Sponsors working on developing drugs for rare diseases should increase their efforts to obtain natural history data, which can improve the rigor of their drug development programs and help support clinical trials.

Natural history control groups can provide safety and efficacy data on rare disease treatments, especially when a placebo can’t be used, and can help justify a biomarker as a surrogate endpoint and make a trial more comprehensive, says Dr. Nathaniel Katz, chief science officer of WCG Analgesic Solutions.

“In rare diseases, it’s become very important, and I think those of us who work a lot in diseases that aren’t rare can actually take a page out of the book of people who are studying rare diseases and probably benefit our programs from studying natural history in the way that has been led by people working in the rare disease space,” Katz said.

The FDA issued draft guidance in 2019 on the strengths and weaknesses of various types of natural history studies, data elements and research plans, and a framework for conducting such studies.

“Collaborate with patients to gather natural history data. Natural history data is often missing from rare disease drug development because it hasn’t been gathered,” advised Steve Smith, president of patient advocacy at WCG. “[There are ways] FDA can use that natural history data to understand the context in which your drug development project data has come across to them.”

Brad Sippy, founder and CEO of Tremeau Pharmaceuticals, a Concord, Mass.-based pharma company developing nonopioid pain treatments, has witnessed the complex nature of rare disease trials firsthand in the development of the company’s hemophilic arthropathy drug candidate, TRM-201 (rofecoxib), which is now in phase 3.

“This is a unique condition [we’re studying] … and applying a one-size-fits-all kind of clinical design that may be used for a larger osteoarthritis trial, for example, doesn’t quite work in a space like this,” Sippy said at a recent WCG webinar on studying pain in rare disease trials.

With TRM-201 and its pivotal trial, for instance, the trial is small by pain study standards but large for an orphan drug indication, Sippy said. The FDA does recognize the complexity of the trial and is giving some leeway, but regulators and investigators both have required education and training on how a trial like this can be successfully conducted, he said.

In Tremeau’s case, Sippy said the company has been “multifaceted” in communicating with patient advocacy groups. For example, the company has engaged with the National Hemophilia Foundation and opted to provide its trial research instrument and study design to hemophilia patient advocacy groups for review, he said.