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
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.
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
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."
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.
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
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."
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
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
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
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.
Pharmaceuticals Inc. (NASDAQ:ALNY), Cambridge, Mass.
Industry Organization (BIO), Washington, D.C.
Venture Capital Association (NVCA), Arlington, Va.
Inc. (NYSE:PFE), New York, N.Y.
Food and Drug Administration (FDA), Silver Spring, Md.
Pharmaceuticals Inc. (NASDAQ:VRTX), Cambridge, Mass.