Washington DC, June 21, 2021 – The Forum for Collaborative Research announced the publication of “The Use of External Controls in FDA Regulatory Decision Making” in Therapeutic Innovation & Regulatory Science. This review describes the circumstances for approval of 45 products based on pivotal studies leveraging external controls, with retrospective natural history studies as the most common source of control data.
“This review confirms that the use of external controls – commonly used in oncology – is ‘neither new nor particularly unusual’ for other diseases,” said Dr. Veronica Miller, Director of the Forum for Collaborative Research. “It helps us to better understand how external controls have been used, often with other information contributing to the totality and consistency of data, for diseases in which severity and rarity preclude the use of traditional randomized clinical trials.”
External controls are most effectively used when objective endpoints are available and when the treatment effect is large. Retrospective historical control data can be supplemented with other sources of evidence, such as dose-finding studies or other pharmacodynamic information. “The totality and consistency of data is what matters,” said Dr. Jerry Vockley, a geneticist treating patients with rare diseases at the UPMC Children’s Hospital in Pittsburgh and one of the co-authors of the study. “Large studies relying on randomization to minimize bias are simply not feasible for many rare diseases, yet many patients with rapidly progressing and often fatal diseases are in dire need of new treatments. We have to learn to use science in innovative ways to ensure development of effective therapies for these unmet medical needs.”
Not surprisingly, the majority (80%) of the 45 approvals leveraging external controls were for rare diseases. Additionally, of the 45 approvals evaluated, historical controls derived retrospectively from natural history data were the most common source (44%) of external control. “While retrospectively collected natural history data may introduce bias, approaches to address bias exist and should be leveraged appropriately to support regulatory decision-making. Collaboration across regulators, clinicians and statisticians, with input from patients and caregivers will be necessary to support continued adoption of innovative approaches to clinical trial design, and to ensure focus on what is clinically meaningful, with the goal of making treatments available to patients,” commented Adora Ndu, Group Vice President, Head of WWRD Strategy, Scientific Collaborations and Policy (SSCP) at BioMarin Pharmaceutical Inc., a member organization of the Forum for Collaborative Research.
“Everyone agrees that prospectively collected natural history data is preferable, but in our real world, relevant prospective studies rarely exist. As more clinicians and patient advocates recognize the need for ‘fit-for-purpose’ data, data sharing and collaboration across stakeholder groups to bring effective treatments to market, we have an opportunity to think pro-actively about the value of clinic generated data for retrospective and prospective use. It will be important to follow the case studies presented here and observe to what extent the new product performs well (or not) in the real-world setting to better inform the path forward,” said Dr. Miller.
The article is available online at: https://link.springer.com/article/10.1007/s43441-021-00302-y
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About the Forum for Collaborative Research
Founded in 1997, The Forum for Collaborative Research (Forum) at the UC Berkeley School of Public Health is a public/private partnership with a mission to catalyze clinical development and improve global health by facilitating research, informing policy, and advancing regulatory science. The Forum’s three-pronged approach (practice, research, education) accelerates safe drug development by increasing clarity, cooperation and innovation, while maintaining standards of evidence. Forum members work in clinical practice, research, academia, industry, regulatory authorities, and patient advocacy. Using proven models for stakeholder engagement they enhance clinical trial efficiency, support fair participation, and expand access programs. Current projects focus on transplantation associated virus infections (TAVI), viral hepatitis B (HBV), human immunodeficiency virus (HIV), nonalcoholic fatty liver disease (NAFLD)/ nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), and rare diseases.
Forum Contact
Brenda Rodriguez, Deputy Director, The Forum for Collaborative Research
This e-mail address is being protected from spambots. You need JavaScript enabled to view it
www.forumresearch.org
External controls are most effectively used when objective endpoints are available and when the treatment effect is large. Retrospective historical control data can be supplemented with other sources of evidence, such as dose-finding studies or other pharmacodynamic information. “The totality and consistency of data is what matters,” said Dr. Jerry Vockley, a geneticist treating patients with rare diseases at the UPMC Children’s Hospital in Pittsburgh and one of the co-authors of the study. “Large studies relying on randomization to minimize bias are simply not feasible for many rare diseases, yet many patients with rapidly progressing and often fatal diseases are in dire need of new treatments. We have to learn to use science in innovative ways to ensure development of effective therapies for these unmet medical needs.”
Not surprisingly, the majority (80%) of the 45 approvals leveraging external controls were for rare diseases. Additionally, of the 45 approvals evaluated, historical controls derived retrospectively from natural history data were the most common source (44%) of external control. “While retrospectively collected natural history data may introduce bias, approaches to address bias exist and should be leveraged appropriately to support regulatory decision-making. Collaboration across regulators, clinicians and statisticians, with input from patients and caregivers will be necessary to support continued adoption of innovative approaches to clinical trial design, and to ensure focus on what is clinically meaningful, with the goal of making treatments available to patients,” commented Adora Ndu, Group Vice President, Head of WWRD Strategy, Scientific Collaborations and Policy (SSCP) at BioMarin Pharmaceutical Inc., a member organization of the Forum for Collaborative Research.
“Everyone agrees that prospectively collected natural history data is preferable, but in our real world, relevant prospective studies rarely exist. As more clinicians and patient advocates recognize the need for ‘fit-for-purpose’ data, data sharing and collaboration across stakeholder groups to bring effective treatments to market, we have an opportunity to think pro-actively about the value of clinic generated data for retrospective and prospective use. It will be important to follow the case studies presented here and observe to what extent the new product performs well (or not) in the real-world setting to better inform the path forward,” said Dr. Miller.
The article is available online at: https://link.springer.com/article/10.1007/s43441-021-00302-y
###
About the Forum for Collaborative Research
Founded in 1997, The Forum for Collaborative Research (Forum) at the UC Berkeley School of Public Health is a public/private partnership with a mission to catalyze clinical development and improve global health by facilitating research, informing policy, and advancing regulatory science. The Forum’s three-pronged approach (practice, research, education) accelerates safe drug development by increasing clarity, cooperation and innovation, while maintaining standards of evidence. Forum members work in clinical practice, research, academia, industry, regulatory authorities, and patient advocacy. Using proven models for stakeholder engagement they enhance clinical trial efficiency, support fair participation, and expand access programs. Current projects focus on transplantation associated virus infections (TAVI), viral hepatitis B (HBV), human immunodeficiency virus (HIV), nonalcoholic fatty liver disease (NAFLD)/ nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), and rare diseases.
Forum Contact
Brenda Rodriguez, Deputy Director, The Forum for Collaborative Research
This e-mail address is being protected from spambots. You need JavaScript enabled to view it
www.forumresearch.org