The Challenge of Rare Diseases – From Drug Development to Approval

Jonathan Goldsmith
Associate Director (Retired),
Rare Diseases Program,
US Food and Drug Administration

Lucas Kempf
Associate Director (Acting),
Rare Diseases Program,
US Food and Drug Administration

Sandra Blumenrath
DIA Science Writer


espite the approximately 7,000 rare diseases that affect millions of people worldwide, there are comparatively few treatments on the market. In addition to the issues pertaining to small markets, drug development for rare diseases poses unique scientific and ethical challenges.

The patient population affected by rare diseases is typically small, heterogeneous, and widely dispersed, complicating study enrollment, design, and replication. In many countries, there are few specialized sites that provide treatment and could serve as study sites, leading to difficulty acquiring large amounts of high-quality patient data. Additional difficulties arise from the frequently progressive, life-limiting or -threatening nature of rare diseases and the fact that over 50% of those affected by rare diseases are children. There are special ethical considerations for children participating in rare disease clinical trials that need to be anticipated. These are just some of the impediments slowing down the development and approval of life-saving orphan drugs.

New approaches in orphan drug development may offer valuable solutions to overcome these hurdles, streamlining both clinical trials and approval processes to bring much-needed treatments to the market more quickly. Here, we briefly outline some of these new approaches and how they differ from traditional practices.

Clinical Trials Adapted to Fit Small Study Populations

Rare drug trials are often hampered by poorly developed study endpoints, insufficient patient data, and inappropriate control groups. In orphan drug development in particular, efficient study designs with appropriate comparators are key to generating interpretable clinical data for approval. Designing efficient rare disease clinical trials with clinically meaningful endpoints, however, requires close collaboration among statisticians, clinicians, and other clinical trial professionals, and a strong focus on patient needs.

Identifying patients’ most critical needs, for example, helps define novel endpoints that are focused, meaningful, and achieved more quickly. But even when endpoints are well-defined, rare disease clinical trials may not generate the amount and quality of data that would help speed up the approval process. Global clinical studies, novel uses of comparator arms, and trial enrichment strategies may offer tractable solutions when small patient populations make enrollment and clinical trial design challenging.

Study designs that follow various trial enrichment strategies, such as prognostic and predictive enrichment, can significantly reduce the heterogeneity of the patient population and avoid large variation in study outcomes:

  • Prognostic enrichment reduces variability in disease progression rates by identifying high-risk subjects more likely to experience poor study outcomes.
  • Predictive enrichment selects subjects more likely to respond to the candidate treatment based on genetic or other markers, supporting smaller trial sizes.

Rare disease drug development plans that include patients that don’t meet the narrowly defined enrichment trial criteria into other parts of the development program can enhance their supportive data and safety database while improving their enrollment and retention.

Rare disease drug development plans that include patients that don’t meet the narrowly defined enrichment trial criteria into other parts of the development program can enhance their supportive data and safety database while improving their enrollment and retention.

Natural history studies can be used in novel ways to address control group issues and increase the statistical power of rare disease clinical studies. For example, Bayesian methods could be used to borrow information from a natural history study to improve the power of a small placebo group. Clinical sites in different regions could follow natural history study master protocols to uniformly collect verifiable patient data that could serve as external controls in future clinical trials. Prospective collection of case histories in parallel to the drug trial may be more robust than natural history data from older sources and shorten developmental time for new drugs.

If chosen carefully, rare disease study designs can additionally benefit from methods commonly used in regular clinical trials. Adaptive enrichment trial designs, for example, may help reveal orphan drug effects more efficiently and tailor either sample size or patient population.

Approval Flexibility and Expedited Programs

Although a special regulatory pathway for orphan drug development does not exist in the US, different expedited approval processes such as Fast Track, Breakthrough Therapy, Priority Review, and the Regenerative Medicine Advanced Therapy Designation are already in place for medicines addressing serious unmet patient needs.
Rare disease drugs often meet the designation requirements and may then receive an expedited approval. Breakthrough and Regenerative Medicine Advanced Therapy designation rely on preliminary clinical evidence demonstrating substantial improvement and lead to more frequent meetings with the sponsor and shortened (priority) review. Fast Track designation relies on clinical or nonclinical data and additionally provides increased guidance and rolling submissions of marketing applications.

Furthermore, current regulations provide flexibility with the kind and quantity of data deemed necessary in the case of less common diseases. A rare disease drug may be approved based on just one appropriately controlled trial as long as the trial provides sufficient evidence and safety information to allow for benefit/risk assessments. In some cases, the FDA even accepts non-traditional data on treatment effectiveness. For example, the FDA recently accepted in vitro data to bridge the approval of a marketing supplement for treatment of patients with certain mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene. The approved therapy had previously been shown to be effective in CF patients with other specific gene mutations, and increased the treatable CF patients from 8% to 11%, including very small groups of patients affected by several mutations. Additionally, the FDA allows pre-approval access to promising treatments through the expanded access program.


Rare diseases pose broad challenges of clinical research, patient recruitment, and long development timelines. As of 2010, only about 200 of the roughly 7,000 officially designated rare diseases were treatable. Fortunately, the number of diseases with available therapies is increasing. Worldwide, there are a large number of development programs for drugs targeting a wide range of rare diseases. Sponsors should be diligent in investigating potentially innovative approaches to orphan drug development to ensure an efficient and effective design that supports this upward trend.

References available upon request.