Regulatory Framework for Drug Development in Rare Diseases

Abstract

Drug development is a highly regulated industry. Therapeutic options for rare diseases must meet the same high standards for the demonstration of safety and efficacy as do those for more common diseases. The approval of the Orphan Drug Act in 1983 has resulted in many more resources for preclinical research, the standardization of patient registries, and the use of real‐world data, among other measures, that, along with the advances in drug development, has resulted in the approval of therapies for some of the most unusual diseases. Increased attention to the diagnosis and treatment of rare diseases has also accelerated the development of gene therapies that may offer significant amelioration and even cures for such diseases in the near future. Rare diseases disproportionately affect children, with severe and debilitating effects. Few effective treatments are available for most rare diseases. To avoid the unnecessary waste of data collected in studies of these patients, and to promote efficient drug development, there is a growing collaboration among patient communities, investigators, clinicians, sponsors, and regulatory authorities. All interested parties are working together to identify the most appropriate research questions and move quickly to make available safe and effective treatments. This article is a survey of the most commonly used regulatory remedies that have been put in place to serve as a framework for drug development in rare diseases.

Think Rare, Think Inside and Out: Simple Question‐Based Approach to Complex Rare Disease Drug Development

“…As discussed in the articles within this issue, rare diseases possess unique traits, many of which are not essentially mutually exclusive: small sample size, heterogeneity of the affected population, limited understanding of the disease pathophysiology, and natural history 1–9 . It is steadily becoming common knowledge how the multiple traits of rare diseases can complicate drug development; currently, there are >9000 serious and life‐threatening rare diseases with not a single therapeutic option 1 …”

“…In certain circumstances, registrational primary end point can be a biomarker or other short‐term clinical response. While there are several regulatory pathways put in place to enable timely access to medications, as reviewed by Korth‐Bradley, 2 understanding the relationship between the biomarker/short‐term clinical response and how the patient feels, functions or survives can avoid the propagation of regulatory uncertainties to drug label and mitigate against extensive postmarket requirements. Moreover, such understanding can inform evidence generation regarding cost‐effectiveness and budget impact.…”

“…This plan is not necessarily binding but provides avenues for the regulators to work with the sponsors and provide guidance and solutions where feasible. Already, regulators have published several general and disease‐specific rare disease guidances and are offering several channels for early interactions as reviewed by Korth‐Bradley 2 . Qosa e 6 highlighted the role of modeling and simulations to inform clinical pharmacology labeling decisions for new drug applications.…”

“…Already, regulators have published several general and diseasespecific rare disease guidances and are offering several channels for early interactions as reviewed by Korth-Bradley. 2 Second, be aware of the potential roadblocks; when thinking in an innovative manner using novel analytical approaches, it is important to be aware of the enablers, that is, what will make these innovative approaches feasible. Liu and colleagues 4 discuss several case studies on the use of real-world data, and what were the data quality attributes that enabled positive regulatory decisions.…”

“…As discussed in the articles within this issue, rare diseases possess unique traits, many of which are not essentially mutually exclusive: small sample size, heterogeneity of the affected population, limited understanding of the disease pathophysiology, and natural history. [1][2][3][4][5][6][7][8][9] It is steadily becoming common knowledge how the multiple traits of rare diseases can complicate drug development; currently, there are >9000 serious and life-threatening rare diseases with not a single therapeutic option. 1 While common disease drug development programs are derisked through a stepwise approach using phase 1, 2a, 2b, and 2 phase 3 studies, rare disease drug development programs may follow an accelerated development paradigm.…”