P100: Biomarkers Used to Support FDA Non-oncologic Rare Disease Drug Approvals Between 2013 and 2022
Poster Presenter
Poster Session
Objectives
Biomarkers that can predict clinical benefit are often used as efficacy endpoints, and they are especially beneficial for rare disease drug development. In this study, we examined biomarkers that supported the approval of novel drugs for non-oncologic rare diseases in the U.S. over a decade.
Method
Using publicly available FDA review documents, we identified pivotal efficacy trials that were used to support novel orphan drug approvals. For those trials, we identified biomarkers that were utilized as primary efficacy endpoints and examined regulatory characteristics, such as therapeutic area.
Results
Of the 428 novel drugs approved by the FDA CDER in 2013-2022, there were 109 therapeutic products approved for non-oncologic rare diseases. Of those 109, 55 (50.5%) were supported by 79 pivotal trials that utilized 41 unique primary efficacy endpoints consisting of either a sole biomarker or multiple biomarkers, alone or in combination with other clinical outcomes. These 55 drugs were most often indicated for hematological conditions (25.5%; 14/55). Among FDA’s four expedited programs, priority review was the most utilized (87.3%; 48/55), and 20% (11/55) received accelerated approval. The examined pivotal trials were mostly randomized (77.2%; 61/79), blinded (63.3%; 50/79), and placebo-controlled (57.0%; 45/79). The median number of study participants was 109 (Range: 4–1472).
Of the 79 trials, 65 (82.3%) utilized a single biomarker as the primary efficacy endpoint, and 14 (17.7%) utilized multiple biomarkers as the primary efficacy endpoint. Of the 79 trials, 15 trials (19.0%) supporting 13 drugs (23.6%; 13/55) utilized primary efficacy endpoints that combined biomarker and clinical endpoints, either as multiple endpoints or into a single variable as composite endpoints.
Of the 41 unique primary efficacy endpoints that include at least one biomarker, 32 (78.0%) supported the approval of a single drug. Two endpoints (4.9%) supported the approval of multiple drugs for the same indications (i.e., dystrophin protein for Duchenne muscular dystrophy and percent predicted forced expiratory volume in 1 second (ppFEV1) for cystic fibrosis). Seven endpoints (17.1%) supported the approval of multiple drugs for different indications, both within the same therapeutic area and across different therapeutic areas. Of those 41 biomarker endpoints, 8 (19.5%) supported 11 drugs that received accelerated approval, and 35 (85.4%) supported 44 drugs that received traditional approval. Two endpoints supported multiple drugs that received both traditional and accelerated approval.
Conclusion
In the past four decades, the number of drugs approved to treat rare diseases has increased, but most rare diseases still lack approved treatment options. This is multi-factorial and can be due to the large number of rare diseases, what is known about the pathophysiology or mechanisms of the condition, and the unique challenges faced during rare disease drug development compared to common disease drug development, such as a lack of well-established direct measures of clinical benefits. In such cases, biomarkers that are reasonably likely or are known to predict clinical benefits can be used as a surrogate endpoint.
To better understand regulatory precedent for rare disease drug approvals, we reviewed novel drugs approved by the FDA CDER to treat non-oncologic rare diseases over the past decade. We found that over half of the approved orphan drugs used biomarkers as primary efficacy endpoints, either alone or in combination with other clinical outcomes. Further, the use of biomarkers was not limited to accelerated approvals. The finding reiterates the importance of biomarkers as efficacy endpoints across rare disease drug development programs. Among approved drugs, biomarkers were more commonly selected as primary efficacy endpoints in certain therapeutic areas.
Our study also revealed that, depending on the context of use and validation, the same biomarkers could be used for additional drugs and conditions. For example, spleen volume change was used as the primary efficacy endpoint in the pivotal trials of drugs for myelofibrosis and Gaucher disease. This finding underscores the value of natural history studies and translational research, which can contribute to a better understanding of the disease’s course and prediction of treatment response, enabling the identification of appropriate biomarkers and expanding their use to facilitate rare disease drug development.
