Rare disease stakeholders are pressing for more specific criteria for biomarker and surrogate endpoint validation that would allow an easier route through accelerated approval, but FDA continues to argue that such general standards may not be possible to enumerate.

The agency still believes the best advice for judging a validation package for a potential biomarker or surrogate endpoint is its past experience.

Investors, who have argued for more agency flexibility and predictability in decision-making, and sponsors, who need their funding, will not be entirely pleased with those comments. It indicates that while FDA wants to work with sponsors to find rare disease treatments, it cannot write general criteria that incorporate the regulatory flexibility the industry also craves.

Marc Walton, associate director of the Center for Drug Evaluation and Research’s Office of Translational Sciences, said during a May 15 workshop on accelerated approval that decisions likely will remain on a case-by-case basis.

“I think it’s really not going to be feasible to create some sort of generalizable but very concrete rules about how to assess this,” Walton said.

“I think the generalizable principles can be discussed … but we need ultimately to have some way of concretely discussing the data in any particular case. And there my only suggestion is to really look at all the cases that we have of past experience as trying to use biomarkers as surrogates and understanding how a strong case was built.”

Evidence Required Depends On Disease, FDA Says

A group of rare disease advocates and others, led by Emil Kakkis, president of the EveryLife Foundation for Rare Diseases, is writing a white paper on the use of accelerated approval in rare diseases that it hopes will inform and influence FDA’s upcoming guidance on the subject Also see "Regulatory Freelancing: Rare Disease Group Hopes To Shape FDA Guidance" - Pink Sheet, 22 April, 2013..

Congress mandated that FDA issue guidance on an expansion of accelerated approval use as part of the FDA Safety and Innovation Act, the 2012 legislation that renewed the prescription drug user fee program and made other changes Also see "FDASIA Is Signed, Not That White House Wanted Anyone To Notice" - Pink Sheet, 16 July, 2012..

A draft of the white paper has been written and, following the workshop, will be revised and submitted for publishing as well as to FDA.

The draft indicates a case-by-case approach to determining the information necessary for biomarker qualification “does not provide adequate regulatory predictability, diminishing support for investment in the development of treatments for some rare diseases.”

Accelerated approval allows for clinical trials to be based on surrogate endpoints when they can be shown to be reasonably likely to predict clinical benefit. The draft white paper argues that FDA has not defined that standard well.

“Criteria are required that provide a scientific framework for qualifying the use of a biomarker endpoint as a surrogate endpoint, without requiring information that is impossible or impractical to collect,” according to the document.

But FDA officials said biomarker and surrogate endpoint decisions are going to be partially contingent on the disease in question.

“In asking whether or not the weight of evidence is higher in one case or lower in the other case, I think that’s not a question that can be answered because the weight of the evidence is always relative to the context it’s in,” Walton said.

As drug development costs have increased, investors have argued FDA must be more flexible, especially in the rare disease area, to attract more capital to the sector.

One venture capitalist, Jonathan Leff of Deerfield Management, has argued that FDA should look at the totality of evidence and could approve products if it believes safety and efficacy has been shown, even without clear statistical proof Also see "Should FDA Be Forced To Consider Development Time And Cost?" - Pink Sheet, 12 November, 2012..

FDA has consistently argued that it can and does use flexibility in the evidence it accepts for approval, including for orphan products Also see "Regulatory Flexibility Staring Contest: Will Industry Or FDA Blink First?" - Pink Sheet, 24 October, 2011..

“We Should … Write Them All Down”

One of the ways FDA can improve its flexibility and predictability is to do a better job of making successful surrogate endpoint and biomarker approvals available to the public.

Robert Temple, FDA deputy director for clinical science, acknowledged during the workshop that the agency should better define its interpretation of the “reasonably likely to predict clinical benefit” standard for sponsors.

“We’ve never written down in much detail what we mean by reasonably likely and maybe that’s something we should do,” he said. “I agree we should give all of our examples and write them all down and we’ll give people an idea of what it means.”

Several potential considerations for qualifying biomarkers were provided in the draft white paper, including clinical trial designs that could be allowed for rare diseases in cases where data is hard to collect.

If long-term clinical outcome data is not available, cross-sectional survey studies using a biomarker and known clinical condition were suggested, which “can be conducted prior to the investment in manufacturing a drug to assist in the determination of the utility of the biomarker, when this is reasonable and practical.”

“The large expense of natural history studies, selection biases, and the long time period for conduct required to make meaningful conclusions have made it exceedingly difficult to collect the kind and quality of data required for assessment of biomarkers in a time frame that allows for a real impact on rare disease programs,” the group wrote in the white paper.

FDA has pushed rare disease advocates and others to invest in natural history studies so new drug candidates can be evaluated faster Also see "Rare Diseases Need Ongoing Natural History Studies To Speed Trials, FDA Says" - Pink Sheet, 14 November, 2011..

How Do We Judge This Information?

One hole FDA found in the draft white paper was a lack of advice on how any biomarker or surrogate endpoint information related to accelerated approval should be assessed by the agency.

Walton said FDA has a much tougher job determining the quality of the data once it has been submitted. He said rare disease patients, advocates and others should try to help FDA make those decisions.

“The really more difficult next step that we all as a community need to try to address … is once you have any given set of information, how does one judge the strength of it,” he said. “Making those judgments is very difficult and I don’t think the paper at the moment tries to attempt that … And whatever headway can be made on that … is valuable.”

FDASIA required more patient involvement in the drug approval process. The agency is conducting several disease-focused meetings to gain patient input on the quality of the existing armamentarium and degree of risk patients are willing to accept.

The next meeting will address HIV ([A#14130514002]).

Walton also said the white paper should be careful not to advise that some data is too difficult to obtain and sponsors should not attempt to collect it.

Temple cautioned that accelerated approval should not always be the primary pathway for a new treatment and sponsors should conduct clinical trials with traditional endpoints where possible.

He also said the white paper should not convey that for severe diseases the standard for evidence can be weaker.

“I don’t think it’s as hard as the white paper suggests to actually get data on these matters for drugs that really work,” Temple said. “One of the things that worries me a little bit in the white paper is it conveys the idea that it’s just impossible to study these things, and I’m not sure that that’s true.”

Kakkis said the goal of the white paper is not to open new doors, especially to lower approval standards. He indicated language could be changed to ensure that sentiment is clear.

FDA’s accelerated approval guidance could be included in a comprehensive expedited approval document that is expected to describe and differentiate the various pathways. It is scheduled for release this year Also see "FDA To Provide Expedited Approval Desktop Reference" - Pink Sheet, 29 October, 2012..

Biomarkers In Orphan Studies Still Need Past Experience, FDA Says

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