Over the past 60 years, pharmacological developments have transformed medicine. With the advent of antipsychotics, doctors were able to effectively treat patients with psychoses. Prior to then, treatments for major depression, schizophrenia, or other psychoses were limited and had very poor outcomes. Lobotomies, high-voltage electroconvulsive therapy, and institutionalization were the standard of care. Today, pharmaceuticals have radically changed all areas of medicine. Cancer survival is at an all-time high and advances in anesthesiology have reconfigured the field of surgery. Modern sedatives and hypnotics are routinely prescribed for a variety of ailments. And the impact vaccines have had on the scourges that have plagued mankind for millennia cannot be overstated. This pharmaceutical revolution has allowed millions to live longer, more active lives, and clinical research is the cornerstone of this revolution. However, drug development can take years and often has tremendous associated costs. Even before a new effective compound is identified, thousands of compounds are evaluated, with maybe 100 that show promise. Of those 100 compounds, perhaps 1 might make it through all the clinical phases and get approval from the FDA. The new drug approval process can take anywhere from 10 to 18 years, with associated costs that can reach upwards of a billion dollars.
There is no doubt that the drug discovery and approval process can be arduous and time consuming. It is because of this that some believe it should have fewer regulations. This “Ayn Randian” drumbeat can be heard across all markets. However, in pharmaceutical development, an Atlas Shrugged vision would have devastating effects. Chants of market-based solutions and the corrective measures that only a “truly” free market can provide don’t apply to the drug discovery and approval process. Perhaps in the financial sector these free-market mechanisms can offer useful, efficient means to deliver cheaper products and/or services, although recent history doesn’t agree with that vision. Outside the usual rhetoric of a Darwinian market that can supply all, their underlying implication is that lives are negatively affected by the approval process and medications of the past would never be approved in the modern era. These same critics seldom point out that over the past 20 years, new drug applications (NDAs) have been approved much quicker (roughly 50%), down from 2.5 years to about 1.1 years. It is true that many common medications may not be approved today because of associated safety issues. A few examples are:
- Aspirin: shown to double the risk for severe gastrointestinal events and bleeding that may require hospitalization
- Acetaminophen: associated with an increased risk of liver failure, particularly when taken with alcohol or other compounds metabolized by the liver
- Penicillin: history of extreme allergic reactions in patients and may be fatal in 50 out of 100,000 people
- Erythromycin: found to double the risk of sudden cardiac death when used in combination with some other medications
Drugs like those have been grandfathered in and aren’t subject to current regulations, but to use them as the argument against regulations is absurd. Opponents also point to the financial burden that’s placed on the manufacturers and ultimately passed along to consumers. Patents allow pharmaceutical manufacturers exclusivity to a new drug for 20 years. However, manufacturers often take out a patent on a compound before clinical trials, essentially reducing market exclusivity from 20 years to 12 to 15 years, and giving them less time to recover costs and make a profit. Pharmaceutical development can be very costly but also very lucrative. Current regulations have been built upon the mistakes of the past and still may be ineffective for the changing face of research.
The 20th century and an unregulated market
Around the turn of the 20th century, America became a more urban nation. As a result, the methods in which we delivered and stored food changed in order to accommodate larger cities. Massive, centrally located supply lines emerged and new canning and preservative methods meant food could now sit longer without spoiling. Meanwhile, the so-called “patent medicine” market seemed to grow exponentially. During this same time, newspapers experienced a sharp growth in circulations, and patent medicine found a new lucrative advertising tool.
Prior to 1906, the federal government took a laissez-faire approach to most business, including the food and drug industries. The job of regulating often fell to the states, which were all too often not up to the task. Eerily similar to today, those industries could use considerable wealth to influence politicians and sway public opinion. However, as those industries grew, a call for stricter regulations could be heard. President Theodore Roosevelt and the chemist Harvey Wiley championed this cause. Industry forces used their tremendous wealth and influence to prevent change, but that altered in 1906. That year, 2 major events converged and incited public outrage, which reversed the political tide in favor of the government intervening in those industries. The first was a series of articles about fraud in patent medicines that appeared in Collier’s magazine. After that publication, the American Medical Association insisted on regulations. The second event was the publication of The Jungle by Upton Sinclair and subsequent investigations into the meat packing industry. In 1906, Congress passed the Pure Food and Drug Act and the Meat Inspection Act. Although the 2 bills gave the federal government oversight, they lacked strong regulatory and enforcement powers. These shortfalls were exemplified when the drug Elixir Sulfanilamide came to market in 1937. Elixir Sulfanilamide was virtually exclusively marketed for use in pediatric patients but it was used by the general population. It was an untested, unregulated analogue of antifreeze and it poisoned thousands, eventually killing over 100 people.
The sulfanilamide disaster was the impetus for passing the Food, Drug, and Cosmetic Act of 1938. For the first time, the FDA had strong regulatory and enforcement powers over the industries, including all cosmetic, medical devices, food, and drugs. After 1938, all drugs had to be labeled with directions for safe usage, and new drugs needed pre-market approval and had to be proven safe and efficacious. Under the supervision of Walter Campbell, FDA regulators essentially adopted what would later be known as the precautionary principle, a concept 60 years ahead of its time.
The diethylstilbestrol tragedy: a failure of oversight or poor science?
The first stress test of the FDA’s new powers occurred during the approval process of diethylstilbestrol (DES). In 1938, DES was the first successfully produced synthetic estrogen. It was cheaply produced from coal tar derivatives and was also 3 times more estrogenic than natural estrogens. In 1940, the FDA rejected the drug due to disturbing animal studies and an overall scientific uncertainty. However, this did not slow DES use in humans. Despite evidence of adverse events in animals, which included thyroid and pituitary damage, links to uterine cancer, sexual differentiation of offspring, abortifactant qualities, and other defects associated with sexual maturity, DES was pushed to market.
Even before DES was approved, Carson Frailey, a lobbyist for the drug companies, sent samples to hundreds of doctors to treat their female patients. This bold move essentially created a market for DES before any FDA approval. It was also de facto human experimentation. Once the doctors prescribed DES, they were asked to write to the FDA and the government insisting it was safe and effective. Under massive political and legal pressure, the FDA relented and approved DES without any human trials. In 1941, DES was approved for the treatment of vaginitis, gonorrhea, and menopausal symptoms, and to suppress lactation, but it was expressly contraindicated in pregnant women. To make matters worse, a federal judgment stemming from a separate estrogen cream lawsuit handcuffed the FDA’s ability to put warning labels on products based on adverse events in animal studies.
Once DES was readily available, an off-label usage was quickly adopted and it was widely prescribed to pregnant woman. Even before 1941, Dr. Karl John Karnaky was experimenting with DES in pregnant women. He praised the benefits of DES and wrote, “all babies in the study were found to be entirely normal.” However, of the 14 women he treated, he only followed 5 patients to full term. At the same time, Harvard, disregarding the FDA’s contraindication for DES, conducted research into prescribing DES to prevent miscarriages. The research was based solely on a faulty assumption that fluctuating and low estrogen/progesterone levels caused miscarriages. Published results appeared in the American Journal of Obstetrics and Gynecology,which prompted drug companies and doctors alike to use DES as a treatment for preventing miscarriages. As more doctors conducted de facto experimentation on women, the drug companies cherry-picked data. Any clinical findings that indicated adverse events with DES usage were either not included in FDA submissions or attributed to something else. An examination of one physician’s notes reveals the tone of the medical community regarding the intervention and women in general: “She started in labor spontaneously delivering a premature baby of 5 lbs.” And his concluding remarks were, “The cause of the ruptured membrane, I am sure, was due to excessive shopping.”
In 1947, besieged with a deluge of unscientific data and mounting pressure, the FDA approved DES for use in pregnant women but with one caveat, that it be used only in women with diabetes. Even though it was widely known that DES crossed the placental barrier, it was widely prescribed for an array of symptoms, including morning sickness, and for the prevention of miscarriages. The proverbial Pandora’s box was opened and, despite its indication, it was soon marketed to all women “to make normal pregnancy more normal.” In 2 separate studies, one in 1953 and the other in 1958, DES was linked to an increased risk of miscarriages. However, those results had little impact on how doctors prescribed DES or how the scientific community perceived DES. In fact, in 1957, the Journal of Obstetrics and Gynecology recommended DES for all women “to produce bigger stronger babies.” What was even more remarkable was the callous nature of the FDA with regard to DES. By this time, the FDA completely disregarded the precautionary principle. Even as the FDA began to receive serious complaints from women that ranged from uterine bleeding to painful breasts and potential cancers, they didn’t act. To make matters worse, the FDA dismissed their complaints and characterized those women as hysterical.
After 1947, DES was also approved as a growth promoter in poultry, cattle, and hogs, and at exceedingly high levels. This new indication essentially exposed the entire population to DES through the food they ate. The FDA received more complaints from the chemical companies that produced DES and from agricultural workers. One chemical company owner wrote the FDA with concerns about male workers who handled DES. He believed that DES was responsible for male impotence and breast growth. The FDA’s response to him was to hire older workers who would be less concerned about DES’s “devirilizing effect.” In 1959, after too many complaints to ignore about agriculture workers suffering from sterility and impotence, the FDA finally acted and placed some restrictions on DES. After 1959, DES was banned for use in poultry. However, it was still readily available for other livestock such as cattle and hogs, and there was no change in its indication for women. It wasn’t until 1971, when researchers in Boston noticed a rare vaginal cancer cluster in women who were exposed to DES in utero, that the FDA finally banned or contraindicated DES for most uses. Between 1941 and 1971, millions of women were given DES and an estimated 2 to 5 million children were exposed in utero. On top of that, millions more were exposed through their food.
DES is now a known endocrine disruptor and has been linked to a multitude of diseases and disorders, including breast cancer. Its long-term effects are being studied over multiple generations. These groups call themselves the DES daughters, sons, granddaughters, and grandsons. Study results have demonstrated higher rates of premature births, miscarriages, ectopic pregnancies, infertility, and early menopause in DES daughters. DES sons have shown to have an increased risk of testicular abnormalities, undescended testicles, and cysts in the epididymis. It may take another 30 years to fully comprehend the long-term effects of DES exposure. Today, DES is the model carcinogen and developmental disrupter used for toxicological studies. Essentially, when formulating new chemicals and running safety tests, the scale used has DES as the most toxic.
In retrospect, it seems hard to imagine that a pharmaceutical agent with so many associated problems and as many complaints could have been the drug of record for over 30 years. The failure of the FDA was egregious and clearly demonstrates a need for an independent strong regulatory authority. However, in this instance, the entire medical and scientific community dropped the ball. Obviously, money and politics had a major influence during the initial FDA approval process and the latter hands-off approach. However, there were at least 15 years when solid evidence against DES as either an intervention or growth promoter was overlooked or disregarded by the scientific community. The DES tragedy was an example of a complete breakdown of the regulatory and scientific process. Research began with a subjective hypothesis that was largely based on flawed observations and was clearly biased, but nonetheless accepted as scientific fact. Experimentation was performed with a complete disregard for the patients’ safety, and the resulting data were manipulated or disregarded. There were seemingly no protocols and no experimental designs, and conceptual fallacies steeped in social-scientific dogma prevailed.
The DES tragedy is a glaring example of what not to do in medicine. There is little doubt that the FDA is more insulated now than it was in 1937, and therefore not as easily influenced by the powers that be. However, over the last 30 years, federal budgets have been cut. Operating staff levels have been reduced and clinical research is often outsourced to private firms. Research that was once conducted at universities and teaching hospitals with institutional review boards (IRBs) that were intrinsically linked to those institutions are becoming a thing of the past. At those institutions, doctors and personnel could implement adequate safety measures and were responsible for establishing internal protocols, experimental designs, and monitoring, while reporting adverse events for study participants. Now a large number of private firms with their own IRBs do this work, and some are located overseas. Often they have no educational or medical affiliations. Conflicts of interest involving the researcher, institution, or how the study is conducted or the participants are recruited/awarded are becoming routine. To make matters worse, there have been documented instances in the US where a chief monitor was not a licensed health professional. Essentially, an individual who can’t practice medicine in the US was responsible for the health and safety of research participants in these studies.
Pharmaceutical discovery is a precarious business. Sometimes a return on investment may take decades to achieve, and good science should be at the heart of the process. One would think that a manufacturer would invest the lion’s share of its budget into research and development (R&D). This is not the case. Today, the average marketing budget is twice that of the manufacturer’s R&D budget. One study reports more than a 3-fold increase in promotional meetings in a 6-year period, jumping from 120,000 in 1998 to 371,000 in 2004. The fact that so much is put into advertising, coupled with some of the recent history surrounding new pharmaceutical agents, has led doctors to be increasingly wary of claims. One study reports that an overwhelming majority of physicians distrust study results in which the primary funder was the manufacturer, regardless of the quality of the study. The same study suggests that when a governmental agency is conducting the trial (eg, NIH), doctors are more trusting of the results. It is important to note that because of the sheer volume of pharmaceutical agents undergoing clinical trials, it is impossible for the government to play such an active role in them.
Outcomes from poor or relaxed regulations can be horrific, and the need for strong regulations has been demonstrated time and again. In 2008, the US experienced the greatest mass poisoning in over 2 decades when contaminated batches of heparin from China killed 81 people and injured close to 800. As recently as last year, a New England compounding company shipped contaminated steroids that caused a fungal meningitis outbreak across the US. Under law, those compounding companies were not held to the same manufacturing standards as pharmaceutical companies were, and it resulted in 32 dead with another 438 infected. New oversight is underway, but if those regulations were in place prior to 2012, many families would still have their loved ones. Strict guidelines and regulations are necessary. Only those agents with the best data from the highest-rigor trials should be approved. As for markets that can regulate themselves, perhaps its best left for markets where a loss of wealth is the only casualty.
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