The biotech industry and FDA agree that pending accelerated approval legislation would facilitate expansion of the pathway to conditions beyond HIV/AIDS and cancer, but they have different opinions about the pace and scope of change that should be expected.

BIO, which hammered out the accelerated approval proposals in discussions with FDA, expects a quick spike in the percentage of drugs marketed under accelerated approval and a boost in funding for emerging companies as investors are persuaded that expansion of accelerated approval will reduce regulatory risk.

But FDA's Janet Woodcock says the Faster Access to Specialized Treatments (FAST) Act (H.R. 4132) and similar provisions in the Transforming the Regulatory Environment to Accelerate Access to Treatments (TREAT) Act (S. 2113) will not be a quick fix.

Woodcock, director of the Center for Drug Evaluation and Research, last week told BioCentury that expanding accelerated approval is contingent on achieving scientific consensus around new endpoints, which will take time.

She also said the process isn't likely to dramatically increase the number of new drugs developed or approved.


The legislation is likely to be enacted this year as part of a package that will accompany PDUFA reauthorization.

The key language in the FAST Act and the accelerated approval provisions of TREAT express the "sense of the Congress" that FDA "should apply the accelerated approval and fast track provisions to the greatest extent possible to help expedite the development and availability to patients of treatments for serious or life-threatening diseases or conditions while maintaining appropriate safety and effectiveness standards for such treatments" (see BioCentury, Feb. 20).

The bills also codify FDA's Fast Track process, which is available to drugs to treat unmet, serious medical needs. Fast Track flags applications for more intense collaboration and makes them eligible for rolling reviews, Priority Review and accelerated approval.

The FAST and TREAT bills would create a system for sponsors to apply for Fast Track designation any time after submitting an IND, and would establish tight deadlines for FDA to respond to requests for the designation.

FAST and TREAT also specify that in addition to a surrogate endpoint that is likely to predict benefit - the criterion usually used in accelerated approval applications - FDA could also grant accelerated approval based on a "clinical endpoint, including an endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit."

FDA already has the authority under existing law and regulations to grant accelerated approvals based on clinical endpoints, but there have been few submissions or accelerated approvals based on those designs.

During a congressional hearing last week, Woodcock told Rep. Joseph Pitts (R-Pa.) that legislation "clarifying" accelerated approval would be useful.

"We have found both in the industry, in the academic community - and even sometimes within FDA itself - there is confusion about the use of accelerated approval," Woodcock said at a March 8 hearing of the Energy and Commerce Committee's health subcommittee. "We believe additional clarity on the use of this would be very beneficial."

In her testimony, Woodcock stressed that clarifying ways accelerated approval could be more widely used would not lower safety and efficacy standards, and that FDA would strongly oppose any effort to lower those standards.

Woodcock told BioCentury that FDA agrees in principle with the FAST Act's goals, but said the legislation has to be carefully reviewed to ensure it will do what its authors intend. "We agree with the sentiment behind it but have to avoid inadvertently lowering the efficacy standard," she said.

Regardless of congressional action, Woodcock said, FDA plans to "issue guidance that will clarify the use of accelerated approval and explain our evidence standards more clearly."

BIO's view

John Maraganore, CEO of Alnylam Pharmaceuticals Inc., told the subcommittee that accelerated approval has "stimulated an explosion of investment" in drugs to treat HIV/AIDS and cancer, and that it is time to expand and modernize the pathway so it is applied to other indications.

Maraganore, a member of BIO's health and emerging company section boards, agreed with Woodcock that "it is important that the ability to utilize an accelerated pathway is better understood by sponsors and more consistently applied by FDA."

He added that the need is especially acute "when it comes to FDA accepting clinical endpoints, including those that can be measured earlier than irreversible morbidity or mortality, to demonstrate a reasonable likelihood of clinical benefit."

Even though FDA has the power to grant accelerated approval based on clinical endpoints, Maraganore said, "in practice the lack of clarity surrounding such approval options has led to very limited use by sponsors and FDA."

Existing law does nothing to limit the diseases that can be treated under accelerated approval, but "current FDA practice leaves many serious or life threatening conditions excluded from the pathway," he said.

Increased regulatory certainty and faster development times would stimulate investment, which in turn will ultimately increase the number of breakthrough drugs available to patients, Maraganore told the lawmakers.

The most important effect of FAST and TREAT would be to change the "culture" at FDA by making it clear that Congress wants accelerated approval to be used more frequently, Maraganore told BioCentury.

Language in the bill encouraging the use of accelerated approval for rare diseases and the application of "modern scientific tools earlier in the drug development cycle" will expand the kinds of data FDA reviewers consider acceptable for supporting accelerated approval, he argued.

Maraganore also said the Fast Track and accelerated approval provisions in the bills would promote investment. Receipt of the designation would go a long way to convince investors that an emerging company has been given a "special recognition" that could lead to accelerated approval, he said. "This could be enormously important for emerging companies for fundraising."

Maraganore predicted the legislation will produce rapid results.

Accelerated approval legislation, combined with trends among biopharma companies away from incremental advances and toward targeted drugs, could result in "a quarter to a third of new drugs being approved through the accelerated pathway" within two to four years, Maraganore told BioCentury.

Last year, FDA granted three accelerated approvals out of a total of 35 approvals of NMEs, including 13 that had Fast Track designation.

Increased certainty around the regulatory environment will create a "big feedback loop" that over time will result in an increase in the number of drugs developed, Maraganore said.

A majority of venture capitalists in a recent National Venture Capital Association survey said regulatory uncertainty is deterring them from investing in life sciences companies.

"If the accelerated approval pathway is modernized, and that is reduced to actual practice so people can see it, you can logically expect investors to feel more bullish about investing in biotech," Maraganore told BioCentury. "As a result, I would expect more investment in breakthrough medicines, and more medicines coming into the pipeline that would take advantage of the accelerated or traditional pathways."

He added: "It is going to take some time for this to read out. We shouldn't expect that all of a sudden if this passes this year, in 2012 or 2013 approvals will go up astronomically."

FDA's view

Woodcock expressed a more deliberate pace, saying the accelerated approval provisions in FAST would lead to incremental improvements that would be phased in over time.

It is not "realistic" to predict that the proposed law would result in a big increase in the number of new drugs approved or rapid increases in the proportion of drugs awarded accelerated approval, she told BioCentury.

"If you are not planning to lower the efficacy standard significantly, you have to wonder how you'd get a huge number of new drugs," Woodcock said.

"The rate-limiting factor is getting safe and effective drugs developed, not the pathway," Woodcock said. She noted FDA has recently granted rapid approval to breakthrough drugs for rare diseases using conventional, or full, approval.

Cystic fibrosis therapy Kalydeco ivacaftor from Vertex Pharmaceuticals Inc., was developed rapidly, reviewed in three months and granted full approval in January (see BioCentury This Week television, March 11).

Woodcock did say there would be real benefits from accelerated approval legislation, including incentivizing companies to develop drugs for indications they not have otherwise targeted.

However, she disagreed with the notion that a large portion of drugs that are reviewed under conventional approval standards would have been eligible for accelerated approval if FDA were more flexible, or that FDA could quickly dial up the proportion of approvals using the accelerated pathway.

"The real problem is the paucity of worked-up endpoints, either as surrogates or as clinical endpoints that could be used for accelerated approval," Woodcock told BioCentury. "It is not that we don't accept them - it is that they don't exist. People need to develop more interim endpoints and more surrogates."

It will take time to generate scientific consensus around new clinical and surrogate endpoints, she said.

In an email to BioCentury, Maraganore said FDA and industry do not need to wait for new science to facilitate much wider use of accelerated approval. "Clarification on the accelerated approval pathway to sponsors and the agency combined with consensus around EXISTING science will go a long way toward increasing the number of approvals under this path," he said.

"New science is icing on the cake," Maraganore said. "It will certainly happen and only strengthen the number of future accelerated approvals. I expect the new science to come from academia, industry, and partnerships."

Woodcock told BioCentury FDA already has been moving to expand the use of accelerated approval. These include screening INDs for serious diseases to flag those where accelerated approval and other regulatory mechanisms could expedite development.

She also said FDA is participating in public-private partnerships, as well as working independent to identify and qualify new surrogate markers that can support accelerated approval.

In her congressional testimony, Woodcock said FDA plans to release draft guidance soon on the use of pathologic complete response (the absence of residual cancer) as a surrogate endpoint to support accelerated approval of new cancer therapies for initial treatment of high-risk breast cancers.

Pathologic complete response could slash development times by years compared to an overall survival endpoint, Tatiana Prowell, a medical officer in CDER's Division of Drug Oncology Products, told BioCentury. She said the marker has been developed based on an assessment of published literature and FDA's experience with the endpoint.

Cancer concerns

Maraganore warned lawmakers there already was "significant uncertainty over how the FDA intends to apply the accelerated approval pathway in the future and this uncertainty is directly impacting investment in innovative new therapies."

Specifically, he told the subcommittee, "there appears to be a fundamental re-evaluation by FDA of the standards for approval of new cancer therapies," which has diminished interest in cancer drugs among venture capitalists.

According to Maraganore, industry and investor concerns date to a September 2009 Oncologic Drugs Advisory Committee meeting at which the committee and Richard Pazdur, director of CDER's Office of Hematology Oncology Products, expressed skepticism about the use of single-arm trials to support accelerated approvals (see BioCentury, Sept. 7, 2009).

Statements Pazdur has made over the last year reiterating limits on the circumstances in which single-arm trials can support cancer drug approvals "have introduced significant uncertainty over how the FDA intends to apply the accelerated approval pathway for cancer drugs," Maraganore told the subcommittee.

In his written testimony, Maraganore told the subcommittee: "In oncology, the FDA appears right now to be moving in exactly the wrong direction. A critical element of the FAST bill is the clear message that it sends: that the sense of the Congress - reflecting the values of the American people - is that FDA should strive to use the Accelerated Approval pathway more for the benefit of patients, not less."

Woodcock pushed back when Pitts repeated claims that FDA is backtracking on accelerated approval for cancer.

"Over the last year we have approved cancer drugs using accelerated approval, sometimes using historical controls," Woodcock told the lawmaker. "We are not backing away."

Woodcock said the single-arm debate Maraganore referred to involves the magnitude of response required to obtain accelerated approval. "If you see in a historically controlled trial maybe a 5% or a 10% response rate, you really don't know the level of benefit to patients," she said.

Woodcock told BioCentury FDA is willing to approve cancer drugs under accelerated approval that provide incremental benefits such as a 10% response rate, "but we would want a comparison arm, not a historical control."

She added: "If you have a really good drug for cancer you'll be able to get through the process quickly, and we've shown that."

For example, Pfizer Inc.'s Xalkori crizotinib for non-small lung cancer (NSCLC), which FDA approved in August 2011, went from discovery to market in four years.


Alnylam Pharmaceuticals Inc. (NASDAQ:ALNY), Cambridge, Mass.

Biotechnology Industry Organization (BIO), Washington, D.C.

National Venture Capital Association (NVCA), Arlington, Va.

Pfizer Inc. (NYSE:PFE), New York, N.Y.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.

Vertex Pharmaceuticals Inc. (NASDAQ:VRTX), Cambridge, Mass.