The Damaging Impact of PDUFA and Why It Should be Repealed

The prescription drug user fee act (PDUFA, 1992), which is up for renewal
this year, linked the Food and Drug Administration to the pharmaceutical
industry in a way that radically transformed the FDA from an oversight
agency into a financially-dependent service provider/client. PDUFA fees pay
for expedited drug approvals. Unlike other government user fee programs, the
FDA negotiates with user agents-the Pharmaceutical Research and
Manufacturers of America (PhRMA)-about how the agency may allocate these
fees. User fees set FDA priority on speeding up the drug approval process.
The re-prioritization of rapid approvals occurred at the expense of drug
safety standards, and the consequences are documented by mounting
drug-induced injuries, hospital emergency admissions, and preventable
deaths.

Drug safety scandals in the post-PDUFA era brought to light evidence that
drug companies failed to disclose results that revealed their drugs were not
only ineffective but posed life-threatening risks. A review in the Journal
of the American Medical Association (J-AMA) found: "The reporting of trial
outcomes is not only frequently incomplete but also biased and inconsistent
with protocols. Published articles, as well as reviews that incorporate
them, may therefore be unreliable and overestimate the benefits of an
intervention." [1]

The companies' concealment of vital evidence occurred under the nose of the
FDA, which is the only agency/ institution that was fully aware of the
results of these studies and was, therefore, complicit in their cover-up.
[2][3] FDA's complicity is the consequence of a financial conflict of
interest. Serious concerns that conflicts of interest in medicine were
tainting the scientific literature began to be raised in medical journals in
the post-PDUFA-era. [4] [5] By now, leading mainstream academic physicians
and journal editors acknowledge that industry's influence has resulted in
the loss of scientific integrity in medicine. [6] [7] [8][9] Yet, Congress
seems poised to renew PDUFA with minor changes of little consequence without
ever examining the adverse impact both direct and indirect that PDUFA has
had on medicine and drug safety.

Financial Conflicts of Interest in Psychiatry
The subject of the current issue of World Psychiatry, the official journal
of the World Psychiatric Association, is Financial Conflicts of Interest in
Pstchiatry: http://www.wpanet.org/publications/docs/wpa022007.pdf

An excellent article by that name, by Dr. Giovanni Fava, [10] (a professor
of clinical psychology, University of Bologna in Italy, and the department
of psychiatry, State University of New York, Buffalo), reviews the extensive
literature documenting the scope of corporate pharmaceutical influence on
medical science rather than on psychiatry. He describes how industry has
brought under its control physicians and scientists as well as institutional
medicine and all of its gatekeepers-including its professional associations,
practice guidelines, continuing medical education, conferences, and
scientific journals. The financial dependence on industry has corrupted the
definition of "evidence-based medicine" leading to an unprecedented
credibility crisis in medicine. He concedes that "evidence-based medicine
may thus be a deceptive instrument of propaganda."

Although the subject is financial conflicts of interest in psychiatry, very
few examples from psychiatry are cited; an exception is selective
publication of SSRI antidepressant trials. Furthermore, an odd disclaimer is
made repeatedly by Dr. Fava and other commentators–"the situation of
psychiatry does not appear to be different from other areas of medicine." To
this critic the disclaimer betrays discomfort of the sort Hamlet's mother
felt when she exclaimed, "the lady doth protest too much." All nine
commentators have financial ties to industry and all (but one commentator)
acknowledge the current credibility crisis.

What's different about psychiatry?
Indeed, more than any other field of medicine psychiatry welcomed drug
manufacturers as "partners" in research and clinical practice. Psychiatry's
weak theoretical foundation, uncertain boundaries of normality and disorder,
and its subjective diagnostic criteria are easily manipulated to expand
markets for drugs.

Psychiatry is so riddled with financial conflicts of interest: the expert panelists who established psychiatry's diagnostic guidelines (DSM-IV) in mood disorders and schizophrenia-the most lucrative
market for industry- ALL had financial ties to drug manufacturers. [11]
Psychiatry embraced industry's marketing claim that mental disorders were
caused by a "chemical imbalance" and drugs fix that unsubstantiated
"imbalance." Furthermore, psychiatry's low bar for measuring favorable
treatment outcomes meant that even ineffective drugs that caused iatrogenic
(treatment induced) harm would be acceptable.

Financial ties have forged a symbiotic relationship between psychiatry and industry. [12] Psychiatry has helped promote biased and misleading clinical
trial reports [13] and provided industry with a shield for its hazardous
drugs by interpreting drug induced manic and psychotic symptoms as "evidence
of the underlying illness." The professional literature in psychiatry is
overwhelmingly biased in favor of the latest patented psychotropic drugs
-even as these drugs-in particular, the second generation antidepressants
and antipsychotics, have failed to demonstrate a clinical benefit for most
patients for whom they are prescribed. To overcome the negative findings,
consensus panels have lent the appearance of legitimacy to commercially
initiated prescribing guidelines. [14]

The field has also exhibited treatment mood swings which have been likened
to the "bubble psychology" of the stock market. Robert Rosenheck, MD, [15] a
leader in the field (professor of psychiatry and epidemiology, Yale
University) who has analyzed the antipsychotic drug data, suggests that
psychiatry's prescribing practices reflect an "irrational exuberance" not
justified by the negative outcome data. Joanna Moncrieff, MD, (senior
lecturer in psychiatry, University of London) points out that psychiatry's
theories and practice are shaped by industry's interests which have pushed
psychiatry into a "biological straightjacket." [16]

Psychiatry has been in denial for almost two decades about the undue
influence of drug companies on their prescribing practices; about the
serious adverse effects these drugs produce; about the drugs' failure to
demonstrate a clinical benefit to justify the risks. Despite the compelling
evidence showing that the new antidepressants and antipsychotic drugs have
caused irreversible harm for some patients, [15] psychiatry defends these
drugs-as though the profession's legitimacy depends on them. Indeed, U.S.
psychiatrists widely and irresponsibly prescribe these drugs for children
for whom they were not approved.

Only after the public learned that these drugs' safety and effectiveness
were not backed by scientific evidence and that companies concealed the
evidence of harm [2] [3] [17] [18]-only then did diehard defenders of
psychiatry's ties to industry admit-as Dr. Michael Thase [19] (University of
Pennsylvania) did-that it is no longer possible, in 2007, to argue against
full disclosure and transparency: "To take such an untenable position would
reflect both ignorance of the data and insensitivity to the issues involving
public trust." Nevertheless he continues to accuse independent analysts who
have criticized industry for its shoddy research methods with providing
"negatively biased evaluations of industry-sponsored studies."

The journal commentaries by industry scientists and academics -with one
exception-seem to have achieved a uniformity of focus: they affirm the need
to "manage" undisclosed individual conflicts of interest but avoid any
mention of enforcement mechanisms or penalties.

To borrow a refrain from Peggy Lee: "is that all there is?"

David Healy, MD [20], in his commentary, "One flew over the conflict of
interest nest," suggests that there is more to it than individuals' failure
to disclose conflicts of interest. The essential underlying source of
corruption, he argues, is industry's hijacking of the scientific process.
The overarching principles of science require transparency of both
methodology and data. The legitimacy of science depends on a communal
sharing of data so that claimed findings can be independently tested and
either replicated or refuted. But corporate studies-and those under
corporate control-fail to meet the standards of science. He argues that the
apparent studies and related reviews that are at the centre of this crisis
are in fact not scientific -"they are a cuckoo's egg in the nest of
science." He notes that a key feature of the clinical trial reports and
review articles that Fava makes reference to is that they do not conform to
the central tenet of science which is to engage with issues that are
replicable and/or to make the data publicly available.

The current problem for medical science involving patented therapeutics, he
notes, is that a significant proportion of trials now remain unpublished and
those that are published are often ghostwritten and bear an ambiguous
relationship with the underlying data. "Company postings of trials on the
internet do little to mitigate this problem. Indeed, an empirical
assessment by scientists from Oxford and the Cochrane Institute in JAMA
(2004) concurs: To ensure transparency, planned trials should be registered
and protocols should be made publicly available prior to trial completion.
[1]

Dr. Healy states that the difficulties "are best symbolized by the case of
the pediatric trials of selective serotonin reuptake inhibitors, where we
have the greatest known divide in medicine between the raw data on an issue
on the one side and the published accounts purporting to represent those
data on the other.This divide, it is important to note, only came to light
as a result of the efforts of journalists and lawyers. It came to light not
because they chased the question of conflicting interests but because it
seemed obvious to lay people that the data did not add up. To our shame, no
clinician or scientist had a hand in questioning the validity of the
"science".

The height of hipocrisy
In light of the contentious legal battle now being waged by Eli Lilly
against patient advocates, family members, physicians, and lawyers who seek
access to vital drug safety information contained in Lilly's secret Zyprexa
documents, [18] a commentary by Lilly scientists, Steven Paul and Mauricio
Tohen [21] who claim to support Dr. Fava's assessment exhibits the height of
hypocrisy:

"The credibility of psychiatric research has been seriously compromised of
late, undermined by both real and perceived – and some would argue
all-too-pervasive – financial conflicts of interest (COI).. In fact, we
believe the problem of financial (and other) COI could well erode the
credibility of the entire enterprise of academic medicine, if not properly
and promptly addressed. .the solution is not to focus solely on the funding
source or potential COI. More importantly, efforts should be directed at
assuring that the research methodology employed is sufficiently robust to
avoid such bias in the first place."

If the Zyprexa documents had confirmed the company's claim that Zyprexa
offers patients superior safety and efficacy-there clearly would be no
reason for Lilly to fight their release to the public. Lilly's motives for
fighting to maintain the documents under court seal are obvious to anyone
who has read The New York Times reports of their content. These documents
contain evidence contradicting Lilly's marketing claims: the company
concealed the drug's potentially lethal hazardous effects from the public
while its sales reps promoted the use of Zyprexa for children.

In an internal FDA memo, dated August 18, 1996, Dr. Paul Leber, [22]
director of Neuropsychopharmacology division of the FDA, criticized Lilly's
methodology in the Zyprexa premarketing clinical trials, specifically for
using: "inappropriate design;" "inappropriate sample of patients;"
"ill-suited titration;" high incidence of dropouts. The evidence submitted
to the FDA, he stated, provided only "proof in principle" of the drug's
acute antipsychotic action. Despite the absence of "robust" evidence or
appropriate methodology, despite serious concerns about its safety-" No one
should be surprised if, upon marketing, events of all kinds and severity not
previously identified are reported in association with olanzapine's use"-in
the post-PDUFA reduced standards for approval, FDA approved the drug . Thus,
statements by Lilly scientists about "robust" "research methodology" are
disingenuous.

In a commentary in the BMJ, psychiatrist, Stefan Kruszeuski, MD (a board
member of AHRP) challenged Lilly to make good on its claim that the Zyprexa
documents at issue were unfairly selective:
http://www.bmj.com/cgi/eletters/334/7586/171-a

"To avoid being hypocritical, Lilly should take the opportunity to release
every clinical scientific document about Zyprexa."We physicians cannot
assume to have or to provide expertise in the effects, effectiveness and
adverse events of prescription medications if our fund of information is
compromised by selectively-released or cherry-picked data. Since Lilly
agrees with this premise in their report to the U.S. Federal Court, let's
ask them to put all of the clinical data where their mouth says it should
be—in the hands of physician-scientists who require it to make
life-changing decisions."

Will Lilly disclose all the Zyprexa clinical trial data? If not, why not?

The hijacking of clinical research occurred with the tacit cooperation of
institutional gatekeepers and clinicians. By gaining control of the entire
process industry has perverted the integrity of science: protocol designs;
the selection of subjects; selection of data for analysis; selection of
named "authors" on ghostwritten articles based on partial data; publication
in ostensibly peer reviewed journals; and dissemination of these ghost
written fake reports bearing prestigious journal insignia to physicians
directly and through professional societies is controlled by the drug
industry. The FDA-whose mandate is to ensure that physicians and the public
are provided accurate information about marketed drugs, and whose legal
authority enables the agency to enforce that statutory mandate-has clearly
failed to meet its public responsibility. Thus, drug companies disseminate
deceptive reports masquerading as "evidence-based science" when they have
been crafted to promote rather than to inform.

What lessons can be drawn from this situation?

The obvious lesson is that none of the institutional gatekeepers that were
supposed to preserve the integrity of science are meeting their
responsibility. None of the gatekeepers is willing to stand up to Big Pharma
because of its considerable financial clout. Instead, they are participating
in a deceptive charade. Dr. Sheldon Krimsky argues for the preservation of
science which must be able to correct itself, unlike religion or political
ideology, which are static, doctrinaire belief systems. "By withholding
information industry violates the communitarian norm of science. It limits
the possibilities of self-correction." [23]

Dr. Healy challenges industry and science gatekeepers along these same
lines: "If companies want to market their product under the banner of
science, they can be required to conform to the norms of science. This will
require journal editors and academic meeting organizers to refuse
publication to articles or presentations on data not freely accessible.
Taking a stand like this will challenge the conflicts of journal editors and
meeting organizers, but this rather than conflict of interest declarations
from individual academic authors or speakers is much more likely to have
teeth."

He pulls the blinders that shield industry's tactic-including commentators
employed by Lilly who readily acknowledge the problem in terms of individual
academics' failure to disclose their competing financial interests, but
avoiding the necessity of holding accountable those who conceal data or
disseminate false and deceptive reports. Although individual academics'
non-disclosure may reveal a lack of personal integrity, it does not itself
corrupt the integrity of the science:
"If I were employed in a company marketing department I would much prefer to
have the field think that all that is wrong is that a few corrupt academics
fail to declare competing interests than to have the field think that
company practices that restrict access to data while still claiming the
moral high ground of science are the real source of the problem."

FDA's gatekeeping authority
The FDA was established to hold industry in check, to protect the public
from harmful foods, drugs and cosmetics. FDA's gatekeeping authority is
enormous-if the agency used its authority. The FDA has in its possession the
data that is concealed from prescribing physicians-and it has the authority
to withdraw a company's marketing license. Therefore, the FDA bears the
greatest responsibility for drug-induced preventable injury and deaths-and
it bears a measure of responsibility for the credibility crisis in medicine.
If the FDA were performing its regulatory function as the public watchdog
companies would not engage in fraudulent marketing for fear of losing their
license.

A recent example involving the withholding of psychiatric drug data confirms
this assessment:

"Calling the Piper's Tune" by David B Menkes, MD, [24] describes the
"perverse effects of disclosure." Dr. Menkes was asked to comment about an
open label clinical trial conducted in an underdeveloped country. The study
was sponsored by a major pharmaceutical company; the study report and the
commentary were provisionally accepted for publication in Primary Care
Community Psychiatry. http://www.librapharm.com/headeradmin/upload/0185C_3.pdf
But the report was withdrawn without explanation, and the commentary was
stripped of the specifics-including deletion of the name of the sponsoring
company.

Ironically, Dr. Menkes notes that financial disclosure requirements have
sometimes had a "perverse effect." Most of the study authors in this study
were acknowledged employees of the company. Others were said to "have no
conflicts of interest to disclose," which he finds perplexing since any
personal or professional consequences of their involvement were not
specified while the statistical analysis by another named individual was
acknowledged, but no information given regarding their employment.

The case underscores the fact that journal disclosure requirements-much like
the published reports-can be manipulated to serve a marketing purpose. In
fact they can be used to deceive rather than to disclose.

*A follow-up Infomail will address cases of scientific fraud and research
misconduct in other medical fields.

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