Timing and data are critical to winning breakthrough therapy designation for rare disease drugs

Many companies developing rare disease drugs have one urgent regulatory question: "How—and how soon—can we get FDA Breakthrough Therapy designation (BTD)?"

Because BTD targets drugs intended for serious conditions with unmet medical needs, it is frequently central to rare disease drug development. However, obtaining BTD can be challenging; success depends on timing and the data supporting the application. 

Companies know BTD confers valuable benefits, including increased FDA interactions and intensive guidance that could expedite drug development. They also know it often provides external validation to a company’s investors that an investigational product has—based on preliminary clinical data—shown significant potential to the FDA and for patients.

BTD has become a core component of the regulatory strategy for rare disease drugs. A Parexel analysis of FDA novel drug approvals from 2017-2022 found that orphan drugs comprised 53 percent (164/307) of all approvals and 72 percent (86/119) of BTD approvals. Additionally, 93 percent of BTD orphan products received an expedited review under Priority Review.

Percentages

Numbers

SOURCE: Parexel analysis based on primary FDA data obtained from Drugs@FDA, annual reports, biological approvals by year, press releases, and databases. We analyzed all new drug applications (NDAs) and biologics license applications (BLAs) approved by the FDA’s Center for Drug Evaluation and Research (CDER) and Center forBiologics Evaluation and Research (CBER) from January 1, 2017, to December 31, 2022. Totals reflect approvals for new molecular entities (NMEs) (novel drugs and original BLAs) and exclude supplemental NDAs/BLAs (new indications), abbreviated NDAs/BLAs (generics), and Type 3 and 5 NDAs (new dosages, new formulations). A total of149 orphan-designated products approved by CDER and a total of 15 orphan-designated products approved by CBER are included in this dataset (CBER approvals exclude assays, fractionated plasma products, patch tests, reagents, vaccines, and tissue transplant products). Breakthrough Therapy (BT) approvals were counted just once, evenif the product was approved in multiple indications simultaneously (the FDA counts each indication as a distinct BT approval). Our analysis includes two 2021 approvals (Tepmetko and Welireg) as BT approvals even though the FDA does not list themas such in its annual report. Agency briefing documents reveal they had BT designation.

Orphan drugs frequently benefit from BTD

The BTD program took effect in 2012 as a new FDA authority under the FDA Safety and Innovation Act (FDASIA), sparked by the efforts of a cancer research group. Investigational products intended to treat a serious or life-threatening disease—and for which preliminary clinical evidence shows substantial improvement over existing therapies on one or more clinically significant endpoints— are eligible to participate.  

It’s not easy to attain BTD status: From the program’s inception through December 2022, the FDA has granted 40 percent of BTD requests (439/1098), denied 47 percent (512/1098), and companies have withdrawn the remaining 13 percent for various reasons. However, drugs for orphan-designated indications are more likely to attain BTD than drugs for common diseases—perhaps because of their comparative advantage in meeting the unmet need criteria. Parexel’s analysis of FDA data shows that 52 percent (86/164) of novel orphan drugs approved since 2017 qualified for the program. 

In addition to BTD, other FDA expedited programs are Fast Track (FT) designation, Accelerated Approval (AA), and Priority Review (PR). Parexel’s analysis shows that 60 percent of approved orphan BTD drugs used two or more expedited development programs. These data align with a recent study of “stacked” expedited program utilization in rare disease drug development.

Use of FDA expedited development programs²

FDA-approved novel orphan BTD drugs and biologicals, 2027-2022 (n=86)

SOURCE: Parexel analysis. See chart above for data sources and methodology.

One recent example of a product that utilized multiple expedited programs in a rare disease setting is Krazati (adagrasib), an irreversible KRASG12C inhibitor for non-small cell lung cancer patients with the KRASG12C mutation. The FDA granted accelerated approval to Krazati on December 12, 2022, about four years after the first patient was dosed in the FIH trial. It won BTD in June of 2021, roughly halfway through development, and also benefitted from FT designation (but did not get PR). Krazati’s overall development time of 4.1 years was six years faster than the recently reported average of 10.1 years for orphan-designated products. In addition to utilizing the AA, BTD, and FT programs, Krazati was reviewed under the FDA’s Real-Time Oncology Review and Assessment Aid programs.

Companies with drugs that receive Breakthrough Therapy designation earlier in development have more interactions with the FDA over time and more opportunities to align on streamlined programs.

Mwango Kashoki 
Senior Vice President, Regulatory Strategy Consulting, Parexel International

Attaining BTD requires optimal evidence and timing

Choosing the appropriate strategy and timing for a BTD request is a crucial challenge for companies. To maximize the program’s advantages, a company should submit a BTD request as soon as possible, ideally before Phase 3 trials begin. When feasible, although uncommon, companies can seek BTD even based on Phase 1 findings. For example, at Parexel, we’ve helped clients design early-phase clinical trials, such as dose-finding studies that include preliminary efficacy assessments to support BTD.

When we assess a drug’s potential to qualify for BTD, we focus on the following:

After this comprehensive, multidisciplinary assessment, we help a company decide if the available (or future) clinical data could “move the needle” of clinical benefit far enough to support a BTD request. Regulators focus on how persuasive the data are—and this is both compound- and program-dependent.

At Parexel, we encourage companies to float the possibility of BTD with the FDA early if their drug shows potential for eligibility. For example, for some drugs, we recommend including a question about BTD for discussion at the pre-IND meeting. We advise clients to ask FDA if it would be reasonable to request BTD at a future time, based on a particular set of investigations and assuming there are data to support the anticipated advantages of the investigational product. In some instances, where there are no prior therapies or the clinical endpoints proposed to support clinical benefit are novel, the FDA may offer high-level feedback on the kind of information they would consider informative for a BTD request. If it is premature to ask this question, the agency will be frank about it.

Recently, one of our clients obtained FDA confirmation at the pre-IND meeting that it would be reasonable to seek BTD for its product, a reformulated version of an approved drug. The reformulation uses a new route of administration and treats a new patient population with a serious disease for which few rapidly acting and effective therapies exist.

The developer can consider the FT program if a drug is not yet eligible for BTD (or never will be). The evidentiary threshold for FT is lower than for BTD, and FT also comes with practical advantages such as frequent interactions with the FDA, increased opportunity for guidance, and other features to shorten FDA review of the marketing submission.

Getting BTD early is best, but it’s valuable at any time

Companies with drugs that receive BTD earlier in development have more interactions with the FDA over time and more opportunities to align on streamlined programs. As a result, they may shorten the development timeline.

However, BTD is not a guarantee of development speed or success. For example, companies developing precision medicines for rare diseases may need to conduct natural history studies or gather external control data. They may need to identify and validate genomic biomarkers, which requires developing assays and identifying laboratories competent to run testing. And they must recruit patients who may be scattered geographically. BTD will not reduce this essential workload.

More commonly, because of the nature of the clinical evidence needed to fulfill BTD criteria, BTD can only be obtained after Phase 2 of development. Getting BTD later in development is still valuable because it guarantees agency interactions and receipt of agency advice on improving the efficiency of drug development.

Contributing Expert