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September 2000 - Issue 11
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?

As always, we thank you for subscribing to The Verdict, your source for top-notch, valuable and current information about issues related to personal injury law.

Thanks for reading!

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with a consideration of those topics before moving on to discussion of a number of drugs which have recently been withdrawn from the market or have had serious questions raised as to their safety.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:

  1. A true need exists for the drug.
  2. A responsible pharmaceutical company undertakes a well-planned and adequately funded research and development program with active FDA participation in the process.
  3. Scientific specialists thoroughly and truthfully document each and every step of development and testing in what is known as an NDA (New Drug Application).
  4. The drug (the NDA) is submitted to the FDA with proof that it is effective and safe in that its benefits outweigh its risks.
  5. The FDA fully and carefully reviews the NDA as well as all supplemental materials and safety update. Supervisory personnel conduct additional reviews.
  6. A decision whether to approve the drug for mark is made based upon two critical factors:
    1. Have well-controlled studies demonstrated the drug to be effective for its intended use?
    2. Is the product safe under the proposed conditions of use?
  7. If approved, the drug will be "on the market" as soon as the manufacturer is able to implement production and distribution.
  8. 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

  1. The FDA Approval Process generally is subject to abuse.
    1. The FDA does not "test" proposed new drugs. It relies almost exclusively on safety and efficacy data provided by the drug's sponsor.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
  2. The FDA Approval of Rezulin Was Subject to Abuse
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. Notwithstanding the extreme dangers posed by Rezulin, the warnings lagged far behind, and required four major revisions between November, 1997 and June, 1999.
    7. 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.
    8. 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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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:

  1. Situations where the drug manufacturer can have no reasonable expectation that its warnings will actually reach those endangered by the use of the drug.
  2. Mass marketed drugs such as vaccines and contraceptives.
  3. If the learned intermediary is controlled by the drug manufacturer or acts in reliance upon information obtained from the manufacturer.
  4. When the warnings conveyed by the drug manufacturers are inadequate.
  5. When the drug is improperly or inadequately labeled by the manufacturer.
  6. 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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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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