12:00 AM
Mar 25, 2013
 |  BioCentury  |  Regulation

Reframing FDA

Dissecting FDA's benefit-risk framework; potential impact on drug reviews

Industry, patient and investor stakeholders say FDA's new benefit-risk framework could become a powerful aid to communication and discussions with the agency. But so far the agency has no plans to share the documentation created by the scheme with sponsors or the public, except after a product approval and probably in advisory committee meetings.

Thus the framework's most near-term effect will be within FDA, where the new tool will assist the agency with its most difficult decisions - including the resolution of internal disagreements about the balance between benefit and risk.

In a draft five-year plan released on March 5, FDA revealed the components of the so-called framework, which will standardize the way reviewers consider benefit and risk for new drugs and biologics using five "decision factors." These include assessments of the severity of the condition the drug is meant to treat, the available treatments, clinical data on both benefit and risk, and efforts that could help mitigate risks after approval.

Patrick Frey, director of CDER's Office of Planning and Analysis, and Theresa Mullin, director of the Office of Planning and Informatics, told BioCentury the framework does not represent a change to the review and decision making process, but rather provides a way to structure the many considerations that already go into reviews.

"It's more enhancing than changing," said Mullin.

"The framework gets all the review issues on the table at the same time so all members of the review team as well as review management can get the full picture of what an application looks like," said Frey.

Getting FDA staff and leadership on the same page and focusing them explicitly on benefit-risk trade-offs will be hugely important, according to sponsors, investors and patient representatives.

"It really puts risk-benefit - not just safety and efficacy - at the center of the review process," said John Maraganore, CEO of Alnylam Pharmaceuticals Inc. "Overall, it's a major step forward."

Maraganore is vice chair of the Emerging Companies Section at BIO.

Jonathan Leff, a partner at Deerfield Management and chairman of the Deerfield Institute, believes the framework could have the biggest impact of any of the regulatory reforms mandated by PDUFA V and the FDA Safety and Innovation Act (FDASIA).

"Breakthrough approval and accelerated approval are good and important, but this benefit-risk framework cuts across all of it and gets to the core challenge FDA faces," Leff told BioCentury.

Leff is a member of the executive committee of the board of the National Venture Capital Association (NVCA), chair of NVCA's Medical Innovation and Competitiveness Coalition and a member of the Emerging Companies Section board of directors at BIO.

From the patient perspective, "this is a huge step," said Marc Boutin, EVP and COO of the National Health Council, an umbrella group for patients with chronic diseases.

Currently, "if you are a patient, and FDA makes a decision, you don't know what the quantitative input was or what the judgment was, so you can't even have a discussion," he said. "You're never really able to get at something that really reflects the judgment of the end-user."

The stakeholders said they hoped the agency would find ways to incorporate the framework into discussions with sponsors earlier in the review process and suggested it was important to more explicitly prescribe the role of patients in weighing risk and benefit.

The agency has completed a pilot of the framework process in anticipation of including it in reviews beginning in fiscal 2014.

Speedy delivery

The creation of a structured benefit-risk framework began in 2009, and completing and implementing it is one of FDA's PDUFA V commitments (see BioCentury, July 2, 2012).

Because FDA leadership believed the framework would be especially useful in reviews where the benefit-risk decision is difficult, the agency began with a retrospective review of four case studies chosen precisely because they had been challenging.

"These cases provoked more internal discussion and deliberation than is generally required for more straightforward benefit-risk decisions," said Frey.

FDA said the case studies included approval, non-approval and postmarketing actions.

Only one of the cases is disclosed - the review in 2006 of an application to resume marketing of multiple sclerosis drug Tysabri natalizumab. Biogen Idec Inc. and then-partner Elan Corp. plc pulled the drug from the market in 2005 after its use was associated with cases of progressive multifocal leukoencephalopathy (PML), including some that were fatal.

Testimony from patients about their willingness to accept the risk of PML, coupled with a unanimous advisory committee vote, helped FDA determine that the risk was outweighed by the...

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