WASHINGTON – The practice of accelerated approval needs to live up to what the law allows, a House subcommittee was told Thursday as it considered a number of issues riding the coattails of PDUFA.

"The accelerated approval pathway has been a great success story, in part," John Maraganore, CEO of Alnylam Pharmaceuticals Inc., testified before the House Health Subcommittee.

While the pathway has "stimulated an explosion of investment in innovation" in therapies for cancer and HIV/AIDS, he noted that promising treatments for other rare and life-threatening diseases have been excluded from the path – not by the statute that established the approval route, but by the way it is being practiced.

Part of the problem is confusion over the use of surrogate and early clinical endpoints in trials. The pathway allows for approval based on endpoints that are "reasonably likely to predict clinical benefit," Maraganore said.

But the FDA has been hesitant to accept, as a demonstration of reasonable likelihood of clinical benefit, surrogate endpoints or clinical endpoints that can be measured earlier than irreversible morbidity or mortality.

Maraganore urged support of the FAST Act, H.R. 4132, which would turn most of the current accelerated approval regulations into law and modernize the program to reflect scientific and medical advances made in the past 20 years.

The FAST Act, introduced in the House this week, calls for the FDA to apply accelerated approval and fast-track provisions to the "greatest extent possible" to expedite access to drugs for serious and life-threatening diseases or conditions while maintaining appropriate safety and efficacy standards.

The bill also would allow expedited withdrawal of approval if a sponsor fails to conduct required post-approval studies in a timely manner, safety or efficacy issues arise, post-approval studies fail to verify efficacy or the sponsor disseminates false or misleading promotional materials about the drug.

Jeff Allen, executive director of Friends of Cancer Research, also testified of the need for enhanced accelerated approval and offered another suggestion – a "breakthrough product" designation for new compounds that show substantial clinical activity in early phase trials.

With that new designation, a sponsor would work closely with the FDA to develop trial designs to abbreviate or combine the traditional phases of drug development. "This would shorten the pathway to approval and avoid giving larger numbers of patients a potentially harmful or ineffective drug as part of a control arm, while maintaining current safety and efficacy standards," Allen said.

In her testimony, Janet Woodcock, director of the FDA's drug center, acknowledged that use of the accelerated approval pathway has been limited somewhat by confusion among industry and agency staff. The FDA is working on a guidance to clarify use of the pathway and explain evidence criteria.

While the agency is open to surrogate and earlier clinical endpoints, Woodcock said there's considerable discussion about the magnitude of the response needed to predict clinical benefit.

Incentives for Antibiotics

Another bill that's being considered as part of the PDUFA reauthorization is the Generating Antibiotics Incentives Now (GAIN) Act, H.R. 2182 and S. 1734. Proposed as an economic incentive to develop much-needed antibiotics, the bill would extend exclusivity for new antibiotics to 15 years with an additional six months of exclusivity if a companion diagnostic is identified.

Besides providing economic incentives, the GAIN Act would require the FDA to grant priority review and fast-track designation for qualifying antibiotic candidates. It also would require the agency to revise clinical trial guidelines for antibiotics to provide clarity and reflect new advances.

As proposed, the bill would include a list of pathogens qualifying antibiotics would have to target. Rep. John Shimkus (R-Ill.) expressed concern about the possibility of the FDA delisting a pathogen after a company had started to develop an antibiotic to target it. That would introduce more uncertainty to the space, make it difficult for small drugmakers to attract investors and discourage innovation, he said.

John Powers, a professor at the George Washington School of Medicine and a former FDA scientist, said rather than focusing on pathogens, the bill should concentrate on life-threatening conditions caused by the pathogens. Targeting pathogens instead of serious infections could ultimately lead to more drug resistance as the antibiotics could be used for minor infections that would heal on their own, he explained.

Woodcock said a good stewardship program should be tied to antibiotic incentives to avoid the overuse of the drugs, which leads to drug-resistant microbial strains.

But Barry Eisenstein, senior vice president for scientific affairs at Cubist Pharmaceuticals Inc., said the days of doctors using antibiotics "willy-nilly" are over. Today's provider community understands the problems overuse creates and is much more careful in prescribing the drugs.

Calling the GAIN Act the best hope to stimulate antibiotic innovation, Eisenstein said it could do for the antibiotic space what orphan drug designation did for increasing treatments for rare diseases.

PDUFA Add-ons

The FAST and GAIN acts are just two bills on a growing list of proposed legislative add-ons to the user fee reauthorization. The Health Subcommittee also heard testimony on regulating medical gases and protecting the drug supply chain.

Noting all the various bills piling on PDUFA, Rep. Henry Waxman (D-Calif.) sounded a word of caution, saying they could weigh down the progress of the underlying user fee legislation. Some of the bills proposed as add-ons deal with issues that merit serious consideration rather than being rushed through with PDUFA, he said. (See BioWorld Today, Feb. 29, 2012.)

However, a number of the bills that could be attached to PDUFA have been sitting in the subcommittee for nearly a year with no action. The GAIN Act, for instance, has been in the subcommittee since last June. And its counterpart, S. 1734, has been in the Senate Health, Education, Labor and Pensions Committee since October. (See BioWorld Today, Feb. 27, 2012.)

Legislative Progress

Meanwhile, a few bills that could affect drugmakers saw some major movement this week:

Thursday, the House passed H.R. 3606, a capital formation package that will benefit emerging growth companies by providing a five-year on-ramp to the public market, raising the SEC's Regulation A cap to $50 million, increasing the SEC registration shareholder threshold to 1,000 and opening the door to crowd funding. The bill will now go to the Senate, which could announce its own proposal this week. (See BioWorld Today, March 7, 2012.)

Wednesday, the Senate unanimously approved reauthorization of the Pandemic and All-Hazards Preparedness Act, S. 1855. It still needs House approval before it goes to the president. (See BioWorld Today, Nov. 16, 2011.)

Tuesday, the Senate passed S. 1886 to stiffen the penalties for counterfeit drugs and referred it to the House.

The Senate Judiciary Committee Thursday unanimously voted to send the SAFE DOSES Act, S. 1002, to the full Senate. (See BioWorld Today, March 5, 2012.)

The House Ways and Means Committee voted Thursday to repeal the Independent Payment Advisory Board, sending H.R. 452 to the full House. The House Energy and Commerce Committee approved H.R. 452 earlier this week. (See BioWorld Today, July 14, 2011, Sept. 20, 2011, and March 2, 2012.)