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FDA proposes collaborative approach for pediatric rare disease research

December 18, 2017

For more efficient development of treatments for pediatric rare diseases, sponsors can implement controlled, multiarm, multi-company clinical trials, according to a new draft guidance that the FDA says could help eliminate the need for certain studies.

The proposed, double-blind design would minimize the number of patients receiving a placebo, using a single control group for multiple investigational drugs. In addition, a single treatment arm could be stopped early following clinical decline.

While the guidance itself focuses on treatments for Gaucher disease, a rare, inherited metabolic disorder, the FDA hopes the plan can be extended as a model for other areas of pediatric drug development, according to CDER Director Janet Woodcock.

The draft follows a joint plan published by the FDA and the European Medicines Agency earlier this summer, which also explored data extrapolation and modeling in pediatric populations (DID, July 5).

Rare disease product development is frequently difficult due to small patient populations, even worldwide. Gaucher disease is estimated to affect 6,000 patients in the U.S. alone, according to the agency, with enzyme replacement therapy being the current standard of care.

“People should really look at this draft guidance,” said former FDA Commissioner Robert Califf Wednesday after the document was published, describing it as a smart approach for rare diseases. Additionally, a ubiquitous electronic health record system would provide an opportunity to recruit patients into trials and assist in postmarket monitoring, Califf said.

The FDA is proposing equal accrual to each product arm, although unequal allocation may be considered, such as a 2-to-1 ratio. Study duration should account for two years of treatment, plus long-term safety monitoring in an extension study at least three years long, although the agency recommends a minimum of five.

The sample size should be large enough to detect noninferiority in the primary endpoint with 80 percent power and a false-positive error rate of 0.025 for each investigational product. The active control group should consist of standard ERT, with add-on placebo designs considered if drugs have different mechanisms of action, the guidance said.

Endpoints should also be chosen based on mechanisms of action. In Gaucher disease, the FDA suggests measuring changes in blood counts, such as hemoglobin, platelet or antibody levels; growth rate in height and weight; pulmonary function; liver and spleen sizes compared to baseline; and bone manifestations, including pain intensity, duration and fractures.

The full guideline is available here: fdanews.com/12-06-17-FDAGaucher Guidance.pdf.