of novel new drugs approved by the FDA’s Center for Drug Evaluation and Research (CDER) had received Fast Track designation. Products receiving Fast Track designation are also likely to earn a Priority Review once their NDA/BLA is accepted.

4) Breakthrough

Breakthrough Designation is typically reserved for drugs treating life-threatening or debilitating disease states. Eligible products have “preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).” One of the most impactful potential benefits of Breakthrough designation is that NDA/BLA submission may be based on results from phase 1 or 2 trials rather than phase 3 trials that are required in nearly all other cases (with a few exceptions). This early submission can greatly reduce the time spent in clinical trials before the drug reaches the market.

Additionally, Breakthrough designation includes all the benefits of the Fast Track program as well as some additional opportunity for FDA guidance related to requirements for approval. In the first few years after the designation was created, it was awarded sparingly, however in recent years it has been given more generously. In 2022, 35% of novel new drugs approved by CDER had Breakthrough Designation. As with Fast Track, it’s reasonable to anticipate products with this designation also getting a Priority Review after their FDA submission is completed.

5) Regenerative Medicine Advanced Therapy (RMAT)

RMAT is a close cousin to Breakthrough designation with the major difference being that RMAT is eligible only for certain biologics that will potentially be reviewed by Center for Biologics Evaluation and Research (CBER) arm of the FDA.

An additional benefit of RMAT not featured with Breakthrough designation is the eligibility for Accelerated Approval. RMAT candidates belong to some of the “cutting edge” mechanisms of action such as cell and gene therapies as well as therapeutic/human tissue engineered products. The requirements for RMAT do not include that the product is a substantial improvement over currently available treatments as is spelled out in the qualifications for Breakthrough.

6) Orphan

Drugs treating diseases with low patient populations were once thought to have limited chances for commercial success. Manufacturers found it more attractive to focus on developing drugs to treat conditions that more people had. This left many low population disease states without any FDA-approved treatments.

The Orphan drug designation was created in 1983 to incentivize drug development for disease states with <200,000 patients in the U.S. Benefits include tax credits for the manufacturer, exemption for certain fees associated with drug development, and an additional opportunity for market exclusivity for a period of time beyond standard patent law protection. The program has been very successful in stimulating drug development for rare diseases.

In 2022, 54% of novel new drugs approved by CDER had an Orphan designation. Disease states eligible for Orphan designation often have few or no FDA approved treatments. This lack of competition is also appealing if you’re a manufacturer that gets an Orphan drug approval. I expect the trend of a strong Orphan drug pipeline to continue. There are about 7,000 identified different rare diseases affecting a total of approximately 30 million people in the U.S. so there are plenty of rare diseases that still need new treatments.

Another commercially appealing aspect of Orphan drugs for manufacturers, related to the lack of competition, is that they can often carry a high price tag. This causes difficulty for patients and insurers, but getting too deep into this debate is beyond the scope of this article. By itself, the Orphan Designation has no direct impact on clinical trial or FDA review timelines.

7) Priority Review Vouchers

Building on the concepts of Priority Review and further incentivizing drug development for certain underserved rare diseases, the Priority Review Voucher program was created. Manufacturers who earn FDA approval for a qualifying drug treating a rare pediatric disease, tropical disease, or material threat medical countermeasure earn the opportunity to have the FDA perform a review on a priority timeline (6 months) for another NDA/BLA that would otherwise only qualify for a standard review (10-month timeline). This Priority Review Voucher can either be applied to another drug from the manufacturer who earned it, or it can be sold to another manufacturer to use on one of their drugs.

Priority Review Vouchers have proven to be valuable, while there has been variation in their selling price, the typical PRV often goes for about $100 million. Selling PRV’s may strike some people as a bit odd at first. Given that in many cases they are earned by small manufacturers who are likely cash strapped from the expenses of getting a drug to the market and who may not have any other pipeline agents nearing FDA submission, it’s understandable that selling a PRV could be more useful than using it themselves.

8) Qualified Infectious Disease Product (QIDP)

Drug resistant bacteria and fungal infections are becoming an increasing concern. Along with relatively few novel new antibacterial or antifungal products in recent years, that led the FDA to create the QIDP designation. In a similar spirit as we saw with Orphan designation, the FDA got this program going to incentivize manufacturers to develop treatments where there is unmet clinical need. To qualify for QIDP, the drug must treat a specific bacterial or fungal infection that is life-threatening and/or a treatment resistant pathogen.

QIDP products also get all the benefits of the Fast Track program. If the drug gets approved, the manufacturer earns an additional 5 years of market exclusivity. The FDA’s QIDP Guidance for Industry was published in May 2021, making it one of the newer specialty FDA programs, so it may take some additional time to determine if the QIDP is working as intended.

9) Real-Time Oncology Overview (RTOR)

The main impact of drugs reviewed under the RTOR program is that they are likely to receive an approval decision from the FDA well ahead of the official PDUFA date. In a small case study, FDA decisions were made 3-4 months earlier than the PDUFA. This expedited review program was initially used for expanded indications (sNDA/sBLA) in oncology only, but had the scope increased to new oncology drugs (NDA/BLA) in 2018. It is still limited to oncology products who have what the FDA considers to be a straightforward study design with easily interpreted endpoints.

Under this program, certain supporting materials are submitted by the manufacturer and reviewed by the FDA prior to the official filing. While the FDA has been known to make approval decisions ahead of the PDUFA date outside of this program, it can be surprising to see how quickly decisions happen for RTOR designated products.

Ready to learn more?

Watch Ryan’s recent webinar, Two Labs Launches to Watch: FDA Pipeline Insights & Analysis 

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