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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.

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