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Innovations in Clinical Development in Rare Diseases of Children and Adults: Small Populations and/or Small Patients

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Abstract

Many of the afflictions of children are rare diseases. This creates numerous drug development challenges related to small populations, including limited information about the disease state, enrollment challenges, and diminished incentives for pediatric development of novel therapies by pharmaceutical and biotechnology sponsors. We review selected innovations in clinical development that may partially mitigate some of these difficulties, starting with the concept of development efficiency for individual clinical trials, clinical programs (involving multiple trials for a single drug), and clinical portfolios of multiple drugs, and decision analysis as a tool to optimize efficiency. Development efficiency is defined as the ability to reach equally rigorous or more rigorous conclusions in less time, with fewer trial participants, or with fewer resources. We go on to discuss efficient methods for matching targeted therapies to biomarker-defined subgroups, methods for eliminating or reducing the need for natural history data to guide rare disease development, the use of basket trials to enhance efficiency by grouping multiple similar disease applications in a single clinical trial, and the use of alternative data sources including historical controls to augment or replace concurrent controls in clinical studies. Greater understanding and broader application of these methods could lead to improved therapies and/or more widespread and rapid access to novel therapies for rare diseases in both children and adults.

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Acknowledgements

No external funding was used in the production of this manuscript. This work is the product of a volunteer organization, the Drug Information Association Innovative Design Scientific Working Group (DIA-IDSWG). We thank Dr Martin Posch for insightful discussions in the area of decision analysis.

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Authors and Affiliations

  1. Departments of Oncology and of Biostatistics, Bioinformatics, and Biomathematics, Lombardi Comprehensive Cancer Center and Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA

    Robert A. Beckman

  2. Statistical Consulting, Abond CRO, Allendale, MI, USA

    Zoran Antonijevic

  3. Data Science and Analytics, Bayer Pharmaceuticals US LLC, Whippany, NJ, USA

    Mercedeh Ghadessi

  4. Data Science and Systems, Nektar Therapeutics, San Francisco, CA, USA

    Heng Xu & Yi Liu

  5. Biostatistics and Decision Research Science, Merck & Co., Inc., Kenilworth, NJ, USA

    Cong Chen

  6. Global Biometrics Department, Clinical Development and R & D, Servier Pharmaceuticals, Boston, MA, USA

    Rui Tang

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  1. Robert A. Beckman
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Correspondence to Robert A. Beckman.

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RAB is a consultant for AstraZeneca Pharmaceuticals, and the Chief Scientific Officer of Onco-Mind, LLC, which owns issued and pending patents on personalized strategic cancer treatment and dynamic precision medicine of cancer. Other authors are employees of for-profit firms as listed in their affiliations.

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Beckman, R.A., Antonijevic, Z., Ghadessi, M. et al. Innovations in Clinical Development in Rare Diseases of Children and Adults: Small Populations and/or Small Patients. Pediatr Drugs 24, 657–669 (2022). https://doi.org/10.1007/s40272-022-00538-7

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