Upcoming prescription drug user fee renewal legislation still may include some form of expansion for FDA’s accelerated approval program, but the early nature of the current proposals suggests major work is needed to get the reforms added to the bill.

Draft language being circulated by the Biotechnology Industry Organization would add more detail on specific types of non-traditional evidence to the accelerated approval regulation.

BIO’s draft language is a substitute for the progressive approval concept intended to help speed up FDA approvals. It was floated in a draft bill by Sen. Kay Hagan, D-N.C., but has been scrapped in the face of opposition from FDA and other parties Also see "BIO Wants Expanded Accelerated Approval In PDUFA Instead Of Progressive Approval" - Pink Sheet, 23 January, 2012..

BIO’s new draft also would include a targeted subpopulation as a basis for the intended clinical effect and add evidence based on biomarkers and other tools as possible to predict a benefit.

Another proposal, known as the Unlocking Lifesaving Treatments for Rare Diseases Act (ULTRA), would insert new language to allow rare disease drug approvals based on surrogate endpoints and “shall not require clinical treatment data or other historical clinical data” as a prerequisite to endpoint assessment, according to bill text. Rep. Cliff Stearns, R-Fla., introduced it Dec. 20.

Concerns about ULTRA arose during a Feb. 1 House Energy and Commerce Health Subcommittee hearing on the Prescription Drug User Fee Act reauthorization.

Co-sponsor Edolphus Towns, D-N.Y., said he has to make major changes to the bill, but would not comment on the planned revisions. He and Stearns said in a written statement they were willing to work with stakeholders to make improvements.

“There’s a lot of problems with it,” Towns said after the hearing. “We’re trying to get stakeholder input. We have to continue to dialogue.”

Expanding the accelerated approval pathway emerged over the last few months as a potential addition to PDUFA reauthorization. Industry wants it to allow FDA to move new treatments to market faster.

ULTRA also is intended to accomplish those goals.

But Rep. Henry Waxman, D-Calif., an influential member of the Energy and Commerce Committee, and a representative of the National Organization for Rare Disorders indicated their opposition to the legislation during the hearing.

Waxman said he was concerned about a proposal that would remove FDA’s ability to require additional clinical data, if needed, to make a decision.

Diane Dorman, NORD vice president of public policy, who testified at the hearing, told Waxman her group also opposed the bill in its current form.

“We feel that ULTRA would require FDA to rely on a surrogate endpoint based on little or no clinical evidence and it could expose patients to undiscovered risk and in our opinion would lower the approval standards of the FDA,” Dorman said.

Towns said during the hearing ULTRA remained a work in progress and tried to gain some support for changing the accelerated approval pathway from a member of industry testifying at the hearing.

Towns did not seem to get an overwhelming endorsement of the bill from Geno Germano, Pfizer Inc. president and general manager of specialty care and oncology, when he asked how accelerated approval could be improved.

Germano supported the goal, but only highlighted portions of the pending PDUFA agreement.

“I think the greater amount of required interaction between the agency and the sponsor, the focus that the agency will put out a risk-benefit framework [will be helpful],” he said. “Rare and orphan disease issues that are components of PDUFA V should be helpful in improving our ability to bring these kinds of medicines to market.”

While ULTRA seems to be a candidate for inclusion in user fee legislation, it is unclear whether the necessary changes could be negotiated in time to meet the deadline. Health Subcommittee Chairman Joe Pitts, R-Pa., wants the user fee package enacted by June.

Clarifying, Not Rewriting, Regulations

The draft language BIO is circulating on the accelerated approval changes, dated Jan. 9, 2012, attempts to clarify the existing regulations by adding more detail, which could increase the pathway’s use.

The proposed changes do not appear to be a major rewrite of the accelerated approval section of the Food, Drug and Cosmetic Act. They mostly affect the requirements for approval and awareness efforts sections.

BIO would not comment on the draft’s details.

FDA already has acknowledged that accelerated approval has not been used as much as it could and that the regulations could be clarified Also see "Accelerated Approval Could Expand As Alternative To Progressive Approval" - Pink Sheet, 23 January, 2012..

The draft would add a clause to the fast-track designation section allowing drugs “alone or in combination with one or more existing drugs” for the treatment of serious or life-threatening conditions to be eligible.

In addition to adding language saying the pathway can be used if the surrogate endpoints show benefit in specific populations or subpopulations, the proposal also gives specific examples of evidence that can be submitted to predict clinical benefit.

The draft states “epidemiological, therapeutic, pathophysiologic or other evidence” can predict clinical benefit. Those already are outlined in the so-called Subpart H portion of FDA regulations dealing with accelerated approval.

The draft also says that endpoints that can be “measured early in the clinical trial process” are eligible.

“Evidence submitted in the application … based on biomarkers or other scientific methods or tools other than or used in conjunction with surrogate or clinical endpoints, to predict clinical benefit…” also would allow an accelerated approval.

Unlike ULTRA, BIO’s draft language says evidence submitted in an accelerated approval application shall include clinical trial data.

The draft also would require FDA to establish programs to encourage development of biomarkers and other scientific methods and tools to help FDA determine if those submitted will predict clinical benefit as required.

Some of those programs are part of the PDUFA agreement. Industry and FDA agreed to devote user fee revenue to expand teams researching biomarkers and pharmacogenomics and create a patient-reported outcome qualification unit Also see "PDUFA V: Final Recommendations Fund Proposals In Two Of Three Tiers" - Pink Sheet, 2 May, 2011..

Accelerated Approval Expansion Proposals Pending, But One Needs An Overhaul

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