PDUFA V Strives to Balance Safety with Timely Approvals
BioWorld Today Washington Editor
WASHINGTON – Amid criticism that the FDA has yet to strike the right balance between risk and benefit, the agency's Janet Woodcock gave a House subcommittee a sneak peak of proposed PDUFA V enhancements that would address those concerns.
Testifying before the House Energy and Commerce Subcommittee on Health last week, Woodcock acknowledged that the FDA's efforts to improve drug safety have "put strains on the review process time frames agreed to" in PDUFA IV, which expires Sept. 30, 2012.
In shifting staff resources to ensure the timely implementation of safety provisions mandated by the FDA Amendments Act (FDAAA), passed in conjunction with PDUFA IV in 2007, the agency slipped in its performance goals for timely approvals of new drugs and biologics, according to Woodcock, director of the FDA's Center for Drug Evaluation and Research.
The agency's resources also were stretched by the growth of foreign sites in clinical trials and the use of foreign manufacturing facilities, which presented challenges in conducting preapproval inspections.
Despite those difficulties, "the agency is working toward getting more products approved in the first review cycle by trying to identify factors leading to first-cycle approval," Woodcock said in her prepared testimony.
With that goal in mind, the FDA and the biopharma industry have agreed to a number of enhancements for the next round of PDUFA.
One enhancement would be to provide for pre-submission meetings, midcycle communications and late-cycle meetings in the review program for new drug applications, new molecular entities and original biologic license applications. To accommodate the additional meetings, the review clock would begin after the 60-day administrative filing period.
The FDA and industry agreed to a number of proposals to enhance the agency's regulatory science and expedite drug development. They include:
improving communications between the agency and sponsors by setting up a dedicated drug development communications/training staff to identify the best communications practices and to train review staff;
developing best practices for use of meta-analyses;
expanding the agency's capacity to address the use of biomarkers and pharmacogenomics to assess safety in early phase trials and select optimal dosing for pivotal studies;
launching an initiative to improve the FDA's clinical and statistical capacity to address submissions involving patient-reported outcomes and other endpoint assessment tools;
providing relevant guidance for the development of drugs to treat rare diseases.
PDUFA V also would enhance the agency's benefit/risk assessment by implementing a more systematic and expansive approach in the review process to "obtain the patient perspective on disease severity and the potential gaps or limitations in available treatment," Woodcock said.
To enhance drug safety, PDUFA V would standardize risk evaluation and mitigation strategies (REMS), a safety measure included in the FDAAA.
"Our experience with REMS to date suggests that the development of multiple individual programs has the potential to create burdens on the health care system and, in some cases, could limit appropriate patient access to important therapies," Woodcock noted.
The proposal also calls for a user fee-funded feasibility study of using Sentinel to evaluate drug safety issues that could require regulatory action, such as labeling changes or postmarket requirements.
The final enhancement Woodcock discussed was phasing in a requirement for electronic submissions with standardized data. "The predictability of the FDA review process relies heavily on the quality of sponsor submissions," she said. The lack of standardized data limits the agency's ability to move toward standardized benefit/risk assessments and impedes the safety analyses needed for REMS and other postmarket requirements, she added.
Of course, biopharma is expected to fund the enhancements, which the FDA projects would cost about $40.4 million, a 6 percent increase over fiscal 2012 user fees, giving the agency a total estimated base of $712.8 million for fiscal 2013.
The FDA will hold a public meeting on PDUFA V, which is to be published Sept. 1, and then formally submit it to Congress by Jan. 15. Rep. Joseph Pitts (R-Pa.), chair of the health subcommittee, said he would like to see the reauthorization signed into law by June 30, well before its expiration date.
Testifying on behalf of the Biotechnology Industry Organization (BIO), Paul Hastings, president and CEO of OncoMed Pharmaceuticals Inc., voiced industry's support for the PDUFA enhancements. But he went further in his written testimony, expressing the need for substantial changes at the FDA to reinvent the idea-to-market pathway, as proposed by BIO at its recent international conference. (See BioWorld Today, June 30, 2011.)
While some of BIO's proposals, such as making the FDA an independent agency, are big-picture policies, others get down to the nuts and bolts of everyday FDA actions. For instance, Hastings said, the FDA should be required to disclose to sponsors the reasons behind a nonapproval decision.
"When FDA makes such a finding, it should communicate to sponsors in clear terms why risk was determined to outweigh benefits," why authorities such as REMS are insufficient and what must be done to address any deficiencies, Hastings said.
Biopharma to FDA: Explain Off-Label 'Promotion'
Tired of ferreting through Department of Justice settlements and informal statements of FDA officials to ensure compliance with the agency's off-label policies, several biopharma firms filed a citizen petition requesting the FDA to clarify those policies.
"The current state of regulatory guidance is not clear or comprehensive, or in some cases, even binding," according to the petition submitted last week by Allergan Inc., Eli Lilly and Co., Johnson & Johnson, Novartis Pharmaceuticals Corp., Novo Nordisk Inc., Pfizer Inc. and Sanofi-Aventis U.S. LLC.
"This lack of clarity places manufacturers at risk of criminal and civil sanctions if they cannot correctly guess where the government would draw the line," the petition continued.
As a remedy, the firms asked the FDA to establish clear, comprehensive and binding regulations to guide industry in the following areas:
manufacturing responses to unsolicited requests;
interactions with formulary committees, payers and similar groups;
dissemination of third-party clinical practice guidelines, such as those put out by medical professional societies.
The companies noted that they dedicate a significant amount of resources to hiring compliance staff and outside counsel to guide their discussions of off-label uses, which are legal, common, reimbursable and, in some cases, the standard of care.
Published: July 11, 2011
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