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Thorough Expert Witness Report Explains Risk of Developing PPH While Taking Fen Phen – Part Two of Two

Here is the second and final part of the expert witness report filed by Lemuel A. Moye in Longs v. Wyeth. 

United States District Court, N.D. Ohio.

                               Ramonia LONGS, et al.,

                                         v.

                                    WYETH, et al.

                                   No. 103CV02042.

                                   March 31, 2005.

101 Combined Endpoints in Khan: For Khan, mitral valvulopathy was just one
component of the combined endpoint for cardiac valvulopathy. It is no surprise
that the high odds ratio seen for the combined endpoint could not be reproduced
for mitral valvulopathy if the number of events was small. It would be
unreasonable to conclude that there is no relationship between anorexigen use and
mitral valvulopathy solely because a high odds ratio could not be reproduced for
this low prevalence component of the endpoint. In general, the practice is to
extend the findings for the combined endpoint to each of its components as long as
there is no discordance in the components (i.e. the OR for mitral valvulopathy
suggests a strong protective effect of anorexigens). If this device were not
admissible, it would be impossible to study links between exposure and diseases of
very low prevalence, since the large number of patients required for the studies
would preclude any meaningful analysis.

102 The Epidemiological Study of Jick Jick[27] conducted a study, which confirmed
the findings of Khan, His confirmatory study was a population-based follow-up
study, which included a nested case-control analysis diet drug exposure, to
evaluate the relationship between fenfluramine exposure and the occurrence of
cardiac valvulopathy. In lick's study, out of 9,281 patients who were unexposed to
the fenfluramines, not a single patient had been diagnosed with cardiac valve
disease. Of the 8,903 patients who had been exposed to the fenfluramines, 11 had
cardiac valve disease (cumulative incidence rate 14.2 95% confidence interval 7.8
to 26.2). Some have somewhat naively criticized Jick for not reporting an odds
ratio for this overall effect However, they misunderstand that the odds ratio is
mathematically impossible to compute because no one in the unexposed group had the
disease. Cardiac valvulopathy only occurred for patients taking the fenfluramines.
Criticism of Jick for not computing an odds ratio in this circumstance is like
criticizing a baseball player for not stealing any bases when, in fact, that
player hits only home runs.

Thorough Expert Witness Report Explains Risk of Developing PPH While Taking Fen Phen – Part One of Two

Lemuel A. Moye filed this expert witness report on behalf of the plaintiff in Longs v. Wyeth. 

                                   Executive Summary

The following is my review of both the scientific literature, federal Food and
Drug (FDA) documents, deposition testimony, and documents from Wyeth that are
directly relevant to the causal link between the fenfluramines (Pondimin and
Redux) and the occurrence of primary pulmonary hypertension (PPH).

The intelligent use of the principles of epidemiology are essential in elucidating
the relationship between the fenfluramines and primary pulmonary hypertension and
2) the fenfluramines and valvular heart disease

To a reasonable degree of scientific and medical certainty, the fenflurarnines
cause primary pulmonary hypertension. Fenfluramines are not effective in producing
health improving weight loss in the obese. The overwhelming epidemiologic
evidence, using state of the art scientific methodology, concludes that the
fenfluramines cause primary pulmonary hypertension. Fenfluramines cause primary
pulmonary hypertension even for short durations of exposure (less than three
months). PPH can be induced by the fenfluramines months or years after the
fenfluramines have been discontinued. The risks of use of fenfluramines exceed the
benefits. Wyeth knew that fenfluramines caused primary pulmonary hypertension.
Wyeth did not keep the FDA, physicians, or patients apprised of the risks
associated with the fenfluramines. Wyeth mislead the FDA Advisory Committee about
the risks associated with Redux and Pondimin. The labels for Redux and Pondimin
are both defective. In fact no label could be written to describe the safe usage
of these compound.

Also, There is overwhelming scientific evidence to support my opinion that
fenfluramine and dexfenfluramine cause valvulopathy. These studies were properly
designed and executed by qualified scientists, followed accepted methodology, and
relied upon objective interpretation of scientific and medical data. These
theories have been subjected to peer-review on countless occasions including but
not limited to the reference articles. Random and systematic errors have been
appropriately controlled for by generally accepted epidemiological methods. These
theories are generally accepted as valid in the scientific community and are based
upon reliable studies. These theories have been advanced in scientific journals
and seminars and not just used for litigation purposes

 

Report Filed By Expert Witness For Wyeth Defends Warning Label For Redux

The central issue in any fen-phen pph lawsuit is whether the manufacturer adequately warned the public of the risks of PPH when taking fen-phen.  The expert witness in this case believes Wyeth did:

The FDA determined that the data submitted for Pondimin established the safety and
efficacy of the drug for short-term use as adjunctive therapy for the treatment of
obesity. Pondimin was found to have a lower abuse potential than amphetamine-like
drugs, which for many years had been used widely as appetite suppressants.

The Redux NDA contained extensive information on safety and effectiveness. This
included years of widespread use in Europe where it had been marketed since the
mid-1980s. Included in the NDA were controlled clinical trials of up to one year
duration demonstrating safety and effectiveness, as well as detailed
post-marketing safety reports. The studies demonstrated that dexfenfluramine was
more effective than placebo in promoting weight loss, when administered to
patients with instructions regarding diet and activity.

Also included in the Redux NDA were results from the International Primary
Pulmonary Hypertension Study (IPPHS), which addressed the risk associated with
anorexigen drug exposure in the development of primary pulmonary hypertension
(PPH). The FDA also convened an Advisory Committee to review the safety and
effectiveness of Redux, including data relating to PPH. The FDA was well apprised
of the risk of PPH in patients who took Redux and Pondimin before the NDA was
approved. After reviewing the data on PPH and the IPPHS, as well as the
post-marketing safety data from Europe, the Advisory Committee recommended the
approval of Redux based on a favorable risk-benefit ratio. FDA approved the drug
for marketing in the United States in April 1996. In my opinion, the initial Redux
labeling adequately and appropriately conveyed the safety data learned in both the
pre-approval studies and the European post-marketing experience with
dexfenfluramine.

Fen Phen Lawsuit Filed in Ohio Alleges Fen Phen Causes PPH

Buchanan v. Wyeth was filed in October of 2003, so it isn’t an example of current lawsuits.  However, it does give a pretty good breakdown of the evidence against fen phen:

35. In its August 26, 1996 issue, The New England Journal of Medicine reported the
results of the International Primary Pulmonary Hypertension Study ("IPPH Study")
entitled "Appetite Suppressants and the Risk of Primary Pulmonary Hypertension."
The IPPH study concluded that fenfluramine-based anorexigens [[such as fen-phen
and dexfenfluramine] increased the risk of primary pulmonary hypertension (PPH) by
30 times more than that which was founding the general population. That is, PPH
occurs at the rate of 1 in 500,000 people in the general population, but increased
to 1 in 16,500 in individuals who took appetite suppressant drugs such as
fenfluramine and dexfenfluramine.

36. The Defendant Manufacturers were aware of the result of the IPPH study by at
least November 1995, well in advance of its official publication in The New
England Journal of Medicine in August 1996, and prior to Plaintiff Mary Buchanan's
use of this drug. Nevertheless, the Defendants failed to apprise the public or
physicians that the risk of contracting PPH was many, many multiples of that
previously reported by the Defendant Manufacturers in their literature.

37. The product warnings in effect prior to and during the time that
dexfenfluramine was prescribed and used by Plaintiff Mary Buchanan were entirely
inadequate to alert consumers like Mary Buchanan of the actual PPH risk associated
with this drug or of the risks of heart valve damage associated with this drug,
although such risks were then known to the Defendants.

Doctor Diagnoses Woman As Developing PPH After Using Fen-Phen For Less Than Two Months

The following expert witness report alleges that a woman developed the fatal disease PPH after using Fen-Phen products for less than two months.

6. As it was formerly called, Primary Pulmonary Hypertension (PPH) is a progressive, incurable and often fatal disease, characterized by elevated pulmonary vascular resistance. This increased PVR results in a progressive loss of cardiac output due to increased right ventricular after load. Pulmonary hypertension is clinically defined as a mean pulmonary arterial pressure (mean PA) of more than 25 mm Hg at rest or 30 mm Hg during exercise. (Rubin, ACCP Consensus Statement: Primary Pulmonary Hypertension. Chest 1987; 104:236-50.) Prior to 2003, pulmonary hypertension was usually classed as either primary or secondary. A diagnosis of Primary Pulmonary Hypertension was made when all types of secondary pulmonary hypertension had been excluded on clinical grounds (Gaine & Rubin, Seminar: Primary Pulmonary Hypertension. Lancet 1998; 352:719-25) Following the consensus WHO conference in 2003, most experts in the field now refer to primary pulmonary hypertension as idiopathic pulmonary arterial hypertension; disease states which would formerly have been noted as secondary pulmonary hypertension are now called associated pulmonary arterial hypertension. Prior to 2003, cases involving diet drugs were called primary pulmonary hypertension when it was the opinion of the treating clinician that diet drugs were the only risk factor for the disease. In the current classification we would recognize anorexigens as a definite risk factor for the development of pulmonary arterial hypertension (much like scleroderma or congenital heart disease.) Therefore, pulmonary arterial hypertension related to diet drugs would be classified as associated pulmonary arterial hypertension (the association being diet drugs). Thus, for the purpose of this affidavit, the terms primary pulmonary hypertension (PPH) and pulmonary arterial hypertension (PAH, either idiopathic or anorexigen-associated) are synonymous. Patients suffering from PAH generally have a progressive pruning of the pulmonary vascular tree (resulting from occluded pulmonary arterioles), elevated pulmonary vascular resistance, and eventual loss of the cardiac output and death. The most recent survival data in the prostanoid era comes from Columbia Presbyterian Hospital where consecutive patients were followed between 1994 and 2002 (Kawut, et al. New Predictors of Outcome in Idiopathic Pulmonary Arterial Hypertension. Am. J. Cardiol. 2005; 95:199-203.) This is the era in which patients should have benefited from advanced pulmonary vasodilator therapy. Despite this, the survival for patients was only 75% at 3 years and 60% at five years.

7. Estimates of the incidence of idiopathic PAH are in the range of 1 to 2 cases per million in the general population for those who have not ingested diet drugs. This incident rate greatly increases for people who have a history of certain diet drugs, especially Pondimin(R) and ReduxTM.

16. According to Becky's deposition [at 115-16] and the history I took, she took Pondimin for two months (she estimates she had 5 left, hence, 58 of 63 pills). Given that her clinical history points to no other identifiable cause that would account for her pulmonary hypertension, elevated PVR and low cardiac output; and because exposure to the fenfluramines are among the most powerful known risk factors for developing PPH, I would consider her to have PAH associated with anorexigens even if she took fenfluramine for a month. There are discordant histories of Ms. Wright's length of use (one week [BW 18], one month [BW 469] and a prescription for 63 pills [BW 2]), but on the sole occasion Dr. Murphy ever discussed fen-phen with Becky, he recorded that she was “extraordinarily nervous”, “very nervous” and that “[s]he feels very pressured at the moment because of the rapid pace of events”. [BW 18-19]. Physician documentation is not infallible, and Dr. Murphy conceded that his entry of a left to right shunt on the same page is in error, but rather that Ms. Wright's echo demonstrated a right to left shunt. In my experience it is common for patients to be anxious and imprecise about historical details; this is all the more true for first time patients at a major referral center learning they have an incurable and deadly disease called PPH. This especially true when they are not given reason to believe that a particular piece of history is pertinent to their care and treatment. Given that Dr. Murphy never followed up with Ms. Wright regarding her fen-phen usage as the source of PPH, I do not think that his single piece of documentation should take precedence over the other data which I have seen. Dr. Scott has a sworn affidavit regarding how much he prescribed, prescription records show what was dispensed, and Becky has consistently testified that she stopped taking the drugs due to the onset of shortness of breath and chest pain [BW 22 & 469]. I am compelled to conclude that we have a more accurate history in 2007 than that recorded by Dr. Murphy in 2002.

Doctor Alleges That Wyeth Hid Safety Problems With Pondimin and Redux

The following expert witness report claims that Wyeth had ample notice that Redux and Pondimin cause PPH, but chose to conceal that information for as long as possible:

Multiple literature articles have reported on the association of fenfluramine/dexfenfluramine with irreversible PH and PPH. These include both animal and clinical data (e.g. Douglas, et al, 1981; Cacoub, et al, 1995; Naeijeet, et al, 1995; McMurray, et al, 1986; Hunsinger and Wright, 1990; Fotiades, et al, 1991). In December 1993, F. Brenot, et al, published their seminal report entitled “Primary Pulmonary Hypertension and Fenfluramine Use” in the British Heart Journal. This five year retrospective case control study evaluated 73 European patients with PPH. Of these, 15 (20%) had used fenfluramine and in 67% of these, there was a clear temporal relationship. These authors conclude that these data established a cause and effect relationship between PPH and fenfluramine use.

In February 1994, the International Primary Pulmonary Hypertension Study (IPPHS) group published their protocol for an international case-controlled epidemiologic study sponsored by Servier and designed to evaluate various risk factors relating to PPH. The interim IPPHS report was available in March 1995. Ninety-five cases were available for the case-control analysis and there were 355 matched controls. The authors report background risk for PPH was calculated to be 1-2 cases per million subjects per year. The absolute risk with anorexigens users was significantly increased to 18 cases per million patients per year. In the preliminary report, absolute risks from all causes were noted to reach perhaps as high as 100 cases per million patients per year. More attention relating to the 1995 IPPHS report and the Wyeth and IPI manipulation of these data are provided in Sections VI and VII.

On August 29, 1996, the final IPPHS report was published by Abenhaim, et al, in the New England Journal of Medicine. The reported risks associated with anorexigenic use were increased from the interim report following the final evaluation of the data. The final risks were calculated for long term use to be 23-46 cases per million patients.

Obviously, this risk significantly exceeds the background rate in untreated patients. Post marketing ADE reports were received contemporaneous with the noted group of publications. These were received in France, Belgium, Switzerland, Italy, U.K., Austria, and the Netherlands. Several of the European regulatory agencies reviewed the escalating numbers of adverse events and required the addition of new labeling warnings relating to PPH between 1991 and 1995. These include the World Health Organization and the French, German, and U.K. pharmaceutical authorities. Unfortunately, Wyeth did not include similar PPH warnings in the U.S. labeling prior to 1996 and 1997. As such, U.S. prescribers and their patients were not afforded with the same critical information as their European counterparts.

The failure of Wyeth to promptly include PPH in the U.S. labeling for Pondimin(R) is incomprehensible. After all, rapidly escalating numbers of reports were received as well. For example, between June 1, 1990 and May 31, 1995, Wyeth had received a total of 60 PH/PPH reports, including multiple U.S. events. However, the Pondimin(R) insert does not even include the term, PPH, until the summer of 1996. In June 1994, an internal effort was made to correct the obsolete U.S. Pondimin(R) insert. However, the necessary PPH additions were delayed by Wyeth executives until after the ReduxTM NDA was approved in April 1996.

Interestingly, it appears that the necessary revisions were also delayed until late enough in 1996 to avoid the cutoff dates for the publication of the 1997 PDR. Finally it does not appear that Wyeth submitted, as required, these reports or the various foreign events with their Pondimin(R) NDA Annual Reports. As Wyeth undoubtedly knew, the failure to fully report increasing numbers of ADE's and delaying the needed revisions in the Pondimin(R) labeling had an important positive impact on the chances for approval of the NDA of Pondimin(R)'s isomer, ReduxTM. Wyeth paraded the supposedly “good” safety record of Pondimin(R) as evidence of safety for ReduxTM. See, e.g., Dr. Dietch Testimony to the Drug Abuse and Endocrinologic and Metabolic Drugs Advisory Committees Joint Meeting, Open Public Session, September 20, 1995.

As emphasized in the ReduxTM New Drug Application (“NDA”), ReduxTM presentation as a “safe” drug to the FDA largely depended on the supposed safety record of Pondimin(R). However, Wyeth mischaracterized safety records through a failure to objectively and fairly disclose the adverse experiences of Pondimin(R) in the areas of VHD and PAH, and a failure to promptly revise labeling. In other words, Wyeth chose not to develop objective science, but instead chose advocacy, putting its own unfair and misleading “spin” on the scientific data.

In part, these problems occurred due to wholesale “under-classification” of adverse events as “non-serious” and/or “labeled,” when they should have been classified as serious and/or unlabeled and reported to the FDA. As stated in U.S. Department of Health and Human Services Public Health Service food and Drug Administration, Guideline for Postmarketing Reporting of Adverse Drug Experiences (Docket No. 85D-0249), March 1992 (hereafter called ADE FDA Guidelines):

21 CFR 310.305 and 314.80 describe a requirement for a sponsor to file 15-Day Reports of Serious, Unlabeled Events. These include all reports of spontaneous adverse events occurring within the united States (domestic reports), and Foreign, literature, and study reports involving serious unlabeled events and increased frequency of serious, labeled events. With respect to foreign reports, only 15-day reports of serious, unlabeled events and 15-day narrative increased frequency reports of serious, labeled events are required to be submitted with respect to foreign reports. Other foreign reports, including serious, labeled events and all non-serious events are not required to be submitted. However, reports of serious, labeled events should be available and submitted to FDA if requested.

Regulatory protocol provides, where a safety change in text is intended to add or strengthen warnings, the company can actually implement a new product labeling without obtaining prior approval by the FDA (Changes Being Effected) (21 CFR 314.70(c)(2). Wyeth had a duty to implement this “CBE” procedure and report contemplated changes in the labeling, especially as to Pondimin(R) and yet failed to do so. Wyeth delayed and withheld updating the PH warning and inclusion of VHD until after FDA approval and release of ReduxTM.[FN3]

FN3. See, e.g., Texas Exhibit 0143, AHP-P-00000003A.

In a similar manner, Wyeth failed to include appropriate adverse event information relating to VHD in the Pondimin(R) and ReduxTM inserts in a timely manner. Despite VHD signals in 1994 and 1995, these events were not included (or even mentioned) in the labeling until 1997, and only immediately prior to the product withdrawals. Although Wyeth delayed the inclusion of the potentially fatal events of PPH and VHD for as long as possible, hair related changes (alopecia) were promptly added in 1996. Section VI examines the changing safety profiles of fenfluramine and dexfenfluramine as a component of its risk-benefit assessments.

FENFLURAMINE AND DEXFENFLURAMINE CAUSE PPH; A PROGRESSIVE AND OFTEN FATAL DISEASE

So claims Dr. Stanley R. Homer in his expert witness report:

1. As it was formerly called, Primary Pulmonary Hypertension (PPH), also known as Pulmonary Arterial Hypertension (PAH) is a progressive, incurable and often fatal disease, characterized by raised pulmonary vascular resistance (PVR). Pulmonary hypertension is clinically defined as a mean pulmonary arterial pressure (PAM) of more than 25 mmHg at rest or 30 mmHg during exercise. Rubin, L., ACCP Consensus Statement: Primary Pulmonary Hypertension. Chest 1987; 104:236-50. Pulmonary hypertension is usually classed as either primary or secondary, and a diagnosis of primary pulmonary hypertension (PPH) is made when all types of secondary pulmonary hypertension have been excluded on clinical grounds. Gaine & Rubin, Seminar. Primary Pulmonary Hypertension. Lancet 1998: 352:719-25, at 719. The patient suffering from PPH (which is synonymous with PAH herein) experiences progressive elevation of pulmonary artery pressure, which eventually leads to right heart failure and death. Persons with fenfluramine-induced PPH have been found to have a poorer survival rate. Rich S, et al., Am J Cardiol. 2003 Dec 1;92(11):1366- 1368. Recent survival data in the postanoid era comes from Columbia Presbyterian Hospital where consecutive patients were followed between 1994 and 2000. This is an era in which patients should have benefited from advanced pulmonary vasodilator therapy. Despite this, the survival for patients was 60% at three years. Kawut, et al., New Predictors of Outcome in Idiopathic Pulmonary Arterial Hypertension, Am. J. Cardiol. 2005; 95:199-203.

2. The association between PPH and the use of anorectic diet drugs has been known since the PPH epidemic in Switzerland, Germany, and Austria from 1968 to 1970, following the introduction of a now-banned anorexic agent, Aminorex. It is generally accepted that the drug caused the epidemic of PPH and subsided when Aminorex was withdrawn from the market. Moride, et al., Epidemiology of Primary Pulmonary Hypertension, in Primary Pulmonary Hypertension (Rubin & Rich, eds., 1997).

3. In 1981, 1986, 1991 and 1993, at least 28 case reports of PPH in association with use of fenfluramine or dexfenfluramine were published in the scientific literature. See, e.g., Douglas, et al., Pulmonary Hypertension and Fenfluramine. British Medical Journal 1981; 283:881-883; McMurray, et al., Irreversible Pulmonary Hypertension After Treatment With Fenfluramine. British Medical Journal 1986; 292:239-240; Fotiadis, et al., Fenfluramine-induced Irreversible Pulmonary Hypertension. Post-Graduate Medical Journal 1991; 67:776-777; Brenot, et al., Primary Pulmonary Hypertension and Fenfluramine Use. British Heart Journal 1993; 70:537-541. Accumulating case reports are important evidence of causation, especially where such reports are consistent with epidemiologic data.

Professor of Medicine Testifies in PPH Lawsuit That Fen Phen Can Cause Primary Pulmonary Hypertension

Dr. Wayne Ray, a professor of medicine at Vanderbilt University, wrote the following report for the plaintiff in Wright v. American Home Products. 

Primary pulmonary hypertension (PPH) is a rare, life-threatening disease that is characterized by raised pulmonary-artery pressures in the absence of secondary causes for this increased pressure.33 Pathological investigations have suggested that the hypertension is due to a variety of types of damage to the small pre-capillary pulmonary arteries. Because this damage is usually irreversible, the only cure for PPH at present is lung transplant. Otherwise, without expensive intravenous treatment, the disease has a rapidly fatal course.33

In a recent review, Runo and Loyd33 described the epidemiology of PPH. The background incidence is estimated at 1 to 2 cases per million in the general population. One of the primary factors that influences risk are drugs and toxins (Table 1). Of these, the De appetite suppressants play a prominent role (Table 1). Smoking, a risk factor for coronary heart and cerebrovascular disease, is not considered a risk factor for PPH.33

The anorexigen aminorex, once widely sold over-the-counter in Europe, was associated with an epidemic of PPH.34 Aminorex is a sympathomimetic amine that works by a mechanism similar to amphetamines. In countries in which this drug was used, there was a 10-fold increase in the incidence of PPH between 1965 and 1972 . It was estimated that the users of the drug had a 2000-fold excess risk of PPH.34

….

There is conclusive evidence that to a reasonable degree of certainty fenfluramine derivative use confers excess risk of PPH. There is no reliable evidence that this excess risk returns to zero after medication use ceases. Indeed, there is reliable evidence to the contrary[FNe]. There is biologic plausibility for long-term risk, the case reports show patients whose disease is diagnosed after drug use ceases. There is no adequately designed epidemiologic study that provides evidence that risk returns to baseline after use ceases. Thus, the balance of the evidence currently points to a persistent risk, of unknown duration. The best estimate of the magnitude of this risk comes from the overall findings of IPPHS, which is an odds ratio of 6.3.

Another FDA Official Testifies in PPH Lawsuit

Dr. Janet Arrowsmith-Lowe, M.D., F.A.C.P., offered the following expert report on Wyeth’s behalf in the case of Wright v. American Home Products.

C. FDA Approvals of Pondimin and Redux

I agree with the FDA that the NDA data for Pondimin and Redux supported a conclusion that the drugs were safe and effective when used in accordance with their labeling. In other words, the potential benefits outweighed the known risks. My opinions on the adequacy of the data and labeling are based on my reviews of NDA data, FDA's reviews of the data, and my experience with the FDA review processes.

The FDA determined that the data submitted for Pondimin established the safety and efficacy of the drug for short-term use as adjunctive therapy for the treatment of obesity. Pondimin was found to have a lower abuse potential than amphetamine-like drugs, which for many years had been used widely as appetite suppressants.

The Redux NDA contained extensive information on safety and effectiveness. This included years of widespread use in Europe where it had been marketed since the mid-1980s. Included in the NDA were controlled clinical trials of up to one year duration demonstrating safety and effectiveness, as well as detailed post-marketing safety reports. The studies demonstrated that dexfenfluramine was more effective than placebo in promoting weight loss, when administered to patients with instructions regarding diet and activity.

Also included in the Redux NDA were results from the International Primary Pulmonary Hypertension Study (IPPHS), which addressed the risk associated with anorexigen drug exposure in the development of primary pulmonary hypertension (PPH). The FDA also convened an Advisory Committee to review the safety and effectiveness of Redux, including data relating to PPH. The FDA was well apprised of the risk of PPH in patients who took Redux and Pondimin before the NDA was approved. After reviewing the data on PPH and the IPPHS, as well as the post-marketing safety data from Europe, the Advisory Committee recommended the approval of Redux based on a favorable risk-benefit ratio. FDA approved the drug for marketing in the United States in April 1996. In my opinion, the initial Redux labeling adequately and appropriately conveyed the safety data learned in both the pre-approval studies and the European post-marketing experience with dexfenfluramine.

Former FDA Official Discusses Fen-Phen in PPH Lawsuit

Dr. David Feigal, Jr., M.D., M.P.H., filed the following expert witness report in the case of Wright v. American Home Products:

Information on pulmonary hypertension was added to the “Precautions” section of the Pondimin label in 1983. In 1987 a revision in the labeling expanded on the information regarding pulmonary hypertension warning that a fatality had occurred. At all times, up to the 1996 revision, information on pulmonary hypertension was appropriately placed in the “Precautions” section as required by the FDA's labeling regulations. This placement communicated to physicians that based on the available information, pulmonary hypertension might be associated with use of the drug. Prior to the Pondimin labeling revisions in 1996 the labeling contained an outdated reference to the number of pulmonary hypertension reports that had been received for patients taking Pondimin. However, the fact that the number of cases was not updated did not render the labeling inadequate. Rather, the label continued to apprise physicians of the known risks involved. Wyeth revised the label in 1996, to add information in the “Warnings” section, derived from the IPPHS. The IPPHS provided Wyeth and the FDA with new information about the risks with PPH in patients taking appetite suppressants.

A review of FDA documents illustrates that Agency did not find it necessary to add any additional information concerning pulmonary hypertension to the Pondimin and Redux labeling until the conclusion of the IPPHS. When the FDA reviewed the labeling in 1994 it determined that the labeling did not require any changes at that time, despite acknowledging that there had be reports of more than 4 case of pulmonary hypertension as mentioned in the labeling. Following the release of the IPPHS results, FDA determined that the results should be displayed on the Redux label. Following the revision to the Redux label the FDA decided to address changes to the Pondimin label. The FDA and Wyeth agreed that instead of listing the number of case reports of pulmonary hypertension, the Pondimin and Redux labels should provide a relative risk calculation based on the IPPHS