Professionalism/Fen-Phen and American Home Products

Introduction

Fenfluramine-phentermine (fen-phen) is a weight loss drug involving two FDA-approved diet pills prescribed together. Neither pill caused ill effects on its own, but the combination led to unnatural serotonin production and heart valve contractions. The widespread legal use of Fen-Phen in the United States raises ethical issues about the production, prescription, and regulatory approval of the drug.

History of Fen-Phen

Fenfluramine is a drug which releases serotonin, and serves as the primary weight loss agent of fen-phen. Using fenfluramine to induce weight loss was discovered and tested by Dr. Richard Wurtman, an MIT neurologist, in the 1980s. He recognized that carbohydrates in the blood produce elevated serotonin in the brain – and hypothesized that people were snacking (and consequently gaining weight) to boost their mood. By replacing food with a drug that essentially acts an anti-depressant, he reasoned, the obesity epidemic could be countered. Although his hypothesis was largely correct, one natural variant of fenfluramine induced significant drowsiness in patients. Thus, fenfluramine alone never gained significant popularity as a weight loss solution.

The combination of fen-phen was created by University of Rochester professor Dr. Michael Weintraub. Phentermine is a type of amphetamine, a more common type of weight loss pill. Taken phentermine with fenfluramine reduced the latter’s side effects while maintaining the weight loss, leading fen-phen to be dubbed a “magic” diet pill.

Effects of Fen-Phen

Fen-Phen was first published in a scientific journal in 1992 and became popular almost immediately after. By 1996, over 18 million prescriptions were given out for the drug. Both constituent pills were individually approved by the FDA. Weintraub stated that he figured that since “these drugs have been on the market for 10, 12 years, everything must be known about them.” Although little long-term research was carried out about the combination, it was still legal to prescribe both drugs for short-term use.

In 1996, pharmaceutical company Wyeth submitted a proposal to the FDA for long-term prescription of dexfen-phen, a slight variant of fen-phen. If approved, it would be the first weight loss drug ever approved by the FDA for long-term use. Although it faced opposition, the FDA ultimately approved dexfen-phen on April 29, 1996. They required follow-up testing and designated the drug to be used as one aspect of a multi-faceted diet regimen. However, with the history of fen-phen, both requirements were always unlikely to be completely fulfilled.

Health problems began to be linked to taking fen-phen the following year. In August 1997, doctors from the Mayo Clinic identified “valvular heart disease in 24 women treated with fenfluramine–phentermine who had no history of cardiac disease.” After their findings were published in the New England Journal of Medicine, the FDA demanded that doctors around the country report any corroborating cases.

Fen-phen revealed a fault with the drug approval process in the United States. Fen-phen was approved by the FDA for long-term use without long-term studies. In addition, the side effects of the drug were discovered by an independent clinic. There is no telling how long fen-phen may have stayed on the market without the indispensable work by the Mayo Clinic. The criticality of the obesity epidemic and the interests of pharmaceutical undoubtedly played roles in affecting the approval of fen-phen.

Social Factors

Obesity in the 1990's

In order to be classified as obese, an individual must have a BMI (body mass index) of 30 or higher. Individuals who are classified as obese have an increased risk of developing additional health issues, such as heart disease, strokes, high blood pressure, diabetes, osteoarthritis, and some types of cancer. Obesity rates have been on the rise in every state since 1990. In 1990, 10 states had obesity rates under 10% and no state had obesity rates higher than 15%. By the time Fen-Phen was released in 1996, no state had an obesity rate under 10%, and 30 states had obesity rates higher than 15%.

Beauty Standards

Aside from the obvious health risks associated with obesity, men and women experienced societal pressure to lose weight. For women, the main beauty ideal of the 1990's was extreme thinness. This desired level of thinness was termed "heroin chic," and encouraged women to look androgynous. The look was also called the "Waif Look," with supermodel, Kate Moss being one of the celebrities who popularized it. Men's ideal body type in the 1990's became the lean and muscular body type. With the fashion industry encouraging the heroin chic look for women and a lean body for men, as well as rising obesity rates, men and women were looking for ways to slim down. From 1990 to 1997, plastic surgeons reported increases of 200% to 300% in the number of liposuction procedures performed. While some turned to surgical means to achieve weight loss, many others turned to weight loss supplements, like Fen-Phen.

The American Home Products Case

FDA Approval and Warnings

In September 1995, a committee of FDA experts met to discuss whether Fen-Phen was safe for consumer use. The committee was initially split: three were in favor of approving, and five were against, citing evidence that Fen-Phen caused a 23- to 46-fold increase in pulmonary hypertension risk. However, one member of the committee made a plea for approval, claiming the obesity epidemic was pressing and the drug really was helpful with weight loss. The committee voted again, this time approving the drug.

During the FDA approval process, the drug's primary reviewer, Leo Lutwak, was an outspoken advocate for not approving Fen-Phen. When American Home Products, the company seeking approval for Fen-Phen, presented the drug to Lutwak, they claimed that the increased risk of pulmonary hypertension was "an extraordinarily rare phenomenon". Lutwak found otherwise; he cited a European study, where the drug had already been approved, that found that "the use of anorexic drugs was associated with the development of primary pulmonary hypertension". He stated in a later interview, "I, as the primary reviewer, felt the drug had had low effectiveness and very high risk for neurotoxicity and pulmonary hypertension".

When Fen-Phen was approved, Lutwak highly recommended including a black box warning about the increased risk of pulmonary hypertension. His warnings were ignored, however, and on April 29, 1996, the FDA approved Fen-Phen with no black box warning.

Widespread Use of Fen-Phen

Upon FDA approval of Fen-Phen, prescriptions skyrocketed. Weight loss clinics popped up, offering prescriptions of Fen-Phen to anyone. These clinics were typically not run by weight loss specialists. Dr. Israel Levavi, an internist, briefly worked for a weight loss clinic run by a chiropractor and overseen by an infectious disease specialist. He remembers "very, very cursory exams" of new patients, often seeing up to six new patients an hour. The drug was often advertised in magazines as a miracle weight loss drug, leading even more people to attend this clinics in search of prescriptions. Fen-Phen's advertising and packaging insisted that any increased risk of pulmonary hypertension was negligible.

On September 15, 1997, Fen-Phen was withdrawn from the market by American Home Products following a request for withdrawal by the FDA. New studies had emerged confirming the increased risk of pulmonary hypertension was not negligible, and the FDA no longer felt that the drug was safe for public consumption. By the time the drug was off the market, an estimated six million Americans had taken Fen-Phen.

Lawsuits and Financial Repercussions

Following the withdrawal of Fen-Phen, users who had developed heart valve problems began to file lawsuits against American Home Products. Debbie Lovett, a 36-year-old Texas woman, filed a case against American Home Products. Her case was the first to reach a jury, who found that American Home Products was entirely responsible for her damaged health. Lovett's lawyer explained that "[American Home Products] had teams of people whose sole job it was to minimize the warnings... [They did] whatever they could do to convince the FDA the warnings didn't need to be strengthened". In response, American Home Products' lawyer claimed that "this is not a dangerous product. The fact that it is not on the market [now] doesn't mean it was a dangerous product at the time. The benefits outweighed the risk".

This lawsuit was only one of many. According to a brief from a 2000 lawsuit, "approximately 18,000 individuals who used Pondimin or Redux filed lawsuits against AHP". American Home Products ultimately payed $7.5 billion to settle their many class actions lawsuits. American Home Products eventually changed their name to Wyeth.

Lasting Impact

By 2010, every state had obesity rates over 20%, and 12 have obesity rates greater than or equal 30%. Nation wide obesity rates rose from 11.1% in 1990 to 30.6% in 2017. Men's ideal body type has continued to be a lean, muscular figure, while women's ideal body type has shifted to promoting a flat stomach and some curves. However, societal beauty standards still do not align with rising obesity rates.

Before Richard Wurtman learned about Fen-Phen and put it on the market, weight-loss drugs were associated with amphetamines and largely avoided. Nowadays, the association of weight-loss drugs with sleazy doctors is gone. 23,000 emergency room visits in 2015 were tied to dietary supplement use. In 2017, 776 unapproved dietary supplements on the market contained banned drugs. There are only five FDA approved weight-loss drugs on the market today: Xenical, Belviq, Qysmia, Contrave, and Saxenda. Belviq and Qsymia are similar to the now banned Fen-Phen. Belviq acts on serotonin receptors, and Qysmia contains phentermine.

Qsymia was initially rejected by the FDA under a different name, Qnexa, because it was shown to be associated with elevated heart rate, psychiatric problems, and birth defects. However, after approving Belviq, the FDA approved Qsymia, which may still lead to birth defects. Belviq is supposed to be safer than Fen-Phen because it only acts on one serotonin receptor, but some doctors fear Belviq will be combined with phentermine. Since Qsymia is contains phentermine, some see its approval as evidence that phentermine is safe. However, all approved weight-loss drugs are only approved for short-term use, indicating that long-term effects are unknown.