OIG Report: FDA Fails to Monitor Adverse Safety Reports_BMJ–FDA Duplicity Exposed

Even pharmaceutical trade newsletters (below) note FDA’s damaged reputation:
"The Food and Drug Administration (FDA) has been left red-faced after a
survey recently released by the Union of Concerned Scientists (UCS), found a
"disturbing level of interference in the agency’s research".

The most recent evaluation was issued by the Office of the Inspector
General, which found FDA’s monitoring of adverse safety reports (ASRs) of
marketed drugs to be grossly deficient.  Indeed FDA acknowledged its lack of
effective management information systems for monitoring postmarketing study
committements:
"FDA cannot readily identify whether or how timely postmarketing study
commitments are progressing toward completion."
"About one-third of ASRs were missing or incomplete."

"FDA reviewers indicated to us that monitoring postmarketing study
commitments is not generally considered a top priority at FDA.
Our analysis
showed that FDA validated only 30 percent of ASRs submitted in fiscal year
2004; five review divisions did not validate any ASRs"
.
ASRs contain information of limited utility.
    a.     Even complete ASRs lack information that would be useful in
monitoring the progress of postmarketing study commitments.
    b.     FDA has limited recourse when drug applicants do not submit
required information or do not demonstrate progress in completing their
postmarketing study commitments.

     FDA reviewers cannot easily identify which annual reports should
include ASRs for outstanding postmarketing study commitments.
    a.     FDA utilizes a confusing numbering system to identify
postmarketing study commitments, and drug applicants do not always provide
numbers for commitments they address in ASRs.
    b.     FDA frequently does not populate the fields of its database
of postmarketing study commitments with information from commitment letters
and ASRs that could assist reviewers in  tracking the progress of commitments.

Monitoring postmarketing study commitments is not a top priority at FDA.

RECOMMENDATIONS by the Inspector General:
To better determine whether and how timely postmarketing study commitments
are progressing toward completion, FDA should:
    a.     Instruct drug applicants to provide additional, meaningful
information in their ASRs;
    b.     Improve the management information system for monitoring
postmarketing study commitments so that it provides timely, accurate, and
useful information; and
    c.     Ensure that postmarketing study commitments are being
monitored and that ASRs are being validated.

See: Office of Inspector General Report: FDA’s MONITORING OF POSTMARKETING
STUDY COMMITMENTS http://oig.hhs.gov/oei/reports/oei-01-04-00390.pdf

"These latest revelations have further damaged the FDA’s reputation, already
tarnished after its involvement in high-profile safety lapses such as with
Vioxx, the inflammatory drug withdrawn in 2004 after risks of heart attack
and stroke were identified, as well as Ketek, an antibiotic found to have
links to liver failure that was allegedly approved on the back of fraudulent
clinical evidence."

See also: a letter published in the BMJ (British Medical Journal)  taking
FDA officials to task for scurrying to find ways to protect the
manufacturers of tainted drugs they approved without disclosing
life-threatening risks. Instead of coming clean to the public– FDA
officials are putting their efforts into burying documented suicides and
attempted suicides that occurred in controlled clinical trials of
antidepressants.

"In 2003, the FDA first presented an analysis of suicide from clinical
trials of antidepressants, most of which had been completed a decade
previously (5). Analyses of suicides and suicide attempts in antidepressants
trials had been published previously by others, each showing that
antidepressants increased the risk of suicide. This result hid for years
behind a statistical smokescreen with the claim that the increased risk of
suicide with antidepressants should be disregarded because it was not
"statistically" significant (6). But the FDA, with a database of more than
40,000 patients in trials from all of the antidepressant manufacturers,
found an increased risk of suicide with antidepressants that was
"statistically significant."

"Instead of concluding that their analysis confirmed the increased risk,
which would necessitate warnings on the drugs and admit the fallacy of their
pre- emption argument (currently being defended in litigation with millions
of dollars hanging in the balance), the FDA concluded that with a few clever
statistical adjustments, all of the increased risk disappeared."

The statistical tricks that FDA officials are using to hide the truth may be
appropriate in the realm of magicians entertaining sleight of hand
tricks–but tricks are inappropriate in the realm of science.

Contact: Vera Hassner Sharav
veracare@ahrp.org
 

http://www.in-pharmatechnologist.com/news/ng.asp?n=69555-fda-ucs-survey-vioxx-ketek
FDA red-faced over claims it is suppressing evidence
By Kirsty Barnes and Ahmed ElAmin

01/08/2006 – The Food and Drug Administration (FDA) has been left red-faced
after a survey recently released by the Union of Concerned Scientists (UCS),
found a "disturbing level of interference in the agency’s research".

According to UCS, the survey  "demonstrates a pervasive and dangerous
political influence of science at the FDA ."

Almost 20 per cent of the nearly 1,000 scientists who responded anonymously
to the survey said they had experienced their work manipulated or
suppressed, having been "asked, for non-scientific reasons, to
inappropriately exclude or alter technical information or their conclusions
in an FDA scientific document."

The scientists in question said they feared retaliation if they expressed
their opinions in public, the UCS reported.

Sixty-two percent of respondents were senior scientists, and nearly
one-third of respondents had been agency employees for more than 15 years.

Most of the allegations levelled by the scientists related to drug research,
and this criticism and the survey’s findings have important implications for
the public’s trust in the FDA’s role in regulating the drug industry, and by
implication in the safety of drug products.

The USC survey found that 61 per cent of the respondents knew of cases where
"Department of Health and Human Services or FDA political appointees have
inappropriately injected themselves into FDA determinations or actions."

Only 47 per cent of respondents think the "FDA routinely provides complete
and accurate information to the public." About 81 per cent agreed that the
"public would be better served if the independence and authority of FDA
post-market safety systems were strengthened."

About 70 per cent disagreed with the statement that FDA has sufficient
resources to perform effectively its mission of "protecting public
health.and helping to get accurate science-based information they need to
use medicines and foods to improve their health."

Many of the complaints were aimed at the agency’s Office of Regulatory
Affairs: one scientist said it should "not ostracise scientists or black
ball them because their foresight sees a problem with a drug, device, food,
biologics, etc. that possess a potential hazard to health now or in the
future."

Respondents also commented that budget cuts were affecting the agency’s work
and that it was being politicised instead of being based on scientific
evidence.

"We need more money. We need new equipment," said one scientist. "We should
be using the latest analysis techniques & modern technology instead of
relying on conventional methods."

Another commentator said: "Over the last several years I have noticed a
significant increase in the number of decisions that have become politicized
(e.g., increasing requests to review even simple regulations and changes,
both by Congress and the Commissioner’s office and to make apparently
politically-motivated changes in language and sometimes to alter bottom line
results), and I think the integrity of scientific work could be improved by
minimising the ‘politics’ of the process."

Another critic alleged: "I have seen violations that were not prosecuted
because legal staff and/or management knew that the time required to
prosecute some violations would take legal resources away from other
violations that would have more immediate and severe health consequences."

In a similar vein one of the respondents called for "increasing resources to
permit FDA to maintain itself as a premier regulator of foods, drugs and
cosmetics."

The FDA is responsible for protecting public health through the regulation
of drugs, food, medical devices, cosmetics, and the blood supply – including
products that, according to the agency, account for 25 cents of every
consumer dollar spent in the US.

However, these latest revelations have further damaged the FDA’s reputation,
already tarnished after its involvement in high-profile safety lapses such
as with Vioxx, the inflammatory drug withdrawn in 2004 after risks of heart
attack and stroke were identified, as well as Ketek, an antibiotic found to
have links to liver failure that was allegedly approved on the back of
fraudulent clinical evidence.

 ~~~~~~~~~~~~~
BMJ
Taming Who?
29 July 2006
David T Healy,
Professor of Psychiatry
Cardiff University LL57 2PW
Dear Sir

After approving SSRI antidepressants in the late 1980s and early 1990s, on
the basis of slender evidence of efficacy, the Food and Drug Administration
(FDA) in the United States (US) asserted there was "no credible evidence"
that these drugs could cause violent and suicidal behaviour in some
vulnerable individuals – despite what the evidence available from the late
1980s indicated. No warning was issued for prescribers or consumers. The new
antidepressant market ballooned to a $20 billion dollar business.

The US is the biggest profit centre for one of the richest industries in the
world. But there remains for the drug companies a significant obstacle
towards even greater profits: product liability awards. When drug companies
fail to disclose important risks, US courts can award large sums, and in an
effort to keep the risks and their concealment hidden, settlement costs are
now a routine part of doing business on company ledger sheets.

At someone’s behest – and this is the key point germane to Fiona Godlee’s
question as to whether we can tame the monster (1) – FDA came to the aid of
the pharmaceutical industry by including in a new rule amending an existing
regulation regarding drug labelling, the argument that in the FDA’s view,
anyone suing a drug company for failing to disclose a risk should not be
allowed to do so because such a lawsuit is pre-empted by federal law (2).
The argument was that if a drug was sold, that meant it was approved by the
FDA, and that all risks that should be known are in fact known and
disclosed.

In selecting a test case for this legislation, the FDA placed itself in a
position of defending the drug companies against law-suits by people who
claimed they had been harmed by undisclosed risks of antidepressants. In so
doing, they have staked a position that it is illegal to warn patients about
a risk of suicide from antidepressants. This position has become
increasingly untenable as evidence accumulates so that even GlaxoSmithKline
now acknowledges the risk to be present (3). But FDA dug in and continues to
defend its claim even as its scientists protested the agency’s subjugation
of science and public health to political aims (4).

In 2003, the FDA first presented an analysis of suicide from clinical trials
of antidepressants, most of which had been completed a decade previously
(5). Analyses of suicides and suicide attempts in antidepressants trials had
been published previously by others, each showing that antidepressants
increased the risk of suicide. This result hid for years behind a
statistical smokescreen with the claim that the increased risk of suicide
with antidepressants should be disregarded because it was not
"statistically" significant (6). But the FDA, with a database of more than
40,000 patients in trials from all of the antidepressant manufacturers,
found an increased risk of suicide with antidepressants that was
"statistically significant." Instead of concluding that their analysis
confirmed the increased risk, which would necessitate warnings on the drugs
and admit the fallacy of their pre- emption argument (currently being
defended in litigation with millions of dollars hanging in the balance), the
FDA concluded that with a few clever statistical adjustments, all of the
increased risk disappeared.

This FDA claim is dubious because in short term randomised drug trials large
amounts of bias sufficient to wipe out a doubling of risk are unprecedented
(6). Indeed, if these trials were so biased, then it would mean that the
studies that formed the scientific basis of FDA approval of these drugs were
seriously flawed. The data present the FDA with a dilemma: was the FDA
decision to approve antidepressants based on biased evidence, or were the
trials valid, in which case so is the "unadjusted" analysis which shows that
antidepressants cause suicide? On these data it would seem that FDA were
faced with the prospect of admitting to a huge mistake – either the mistake
of failing to warn against increased risk of suicidal behaviour or a mistake
in approving antidepressants in the first place. Fortunately for FDA, this
analysis only appeared as an abstract in a little read journal and their
dilemma went unnoticed.

In the meantime, an FDA employee created a scandal by finding that
antidepressants increased suicidal behaviour in paediatric trials, and an
advisory committee recommended a black box, the highest level of warning,
indicating the increased risk for children to all antidepressants. And one
manufacturer, GlaxoSmithKline, admitted that trials in adults showed an
increased risk of suicidal behaviour too. But FDA continues on the path of
denial. This year, they released the "full" publication of their analysis of
suicidal behaviour in trials of antidepressants in adults (7). In their
latest release, which fails to mention or cite their previous analysis, the
FDA has claimed that the cases of suicide on the new antidepressants have
mysteriously vanished, and with them the previously reported increased risk.
In addition to all the unanswered questions raised previously, the FDA’s
latest story only raises more embarrassing questions. What happened to the
suicides? Why does the FDA now claim to be unaware of suicides that they
previously analysed and of a risk that even manufacturers have admitted?
(8).

The FDA is in a shambles, and there is considerable evidence that Britain’s
Medicines and Healthcare Regulatory Agency (MHRA) is not in any better shape
(9). The claims of these regulators in general are now no more credible than
their claims that Vioxx was safe and effective. Given that these are the
bodies that are supposed to tame the monster, the question posed by Fiona
Godlee can only at present be answered in the negative – unless the answer
is that our first step must be to radically reform these bodies. The key
questions otherwise are first who’s bidding precisely are the regulators now
following (are these politicians or businessmen or who are they?) and second
what can we do about that?

1/ Godlee F (2006). Editorial: Can we tame the monster? BMJ 333

2/ Dept. of Health and Human Serv., Docket No. 2000N-1269, "Requirement of
Content and Format of Labeling for Human Prescription Drug and Biological
Products," p. 38 (Jan. 18, 2006).

3/ GlaxoSmithKline. Letter to healthcare professionals, May 2006.
www.gsk.com/media/paroxetine/adult_hcp_letter.pdf (accessed 13/05/2006).

4/ Union of Concerned Scientists survey:
http://www.ucsusa.org/scientific_integrity/interference/fda-scientist-
survey.html).

5/ Hammad TA, Mosholder A, Boehm G, Racoosin JA, Laughren T. Incidence of
suicides in randomized controlled trials of patients with major depressive
disorder. Pharmacoepidemiol Drug Safety 2003;12(suppl 1):S156.

6/ Healy D (2006). Did regulators fail over selective serotonin reuptake
inhibitors. BMJ 333, 92-95.

7/ Hammad TA, Laughren TP, Racoosin JA. Suicide rates in short term
randomised controlled trials of newer antidepressants. J Clinical
Psychopharmacology 2006; 26, 203-207.

8/ Healy D. bmjjournals.com/cgi/eletters/333/7558/92

9/ See correspondence on MHRA’s handling of trial suicide on
www.socialaudit.org.uk/6060116.htm#FOI

Competing interests: DH has links to all the major pharmaceutical companies
and has been an expert witness in legal actions involving antidepressants
and suicide

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