The Drug Hunters Read online

  More than one hundred people around the country died from S. E. Massengill’s sulfa formulation, including many children who had been prescribed the elixir for sore throats. One of these children’s mothers, Mrs. Maise Nidiffler of Tulsa, Oklahoma, also wrote to Roosevelt:

  The first time I ever had occasion to call in a doctor for [Joan] and she was given Elixir of Sulfanilamide. All that is left to us is the caring for her little grave … we can see her little body tossing to and fro and hear that little voice screaming with pain and it seems as though it would drive me insane…. It is my plea that you will take steps to prevent such sales of drugs that will take little lives and leave such suffering behind and such a bleak outlook on the future as I have tonight.

  In the 1930s, the federal government treated drugs the same way they treated paper clips or trousers, as products that required no special safety regulations. The American Medical Association (AMA) was not involved in approving drugs either—the leading professional medical organization merely shared information they received voluntarily from drug manufacturers or physicians about particular drugs. S. E. Massengill had not shared any information about Elixir Sulfanilamide, and therefore the AMA possessed none.

  After reports of patient deaths from Elixir Sulfanilamide reached the AMA, they telegraphed Samuel Evans Massengill himself to request the composition of his company’s drug. Massengill admitted that it contained diethylene glycol, but insisted that this fact be kept strictly confidential—though not because he believed the solvent was dangerous. He worried that other companies might try to steal his formulation for themselves. When the AMA confronted him about the growing number of deaths from Elixir Sulfanilamide, Massengill and his chief chemist Watkins confessed that no toxicity tests had been performed but proposed that the fatalities might have resulted from taking the elixir with other drugs in some harmful combination. To demonstrate his confidence in his product, Watkins swallowed small amounts of Elixir Sulfanilamide and was “pleased to report that I have noted no adverse effects.”

  Less than two weeks after Watkins’ blithe self-experimentation, there was an abrupt about-face at his company. On October 20, 1937, Dr. Massengill sent a brief telegram to the AMA: “Please wire collect by Western Union suggestion for antidote and treatment following use of Elixir Sulfanilamide.” The AMA replied equally tersely: “Antidote for Elixir Sulfanilamide-Massengill not known. Treatment presumably symptomatic.” In other words, there was no way to counteract the kidney-destroying effects of the elixir.

  The FDA did the best it could with its limited resources to respond to the crisis. It dispatched inspectors to S. E. Massengill’s headquarters in Bristol, Tennessee. When they arrived, they learned that the company had already sent a telegram to salesmen, pharmacists, and physicians requesting the return of their remaining supply of the Elixir. This telegram was not exactly an urgent klaxon of alarm, however: “Have withdrawn product elixir sulfanilamide. Please return unused stocks immediately.” The FDA inspectors insisted that Massengill issue a more forceful telegram, and on October 19 he sent a new message: “Imperative you take up immediately all elixir sulfanilamide dispensed. Product may be dangerous to life. Return all stocks, our expense.”

  In the country’s first-ever response to a drug crisis, almost every single one of the 239 existing FDA field inspectors was dispatched around the country to recover the toxic medicine. This was a particularly admirable effort, considering that drug safety was not actually part of the FDA’s mandate. The inspectors painstakingly tracked down every physician who prescribed Elixir Sulfanilamide, every drugstore that sold it, and every patient who swallowed it. They managed to recover 234 gallons and one pint of the 240 total gallons that had been distributed. The missing six gallons, however, caused more than one hundred deaths.

  The media erupted with perhaps the greatest public outrage over business practices since Upton Sinclair exposed the meatpacking industry in his muckraking novel The Jungle. When asked about his personal culpability in the scandal, Samuel Evans Massengill declared, “My chemists and I deeply regret the fatal results, but there was no error in the manufacture of the product. We have been supplying a legitimate professional demand and not once could have foreseen the unlooked-for results. I do not feel that there was any responsibility on our part.”

  Legally speaking, Massengill was correct—based on the existing laws, his company had done nothing that could be considered a felony. The federal court in Greeneville, Tennessee, found S. E. Massengill Company guilty of violating a minor regulation in the 1906 Pure Food and Drug Act that prohibited the labeling of a preparation as an “elixir” if it contained no alcohol. For this violation, the company paid a fine of $150 for each of more than 170 counts of misbranding, totaling $26,000. The families of the 121 victims, however, received nothing.

  Harold Watkins, the chemist who formulated Massengill’s lethal preparation of sulfanilamide, was not nearly as sanguine as his boss. He was tormented by his role in the catastrophe. While awaiting the federal trial, Watkins shot himself in the head. Samuel Evans Massengill, on the other hand, stayed on as chief executive; he was the sole owner of the business and could not be ousted. The S. E. Massengill Company continued to operate as a private family-owned pharmaceutical firm until 1971, when it was acquired by Beecham, plc. Beecham merged with another drug company in 1989 to become SmithKline, which merged again in 2000 to become GlaxoSmithKline. Thus, the corporate descendant of S. E. Massengill still endures today, selling billions of dollars of drugs each year.

  The massive outcry over the Elixir Sulfanilamide poisonings, including well-publicized letters to President Roosevelt from relatives of the victims, prompted Congress to pass the Food, Drug and Cosmetic Act in 1938 to regulate the sale and marketing of pharmaceuticals. This act established the modern FDA. These days, the Food and Drug Administration oversees the development of drugs from the very beginning, well in advance of any human testing. All pharmacological research that may eventually lead to the development of a commercial drug must be conducted under a system of management controls called “good laboratory practice” or GLP. An executive at the Big Pharma company Cyanamid once told me that GLP was a system “designed to force you to prove that you are not a crook.”

  Before approving human trials, the FDA reviews a comprehensive dossier of safety testing results from studies performed by the manufacturer in test tubes and on lab animals. If satisfied with this safety data, the FDA approves the manufacturer to proceed with testing on humans, under FDA oversight. A drug is approved for sale only if the FDA determines that it is safe and produces the claimed effects. FDA oversight continues even after the drug is marketed to the public; the agency looks for unexpected or rare reactions to the drug that might have escaped detection during testing.

  In 1937, during the height of the sulfa craze, the original FDA had a total field force of 239 inspectors and chemists. In 2013, the FDA had over nine thousand employees and an annual budget in excess of $1.25 billion. As a patient and a consumer, I firmly believe that any industry as potentially hazardous to the public as the pharmaceutical industry needs attentive regulatory oversight. The real question is, what is the proper balance between government regulation and freedom to innovate?

  In 1937, there was the wrong balance. Drug companies were given far too much license to take risks at the public’s expense. Today things are more complicated. Think about the early days of the AIDS crisis when activist groups like ACT UP petitioned the FDA to loosen its criteria for the clinical testing of potential AIDS drugs. Victim advocates argued that AIDS patients were already dying, so why not give them a remote chance at living by allowing companies to test experimental anti-HIV medications? That was a situation where it seemed to make sense to tilt the balance away from safety and back toward innovation.

  Personally, after spending almost four decades in the pharma industry, I believe the vast majority of drug researchers are honest men and women dedicated to finding medicines that will tru
ly help sick people. Despite the public’s general antipathy towards Big Pharma, most drug recalls are not the result of deception or greed but authentic mistakes made by people working at the frontiers of what is known about human biology. At the same time, considering the staggering sums of money involved in contemporary drug development, the temptation for cutting a few corners remains high.

  I was working for the pharmaceutical division of American Home Products (AHP) during the heyday of the fen-phen diet drug fad. Fenfluramine was first clinically introduced by AHP as a weight-loss drug in the 1970s, but it never became very popular because the weight loss it produced was temporary. The drug sold modestly until 1992, when researchers at the University of Rochester published a study showing that when fenfluramine was combined with a second weight-loss drug called phentermine (also manufactured by AHP), it was more effective at reducing the weight of the chronically obese than dieting or exercising.

  The fen-phen cocktail became an overnight sensation. By 1996, 6.6 million prescriptions for fen-phen were being written annually in the USA. Unfortunately, though AHP manufactured both drugs, they had never conducted any experiments on the fenfluramine-phentermine combination. I, along with several of my research colleagues at AHP, argued that the company should launch an effort to develop knowledge about this suddenly popular drug combination. We warned the executives that AHP was now selling something to millions of people that it did not fully understand.

  Management brushed aside our concerns. After all, the FDA had approved both drugs and getting FDA approval was neither easy nor economical. Furthermore, the University of Rochester scientists had independently recommended the drug combo as a safe and effective method of weight loss. AHP had already done everything they were supposed to do, the executives argued, so there was no need to spend additional resources on new research or testing. They would soon come to regret their budget-protecting decision.

  In 1996, a paper appeared in the New England Journal of Medicine reporting on twenty-four patients who had used fen-phen. The authors described a correlation between the use of the drug combo and mitral valve dysfunction. Later that year, a thirty-year-old woman developed heart problems after taking fen-phen for a month. She died. Soon, the FDA received over a hundred reports of mitral valve-related heart disease in patients taking fen-phen. Further investigation revealed that, even though it was very rare for either drug alone to exhibit toxicity, when they were used together the combination was more likely to cause heart problems. Eventually, the FDA determined that fenfluramine was the bad actor in the cocktail, and in 1997 the agency ordered the withdrawal of fenfluramine from the market.

  Patients began to sue AHP in droves. American Lawyer magazine ran a cover story on fen-phen, observing that more than fifty thousand product liability lawsuits had been filed by alleged victims of the weight loss cocktail. As of 2005, AHP (later renamed Wyeth and now part of Pfizer) was offering settlements of $5,000 to $200,000 to many victims who had sued. These offers were often rejected as too low. Estimates of AHP’s total liability have run as high as $14 billion.

  The fen-phen debacle points to the difficulty of getting the regulatory balance right. Unlike the development of Elixir Sulfanilamide, there was tight, cautious oversight at every stage of the development of each of the two weight-loss drugs. While AHP had never explicitly tested the fen-phen combination, it was neither unusual nor illegal for physicians to prescribe legitimate drugs in new combinations. Even though AHP management had decided to skip further experimentation on fenfluramine once the drug suddenly became popular, it is not obvious that this decision was ethically objectionable. After all, they had always hoped that the drug would become popular, and the rigorous system of FDA testing presumes that a drug’s use might be widespread.

  With Elixir Sulfanilamide, both the owner and the chemist at S. E. Massengill were clearly culpable for bypassing even the most rudimentary forms of safety testing. In contrast, while AHP as an organization remains morally and legally accountable to the victims of fen-phen, it is difficult to point the finger at any one person—one greedy villain or one clueless executive—whose poor judgment renders him or her ethically responsible for the drug cocktail–induced injuries. The mitral valve problems were a very rare response that simply did not show up until extremely large numbers of people began extensively using the two drugs in combination.

  To my mind, where AHP appears to have crossed the line was in their marketing. While it was entirely legitimate for its salespeople to remind doctors about the University of Rochester study, it was both unethical and illegal for the salespeople to explicitly recommend that doctors prescribe the two drugs together unless the FDA had actually approved the use of the fen-phen drug combination. Despite this, AHP sales representatives frankly encouraged physicians to prescribe the cocktail.

  The stories of Elixir Sulfanilamide and fen-phen underscore one of the most troublesome aspects of developing any new drug: side effects. In the case of Massengill’s drug, the primary side effect (the lethal destruction of an imbiber’s kidneys) resulted not from the drug’s active agent but from the formulation—the manner in which the medicine was prepared for human consumption. Today, the regulations of the FDA are designed to ensure the impossibility of a drug company releasing a formulation containing any toxic adulterant.

  In contrast, the dangerous side effects arising from the fen-phen cocktail resulted from two different sources: first, an unexpected interaction between the active agents in the two drugs; second, the occurrence of rare side effects from fenfluramine that never appeared in the drug’s clinical trials. Side effects from drug interactions remain a fairly common risk today. For instance, combining alcohol with benzodiazepines (such as Librium) or combining MAO inhibitor antidepressants (such as Nardil) with SSRI antidepressants (such as Prozac) can potentially be lethal. Though the FDA monitors a drug’s performance after its launch in order to rapidly identify unexpected side effects that may result from drug combinations, it is certainly possible that dangerous or deadly side effects may emerge from future combinations of FDA-approved drugs.

  Why do drugs seem to produce so many unwanted side effects in the first place, even when you are only taking one particular drug for one particular reason? To my mind, there are two basic mechanistic explanations. First, many drugs affect multiple physiological targets in the body because different parts of the body often share similar biological targets. A good example are the classic chemotherapeutic agents that attack cancer. “Chemotherapy” destroys cancer cells by acting on the process of rapid cell division in the cancer cells. However, many other cells in the body also undergo rapid cell division (such as the bone marrow cells that create new blood), and they too are negatively impacted by chemotherapy. Another example is Viagra, which targets the PDE5 enzyme in the penis. PDE5 is also present in the cardiovascular system, which is why Viagra causes unintentional flushing and headaches. In addition, an extremely similar enzyme known as PDE6 is found in the retina of the eye, so high doses of Viagra can produce blindness.

  Because any given type of receptor in our body usually exists in multiple locations and is often similar to other types of receptors, it is very difficult to find a chemical that affects only one specific physiological target. Sometimes, however, the fact that a drug acts on multiple targets simultaneously can be beneficial. For example, antipsychotic drugs activate multiple targets—but the effects on two of these targets (dopamine receptors and serotonin receptors) fortuitously cancel each other out. The action of an antipsychotic drug on dopamine receptors can generate uncontrollable movements, but the actions of the same drug on serotonin receptors attenuates these movements.

  There is another basic mechanical reason that drugs produce unwanted side effects. Drugs are chemicals. Whenever foreign chemicals are introduced into the body, they can interact with our body’s natural free-floating chemicals (known as metabolites, the by-products of healthy physiological processes) in undesirable ways. A drug can serve as
an imperfect substitute for the metabolites, for instance, causing our body’s processes to operate in a flawed manner. A drug can even undergo a direct chemical reaction with our body’s metabolites, producing new and possibly toxic compounds.

  Very often it is simply not possible for a chemical to produce beneficial effects without also producing unpleasant, harmful, or dangerous effects, so the drug hunter (and the FDA) must always weigh the balance between these positive and negative responses before deciding if a particular drug is suitable for human use.

  To find new cures and remedies, we must be willing to take some risk. Without risk, it is simply not possible to develop novel drugs. We can reduce this risk by establishing more regulations, but these regulations impose ever increasing costs on drug development, to the point where today the average cost of developing a new drug has been estimated to be in the range of 1.4 to 1.6 billion dollars. This exorbitant financial bar ensures that very few promising drugs will ever make it out of the planning stages. If we want to eliminate the prospect of another fen-phen disaster, the only solution is to expand the regulations for approving drugs to ensure that a wide variety of drug combinations is also evaluated, thereby increasing the cost of developing new drugs even further—which will reduce the number of new drugs even further. This remains the most daunting barrier to drug hunting in the modern era. It is almost inconceivably expensive to safely search for new drugs, but without those exorbitant safety expenses, vulnerable people might get injured or die.

  In addition, the FDA remains a government bureaucracy, with certain ineliminable inefficiencies that can disrupt or deter the development of useful drugs. As one example, in the late 1980s one of my colleagues at the pharma company I was working for resigned in a pique of anger at our bosses and took a job at the FDA. This type of career move from Big Pharma to the FDA happens all the time, so I did not think too much about it. I continued my daily work on drug development. But then I started to notice that some of our submissions to the FDA were receiving extraordinary scrutiny. Each time we submitted a report, the FDA found trivial and obviously unintentional errors, and demanded that we revise and re-submit our work. Delays stretched on and on. Even worse, all these re-submissions meant our costs were steadily mounting.