Drugmakers Seek US, EU Harmonization on NASH Drug Development Guidance

Regulatory NewsRegulatory News | 15 August 2019 |  By 

Novartis, Gilead, Regeneron, Novo Nordisk, Boehringer Ingelheim and others recently told the US Food and Drug Administration (FDA) to better align its draft guidance on drugs to treat nonalcoholic steatohepatitis (NASH) with compensated cirrhosis with the European Medicines Agency (EMA).

They also took issue with the way that the latest NASH draft guidance, released in June, does not seem to allow for the use of the accelerated approval pathway. The draft guidance follows a separate draft guidance issued in December that provides recommendations for early NASH drug development and developing drugs to treat noncirrhotic NASH.

Boehringer explains how harmonizing both FDA draft NASH guidances with the EMA’s NASH reflection paper from last November could advance drug development. Novo Nordisk similarly says a lack of such alignment “will make comprehensive global development programs in NASH extremely challenging. Sponsors may thus be discouraged from including patients with NASH and compensated cirrhosis in their development programs due to the long timeframe, high risk and high investment required for this population.”

And Regeneron suggests that where there is agreement about scientific and regulatory principles between FDA and EMA, recommendations should be harmonized.

Novartis, meanwhile, explains how FDA in its final guidance “should consider including hepatic venous pressure gradient (HVPG) or change in model for end-stage liver disease (MELD) and possibly other potential (surrogate) endpoints worthy of exploration in Phase II and potentially Phase III,” noting that both HVPG and change in MELD are mentioned in the EMA reflection paper, “therefore inclusion would lead to closer alignment in this area of NASH development between the two regulatory agencies.”

Novo Nordisk also notes how if outcome trials are required, “This will prevent or halt the development of new treatments in NASH.

“By excluding the possibility for using the accelerated approval pathway for NASH compensated cirrhosis at present, FDA is limiting generation of new important data on histological changes as a surrogate or as a clinical endpoint in NASH compensated cirrhosis. This data may indeed demonstrate prevention or reversal of liver damage, thus, meeting the need for new treatments in the compensated cirrhosis NASH population with the highest unmet medical need,” Novo adds. “If surrogate endpoints are demonstrated to be effective in noncirrhotic (fibrosis stage 2 and 3) NASH patients, we do not understand why the same surrogate endpoint would not be useful to assess compensated cirrhosis NASH patients.”

Gilead similarly calls on FDA to reconsider its “strong recommendation for clinical outcome trials.”

“Patients with cirrhosis due to NASH represent the population that may progress to serious clinical complications the fastest and are therefore the population with the greatest unmet medical need,” Gilead says. “The development of a treatment using a surrogate endpoint reasonably likely to predict clinical benefit will allow patients with cirrhosis to receive therapy while clinical outcome trials of longer duration are ongoing. Surrogate endpoints accepted for noncirrhotic patients should be acceptable for cirrhotic patients. There is significant overlap between F3 and F4 populations.”



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