Timing and data are critical to winning Breakthrough Therapy designation

By Mwango Kashoki MD MPH , Senior Vice President, Regulatory Strategy

Companies developing therapies for rare diseases have one common 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 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.

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—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December 2022, the FDA granted 40 percent of BTD requests (439/1098), denied 47 percent (512/1098), and companies have withdrawn the remaining 13 percent. 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.

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 with preliminary efficacy assessments to support BTD.

Regulators focus on how persuasive the data are—and this is both compound- and program-dependent. Parexel encourages 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 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 advise.

Conclusion: 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 for 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.

To learn more about BTD, check out Parexel’s?New Medicines, Novel Insights, Rare Disease report.

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