Redux, Fen-Phen and the Products Liability Act
By Armand Leone, Jr.
*The author, an attorney and medical doctor, is of counsel to Chatham’s Blume, Goldfaden, Berkowitz, Donnelly, Fried & Forte.
Plaintiffs have already filed numerous lawsuits alleging injuries caused by the use of the diet drugs, Dexfenfluramine (Redux), Fenfluramine (Pondimin) and Phentermine. The litigation centers on four classes of defendants — pharmaceutical manufacturers, physicians, and to lesser extent, pharmacies and commercial weight loss centers. However, plaintiffs seeking recovery in New Jersey state courts may have some difficulties in pursuing pharmaceutical product liability claims that are unique. Accordingly, the medical malpractice claims will probably play a larger role in New Jersey diet drug litigation.
The New Jersey Product Liability Act, N.J.S.A. 2A:58C-1 et seq., specifically provides an evidentiary presumption in the favor of drug manufacturers against failure-to-warn claim:
If the warning or instruction given in connection with a drug or device or food additive has been approved or prescribed by the federal Food and Drug Administration under the Federal Food, Drug and Cosmetic Act, 52 Stat. 1040, 21 U.S.C. Sec. 301 et seq., … rebuttable presumption shall arise that the warning or instruction is adequate.
N.J.S.A 2A:58C-4. Because of the Act, it will be more difficult to recover under a failure-to-warn theory, which is the major product liability claim in this litigation.
This article examines the potential claims that litigants in New Jersey may bring, the factual predicates for these claims and the likelihood of prevailing. In addition to the plaintiffs’ claims, the pharmaceutical manufacturers can be expected to rely for a defense on both the rebuttable presumption of adequate disclosure and the learned intermediary defense. Id. Whether one is counsel for plaintiffs, physicians or pharmaceutical defendants, one needs to be familiar with the various liabilities that can attach to the physicians who prescribed these drugs.
Because of the differences in approved drug information for each one of these diet drugs, a thorough understanding of the information submitted to the Food and Drug Administration in the New Drug Applications, as well as the approved drug information for each one is necessary to properly prosecute and defend these claims.
The Drug Approval Process
Before a drug can be released into the marketplace, the FDA must establish that the drug is safe and effective for the intended uses and approve the drug’s labeling and packaging information, including the information provided on recommended use, warnings and side effects. 21 U.S.C. Sec. 355. A pharmaceutical manufacturer submits scientific data to the FDA as part of its New Drug Application for the drug. After FDA reviews the submitted data and any additional data it requires, it determines whether or not the new drug is safe and effective for its intended purposes, approves the labeling and packaging information and allows the drug to be marketed for the approved indications. However, FDA drug approval is not an investigative process, but rather an evaluation that is dependent on the information supplied to the FDA by the drug manufacturer. See generally, R.A. Merrill and P.B. Hutt, Food and Drug Law (Foundation Press, 1980).
Perhaps the reason why the Products Liability Act creates only a rebuttable presumption that the information disclosed in the Physician’s Desk Reference and package insert is adequate is that the NDA approval process is entirely dependent upon the information submitted to the FDA by the pharmaceutical manufacturer. If the manufacturer does not provide all the relevant information to the FDA and omits unfavorable data, then the FDA approval has little, if any, validity. If the FDA approved the drug information based upon complete and truthful disclosure of the scientific evidence by the drug manufacturer, it seems unlikely that a jury would find against the evidentiary presumption in favor of adequate disclosure. Thus, the proof necessary to overcome the rebuttable presumption of the adequacy of the FDA-approved disclosures may be the equivalent of having to prove intentional misrepresentation and the nondisclosure of adverse information by the manufacturers in the NDA approval process.
The PDR and Malpractice
Physicians frequently rely upon the PDR when making decisions concerning the safe administration and dosages of drugs. Even though drug manufacturers may be in a better position than physicians to determine the appropriate usage and dosage of drugs, manufacturers argue that they do not design the package inserts and PDR warnings to establish a standard of medical care. Morlino v. Medical Ctr. of Ocean County, No. A-36-97 (N.J., Decided Feb. 26, 1998). Accordingly, the Courts measure a doctor’s duty in a traditional medical malpractice action by an objective standard of care. With rare exception, proof of this standard requires testimony by a medical expert. Rosenberg ex. rel. Rosenberg v. Cahill, 99 N.J. 318,325 (1985).
The PDR contains detailed information relevant to the proper usage of the drugs by physicians, and expert testimony often is needed just to understand it. Deviation from the FDA recommended usage does not generally establish a deviation from the standard of medical care required by a doctor in the absence of expert testimony. The decision of whether to prescribe a drug and, if so, the manner in which it is used, is usually a matter of judgment for the physician. In addition to considering the individual patient, the physician may consider all available information including the package insert, the PDR, medical journals, peer advice and the physician’s own experience. When supported by expert testimony, however, the PDR provides strong evidence of the applicable standard of care in malpractice actions.
The PDR has a different role in an action for lack of informed consent. The objective reasonable person standard is used to determine whether an undisclosed risk of the treatment was material and whether a reasonable person, having been advised of the undisclosed risk, would have undergone the treatment. In these cases, there is a reduced need for expert testimony, because the court need only find that the risk of injury was a material one that was recognized in the medical community. Largey v. Rothman, 110 N.J. 204 (1988); Adamski v. Moss, 271 N.J. Super. 513, 518-22 (App. Div. 1994).
The recognition of a risk in the medical community can be established through the testimony of an expert relying upon the PDR, since it is a medical treatise that identifies specific risks associated with the use of diet drugs. A court could even take judicial notice of the PDR, as it can with other established medical treatises. Even without judicial notice, the reliability of the PDR can be established when a medical expert or even the defendant testifies that physicians generally rely upon it when prescribing medications. Plaintiffs may also present additional testimony that physicians generally rely upon the PDR and package inserts to learn the risks of the drugs they prescribe. Accordingly, the plaintiffs in lack of informed consent cases will be able to rely almost exclusively on the risks warned of in the PDR in proving liability, since the PDR will be found reliable through judicial notice, expert testimony, or the defendants’ own admissions.
Product Liability Claims
Product liability relies primarily on failure-to-warn claims and possibly design defect claims. In the context of diet-drug litigation, proof of failure-to-warn claims will require a demonstration that the manufacturers failed to provide sufficient warning of the potential injuries in view of the known clinical trial data and European product experience. In New Jersey, plaintiffs may even be required to show that the manufacturers failed to advise the FDA of adverse effects that were known to them but not disclosed to the FDA and the medical community. In essence, New Jersey plaintiffs may have to make a prima facie showing of fraud in the NDA approval process in order to overcome the rebuttable presumption of adequate disclosure.
Claims based on design defect are more difficult to postulate but are not inconceivable. There was a considerable amount of available medical research and knowledge on the adverse effects of excess systemic seratonin on heart valves before the approval of Dexfenfluramine, Fenfluramine and Phentermine for marketing. In fact, recognition of the diet-drug injuries was possible, in part, because of the rare but well-known cardiac valve abnormalities associated with seratonin-secreting carcinoid tumors of the lung. Fenfluramine and Dexfenfluramine are seratonin-like chemicals whose anti-obesity action depends on their ability to bind to act like seratonin in the brain. A design defect claim might be based on the known danger to heart valves of using a seratonin-like drug, since valve injuries were known to be associated with high systemic levels of seratonin.
Medical Malpractice Claims
The two malpractice claims that play a role in this litigation are lack of informed consent and deviation from standard of care. Both of these liability theories will depend for support upon the FDA-approved usage and warnings in the PDR, which unfortunately differ for each drug. Informed consent claims will be for the undisclosed increased risk of primary pulmonary hypertension (PPH) and the unknown risks associated with the use of the popular combination known as “Fen-Phen.” Deviation claims will depend on the following theories: inappropriate patient selection, prolonged use, overdosing, negligent monitoring, unapproved uses and failure to discontinue.
Primary Pulmonary Hypertension. PPH has a four-year fatality rate of 45 percent, and was listed in bold in the warning section as a known risk of Dexfenfluramine and Fenfluramine when used for three months or longer. The original FDA warnings in April 1996 indicated that use for longer than three months created a relative risk of developing PPH that was nine times greater than normal. On August 22, 1996, Wyeth-Ayerst and Interneuron Pharmaceuticals issued a press release advising doctors that the labeling for Dexfenfluramine would be revised, because the actual relative risk of developing PPH was at least 23 times normal. Any physician who failed to advise the patient of this risk should be liable for lack of informed consent, if PPH subsequently developed.
It is probable that a jury would agree that a reasonable person in the plaintiff’s condition, having been informed of the nine-fold and, later, at least a 23-fold increase in PPH, would have opted not to take the drug for longer than three months. On the other hand, physicians would not be liable for lack of informed consent to plaintiffs who developed cardiac valve injuries, unless the plaintiff was treated with the unapproved combination of Fenfluramine and Phentermine (Fen-Phen). Liability for lack of informed consent can only attach to known risks that become actual complications, and cardiac valve injury was not disclosed as a risk in the PDR. Of course, a product liability claim against the manufacturers for failure to warn physicians, the FDA and the public of these cardiac valve injury risks does remain.
Unapproved Uses of Approved Drugs. The unapproved use of the approved drugs Fenfluramine and Phentermine in the combination known as Fen-Phen creates an interesting informed consent issue, because the risks of these drugs in combination were unknown. Plaintiffs can claim that physicians probably should have disclosed that the use of the Fen-Phen combination was not a recognized use of the drugs; that there were no studies showing that it was a safe combination to use; and that the risks of the Fen-Phen therapy were unknown. A patient would then have to accept this risk of the unknown and be willing to use the drug.
The manufacturer Wyeth issued a letter to physicians in January 1997 advising that Pondimin (Fenfluramine) had not been tested with other drugs and combining was not recommended. The letter specifically advised that combination use is not “approved use, and that Fenfluramine is indicated for short-term use only.” On July 8, 1997, the FDA issued a Public Health Advisory to doctors requesting reports of Fen-Phen side effects and reminding physicians that the safety and efficacy of the Fen-Phen combination had not been proved and serious concerns about its use had been raised. Considering the specificity with which the manufacturers and the FDA advised physicians against using the Fen-Phen combination, the duty to disclose the risk of using this unapproved combination may be further increased.
The use of an unapproved combination of approved drugs on patients seems similar to the use of an experimental drug under an Investigational New Drug Application (INDA). The consent process for use of an experimental drug as part of an INDA is extremely detailed and heavily regulated. See, e.g., W.K. Simpson, “Investigational Drugs Likely Have Immunity,” Product Liability Law and Strategy, Sept. 1993. It would appear that the same consent requirements should have existed when physicians prescribed the unapproved combination of Fen-Phen for their patients. Arguably, any complicating injury that occurred from the use of Fen-Phen could be compensable under a lack of informed consent theory.
Inappropriate Patient Selection. Physicians may face liability for use of these diet drugs in patients who were treated only for cosmetic weight reduction rather than for medically significant obesity. Dexfenfluramine was approved by the FDA for individuals with a threshold Body Mass Index (BMI) equal to or greater than 30kg/m2 or for individuals with BMIs greater than 27kg/m2 who had other risk factors such as hypertension, diabetes and hyperlipidemia. It was also contraindicated for use in patients with organic causes of obesity and with glaucoma. Physicians who prescribed Dexfenfluramine for patients with lower BMIs may be liable for all causally related adverse effects, since the exposure to the drugs was medically unnecessary. The PDR even included a BMI Height-Weight Reference Chart to aid physicians in selecting appropriate patients on which to use the drug.
FDA approval requires that a drug be safe and effective, including the demonstration of an acceptable risk-benefit analysis between the known complications of the disease or condition the drug is intended to treat and the side effects of the drug. 21 U.S.C. Sec. 505(d). When Dexfenfluramine was approved for use above specific threshold BMIs, the FDA determined that the benefits of weight reduction in this group of obese patients outweighed the risks of the medication that had been reported to the FDA. However, the FDA felt that the risks of using Dexfenfluramine in patients with lower BMIs outweighed any potential benefits from weight reduction.
Fenfluramine and Phentermine did not have as clearly defined threshold BMI’s for which the drugs had been approved for use in weight loss. The PDR indicated that these drugs should be used for the management of “exogenous obesity”, but did not quantify what level of obesity is appropriate for these anorexigens. It may be reasonable to assume that the same BMI thresholds that applied to Dexfenfluramine should have applied to these drugs as well.
Physicians who prescribed diet drugs for longer than the recommended treatment periods may face liability because of the prolonged exposure to the drugs. Fenfluramine and Phentermine were approved for management of exogenous obesity “as a short-term (a few weeks) adjunct in a regimen of weight reduction based on caloric restrictions.” The PDR stated that tolerance to the anorexic effect usually develops in a few weeks for both Fenfluramine and Phentermine. When this occurred, the drug was to be discontinued rather than increased in dosage in an attempt to regain the anorexic effect. Once the anorexic effect was removed, no benefits from the use of these drugs could have remained and the risks of continuance would have been unacceptable. Prolonged usage may create liability for all injuries, even in patients meeting the appropriate BMI thresholds.
There was conflicting information in the PDR concerning the appropriate length of treatment with Dexfenfluramine. Under the Indications & Usage and the Dosage & Administration Sections, the PDR stated that “the safety and effectiveness of Redux beyond 1 year have not been determined at this time.” However, under the Warnings Section, the PDR stated that in a two-year international case-control study, the use of anorexigens for longer than three months was associated with a nine-fold increase in the risk of developing primary pulmonary hypertension. Liability for prolonged use would appear to attach to physicians who prescribed Dexfenfluramine for longer than a year, but it is unclear whether physicians who prescribed it for more than three months also would be liable.
The FDA approval specified maximum daily doses for these drugs that arguably should not have been exceeded by physicians when prescribing them. The maximum daily doses were: Fenfluramine, 120mg per day in three divided doses; Phentermine, 30 mgs per day taken once daily; and Dexfenfluramine, 30 mg per day in two divided doses. Since larger doses would increase the cumulative exposure to these drugs, physicians who prescribed them above the recommended dosage may be liable to patients who sustained heart valve injuries as well as PPH. Arguably, the physician did not follow safe medical practice that would have limited the patients’ cumulative exposure to the drug and have prevented these injuries.
Physicians who prescribed these drugs had a responsibility both to monitor patients for signs of cardiopulmonary injury and to use these drugs only as an adjunct in a regimen of weight reduction based on caloric restriction. Plaintiffs will argue that this created a duty in the prescribing physicians to provide nutritional counseling and to monitor a dietary program for the patient. The significance of recognizing obesity as a chronic problem means that successful treatment requires a coordinated program of medication, diet and exercise. Negligent monitoring could arise in cases where a plaintiff developed signs and symptoms of cardiopulmonary problems and was not removed from the drug. It could also arise in cases where these drugs were used as the sole means to achieve weight reduction. In such cases, physicians may be liable for all causally related injuries.
The Fen-Phen Combination
Before the introduction of Dexfenfluramine, many doctors prescribed the Fen-Phen drug combination. The Fen-Phen combination was an unapproved use of approved drugs for which no safety and efficacy data existed. The unapproved use of approved drugs usually does not constitute a deviation from accepted standards of medical care. The forward to the 1997 PDR stated:
The FDA has always recognized that the [law] does not, however, limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may choose to prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. The FDA also observes that accepted medical practice often included drug use that is not reflected in approved drug labeling.
But recall that Wyeth issued a warning in January 1997 and the FDA issued a Public Health Advisory in July 1997. So the prior discretion afforded to physicians who used approved drugs in unapproved ways may not provide immunity from malpractice liability in this situation. This may be even more of an issue for physicians who used this combination after the Wyeth warning.
In addition, in August 1997, Fen-Phen was reported in the New England Journal of Medicine to cause heart value injuries that prompted its voluntary removal from the market on September 15, 1997. H.M. Connelly, et al, “Valvular Heart Disease Associated with Fenfluramine-Phentermine,” N. Eng. J. Med., 337:581 (1997). Any physician who continued to prescribe or failed to advise patients to discontinue use of these drugs within a reasonable period of time from the recall announcement, could be liable for all injuries. Liability most clearly attaches in situations where the physicians actually initiated use of these drugs after the recall date. Liability is most doubtful in those situations where patients only took the drug for a short period of time subsequent to the recall and, in any event, for no longer than the recommended treatment periods.
The Learned Intermediary Defense
Pharmaceutical manufacturers have a defense to failure to warn claims when physicians use their drugs contrary to the approved package insert and PDR information. Facts that support plaintiff malpractice claims also support the learned intermediary defense. Even if the drug manufacturers don’t directly assert cross-claims, proofs of this defense indirectly support plaintiffs.
A Georgetown University study reported on April 1, 1998 sheds some interesting light both on the issue of physician liability and the Learned Intermediary Defense. Leaving aside potential bias caused by its sponsor, Wyeth-Ayerst, the Georgetown study reported that there was no increase in heart damage from short-term use of the diet pill Redux. The participants took the drug for 77 days and no valvulopathies were detected. An FDA physician nevertheless commented: “We believe that there is a significant rate of valvular abnormalities. The data suggest it is related to the duration of exposure.” The FDA estimates that one-third of people taking the diet pills suffered significant heart damage as a result.
While the Georgetown study has yet to be confirmed by others, it supports the proposition that the FDA approved usage of Redux by physicians, both in terms of length of use and maximum dosage, is not associated with adverse cardiac and pulmonary effects. This study may be used to deflect liability from the manufacturers to the prescribing physicians who prescribed Redux inappropriately, for prolonged periods or in excessive amounts.
The article is reprinted with permission from the April 20, 1998 issue of the New Jersey Law Journal. © 1998 NLP IP Company.