There are nearly 7,000 diseases that are considered rare in the United States. The majority of these diseases, which collectively affect 25 million Americans, are serious, life-altering, life-threatening, or fatal. A large number also have a genetic component or are the result of infectious agents. There have been several meaningful advances in rare disease product development over the last 30 years. More than 400 drugs and biologics have been marketed since enactment of the Orphan Drug Act in the 1983. In comparison, fewer than 10 industry-supported products for rare diseases came to market between 1973 and 1983 (with 38 approved in total). In 2014 alone, approximately 49 orphan drugs were approved, and FDA’s numbers for 2015 are pending as this year draws to a close.
Rare disease product developers must tackle and overcome several regulatory challenges in order to achieve marketing authorization in the United States and abroad. The International Conference on Harmonisation (ICH) guidelines have addressed non-rare disease and cancer indications, however, there are no ICH guidelines for rare disease product development for nonclinical (or other technical areas such as Chemistry Manufacturing Controls [CMC]) or for clinical development. The US FDA has advanced this effort by releasing the draft guidance, “Rare Diseases: Common Issues in Drug Development Guidance for Industry,” in August 2015.
Although orphan drug laws do not provide for a lesser degree of evidence for safety or efficacy, FDA is willing to consider a flexible development approach for rare disease therapies. Medically essential orphan products often qualify for FDA’s expedited product development programs (eg priority review, fast-track, breakthrough, and accelerated approval pathways). However, it’s important to recognize that expedited development programs typically yield “accelerated” operational timelines for both industry and FDA. For example, from a CMC (Quality) point of view, there may be limited (if any) full-scale batch experience, and therefore less registration stability and few batches to set realistic specifications to support marketing approval.
In the United States, a rare disease is defined as having a prevalence of fewer than 200,000 patients per year for a specific disease. It can be difficult to enroll and treat small populations of patients in clinical trials and to determine the sample size needed to obtain regulatory approval. In addition, meaningful effect size may not be detectable in small populations. The natural history and progression of rare diseases are often poorly understood and not well-documented. Ideally the pathogenesis of the disease and mechanism of action of the drug should be well understood. The duration of treatment may also be uncertain. It’s not always clear how long it will take to see improvement and lengthy placebo comparisons may be impractical. Establishing endpoints that can predict outcomes is also challenging. Patients may have varying disease characteristics that can potentially modify the effects of treatment or patient outcomes.
These regulatory obstacles can be tackled with appropriate regulatory and strategic planning for patient recruitment, and through the identification of outcome measures that reflect efficacious variations in disease manifestation. Development of rare disease therapeutics can be accelerated by considering available assessment tools for reliability and validity, the identification of disease variations, and through statistical methods to limit bias. Perhaps most critically, the fulfillment of unmet medical need in rare disease patient populations directly depends on adequate coordination and alignment between the patient population, industry, regulatory authorities and study investigators.
Given the limited precedence and prior approval pathways for sponsors to follow, compromise, innovation, and trade-offs will be necessary in order to realize growth in the rare disease product arena. FDA and other regulatory agencies will need to be willing to make key decisions in the absence of ideal information. To streamline the regulatory process, companies should engage regulators, study investigators, and patient advocacy groups early in the drug development program. With a thorough understanding of these facets of the rare disease investigational paradigm, companies will be able to optimize the probability of regulatory and technical success of their product portfolios and strengthen relationships with agencies, stakeholders, partners, and investors.