In this issue:
1: What's
The Verdict?
2: Featured
Article: The FDA Approval Process and the Obligations of the
Private Physician in the World of Prescription Drugs
What's The Verdict?
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Jerrold S. Parker and Herbert L. Waichman
The FDA Approval Process and the Obligations of the
Private Physician in the World of Prescription Drugs
The questions and comments regarding our series of articles
on the pharmaceutical industry indicate that many of our
readers are interested in receiving more information
concerning problems with the FDA approval process and the
obligations of the private physician in the world of
prescription drugs. Thus, we begin this newsletter with a
consideration of those topics before moving on to discussion
of a number of drugs which have recently been withdrawn from
the market or have had serious questions raised as to their
safety.
I. The FDA - Trusty watchdog or paper tiger?
To the average member of the public, the FDA was always
considered the agency that strictly monitored the approval and
marketing of prescription drugs as well as the safety of all
drugs already on the market. Indeed, there was a time when
this perception could at least, be justified in most
circumstances.
Recently, however, the FDA's reputation has been badly
tarnished. A shocking number of drug withdrawals within a
relatively short time period has shaken the public's
confidence in FDA to the point where few believe it to be
acting as the type of responsible watchdog it was intended to
be. In fact, problems within the agency coupled with
questionable conduct by officials have led many to believe the
FDA has failed in its mission at a most crucial time.
In a perfect world, the scenario surrounding the
development and marketing of a new prescription drug would be
something like the following:
- A true need exists for the drug.
- A responsible pharmaceutical company undertakes a
well-planned and adequately funded research and development
program with active FDA participation in the process.
- Scientific specialists thoroughly and truthfully
document each and every step of development and testing in
what is known as an NDA (New Drug Application).
- The drug (the NDA) is submitted to the FDA with proof
that it is effective and safe in that its benefits outweigh
its risks.
- The FDA fully and carefully reviews the NDA as well as
all supplemental materials and safety update. Supervisory
personnel conduct additional reviews.
- A decision whether to approve the drug for mark is made
based upon two critical factors:
- Have well-controlled studies demonstrated the drug to
be effective for its intended use?
- Is the product safe under the proposed conditions of
use?
If approved, the drug will be "on the market" as soon as
the manufacturer is able to implement production and
distribution.
The manufacturer and the FDA continue to monitor and
evaluate all reported adverse events associated with the
drug as well as the results of any additional or long-term
studies. If necessary, label information and product
information is modified or supplemented. Warnings may be
added, modified or strengthened. In the most extreme
situations, the drug is removed from the market.
Unfortunately, we do not live in a perfect world. The
history of the pharmaceutical industry and its interaction
with the FDA is replete with well-publicized instances of
fabricating and falsifying data, concealing negative
information and adverse event reports, ethical violations,
conflicts of interest, undue influence, favoritism and other
forms of conduct designed to improperly influence FDA decision
making. When such factors are considered in conjunction with
the administrative problems faced by the FDA on an ongoing
basis, the mix is quite problematic. This is most disturbing,
however, in situations where a drug, which should never have
been marketed in the first place, must be withdrawn from the
market. In those cases, the pharmaceutical company, involved
will invariably seek to avoid liability by setting up the
defense that the FDA's approval of the drug is the best
evidence that the drug is safe and effective.
When it comes to approving new drugs, however, is FDA
approval the "gold standard" or something dramatically less?
An analysis of the FDA's review process (generally) with
particular emphasis on what occurred in the case of Rezulin
demonstrates the degree to which FDA approval is open to
question.
II. Approval by the FDA - Evidence of a drug's safety
and effectiveness or simply the illusion of both?
At a Rezulin Litigation Conference held in Washington D.C.
on June 14-15, 2000, Christopher Tisi, Esq. of the law firm of
Ashcraft & Gerel submitted an analysis of this very issue.
The following is a brief summary of that analysis.
The FDA's Review Process is Flawed and Resulted in an
Inadequate Review of Rezulin
- The FDA Approval Process generally is subject to abuse.
- The FDA does not "test" proposed new drugs. It relies
almost exclusively on safety and efficacy data provided by
the drug's sponsor.
- The FDA is increasingly understaffed. A single Medical
Officer is primarily responsible for each NDA. That
reviewer may be responsible for many new drugs at the same
time.
- Since there is no limit to how much information a
company can submit to the FDA, a sponsor has ample
opportunity to bury or hide data or to present data in a
biased or misleading fashion.
- FDA resources have been further stretched in the past
ten years by increased pressure from Congress and the
industry to approve drugs at an accelerated rate.
- Although the FDA claims that the removal of over 10
drugs from the market since 1996 indicates that the system
"works," the facts are to the contrary.
- The FDA Approval of Rezulin Was Subject to Abuse
- Rezulin was the first drug to be granted "fast track"
status under the Food and Drug Administration
Modernization Act of 1997. This meant that the FDA had
only 6 months to review the NDA before Rezulin was
approved in January, 1997.
- The FDA Medical Office initially in charge of
reviewing the Rezulin NDA (Dr. John Gueriguian) a twenty
year veteran of the FDA, was removed from the project in
November, 1996, only weeks before the FDA's Medical
Advisory Board was set to consider whether to recommend
approval of the drug. The removal came at the request of
Warner Lambert, ostensibly because he had used intemperate
language in describing the safety and efficacy profiles of
the drug. Significantly, this Medical Officer had
concluded that Rezulin was no more effective in treating
diabetes than other drugs already on the market yet it had
potential hepatic (liver) and cardiac (heart) side
effects.
- As a result of inadequate study, Rezulin was marketed
in March, 1997 without any warning of liver toxicity while
representing its adverse effects were no worse than those
seen with placebo.
- Almost immediately, the FDA began receiving reports of
severe liver failure (as predicted by Dr. Gueriguian). By
November, 1997, the FDA had received 35 reports of liver
damage, including liver transplants and death.
- Although Rezulin was withdrawn from the market in
England in December, 1997 and despite the warning of the
FDA's own (new) Medical Officer, Dr. Robert Mishbin, that
12,000 patients may suffer liver damage, the FDA
reaffirmed its commitment to Rezulin.
- Notwithstanding the extreme dangers posed by Rezulin,
the warnings lagged far behind, and required four major
revisions between November, 1997 and June, 1999.
- Even in the face of overwhelming evidence that the
risks posed by Rezulin far outweighed any benefit the drug
had, the FDA Advisory Panel did not recommend withdrawal
of the drug.
- On March 21, 2000 the FDA withdrew Rezulin from the
market. By that time, the FDA was aware of 90 liver
failures, 63 deaths and 7 liver transplants.
Based upon the above, Mr. Tisi concluded that the FDA is
not "the Gold Standard" for the safety and efficacy of a new
drug, particularly Rezulin. In addition to the information in
Mr. Tisi's analysis, the Rezulin debacle presented additional
indications that the FDA approval process is highly suspect.
Dr. Anne Peters, an endocrinologist at the University of
California at Los Angeles, noted that the serious problems
associated with Rezulin had been apparent while the drug was
being tested. In fact, the abnormal test results were so
extreme, Dr. Peters stated that they should have been regarded
as a "red flag."
Many doctors believed that Rezulin should have been
marketed from the very beginning with strong warnings and the
requirement that those taking the drug have frequent tests of
liver function. The drug was marketed with no such warnings.
In addition, the FDA threatened its own Medical Officer, Dr.
Peters stated that they should have been regarded as a "red
flag."
Many doctors believed that Rezulin should have been
marketed from the very beginning with strong warnings and the
requirement that those taking the drug have frequent tests of
liver function. The drug was marketed with no such warnings.
In addition, the FDA threatened its own Medical Officer,
Dr. Mishbin, with disciplinary action and dismissal from
federal service for his January 24, 2000 e-mail to his
superiors which stated: "I see no reason why any well-informed
physician would continue to prescribe {Rezulin}." He also
stated that he saw no reason why the "FDA should delay in
taking steps to remove {Rezulin} from the market." Dr.
Mishbin, who had originally supported the approval of Rezulin,
was joined by four senior FDA physicians in calling for the
withdrawal of Rezulin. In 1999, Dr. David Graham, a senior
epidemiologist with the FDA warned the agency's Advisory
Committee that every Rezulin user was at risk for sudden liver
failure even with monthly monitoring.
Finally, remember Dr. Gueriguian who was removed from the
review of the Rezulin NDA in November, 1996 after voicing
strong reservations about the drug? Well, his negative review
of Rezulin as actually purged from FDA files! What does that
say about the agency's commitment to safeguarding the public
by conducting comprehensive reviews that are beyond reproach?
III. Betwixt and Between - The Physician's Dilemma
Although most patients are unaware of it, each time a
physician writes a prescription, numerous considerations
automatically come into play. Individually and collectively,
these considerations" impose enormous responsibilities on
doctors to take medical and ethical judgments, keep fully
abreast of the latest medical and scientific information,
thoroughly investigate the patient's background and relevant
medical history, and respect the informed choices and
expectations of the patient. This is certainly not always easy
to do. In fact, in some situations it is virtually impossible
to do with complete certainty. The following are some of the
factors a physician must consider when writing a prescription:
- Possible undue influence - As we pointed out at length
in our previous newsletter, the pharmaceutical industry's
bombarding of the medical profession with an array of lavish
gifts and funding has raised serious ethical questions. A
physician must resist the temptation to prescribe a drug
base, in whole or even in part, on gratuities received from
the manufacturer of the drug. Many fear, however, that,
currently, prescriptions are often written as a direct
result of the quality of the gifts associated with the drug,
rather than the quality of drug associated with the gifts.
- Contraindications - The literature associated with every
drug includes any and all known contraindications. A
"contraindication" is any situation, condition, factor or
other circumstance that makes the use of the particular drug
inappropriate, inadvisable or dangerous. As with many of the
considerations discussed below, knowing when a drug is
contraindicated requires that a physician keep abreast of
the latest scientific and medical information and releases.
A doctor must also know his patient's medical and personal
history insofar as it relates to the drug in question.
- Interactions - As we discussed in our last newsletter,
interactions between different prescription drugs, between
prescription and non-prescription drugs, or between
prescription drugs and other substances like alcohol, food
or chemical compounds can be dangerous or even deadly. A
physician must be aware of any potential for such an
interaction by being thoroughly familiar with a patient's
medical profile as well as any relevant personal habits or
occupational factors.
- Product Warnings - Although prescription drugs are
marketed with various and wide-ranging warnings as to their
use and potential side effects, that is not the end of the
story. As effects, that is not the end of the story. As we
have seen with the drugs Rezulin and Propulsid, for example,
the original warnings can be grossly inadequate and require
numerous updates which are progressively stronger. Since
patients rarely read the warnings themselves, a physician
must keep abreast of all updated warnings and let his
patients know when those enhanced warnings affect them.
- Monitoring - Many prescription drugs require careful
monitoring at regular intervals in order to avoid dangerous
side effects. Blood, liver, kidney, heart and other tests
are strongly recommended for a wide range of drugs which can
have severe or even deadly side effects if left unmonitored.
A physician must insist on proper monitoring when
prescribing any drug with such potentially dangerous side
effects. Sometimes the patient will ignore or resist
monitoring. This is a real problem which a doctor must deal
with in order to protect the patient and avoid potential
liability.
- Adverse Reactions - A physician should be aware of the
nature of any reported adverse reactions associated with the
drugs he or she is prescribing. This will enable the doctor
to warn patients to be on the look-out for such reactions so
that a drug's use can be discontinued or modified
immediately. A doctor should also advise patients to report
any unusual occurrence or reaction which may be related to
the drugs he or she is taking. The only way adverse
reactions can be monitored and documented is to have them
properly and adequately reported.
- Expectations of Patients - A physician should always be
forthcoming and honest when discussing the use of any
prescription drug with a patient. Thus, a patient will have
realistic expectations with respect to what a particular
drug can be expected to do when taken for a specific
condition. The doctor should also use this opportunity to
advise a patient against any misuse of the drug which might
negate its effect or lead to harmful consequences.
- Common Sense - A physician should always use common
sense when prescribing any drug. For example, many doctors
stopped writing prescriptions for Rezulin long before the
drug was withdrawn from the market because they had was
withdrawn from the market because they had become convinced
that the risks posed by the drug far outweighed any benefits
it might provide patients. Thus, keeping abreast of medical
literature, news releases and other sources of information
regarding a drug's performance and risks may lead a doctor
to conclude a particular drug should not be prescribed
despite its still being on the market or even if the
warnings associated with it have not yet been revised.
Finally, every physician should be acutely aware of what is
known as the "Learned Intermediary Defense" available to
pharmaceutical companies which exists "when a drug
manufacturer properly warns a prescribing physician of the
dangerous propensities of its product, the manufacturer is
excused from warning each patient who receives the drug. The
doctor stands as a learned intermediary between the
manufacturers and the ultimate consumer." (In re: Norplant
Contraceptive Products Liability Litigation, 165 F.3d 374).
This defense evolved from the belief that physicians should
exercise their medical judgment on an individual basis with
respect to their patients when making determinations involving
the use of pharmaceutical products. A further rationale for
the defense is that drug manufacturers are not in the position
to make the individualized judgments as to which patients
should take a particular drug.
Of course, as with every rule, there are exceptions to the
Learned Intermediary Defense. These exceptions include:
- Situations where the drug manufacturer can have no
reasonable expectation that its warnings will actually reach
those endangered by the use of the drug.
- Mass marketed drugs such as vaccines and contraceptives.
- If the learned intermediary is controlled by the drug
manufacturer or acts in reliance upon information obtained
from the manufacturer.
- When the warnings conveyed by the drug manufacturers are
inadequate.
- When the drug is improperly or inadequately labeled by
the manufacturer.
- Misconduct on the part of the manufacturer.
Thus, as an integral part of the pharmaceutical marketing
rocess, physicians owe their patients a very high degree of
care when prescribing any drug.
IV. Six Unsafe Drugs - The Importance of the "Five-Year
Rule."
During the past 30 months, six drugs have been withdrawn
from the market on safety grounds. In fact, the week of March
19, 2000 was the first time two drugs (PROPULSID and REZULIN)
were withdrawn or safety reasons in the same week.
Each of these drugs was either removed from the market or
required strengthened warnings within five years of being
placed on the market. Five of the six drugs were approved
since 1996. When this is considered in conjunction with a
recent survey in which 19 FDA Medical Officers identified a
total of 27 new drugs that they had determined should not have
been approved in the first place, the "Five-Year Rule"
advocated by WORST PILLS, BEST PILLS NEWS is more important
than ever. (see Parker & Waichman Newsletter of July,
2000).
The six drugs withdrawn from the market are:
- cisapride (PROPULSID) - Approved for night-time
heartburn in July, 1993 and withdrawn in March, 2000.
Warnings concerning life-threatening drug reactions were
made progressively stronger five times between 1993 and
January, 2000. Cisapride has now been associated with
hundreds of reports of heart rhythm abnormalities and
deaths.
- troglitazone (REZULIN) - Approved for treatment
of type-2 diabetes in January, 1997 and withdrawn in March,
2000. Warnings regarding liver toxicity strengthened four
times. This drug is suspected of having caused hundreds of
cases of liver failure, deaths and the need for liver
transplants.
- grepafloxacin (RAXAR) - Approved in November,
1997 and withdrawn in October, 1999 after being associated
with a number of deaths and reports of hear rhythm
disturbances.
- bromfenac (DURACT) - Approved in July, 1997 and
withdrawn only 11 months later in June, 1998 because of
liver toxicity. Deaths and liver transplants have been
associated with this drug.
- mibefradil (POSICOR) - Approved in June 1997 and
banned in June, 1998. This calcium channel blocker for high
blood pressure was banned because of numerous cases of drug
interactions causing fatal heart rhythm disturbances.
- dexfenfluramine (REDUX) - Approved in June, 1996
and banned in September, 1997. This diet drug has now been
linked to thousands of cases of primary pulmonary
hypertension (PPH) and heart valve damage.
We hope that the last several newsletters dealing with the
pharmaceutical industry have been both interesting and helpful
to our readers. We may return to the subject in future issues,
however, we anticipate moving on to new areas next month in
order to provide more variety to our readers, especially for
those subscribers who may be interested in other subjects.
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