Surrogate Marker Has to Suffice for Rare Disease, FDA Says

Susan London

March 26, 2015

Forced vital capacity (FVC) is an acceptable surrogate endpoint when it comes to approving new agents for the treatment of idiopathic pulmonary fibrosis (IPF), the US Food and Drug Administration (FDA) has decided. Now, two physicians explain the agency's rationale in a perspective article published in the March 26 issue of the New England Journal of Medicine. Outside experts said the agency made the right call.

The agency initially rejected a marketing application for pirfenidone (Esbriet, InterMune) in 2010, because it was unclear whether FVC was an adequate marker for clinical benefit.

However, in a turnabout, last fall, the agency approved pirfenidone and a second agent, nintedanib (Ofev, Boehringer Ingelheim), for IPF on the basis of studies showing a slowing of the decline in FVC with the drugs compared with placebo. This benefit was supported by nonsignificant trends toward reduced mortality, but the studies were too small to adequately assess this endpoint.

"Both drugs posed a similar regulatory challenge, in that the primary efficacy variable studied in both cases was the change in [FVC]," write Banu A. Karimi-Shah, MD, and Badrul A. Chowdhury, MD, PhD, from the Division of Pulmonary, Allergy, and Rheumatology Products, Office of New Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland. "Given that IPF causes a progressive decline in pulmonary function in a restrictive, or scarring, pattern, it seems logical to monitor for a change in a lung-function parameter such as FVC that reflects such changes. But the threshold for a clinically meaningful decline in FVC is uncertain, and the variable had not been validated as a surrogate for likelihood of death or other clinically meaningful efficacy variables in IPF."

They continue, "In the absence of a valid surrogate or biomarker for a clinically meaningful measure of efficacy, the FDA took the position that an effect on mortality would be the most unequivocal and clinically important measure of efficacy against this progressive and ultimately fatal disease. Academic and industry experts, however, asserted that it was impractical to design studies to examine mortality among patients with IPF, given the large number of patients and long duration that would be required. The FDA was therefore persuaded to accept study designs using FVC decline as the primary efficacy variable."

Roham T. Zamanian, MD, an associate professor of medicine and director of the Adult Pulmonary Hypertension Service at the Stanford University School of Medicine in California, endorsed the FDA's acceptance of FVC data.

"Nothing is ever a great endpoint in any of these rare diseases," he told Medscape Medical News. "But in reality, it's the best that one could do for IPF, just because of the aggressive nature of the disease and the significant morbidity and mortality that's associated with it." He added that it would be very difficult to adequately power a study to detect reductions in mortality, and that a meta-analysis might be at least 5 years away.

"Something very, very important seems to have happened in the field, and it's great that it happened: evolution of the perspective of the FDA in accepting an endpoint that they initially did not want to accept," he said. "Now they have come to realize, through collaboration with academics and industry, that it's necessary to develop therapeutics to accept FVC as a relevant clinical endpoint for IPF. Without that collaboration, there probably would not be any therapeutics yet for this deadly disease."

There have been precedents for accepting surrogate endpoints in some other rare pulmonary diseases, according to Dr Zamanian. For example, the 6-minute walking distance has been used as a surrogate for other clinical outcomes in pulmonary arterial hypertension.

"We have to come down to reality and realize that in order to get approval and do scientific studies for rare diseases, we have to accept some of these markers that are not excellent markers of outcome," he said. "But they are what they are. They are sort of [real-world] markers. They are measurable, they are standardizable across different centers, and common practicing physicians will sort of have an impression of what [a change in that marker] will mean for their patient."

David M. Perlman, MD, an assistant professor of Pulmonary, Allergy, and Critical Care Medicine, and codirector of the Interstitial Lung Disease Program at the University of Minnesota in Minneapolis, likewise agreed that accepting FVC data was a wise pragmatic move in a difficult situation.

"I think that most people would rather have mortality as the primary endpoint, but knowing that it's probably not feasible to do that, FVC is a good substitute for that. It's probably as good as we have," he told Medscape Medical News.

"The general feeling, for myself and most people, is that FVC is a clinically meaningful endpoint. A decline in FVC has been shown to be associated with increased risk of mortality," he added.

Dr Karimi-Shah and Dr Chowdhury disclosed no conflicts of interest. Dr Zamanian disclosed that his wife is an employee of Genentech/Roche, which recently acquired InterMune. Dr Perlman disclosed that he has done advisory work for InterMune and that his institution was a site for trials of both drugs.

N Engl J Med. 2015;372;1189-1191. Abstract


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