Orphan drugs are used to treat rare diseases and disorders. This year marks the 35th anniversary of both the landmark Orphan Drug Act, a law passed by the US FDA that created legal and financial incentives for pharma and biotech to pursue rare disease R&D, and the formation of the National Organization for Rare Disorders (NORD), a leading advocacy organization for patients with rare diseases. An estimated 7,000 rare diseases effect approximately 350,000 people worldwide including 10% of the US population and an estimated 1 in 25 Europeans. Fifty percent of people affected with a rare disease are children. Although the fight to develop orphan drugs has significantly progressed since the inception of the Orphan Drug Act in 1983, only 5% of rare diseases have an approved treatment.
The inherent challenges associated with rare disease drug development make it one the most difficult scientific and technological tasks faced by the healthcare industry. Limited knowledge of underlying disease mechanism(s) makes it difficult to plan and design development strategies. Finding and recruiting patients with a rare disease—especially for pediatric population studies—can impede clinical trial studies. Furthermore, many clinicians have little or no exposure to patients with rare diseases, resulting in the inability to adequately identify and diagnose these types of diseases.
Leveraging modeling and simulation approaches for orphan drug development
Substantial advances in the fields of genomics, proteomics, metabolomics, bioinformatics, and other disciplines, combined with improved technologies and tools for biomedical analysis and diagnoses, have made a significant impact on orphan drug development. As of 2016, over 500 orphan drug products have received marketing authorization in the US and EU. Since its introduction, the Orphan Drug Act has stimulated the orphan drug market by facilitating the development of orphan drugs and led to programs being established in the EU, Japan, Australia, and other nations.
Model-informed drug development (MIDD) approaches such as physiologically-based pharmacokinetics (PBPK), population pharmacokinetics (PopPK), and pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation, combined with translational medicine strategies, have become an integral component of orphan drug development. Sponsors and regulatory agencies use these quantitative modeling tools to predict drug-drug interactions (DDIs), interpolate and extrapolate dosing regimens with models of varying complexity, inform and optimize clinical trial designs, and evaluate exposure-response relationships.
MIDD approaches have been integrated into a recent draft guidance developed with the European Medicines Agency (EMA), to develop new drug therapies for rare pediatric diseases. The new guideline incorporates modeling and simulation (M&S) approaches that will enable the timely development of multiple drug products while minimizing the number of placebo-treated patients needed for studies. Quantitative approaches, eg, PBPK, and mechanistic disease PK/PD, are recommended for dose characterization. M&S tools are also recommended to inform dosing rationale and optimize pediatric study design, sample size, starting dose, and dosing regimen.
Addressing unmet medical needs through orphan drug development
The ongoing investment by the US, EU, Japan, and other key countries to hasten developing drugs for rare diseases highlights their commitment to improve health care for patients with unmet medical needs. To address the urgent need for pediatric drug development, the FDA and EMA now require pediatric trial plans as part of the approval process for new drugs. The guidance recommends the use of M&S to reduce the uncertainty of dosing pediatric populations. PBPK has been increasingly used in pediatric drug development programs to help optimize pediatric study designs, especially in the 0-2 year old age group.
MIDD has been used successfully to determine exposure-response models from small populations, gain insight into biomarkers and endpoints, facilitate dose selection, identify drug-drug interactions, design extrapolation studies in pediatric trials, and model the impact of a drug on other disease states.
Certara uses PBPK, PK/PD, PopPK, and other quantitative clinical pharmacology modeling and simulation tools to support orphan drug development programs in a range of therapeutic areas including oncology, blood disorders, CNS, gastrointestinal, bone and muscle diseases, infectious diseases, and genetic inherited diseases.
To learn more about how translational medicine strategies using quantitative MIDD tools can be used for pediatric orphan drug development, please watch this webinar by my colleagues, Drs. Craig Rayner and Patrick Smith.