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 Prior to the Pondimin labeling revisions in 1996 the labeling contained an outdated reference to the number of pulmonary hypertension reports that had been received for patients taking Pondimin.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
I. Qualifications
I have held senior positions at the United States Food and Drug Administration (FDA). As noted in my curriculum vitae, attached as Exhibit A, in my 12 years at FDA I held the positions of Director of the Division of Anti-Viral Drug Products and acting Director of the Anti-Infective Drug Products and in addition during much of that time I was Director of the Office of Drug Evaluation IV within the FDA's Center for Drug Evaluation and Research. I subsequently was the Medical Deputy Director of the Center for Biologics Research and Evaluation, and the Director of the Center for Devices and Radiological Health.
I am Board Certified in Internal Medicine and have a Master's Degree in Public Health in the fields of epidemiology and biostatistics. Prior to my 12 years at FDA I was Associate Director of the Clinical Epidemiology program at the University of California at San Francisco and Assistant Professor of Medicine with joint appointments in Epidemiology and Biostatistics and a member of the Pharmacology faculty. I was also Director of the Data Center at the AIDS Clinical Research Center.
During the course of my career I have also practiced medicine and treated patients at a general internist in a faculty practice at the University of California. I have designed and conducted clinical trials and have published a number of those studies.
My career has included extensive experience in the evaluation of safety and effectiveness of pharmaceuticals as well as other therapeutic modalities. At FDA I was responsible for the evaluation of safety and efficacy of new drugs, including the approval process and continuing oversight of the safety and effectiveness of those drugs after approval. I understand fully the process and criteria utilized by FDA in assessing the safety and efficacy of new drugs, and I participated directly in that process for years.
II. Materials Reviewed
The documents I have reviewed are listed in Exhibit B, attached to this report.
I have reviewed a large number of documents relating to Pondimin and Redux. These documents included substantial portions of the new drug applications (NDA's) for both drugs as well as company and FDA documents relating to the approval process, and the FDA Advisory Committee transcripts for Redux. I have reviewed documents relating to the post-marketing safety surveillance at Wyeth, and have reviewed all of the adverse event reports for both fenfluramine and dexfenfluramine that have any mention of aortic or mitral valvular regurgitation. I have reviewed materials relating to pulmonary hypertension and primary pulmonary hypertension including, but not limited to, scientific studies, ADE's, internal Wyeth documents, FDA documents, transcripts from Advisory Committee meetings, labeling, Dear Doctor Letters, and other public statements by Wyeth, FDA, and others. I have reviewed a number of company employee and expert testimony transcripts. In addition I have reviewed medical literature including published clinical studies related to fenfluramine and dexfenfluramine.
III. FDA Practice and Requirements
A. FDA's Regulatory Role
The Food and Drug Administration is an100 year-old consumer protection agency with enforceable legal authority to assure that before drugs are sold that they are shown to be safe and effective and that the drug's benefits outweigh risks. FDA requirements are specified in law by the Food Drug & Cosmetic Act passed by Congress. The requirements of the law are described in detail in the regulations. The agency monitors the study, manufacturing, labeling, distribution, and post-market surveillance of all prescription drugs within the United States.
The FDA primarily performs these tasks through its drug division, The Center for Drug Evaluation and Research (CDER) one of the world's largest regulatory agencies. The CDER regularly sets the standards for drug and other product regulation, and many regulatory agencies in Europe and across the globe have adopted its standards.
B. The New Drug Approval Process
FDA regulations and section 505 of the Federal Food Drug and Cosmetic act require all pharmaceutical companies to go through the new drug approval process before producing and marketing a new drug.
1. Investigational New Drugs
Prior to introducing a new pharmaceutical compound to the US market the FDA requires every pharmaceutical company to first submit an Investigational New Drug application (IND) to the agency. This application provides the FDA with data on the manufacture of the drug, animal studies demonstrating it safety, in vitro studies, and protocols for future studies on human participants. If the FDA accepts the application based on these studies, the product then undergoes further clinical trials to establish safety and effectiveness in the intended population. In the IND phase of development the FDA has the authority to place a hold on further development of a drug product if the safety of the drug is in question. The foremost consideration for FDA during clinical investigations is drug safety.
2. New Drug Application Review
Following the IND phase, the drug product's sponsor provides the FDA with a new drug application (NDA) containing all the data it has gathered on the product's safety and effectiveness. Generally, the NDA contains the following information: (i) reports of all preclinical and clinical studies; (ii) a summary of all safety data; (iii) pharmacological data on the drugs composition; (iv) methods and facilities used in the drug's manufacturing; (v) samples of the product; (vi) proposed labeling.
The FDA employs a number of resources in reviewing the NDA data, including a team of physicians and scientists who are experts in their respective fields. This team prepares detailed reports for the FDA on their findings. On occasion the FDA also assembles Advisory Committees to provide expert opinions on issues typically relating to the drugs' safety and effectiveness identified during the FDA review. Using this data, the FDA determines whether the information submitted in the NDA sufficiently establishes that the drug meets the FDA's safety and efficacy requirements. Upon passing this rigorous review, the FDA will issue a letter to the drug sponsor approving the NDA. However, if the FDA rejects the NDA it will issue a letter outlining any deficiencies or faults in the application.
In addition to reviewing preclinical and clinical data within the NDA, the FDA also reviews the sponsor's proposed label. While the contents of the label are initially the results of discussion between the sponsor and the FDA, it is the FDA that makes the final determination regarding the content, format, and language of the label. Even following the approval of the label and the product's release on the market, the labeling is continually reviewed by the FDA for possible revisions based post-marketing safety data and other information provided by both the company and the FDA.
3. Risk-Benefit Assessment
When the FDA makes a final determination that the sponsor's drug is safe and effective and has adequate labeling, it will approve the NDA. The NDA approval means that the FDA determined that the sponsored product's benefits outweigh any known risks that may occur when the product is used in accordance with the approved labeling. This risk-benefit assessment is conducted with every FDA-approved drug on the market and is a crucial element of the drug approval process.
C. FDA Approval of Pondimin and Redux
I have had access to the entire Pondimin and Redux NDA's and have reviewed the study reports of the key efficacy studies, the summaries of safety and effectiveness, and looked at specific safety reports and case report forms. I have also read the advisory committee transcripts of the two meetings to discuss Redux. The FDA approved Pondimin in 1973 and Redux was approved in 1996. The FDA's Redux review included information from both pre-market controlled trials of dexfenfluramine and multinational post-market surveillance of dexfenfluramine and fenfluramine.
I agree with the FDA new drug review staff decisions to approve Pondimin and Redux based on the available scientific information relating to these drugs. FDA considered the known risks and concluded that the overall benefit-risk ratio justified the drugs approval.
The FDA's conclusions were reasonable in light of available evidence. The health consequences of obesity include increased risk of heart disease, diabetes and other serious conditions and reduction of excess weight has been shown to be beneficial. The NDA data on this point supported the FDA's conclusion that the drugs were safe and effective when used in accordance with their labeling.
The NDA for Redux contained extensive information on safety and effectiveness including data from Europe where the drug was first marketed in the mid-1980's. The NDA also included clinical trials showing that the drug was effective in promoting weight loss in obese patients.
Among the data included in the NDA were the results of the International Pulmonary Hypertension Study (IPPHS). This study addressed the risks associated with anorexigen exposure in the development of primary pulmonary hypertension (PPH). The IPPHS was the best information available about the risks of PPH at that time. Wyeth and Interneuron provided FDA with the results of that study, which were independently analyzed by the FDA.
The FDA also consulted directly with the authors of the IPPHS to better understand that study. In addition, the FDA was provided with substantial information about PPH adverse drug events in both Pondimin and Redux as part of the Redux approval processes. The FDA and its Advisory Committee considered all available information about PPH, including the IPPHS study, as part of the Redux approval process. As a result the FDA was aware of any known risk of PPH associated with fenfluramine and dexfenfluramine before the Redux NDA was ever approved.
D. Post-marketing Requirements at Companies and FDA
When a drug is approved by FDA there is detailed safety information on several thousand patients who participated in the pre-market clinical trials. Many of the trials have control groups allowing the comparison of adverse effects in patients who took a drug to those that did not. Adverse effects detected during pre-market testing are described in the product label. Pre-market safety studies may not pick up all of the adverse effects related to the drug because the testing is conducted in a limited number of patients. For that reason manufacturers are required to continue to collect and report, per 21 C.F.R. Section 314.80, any adverse experience information after approval. This post-market surveillance includes spontaneous reports of individual cases from health care practitioners or patients, foreign adverse experience reports, and information from the medical literature. These reports are analyzed by two groups within the FDA. First, the Office of Epidemiology and Biostatistics, comprised of physicians, epidemiologists and other scientists, codes and process any reports received by the FDA. Then the reports are reviewed separately by the review team responsible for the approval and labeling of the drug in question.
The purpose of spontaneous reporting is to detect a “signal” of a potentially adverse effect that was not known prior to marketing. These signals do not establish whether the association of the drug and the adverse effect are related to use of the drug, but instead identify potential problems. There are limitations to spontaneous reports which have to be taken into account. Patients may have multiple medical problems and may have taken many different medications, and reports may have incomplete information. Spontaneous reports also lack controls. The reports ask for the patient's demographic information, medical history and physical condition, drug use and lab results. The reporter is asked to identify the adverse event and the drugs that potentially could be involved.
FDA specifies in its regulations when and how to report, with a particular focus on reporting serious and unexpected events which FDA has defined in the regulations. These potentially significant events are to be reported within 15 days after they are received by the manufacturer. Some other reports are grouped together in periodic and annual reports. FDA specifies that foreign reports that are not serious and unexpected are not reportable.
Wyeth complied with the reporting requirements in effect during the marketing of Pondimin and Redux as evidenced by a 1997 inspection Wyeth's ADE reporting system, which found no fault with the company for failing to submit any reports.
E. Labeling Requirements
21 C.F.R. Section 201.57 enumerates the labeling requirements for prescription drugs and spells out what must be included in each section of the labeling. Adverse events are events which occur during the use of the drug, but are not necessarily caused by the drug or necessarily related to its use. Only those events which are considered to be reasonably associated with the drug are to be included in the “Adverse Reaction” section of the labeling. I believe that Wyeth was in compliance with the labeling requirement with both Redux and Pondimin.
On occasion a drug with certain risks will contain a warning enclosed in a black box on the label to highlight certain risks. The FDA has complete authority over which labels contain these “black box” warnings. FDA limits the use of these warning so as to avoid over use, which would ultimately dilute the warning's impact. On many occasions, the FDA has reviewed serious and fatal side effects in drugs and has made the determination that a black box warning is not necessary. At one point the FDA considered the use of a black box warning for Pondimin and Redux and determined that no such warning was necessary for PPH. Instead, the agency determined that a bold type warning at the beginning of the “Warnings” section of the labeling was appropriate for this risk.
F. Pondimin and Redux
At all times the Pondimin and Redux labels provided information on the known risk of pulmonary hypertension, including death. The FDA documents reflect that the Agency was specifically aware of the information regarding Pondimin and pulmonary hypertension but determined that no change was necessary until the IPPHS results were finalized. Additionally, the Redux label appropriately and adequately conveyed known risks of Redux during the time it was on the market.
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.
Wyeth complied with all applicable FDA regulations in submitting reports of pulmonary hypertension to the FDA. There is no evidence suggesting that Wyeth concealed any adverse event data from FDA with respect to Pondimin and Redux.
I have reviewed the post-market surveillance information available to Wyeth pertaining to valvular regurgitation and Pondimin and Redux. Based on my review, Wyeth complied with the FDA reporting requirements with respect to reports that make reference to valvular regurgitation. I have concluded that Wyeth acted as a reasonable and prudent manufacturer with respect to post-market surveillance.
In my opinion, prior to the reports from the Mayo Clinic and Fargo, N.D., in 1997, there was not a signal of valvular regurgitation. There are a number of reasons supporting my conclusions. For example, there is a fairly high background rate of valvular regurgitation in the population not exposed to the drugs. Valvular regurgitation is not typically associated with drug therapy. Valvular regurgitation had not been observed in any of the clinical studies in the NDA's. There were no published reports prior to 1997 suggesting a connection between the fenfluramines and valvular regurgitation. This was the case even though fenfluramine had been marketed since the 1960's and dexfenfluramine since 1985 with substantial use.
In most adverse event report cases which mention valvular regurgitation, the patients had complex medical problems such as pulmonary hypertension. Valvular regurgitation was noted only because echocardiography was obtained to measure pulmonary artery pressures and was not the focus of the report. Other patients who took a mixture of drugs, Chinese herbs and other compounds had multiple severe medical problems including renal failure which confounded the interpretation and identification of drug effects and their medical conditions.
The FDA reviewers assessing Redux and Pondimin adverse reactions did not conclude that there was a valvular regurgitation signal. The Belgian Center for Pharmacovigilance did not find an association. Likewise it is understandable that Wyeth had not seen a signal nor an association between fenfluramine or dexfenfluramine and valvular regurgitation before 1997.
When the Mayo Clinic/Fargo North Dakota valvular regurgitation cases were reported a signal evolved. Distinctive valvular pathology had been identified in patients who had undergone valve surgery and a potential mechanism of drug injury was proposed. Wyeth acted responsibly and reasonably in responding to the Mayo/Fargo reports. There were no prior reports of this unusual valvular pathology.
The company responsibly and promptly took steps to evaluate and report the events of valvular regurgitation to the FDA and to update the drugs' labels. Wyeth acted responsibly in handling these ADE's and in its labeling decisions. A reasonable basis for including a reference to valvular regurgitation in the product labeling did not occur until these reports.
In my opinion, the actions of the company to initiate studies after the voluntary withdrawal of the products was reasonable and prudent and the studies were conducted in accordance with accepted scientific standards.
I am aware that physicians prescribed Pondimin for periods of time beyond the few weeks recommended in the products label. I am also aware that the product was often prescribed in conjunction with phentermine. However, the fact that physicians prescribed the drug for extended periods of time or for combination use does not mean that the company violated FDA regulations. The company was under no obligation to discourage such use. The FDA does not interfere with physicians' practice of medicine. As such, physicians may prescribe drugs in a manner not stated in the labeling if they feel that the patient would benefit from such use. Additionally, National Institute of Health studies supported the safety and efficacy of Pondimin and phentermine when used together for more than a year. Moreover, physicians often prescribe drugs in combination even when such use is not described in the labeling.
I reserve the right to testify in my areas of expertise in response to testimony of the plaintiff's experts. I also reserve the ability to supplement the opinions included in this report based on new information.
I am being compensated at the rate of $500 per hour.
I have not testified in any cases in the last four years.
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