Model‐Informed Approach Supporting Drug Development and Regulatory Evaluation for Rare Diseases

Abstract

A rare disease is defined as a condition affecting fewer than 200 000 people in the United States by the Orphan Drug Act. For rare diseases, it is challenging to enroll a large number of patients and obtain all critical information to support drug approval through traditional clinical trial approaches. In addition, over half of the population affected by rare diseases are children, which presents additional drug development challenges. Thus, maximizing the use of all available data is in the interest of drug developers and regulators in rare diseases. This brings opportunities for model-informed drug development to use and integrate all available sources and knowledge to quantitatively assess the benefit/risk of a new product under development and to inform dosing. This review article provides an overview of 4 broad categories of use of model-informed drug development in drug development and regulatory decision making in rare diseases: optimizing dose regimen, supporting pediatric extrapolation, informing clinical trial design, and providing confirmatory evidence for effectiveness. The totality of evidence based on population pharmacokinetic simulation as well as exposure-response relationships for efficacy and safety, provides the regulatory ground for the approval of an unstudied dosing regimen in rare diseases without the need for additional clinical data. Given the practical and ethical challenges in drug development in rare diseases, model-informed approaches using all collective information (eg, disease, drug, placebo effect, exposure-response in nonclinical and clinical settings) are powerful and can be applied throughout the drug development stages to facilitate decision making.

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 …”

“…Qosa e 6 highlighted the role of modeling and simulations to inform clinical pharmacology labeling decisions for new drug applications. Moreover, Li et al highlighted several examples within the Center for Drug Evaluation and Research where model‐informed drug development program played a significant role in rare disease drug development and approvals 3 . Their article highlighted further opportunities for collaboration beyond the Center for Drug Evaluation and Research to enable informed decisions for novel modalities, though currently in the infancy stage.…”

“…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. Also, as highlighted by Li et al, 3 the quantitative toolbox available for clinical pharmacologists is expanding, with several tools that range from population pharmacokinetics and mechanistic quantitative systems pharmacology models to artificial intelligence and machine learning. What is the right tool to use to address the situation at hand?…”

“…As highlighted from several articles within this issue, the role of clinical pharmacology is expanding and is especially important for rare diseases. 1,[3][4][5][6][7][8] To that end, there are a few key factors for success that are worth highlighting.…”

“…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.…”