To Increase Pace and Volume of Drug Approvals for Rare Diseases, Report Recommends FDA Enhance Information Sharing, Improve Collaboration

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To Increase Pace and Volume of Drug Approvals for Rare Diseases, Report Recommends FDA Enhance Information Sharing, Improve Collaboration

News Release| September 12, 2024

WASHINGTON - The Food and Drug Administration should enhance information sharing, advance the regulatory science needed to evaluate rare disease drugs, improve engagement with people with rare diseases and their caregivers, and enhance collaboration with the European Medicines Agency to increase the pace and volume at which drugs to treat rare diseases and conditions are developed and approved, says a new report from the National Academies of Sciences, Engineering, and Medicine.

The challenges for people living with rare diseases - those with a patient population smaller than 200,000 - are numerous and often daunting, including the scarcity of drugs approved to treat their illness. Together, rare diseases affect up to 30 million individuals in the United States, 36 million in the European Union, and at least 300 million across the globe.

Historically, rare disease drug development has been largely neglected by the pharmaceutical industry. Following passage of the Orphan Drug Act in 1983, which was intended to spur development and innovation, there has been a marked increase in the investment and successful development of drugs to treat rare diseases and conditions, the report says. And yet less than 5 percent of all rare diseases have approved products on the market today.

The report points to several underlying barriers to rare disease drug development, including the general lack of understanding of many rare diseases compared to common diseases, a lack of defined endpoints in rare diseases by which to evaluate the efficacy of a drug, and limited patient populations.

"While rare diseases by definition have small patient populations, together, they afflict hundreds of millions of people - meaning very large numbers of people across the world have no drug designed to treat their condition," said Jeffrey Kahn, chair of the committee that wrote the report and Andreas C. Dracopoulos Director of the Johns Hopkins Berman Institute of Bioethics. "Our report shows that regulators can improve their processes for reviewing and approving rare disease therapies by better engaging patients in the process from start to finish, advancing regulatory science, and improving collaboration between government agencies in the U.S. and the EU."

The report also analyzes the differences and similarities between FDA's process for evaluating rare disease drugs and that of EMA, which is responsible for evaluating drug safety and efficacy in the EU. Despite some key differences, the two agencies have similar approaches and often come to similar decisions about the same drugs. Due to the nature of rare disease drug development (e.g., small patient populations and high rates of morbidity and mortality), early collaboration and information exchange between the agencies to coordinate on study design and align on data requirements could help reduce duplication of clinical testing and streamline the regulatory process for sponsors submitting marketing authorization applications to both agencies. The report says more collaboration between them would stimulate global innovation and drug development for rare diseases.

"In recent years, the world has seen incredible innovation in developing new and effective therapies," said Victor J. Dzau, president of the National Academy of Medicine. "This report provides a path forward for increasing the odds that those living with a rare disease will also be able to benefit from these advances."

If researchers and sponsors working on rare disease drug development had a better understanding of the reasons for successes and failures of drug authorization applications, they could design new therapeutics that have a higher likelihood of reaching people living with a rare disease, the report says.

FDA should take steps to make information publicly available and accessible on authorization submissions, review milestones, negative reviews and approvals, and the use of regulatory flexibilities for rare disease drugs, the report says. This information can inform sponsors, people living with a rare disease, researchers, and other FDA reviewers on the rationale for FDA's decision on individual rare disease drugs, and when and how policies have been applied. The report acknowledges potential legal challenges in disclosing some of this information, but it says FDA should work to mirror the level of information disclosed by EMA, build on the efforts of the 2010 FDA Transparency Task Force, organize information so that the public can identify trends, and link clinical trials to FDA decisions to help the public better understand the process.

The report finds that FDA is using available mechanisms to gather input from people living with a rare disease, but there are opportunities for improvement, and more clarity is needed on how their input is currently being used in the regulatory decision-making process. The FDA should strengthen mechanisms to integrate input from people with rare diseases or their caregivers throughout the full continuum of the drug development process. FDA and NIH, working with EMA, should also implement new navigation services for drug sponsors, investigators, and patient groups to provide advice on the best regulatory pathway for a new drug, and to provide more clarity on meeting FDA requirements and policies.

There are several existing programs to support drug development for rare diseases. The report recommends FDA assess the impact of these programs, share the results publicly, and then scale up and expand successful programs and modify or sunset those that are not improving the regulatory process.

Much of the data to support licensure applications for new drugs submitted for FDA approval comes from randomized controlled clinical trials (RCTs), which often include large numbers of patients and test the efficacy of the drug against a control group - a method considered the gold standard for research. Data from sources other than RCTs is referred to as "alternative and confirmatory data." For many rare diseases, the population of people living with the disease is so small that RCTs are infeasible. The report says natural history data - a type of alternative and confirmatory data that describes changes to a patient's disease state over time - is important for determining the effectiveness of a rare disease drug. Several other types of alternative and confirmatory data, such as information from patient registries, claims, and electronic health records, could also help inform regulatory decision-making. The report recommends FDA enable the collection of natural history data and enhance the quality and accessibility of natural history data.

To help improve the use of this type of information, FDA should also invite EMA to conduct a joint systematic review of drug applications for rare diseases and how alternative and confirmatory data contributed to regulatory decision-making, the report recommends. FDA should collect and disseminate information on state-of-the-art regulatory science, including effective ways to use alternative and confirmatory data.

The majority of rare diseases affect children. The report says congressional action is needed to encourage and incentivize more research to develop therapies for rare diseases in pediatric populations, and FDA and NIH should also take steps to provide clarity on regulatory policies for including pediatric populations early on in clinical trials.

Undertaken by the Committee on Processes to Evaluate the Safety and Efficacy of Drugs for Rare Diseases or Conditions in the United States and the European Union, the study was sponsored by the U.S. Department of Health and Human Services.

The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, engineering, and medicine. They operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln.

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