NATIONAL HARBOR, Maryland — A crucial part of getting new therapies approved by the US Food and Drug Administration (FDA) is having regulatory-caliber natural history studies of the disease a given therapy is designed to treat.

Lucas Kempf
Parexel’s Lucas Kempf, MD, discusses the importance of natural history studies in rare diseases. Credit: Larry Luxner

That was the message delivered by Lucas Kempf, MD, when he spoke at an August 26, 2021, roundtable during the 3-day World Orphan Drug Congress USA 2021. Dr. Kempf is technical vice president at Parexel, a clinical research company, and a former official at both the FDA’s Center for Drug Evaluation and Research (CDER) and the US National Institutes of Health (NIH).

“A lot of pitfalls in developing rare disease drugs are because we don’t really know the natural history of the disease,” he said. “What you need to do in the context of developing drugs is get that natural history data in order to inform how you design the study.”

As associate director of CDER’s Rare Diseases Program, Dr. Kempf wrote much of the FDA’s natural history guidance. At the NIH’s National Institute of Mental Health, he supported research into experimental therapeutics for rare and major mental illness and translational biomarker development, with a focus on genetics and neuroimaging.

“About 10 years ago, when they started the rare disease program for CDER, the whole purpose was to accelerate drug development for rare diseases,” he said. “They did a survey of all the drugs that got approved, and what factors were key to faster approval. And one of the major things is having a better understanding of the disease. Having to alter studies as you go along is a super-inefficient way to do it.”

Over the course of a decade, Dr. Kempf’s team collected data, eventually forming a collaboration with the National Organization for Rare Disorders (NORD), which received funds to set up some natural history studies. In a natural history study, researchers collect information about the progression of a disease in the absence of an intervention, from its onset until either its resolution or the individual’s death.

The Evolution of Clinical Development for Rare Diseases

Parexel often works with small biotech companies that seek to advance therapies to the next stage then get acquired by the pharmaceutical giants. But the smaller startups frequently don’t have sufficient natural history data, he said.

“They’ve been collecting data on survival, but not how often you were hospitalized, or how much home health care you’ve had,” he said, noting that the natural history of rare diseases is often poorly understood. In addition, the small populations typical of rare diseases often restrict study design and replication, and well-defined and validated endpoints, outcome measures, and biomarkers are often lacking.

“We advise how to launch and design natural history studies in such a way that they’ll have regulatory quality, so you can leverage that for whatever you need, such as validating endpoints, developing biomarkers, and figuring out what’s feasible within that patient population,” Dr. Kempf said. “We also have a statistical group that does this for companies, to make sure they’re analyzing the data in a statistically meaningful way that will meet the threshold of regulators.”


Retrospective or prospective: designing patient-centric and regulatory-calibre natural history studies. Presented at: World Orphan Drug Congress USA 2021: August 26, 2021; National Harbor, MD.