22217 hpo no. 12 2007new
No. 12 • September 2007
Reform without Reason: What’s Wrong with
the FDA Amendments Act of 2007
By John E. Calfee
The recently passed Food and Drug Administration Amendments Act (FDAAA) actually combines atleast two laws. One renews the Prescription Drug User Fee Act (PDUFA), which sets deadlines forFDA action on new drug applications and assesses user fees to cover the salaries of extra FDA employees.
PDUFA expires on September 30. Hardly anyone wants to see the massive FDA layoffs that wouldensue if user fees cease to flow, so FDAAA was must-pass legislation. The second part of FDAAA isCongress’s response to the perceived drug safety crisis that burst forth in October 2004 after the arthritispain reliever Vioxx was pulled from the market because of excess heart attacks (Calfee 2005). With thetwo parts intertwined, reform of FDA’s drug safety oversight will also arrive by October 1. As far as this
Health Policy Outlook is concerned, FDAAA is an FDA reform law. It commands attention becauseit promises to bring the most important changes in FDA regulation in at least a decade and probablysince the landmark 1962 amendments that created the modern FDA.
FDAAA rests upon two foundations. One is the
FDA’s competence and culture while suggesting
assumption that we are in the middle of a drug
numerous legislative and regulatory solutions
safety crisis. The other is that there is something
(e.g., Topol 2004b; Furberg et al. 2006; Strom
seriously wrong at the FDA in the sense that the
2006; Avorn 2007; Hennessy and Strom 2007).
agency has become too friendly to the pharma-
By all accounts, however, a central influence
ceutical industry and has downplayed drug safety
has been a September 2006 report, The Future of
Drug Safety: Promoting and Protecting the Health of the Public
(NAS 2006; all citations are to the
The Institute of Medicine Report and
“uncorrected proofs” released at that time), pub-
lished by the Institute of Medicine (IOM),which is part of the National Academy of Sci-
Before explaining why these assumptions are mis-
ences. The IOM report was actually commissioned
taken, a few words about their origins will be use-
by the FDA itself, but it offered harsh criticism of
ful. FDAAA and FDA reform have been supported
the agency and recommended sweeping changes.
by the editorials, a wide array of members of Con-
gress, a highly visible dissident FDA staffer (Kohn
mendations. Reform proponents, especially in
and Bor 2004), and, especially, high-profile medical
academia, routinely cite the IOM report (e.g.,
journals, which have mounted an assault on the
Curfman, Morrissey, and Drazen 2006; New YorkTimes
2006; Smith 2007).
Despite its influence and provenance, the
John E. Calfee ([email protected]
) is a resident scholarat AEI.
IOM report was deeply flawed. One problem is
that none of the authors were drug development special-
evidence. Sifting through the rapidly accumulating
ists, which virtually guaranteed that the exigencies of
literature on the episodes that animated the IOM and
new drug development would be slighted in comparison
Congress, one is struck by two things. First, there is no
to drug safety. Worse, the report was remarkably
evidence of a drug safety crisis or even a worsening of
unscholarly and provided only cursory scientific support
drug safety. And second, there is little in the most telling
for much of its analysis and recommendations. On
drug safety episodes for which the FDA could be held
direct-to-consumer advertising of prescription drugs, for
example, the authors cited a few largely irrelevant olderarticles while ignoring a flood of recent econometric
Vioxx, SSRIs, and More.
The triggering event for
research (Berndt 2006; Calfee 2007) and a much-cited
FDAAA was Merck’s withdrawal of Vioxx on Septem-
randomized trial that revealed large health benefits from
ber 30, 2004, after an ongoing clinical trial revealed
antidepressant advertising (Kravitz et al. 2005). On
excess heart attacks among Vioxx users (Psaty and
another crucial topic—“off-label” prescribing for uses
Furberg 2005). As the FDA presciently pointed out at
not explicitly approved by the FDA—the only citation
the time, it was far from clear that Vioxx or its competing
(pp. 2–7) was to a Washington Post
Cox-2 inhibitor, Celebrex, was significantly riskier than
2006) instead of the Archives of Internal Medicine
the much older non-steroidal anti-inflammatory drugs
(Radley et al. 2006) that the Post
article was about. On
(NSAIDs) they replaced, given that these older drugs
yet another central issue—whether FDA drug warnings
had never been subjected to rigorous clinical trials like
are effective—the report (pp. 2–16) cited a trade press
the one that brought Vioxx down. Subsequent research
report (Medical News Today
2006) rather than the
has largely vindicated that view, with the entire class of
Archives of Internal Medicine
study it was about (Lasser
NSAIDs (old and new, Cox-2s or not) now bearing heart
et al. 2006). That article actually found that medical
attack warnings (Calfee 2005; Kearney et al. 2006).
harm from prescriptions that violated warnings was
The second-ranking triggering event was controversy
extremely rare (an estimated total of sixteen such events
over previously non-public clinical trial results in which
among the 324,548 patients in the study).
children and adolescents taking one of the SSRI class of antidepressants (Prozac or Zoloft, for example) weremore likely to exhibit suicidal “ideation” or thoughts
(but not to attempt or commit suicide). Faced withrelentless criticism from litigators, politicians, popular
press editorialists, and elite medical journals, the FDAimplemented its strongest warning (a “black box,”
Amazingly, the IOM report avoided the most impor-
which appears on the FDA-approved label) for all
tant question: is there a drug safety crisis at all? The report
antidepressants, not just SSRIs (because again, there
stated at the outset, “The committee did not attempt to
was little reason to think that older drugs, which can
document whether or not a drug safety crisis exists, and
cause fatal overdoses, are safer). Subsequent research
this report should not be interpreted as commenting on
taking a variety of approaches has found that SSRI use is
that claim one way or the other” (p. 1-1). The authors
strongly associated with lower, not higher, suicide rates,
argued, however, that various events—notably the with-
and that the highly publicized warnings probably did
drawal of Vioxx and a controversy over clinical trial
more harm than good by reducing antidepressant use.
results suggesting a suicide risk from the widely prescribed
In particular, a series of reports has found that there is a
selective serotonin reuptake inhibitor (SSRI) class of anti-
striking, inverse relationship between SSRI prescriptions
depressants—had “contributed to a public perception that
and youth suicides in a variety of data sets and that the
the drug safety system is in crisis” (p. 1-1). The rest of the
imposition of new FDA warnings (beginning with public
report essentially assumed that this perception is true.
health alerts) is strongly associated with reduced anti-depressant prescribing for children (and younger adults)
The Drug Safety Crisis That Wasn’t There
and higher suicide rates (Shogren 2004; McKeown,Cuffe, and Schulz 2006; Ludwig, Marcotte, and Norberg
The widespread perception of a drug safety crisis has
2007; Brent 2007; Gibbons et al. 2007; Lubell et al. 2007;
been driven by elaborate anecdotes rather than systematic
Other frequently cited examples of FDA failure also
2007, an editorial in the journal Nature Clinical Practice
do not withstand scrutiny. An example is the pioneer
vigorously attacked the Avandia meta-analysis on
antibiotic Ketek. The FDA was actually slow in approving
methodological grounds and criticized the New England
this drug, mainly because of fraud in one of the pivotal
for rushing it into print and causing confusion
clinical trials, and it finally approved Ketek partly on the
among patients (Fuster and Farkouh 2007).
basis of five years of experience in Europe (where it
Academic controversy over the New England Journal
remains in use). This unorthodox process provoked much
meta-analysis and its meaning has continued. Some of
criticism, but any new class of reasonably safe and effec-
this appeared in the New England Journal
tive antibiotics is a valuable addition, and despite the
communications focused on methodological weaknesses
controversy, there is little reason to think this particular
that strongly undermined the basic results of that analysis
drug is especially dangerous (Usdin 2006a, 2006b).
(see the letters by Bracken; Brett; Diamond and Kaul;and Mannucci et al. 2007). Nonetheless, the New England
Avandia and the New England Journal’s FDA Reform
published another editorial endorsing stronger
Finally, there is Avandia, a popular diabetes drug
FDA reform (Psaty and Furberg 2007b). On September
first approved in 1999. On May 21, 2007, the New
11, 2007, the Journal of the American Medical Association
England Journal of Medicine
published a meta-analysis of
) published two more meta-analyses. One found,
adverse cardiovascular events in clinical trials of Avandia
again, excess heart attacks (but slightly fewer deaths) for
(Nissen and Wolski 2007). Coauthored by a prominent
Avandia users (Singh et al. 2007). The other revealed
critic (Nissen) of the FDA’s handling of Vioxx, the meta-
slightly reduced cardiovascular risk for Actos, Avandia’s
analysis revealed excess heart attacks and strokes among
chief competitor (Lincoff et al. 2007). A JAMA
Avandia users. Accompanying the meta-analysis was an
largely echoed the earlier New England Journal
editorial by two well-known advocates of FDA reform
(Psaty and Furberg 2007a), one of whom (Psaty) wasamong the IOM authors. They declared that the Avandia
meta-analysis revealed FDA neglect and was reasonenough to implement one of the more radical reforms,
the creation of an independent drug safety board (some-
strongly associated with lower, not higher,
thing the IOM report declined to recommend).
Events since publication of the New England Journal
suicide rates, and that the highly publicized
meta-analysis have been instructive. Very soon, the pub-lic learned that the meta-analysis authors and the journal
editors were politically motivated (Usdin 2007b, Gottlieb
good by reducing antidepressant use.
2007c [May 29]), with Nissen having worked closely withRepresentative Henry Waxman’s (D-Calif.) pro-reformstaff. Dissent quickly emerged from the academic medical
In the middle of all this came a July 30, 2007, joint
community regarding both policy and research methods.
meeting of two FDA advisory committees. The members
Endocrinologists (who research and treat diabetes) and
voted 23–1 that Avandia involves an elevated risk of
the editors of The Lancet
, a leading British journal often
(minor) heart attacks compared to placebos, but they
critical of the FDA, declared themselves deeply troubled
offered no consistent view on cardiovascular risks com-
by the precipitous May 21 New England Journal
pared to alternative drugs, including Actos (Hampton
and its reliance upon what was clearly very tentative evi-
2007; Usdin 2007d). The committee also voted 21–3 in
2007). FDA staff, researchers at Glaxo-
favor of keeping Avandia on the market and in support of
Smith-Kline (GSK, the manufacturer of Avandia), and
new label warnings, but not the FDA’s strongest “black
others pointed out that significant cardiovascular risk
box” warning. In the meantime, the liability bar began its
had not been revealed by large randomized trials, includ-
inevitable work on Avandia litigation (Usdin 2007c).
ing the ongoing Rosiglitazone Evaluated for Cardiac
These results are very mixed. The imprecision and
Outcomes and Regulation of Glycaemia in Diabetes
questionable reliability of meta-analyses have been
(RECORD) trial, which was designed to address cardio-
made clear, as articles have demonstrated how modest
vascular safety (Krall 2007; Home et al. 2007). In July
changes in data and statistical methods (which involve
considerable judgment even on such basic matters as
materials) amidst vast regions of opacity (cf. Calfee
whether to include trials in which no adverse events
2006). It is surely plagued by dysfunctions of all sorts, but
occurred) can dramatically alter the results. Many, if
reform advocates have fixed upon the utterly implausible
not most, endocrinologists clearly want to maintain
argument that the FDA staff tends to slight drug safety
treatment options for a condition (diabetes) that is
while catering to the industry. Part of their argument is
notoriously variable among patients and correspond-
that the FDA’s partial reliance on industry user fees
ingly difficult to treat. Avandia clinical trials continue,
undermines safety (Okie 2005). But user-fee deadlines
under FDA oversight as always. Obviously, experts can
only require faster decisions, not decisions that are favor-
disagree over such matters as the nature and timing of
able to the applicant. The IOM report reviewed the lit-
cardiovascular warnings for Avandia, but that is very
erature on user fees (pp. 3; 5–8) and found no evidence
different from a finding that the FDA tended to down-
of a diminution in drug safety from faster new drug
play risks while approving Avandia and monitoring its
approvals since 1992 (the report later ignored that evi-
dence, however). The IOM authors also could havecited an estimate that the advent of user fees saved at
Are New Drugs Riskier than Old Ones?
least several times as many lives through faster drug
through the drug safety debate is a common assumption
approvals as might have been lost through safety prob-
that new drugs tend to be riskier than old ones. The
IOM report, for example, recommends that all newlyapproved drugs and indications carry a prominent black
Running through the drug safety debate is
triangle, and that direct-to-consumer advertising berestricted for the first two years (NAS 2007, p. S-10).
This attitude has little basis. Certainly it is true that
much of the most important safety information aboutdrug risks is revealed only after FDA approval, but thisdoes not mean that new drugs are riskier. They are often
What is far more important—but was ignored by the
designed (successfully) to avoid the side effects caused by
IOM—is the biased incentive structure that causes the
older drugs. The first non-sedating antihistamines, for
FDA staff to put too much weight on drug safety rather
example, probably began to prevent fatal automobile
than too little. The avalanche of criticism thrown at the
accidents as soon as they came into use (Weiler et al.
agency since 2004 is the latest illustration of the single
2000). Also relevant is that many new drugs are studied
most powerful and enduring force impinging upon the
more intensely than older ones both before and soon
FDA staff: a profound disparity in how types of errors are
after approval. The effect is to reveal more risk informa-
penalized. When deciding whether the benefits of a pro-
tion faster, which can make newer drugs appear less safe
posed new drug exceed its risks, FDA staff know that if
relative to older ones than they really are. In each of the
they commit what is often called a Type I error—the
three major drug safety episodes that captured the atten-
approval of a drug that turns out to be insufficiently safe
tion of Congress (Vioxx, SSRI antidepressants, and
once marketing begins—their error will usually become
Avandia, discussed below), the safety crisis was triggered
known (a “public error”). This can and often does lead
mainly by post-approval clinical trials, and additional
to impassioned criticism of the agency and correction of
research and analysis soon revealed either a lack of a
the error (although more often than not, critics fix upon
safety problem (in the case of SSRIs) or risks for the
something that was probably not an error at all). On the
entire classes to which these drugs belonged. Thus,
other hand, a Type II error—the failure to permit mar-
slowing down the uptake of newer drugs would not
keting of a drug that would in fact provide benefits in
necessarily improve safety, although it would sacrifice
excess of harms—is typically detected by relatively few
people (a “private error”), and its deleterious effects canpersist more or less indefinitely.
The FDA Problem That Was Not There
The net effect of this asymmetry in publicity over
Type I and Type II errors is to bias even the best-
The FDA is an immensely powerful bureaucracy with
intentioned FDA regulators toward excessive caution
islands of transparency (cf. advisory committee meeting
and excessive drug testing. Research on the “drug lag” of
the 1960s and 1970s, when FDA approvals trailed far
accepted views of such basic matters as, for example, the
behind those in European nations, revealed no consumer
benefits of lowering serum cholesterol or the safety of all
benefit in terms of safer drugs (Peltzman 1973, 1974;
NSAID pain relievers (Topol 2004a; Wadman 2007).
Wardell and Lasagna 1975). Subsequent research
FDAAA is best seen as fixing upon a target of oppor-
revealed that similar patterns persisted long after
tunity. The relative ease with which post-approval drug
(Katin and Brown 1995). Yet slow drug approvals here
safety problems become widely known (“public errors”)
did not bring extra safety. An analysis of the United
guarantees a steady drumbeat of criticism and proposals
States, Spain, and the United Kingdom yielded essen-
for reform (for example, Friedman et al. 1999; Wood,
tially identical drug-withdrawal rates despite the more
Stein, and Woosley 1998; Kleinke and Gottlieb 1998;
rapid drug-approval timelines in the European countries
Moore, Psaty, and Furberg 1998). Although there is lit-
tle, if any, systematic evidence of real declines in FDAscrutiny or effectiveness in dealing with drug safety,individual episodes can create pressure for change, as
occurred after the Vioxx withdrawal and the SSRI anti-depressant safety debate. In this context, the prospect of
drug safety provisions of FDAAA will work
user-fee renewal in 2007 provided a potent vehicle for
FDA reform. It is no surprise that in its final paragraph,the IOM report proclaimed: “Now is the time to renew
and transform Center for Drug Evalution and Research’s
ultimately, the welfare of patients.
culture, its authorities, its scientific capacity, and its abil-ity to communicate with health care providers and thepublic.” Chiming in were the New England Journal of
There is considerable anecdotal evidence that the
(Hennesy and Strom 2007) and the American
FDA quickly became even more cautious in approving
Medical Association’s Archives of Internal Medicine
new drugs and indications after the Vioxx uproar began
in October 2004 (Harris 2005). Earlier this year, forexample, the FDA refused to approve the pain reliever
The Perils of Passing Unnecessary
Arcoxia and the weight-loss drug Accomplia even
though both had been approved by the European Unionand many other nations (Gottlieb 2007b [April 17];
Trying to fix something that is not broken provides a
Wadman 2007). The FDA has also been unreceptive to
reliable path to unintended consequences. There are
some promising new drugs for advanced cancer, includ-
many reasons to think that the drug safety provisions
ing Provenge, Genasense, and others (Usdin 2007a;
of FDAAA will work badly from the standpoint of drug
Miller and Henderson 2007; Miller 2007).
development, new drug approvals, and ultimately, the
Neither Congress nor the IOM report has paid much
attention to another potent force: market-driven manu-facturer incentives to maintain drug safety. Such incen-
Unnecessary Additions to FDA Power.
tives operate with powerful effect in far less regulated
increase FDA authority in a number of ways. This is
high-tech industries such as automobiles, petroleum, and
unfortunate because the FDA can easily persuade pharma-
electronics. As in other industries, pharmaceutical
ceutical firms to do virtually anything it asks, up to and
manufacturers rely heavily upon maintaining their repu-
including the imposition of severe warnings, controls
tation among customers (especially physicians) for prod-
over prescribing, cessation of advertising campaigns, and
uct safety and efficacy. Post-approval clinical trials play a
the removal of drugs. The FDA will be expected to use
central role in this process. These trials are undertaken
the new powers granted by FDAAA. The staff will be
to expand markets, but they necessarily open the door to
under considerable pressure to take stronger measures
new and possibly alarming (as well as reassuring) safety
even when those measures would be inappropriate in the
information. Often, post-approval trials are bigger,
complex and obscure circumstances that surround virtu-
longer, and more informative than the trials under-
ally all important regulatory decisions. An example is
girding drug approvals. Often, they force revisions in
the power to require manufacturers to complete so-called
phase 4 trials for newly approved drugs. The IOM report
drug development (as pointed out by Brett 2007). Critics
(pp. 4-8–4-9) explained very clearly why last-minute
who support FDAAA or stronger measures also want the
negotiations in the drug-approval process often cause the
FDA to avoid approving drugs that are only on a par with
FDA and manufacturers to agree to post-approval trials
(rather than superior to) existing drugs (Avorn 2005).
that turn out to be unnecessary or even harmful. FDAAA
They applauded when the FDA refused to approve Prexige,
will worsen the dilemma already faced by FDA when they
a Cox-2 pain reliever for arthritis, on exactly those grounds.
are criticized for failing to do things that should not havebeen committed to in the first place.
Making Clinical Trial Data Public
. FDAAA will expand
upon a recent trend toward revealing unpublished clini-
Inappropriate Responsibilities for Post-Approval Drug
cal trial results to which the FDA staff is already privy.
Use and Safety.
FDAAA will be a powerful force in mak-
This public registry of undigested clinical trial data will
ing the FDA responsible for post-approval drug use and
probably reinforce the tendency for FDA staff to give
safety. Today’s question—“Why didn’t the FDA catch the
disproportionate weight to risks vs. benefits of drugs. It
problem with that drug?”—will be replaced by a very dif-
will also tempt medical journals and researchers to cherry-
ferent one: “Why did the FDA let doctors do that with
pick the data to support political agendas, at the cost
that drug?” This will trigger a series of unfortunate actions.
of alarming the public and scaring patients away from
Faced with the possibility of being blamed when physi-
ongoing clinical trials. Finally, it can undermine R&D
cians and others fail to use drugs as it had intended, the
incentives by alerting competitors to R&D and market-
FDA will have to be far more intrusive in its regulation of
ing strategies (Lassman 2006). This provision may turn
medical practice, but the FDA possesses few tools and
out to be far more important and troublesome than one
even less knowledge or other preparation for regulating
would infer from its noncontroversial status in the
how doctors go about their work. Forced again to choose
among unattractive alternatives, the agency will employcrude measures such as onerous tracking requirements and
FDA Reform is a One-Way Street.
Finally, we should
restrictions on who may treat certain patients.
give considerable weight to the fact that this FDA
All this is a logical result of what the IOM report and
reform will probably be a one-way street. FDAAA will
many other FDA reform advocates have propounded as
increase FDA power, extend its reach beyond normal
the necessity of a “life-cycle” approach to drug safety
bounds, and expose FDA personnel to yet more scrutiny
monitoring and regulation. This principle offers virtually
and criticism for safety problems no matter how unpre-
no guidance beyond the general principle of a steady
dictable. There will be no tests or benchmarks for how
expansion of FDA authority and responsibility. We have
well this new regime will work. In a world of ever more
to assume that if the FDA is to be held responsible for
extensive post-approval clinical trials and database
whether especially risky drugs are used properly (as sug-
dredging, there is no reason to think drug safety data will
gested, for example, by the IOM report’s recommendation
become more reassuring or less alarming as time passes.
5.1 and 5.2), it must be able to exercise commensurate
The FDA will find it very difficult to retreat from any
power over physicians and other health care providers.
The impetus for regulating medical practice will also
Perhaps the only hope is that the FDA, whose
arise from a more general aspect of FDAAA. It will
resources include some leaders of exceptional ability,
reinforce and strengthen the bias toward preventing
will take due account of its inability to regulate usefully
Type I errors (a safety problem with an approved drug)
medical practice and of the ease with which the agency
at the cost of Type II errors (such as moving too slowly
can slow down the most innovative kind of R&D. If the
to facilitate new drug development and approval). For
FDA leadership proceeds with an exceptional measure
example, a crucial issue in adapting regulation to scientific
of wisdom and restraint, they may be able to prevent
advances is revising and expanding the use of surrogate
FDAAA from doing great harm. We shall see.
markers (such as LDL cholesterol levels rather than heart
AEI research assistant Walton Dumas and web editor Laura Drink-
attacks for cardiovascular drugs, or glycemic levels for
wine worked with Mr. Calfee to edit and produce this
diabetes drugs). Many FDA critics see reform as a tool for
icy Outlook. Additional research assistance was provided byRobert Ward, an AEI intern and George Washington University
reining in or nearly eliminating surrogate markers (Psaty
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