Paying for Drug Approvals - Who's Using Whom?
Vince Boehm
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Vince Boehm ****
http://content.nejm.org/cgi/content/full/NEJMp078041
*Published at www.nejm.org April 13, 2007 (10.1056/NEJMp078041)
*
**
*Paying for Drug Approvals Who's Using Whom?*
/ Jerry Avorn, M.D. /
Years ago, an administrator at a community hospital explained^ to me how
well his institution's grand-rounds program worked.^ "The drug companies
find the speakers, pay their honoraria,^ and provide free food for the
doctors, which helps a lot with^ attendance," he said. "It works well
for us, especially with^ our budgets so tight." Yet those lunches were
actually quite^ costly for the hospital: attendees at such events
predictably^ go on to prescribe the products promoted there which^ is
precisely why the drug companies so willingly pay for these^ programs.^
This penetration of commerce into the province of science isn't^ limited
to continuing medical education. Since 1992, the United^ States has
relied heavily on the pharmaceutical industry to^ pay the salaries of
Food and Drug Administration (FDA) scientists^ who review new drug
applications. The Prescription Drug User^ Fee Act (PDUFA) is now up for
its periodic 5-year renewal, and^ Congress seems ready to reauthorize it
with the same short-sightedness^ that afflicted that naive hospital
administrator.^
PDUFA was enacted at the end of the presidency of George H.W.^ Bush,
when many in Washington believed that government was at^ the root of
most of the country's problems. At that time, the^ FDA was having
difficulty evaluating new drugs quickly and efficiently.^ The agency had
been shaken by sit-ins held by AIDS activists^ protesting long review
times, which they argued were killing^ them. The staff of the FDA was
too small to adequately assess^ all the new drug applications the agency
received. But the era's^ dominant ideology derided "bloated government"
and demanded^ that Congress rein in "runaway spending." In that climate,
the^ sensible policy solution provide the FDA with more federal^
funding to hire enough people to carry out its mission ^ was a
nonstarter. But just as the FDA's slowness may have been^ costing
patients with AIDS their lives, it was costing pharmaceutical^
manufacturers their income. So the industry stepped in and helped^ to
design a plan under which companies would pay the salaries^ of agency
employees who reviewed the companies' submissions.^
There were problems with the user-fee approach from the beginning.^ The
original legislation required that no portion of companies'^ fees (about
half a million dollars per drug reviewed) could^ be spent to evaluate
drug side effects after approval ^ the time when many important safety
concerns become apparent.^ The new law mandated strict deadlines for
approval decisions.^ To comply, the FDA reassigned staff scientists to
work on new^ drug applications, pulling the scientists from other
regulatory^ activities. Several were taken from the Office of Drug
Safety,^ which conducts adverse-effects surveillance a move that^
helped to shrink and demoralize that unit.^
User fees now account for more than 40% of the budget of the^ FDA
division that reviews new drug applications (see bar graph
<http://content.nejm.org/cgi/content/full/NEJMp078041#F2>).^ Colleagues
at the FDA have told me of a worrisome side effect^ of PDUFA: the
growing sense that the organization is accountable^ to the industry it
regulates. One FDA scientist who was often^ criticized for being too
concerned about drug-risk data was^ told by his supervisor to remember
that the agency's client^ was the pharmaceutical industry. "That's odd,"
he replied. "I^ thought our clients were the people of the United
States." Other^ agency staffers report pressure to rush through the
drug-approval^ process, although the FDA's regulatory review times are
already^ among the shortest in the world. Evidence is accumulating that^
this emphasis on speed may lead to problematic decision making.^ Data
analyzed by Daniel Carpenter, a professor of government^ at Harvard
University, suggest that drugs approved just before^ PDUFA deadlines are
far more likely than those approved at other^ points in the review cycle
to cause safety problems after they^ are in widespread use.^1
<http://content.nejm.org/cgi/content/full/NEJMp078041#R1>^
Figure 2 <http://content.nejm.org/cgi/content/full/NEJMp078041v1/F2>
*View larger version* (21K):
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[in a new window]
<http://content.nejm.org/cgi/content-nw/full/NEJMp078041v1/F2>
Get Slide <http://content.nejm.org/cgi/powerpoint/NEJMp078041v1/F2>
Funding for the FDA's Center for Drug Evaluation and Research.
Data are from the FDA.
Most federal regulatory agencies do not derive such a large^ proportion
of their operating budgets from the industries they^ oversee. Nor is it
typical for such relationships to be negotiated^ so cozily between the
government and the trade group representing^ the industry. Yet the
current FDA proposal for PDUFA renewal^ was developed in concert with
the Pharmaceutical and Research^ Manufacturers of America.^2
<http://content.nejm.org/cgi/content/full/NEJMp078041#R2> No similar
influence has been exerted^ by any other group.^
In 2004, the public was shocked to learn that rofecoxib (Vioxx,^ Merck)
could remain in widespread use for 5 years even though^ the drug nearly
doubled the risk of myocardial infarction and^ stroke. Its withdrawal
from the market aroused serious doubts^ about the adequacy of the FDA's
drug-safety surveillance system.^ Last year, the Institute of Medicine
(IOM) and the Government^ Accountability Office (GAO) released
influential reports concluding^ that the country's capacity for
identifying drug risks was greatly^ in need of repair^3
<http://content.nejm.org/cgi/content/full/NEJMp078041#R3>^, ^4
<http://content.nejm.org/cgi/content/full/NEJMp078041#R4>; the IOM
report proposed a number of specific^ and plausible recommendations for
reform. By coincidence, this^ year PDUFA is up for renewal.^
For a time, it seemed possible that this combination of forces^ would
lead to concrete steps to build a better system for drug^ approval and
adverse-effects surveillance. But the legislative^ plans that are likely
to be enacted do not even come close to^ achieving that goal. At a
recent meeting on the FDA's future,^ all four former FDA commissioners
in attendance agreed that^ the agency should be funded directly through
the Treasury, rather^ than through industry payments. But Congress and
the agency's^ leadership still don't get it. The FDA supports
reauthorization^ of PDUFA and proposes that a trivial less than 7% of
the user^ fees be used to strengthen its capacity for adverse-effects^
surveillance an amount far short of what would be needed^ to repair
the inadequate system described by the IOM and GAO.^
Another key problem may not be fixed by Congress either. The^ FDA
currently lacks the authority to require companies to conduct^ follow-up
studies of suspected safety problems. Most such studies^ are therefore
not performed, even when they are requested (see^ pie charts
<http://content.nejm.org/cgi/content/full/NEJMp078041#F1>). But the
requisite legislation to give the agency^ this vital authority also
seems unlikely to emerge from this^ Congress.^
Figure 1 <http://content.nejm.org/cgi/content/full/NEJMp078041v1/F1>
*View larger version* (25K):
[in this window] <http://content.nejm.org/cgi/content/full/NEJMp078041v1/F1>
[in a new window]
<http://content.nejm.org/cgi/content-nw/full/NEJMp078041v1/F1>
Get Slide <http://content.nejm.org/cgi/powerpoint/NEJMp078041v1/F1>
Status of Open Commitments for Postmarketing Studies Requested by the
FDA, as of September 30, 2006.
Data are from the Federal Register.
Proponents of retaining PDUFA argue that the discretionary federal^
budget has been so decimated that it's impossible to find public^
dollars to replace the $438 million in user-fee revenues projected^ for
2008. Yet with Medicare now the largest purchaser of drugs^ in the
United States, this is a fiscally irresponsible excuse.^ Many
drug-safety researchers believe, for example, that appropriately^
conducted studies would have revealed the cardiovascular toxicity^ of
rofecoxib well before the end of its 5-year run. By that^ point, the
country was spending $2.5 billion per year on the^ drug, about a billion
of which was public money. Documenting^ the drug's risks and getting it
off the market just 1 year sooner^ would have paid for a robust system
of drug-safety surveillance^ for 4 years, without relying on a dime of
user fees or additional^ taxpayer dollars. We spend more than $2 billion
on the Iraq^ war in about a week. A nation as wealthy as ours can
afford^ what it chooses to afford.^
The present confluence of events surrounding PDUFA reauthorization^
could have provided the best opportunity in a generation to^ act
decisively in mending our dysfunctional drug-approval and^ surveillance
system. But Congress, the FDA, and the drug industry^ risk missing this
opportunity. "The train has left the station"^ is how Capitol staffers
describe the inevitable renewal of the^ plan and the rushed schedule of
its legislative trajectory.^ But that needn't be the case. Recently, I
joined a group of^ drug-safety experts several of them former FDA
scientists^ or authors of the IOM drug-safety report in calling^ for
the FDA's drug-related work to be funded by general federal^ revenues,
rather than by the industry it regulates. We argued^ that if this change
cannot be accomplished before the current^ user-fee act expires on
September 30 (and with it the salaries^ of many FDA drug reviewers),
then PDUFA should be renewed for^ 6 to 12 months at most, to give the
country time to have the^ debate we deserve over the best way to ensure
the efficacy and^ safety of our medications.^5
<http://content.nejm.org/cgi/content/full/NEJMp078041#R5>^
Many in Congress still believe that the user-fee system is saving^ the
public money. That view is as invalid as the smug conclusion^ of the
hospital administrator I spoke with years ago. In regulatory^ policy, as
in grand rounds, there's no such thing as a free^ lunch.^
^
*Source Information*
Dr. Avorn is a professor of medicine at Harvard Medical School and chief
of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham
and Women's Hospital both in Boston.^
An interview <http://content.nejm.org/cgi/content/full/NEJMp078041/DC1>
with Dr. Avorn and Dr. Mark McClellan can be heard at www.nejm.org.^
This article (10.1056/NEJMp078041) was published at www.nejm.org on
April 13, 2007.
*References*
1. Carpenter D, Bowers J, Grimmer J, Moffitt S, Nall C, Zucker EJ.
Deadline effects in drug regulatory review. Robert Wood Johnson
Scholars in Health Policy Research Program, Working Paper Series,
February 2007. (Accessed April 5, 2007, at
http://www.healthpolicyscholars.org/sub-news/working_papers/working_paper_35.htm.)
2. Food and Drug Administration. Prescription drug user fee act. Fed
Regist 2007;72:1743-1753.
3. Drug safety: improvement needed in FDA's postmarket
decision-making and oversight process. Washington, DC: Government
Accountability Office, 2006. (Document no. GAO-06-402.)
4. Committee on the Assessment of the US Drug Safety System, Baciu A,
Stratton K, Burke SP, eds. The future of drug safety: promoting
and protecting the health of the public. Washington, DC: National
Academies Press, 2006.
5. Angell M, Avorn J, Bingham E, et al. An open letter to Chairman
Edward Kennedy and Senator Mike Enzi, Chairman John Dingell and
Representative Joe Barton, Members of the Senate Health,
Education, Labor and Pensions Committee, Members of House Energy
and Commerce Committee. March 14, 2007. (Accessed April 5, 2007,
at http://www.defendingscience.org.)
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