I frequently read comments from pundits and politicians decrying the US drug regulatory system, specifically the FDA. Many of these people, reading from the same PR playbook, will try to convince you that regulation is the primary factor in stifling innovation.
But based on history, I am convinced that without adequate government regulation, companies in a number of industries, including pharmaceuticals, would run roughshod over the citizenry in an effort to maximize their profits. It’s painful to see how the drug industry has sullied its once excellent reputation by employing a variety of unethical practices, as has been widely reported.
Magazine publisher Steve Forbes recently opined how regulation was destroying the pharmaceutical industry and how it might “kill millions of us.” He claims that the declining number of new drug approvals is not a result of the failure of the industry to innovate but instead “the chief villain is the FDA.” His “insight” that the industry’s notable lack of success in developing a new class of antibiotics is a failure of the government (both the FDA and the NIH are blamed) is both reckless and overly simplistic. Forbes fails to mention the fact that many drug companies have chosen to maximize their profits by investing in drugs for chronic conditions that need to be taken for years (e.g. heart disease, arthritis) over short term medicines like antibiotics. A more balanced view of the problem can be found in a recent report on what happens “When the Drugs Don’t Work”.
The FDA is not close to being perfect. It responds to shifting political winds and is forced to make high-stakes decisions under great scrutiny while being chronically under-funded. However, I hate to imagine what the marketplace would look like without regulatory agencies balancing out the enormous marketing and lobbying efforts employed by drug companies both large and small. Let’s review some of the less savory and injudicious practices employed by drug makers before numerous laws were passed to safeguard consumers. I’ll focus on just a few chapters from the past century of drug development to illustrate problems caused by a lack of regulation.
We want our drugs to be both safe and effective. History is filled with examples of drugs (referred to then as tonics and elixirs) that were neither; they caused serious harm or even killed those who took them while providing no benefit. From 1918 to 1928, the Bailey Radium Laboratories of New Jersey promoted a tonic advertised as “A Cure for the Living Dead.” Known as RadiThor, it consisted of distilled water containing two different isotopes of radium. It was promoted as being “harmless in every respect” and was used as a recreational drug by the wealthy. As an elixir, it was meant to capitalize on the public’s fascination with the recent discoveries of radioactivity and X rays. The company even published a book in 1928 entitled “RadiThor, the Modern Weapon of Medical Science,” although they did no studies to support this claim. Sales derailed soon after the Wall Street Journal published an expose detailing the gruesome death of socialite and sportsman Eben Byer, who had consumed large quantities of this “medicine.” The article was entitled “The Radium Water Worked Fine Until His Jaw Came Off.”
During Prohibition, safe legal alcohol was replaced with illegal hooch that was frequently adulterated with deadly intoxicants such as methanol. Bootleggers and manufacturers, operating outside of laws and regulations, made large fortunes. Sadly, though, their deadly brews killed and sickened thousands of people nationwide. The story is nicely recounted in Deborah Blum’s “The Poisoner’s Handbook: Murder and the Birth of Forensic Medicine in Jazz Age New York.” The horrendous body count was one of the primary factors that eventually led to the repeal of Prohibition in 1933.
Quackery was not limited to drugs, drinks, and devices, but encompassed medical procedures as well. One of the most interesting chapters in medical history is wonderfully depicted in “Charlatan: America’s Most Dangerous Huckster, the Man Who Pursued Him, and the Age of Flimflam” by Pope Brock. The book details the career of John Brinkley, a patent medicine huckster with a purchased medical diploma. In the 1920s and 30s, he popularized the technique of transplanting goat testicles (whole or in pieces) into impotent men to restore their “vigor.” Not surprisingly, the technique provided no benefit but was associated with significant sickness along with the death of a number of recipients. Seeking to end his career was Dr. Morris Fishbein, Editor of the Journal of the American Medical Association. The two engaged in a cat and mouse game over a number of years that finally ended when Brinkley sued Fishbein for libel and lost in a spectacular trial.
Before the advent of modern antibiotics such as penicillin, sulfa drugs were the wonder medicines of their age for treating infections. The discovery of these agents is beautifully described in “The Demon Under the Microscope: From Battlefield Hospitals to Nazi Labs, One Doctor’s Heroic Search for the World’s First Miracle Drug” by Thomas Hager. Back in 1937, however, corporate greed and incompetence turned a lifesaving medicine into a killer. The pharmaceutical firm S.E. Massengill Co. decided to formulate a version of the sulfa drug sulfanilamide so that it could be easily administered to children. To give their drug a sweet, pleasant taste they dissolved it in the highly toxic solvent diethylene glycol (more widely used today as automobile antifreeze). They did no testing to ensure that this solvent was safe. Their Elixir Sulfanilamide killed 105 people in 15 states, and was the primary impetus for passage of the Federal Food, Drug, and Cosmetic Act of 1938. Amazingly, the only law that Massengill broke at the time was labeling their medicine an Elixir, since that term was reserved for medicines containing alcohol, and their drug did not.
One FDA scientist who helped pinpoint diethylene glycol as the poisonous agent in Elixir Sulfanilamide was Dr. Frances Kelsey. She went on to become a legend at the FDA in a separate context. The drug thalidomide was developed by the German pharmaceutical company Grünenthal and sold in Europe in the late 1950s. It was promoted as a tranquilizer and painkiller, and also to combat nausea, i.e. morning sickness, in pregnant women. Dr. Kelsey refused to approve an application by the Richardson-Merrell Company to sell thalidomide in the U.S. without further studies. Later, scientists learned that the drug causes birth defects, and the consumption by pregnant women led to the birth of over 10,000 deformed children worldwide. Many of us who came of age in the 1960s recall the widely published photos of children born with missing or truncated limbs. The thalidomide disaster led the U.S. Congress to pass new laws requiring that drugs be tested for safety during pregnancy before they can be approved. Kelsey received an award from President John F. Kennedy for her actions, and in 2010 an annual award was established in her name at the FDA (with Kelsey being the first recipient). Incidentally, thalidomide was more recently developed into an effective treatment for multiple myeloma and for treating lesions in leprosy patients. Its use is now very carefully controlled to keep it away from pregnant women.
Many of you reading this are probably thinking, “These stories are all from years ago. What does this have to do with modern medicine? No one is selling snake oil these days. The only drugs on the market now are those that have been approved by the FDA.”
Unfortunately, this simply isn’t true. In 2006, the FDA started the Unapproved Drugs Initiative to remove unapproved prescription drugs from the market, which are mostly medicines used for coughs, colds, and allergies. The goal is to eliminate prescription medicines that have not been evaluated by the FDA for “safety, effectiveness, or quality” and which are being sold illegally. Efforts to have these drugs yanked off the market are continuing, and the list is surprisingly lengthy, with hundreds of unapproved medicines on it.
Diethylene glycol made a return visit to the annals of medical infamy in 2007 when The New York Times reported it was discovered as a counterfeit substitute for glycerin in cold medicines imported into Central America from China. It also turned up in medicines given in China and in Bangladesh. Once again, hundreds of innocent people died. This was not an industrial accident. Laboratory reports and licenses were forged in order to deceive pharmaceutical manufacturers into buying the counterfeit glycerin.
Not all problematic drugs are made by third world manufacturers. It was discovered in the late 1980s that several generic drug manufacturers had submitted falsified data on applications for their generic medicines. One approach they took to gain approvals: substitute the branded drug for testing in place of the generic drug they were planning on manufacturing. The investigation led to the suspension or recall of dozens of drugs.
Drugs that don’t work are not necessarily harmless. There are three problems associated with them. First, they may actually be toxic and injure you. Second, taking a worthless drug, even if it does no harm, may inhibit you from taking a drug that might actually provide you with some benefit. Finally, even if the drug you are taking is harmless, you are wasting money that could be used to enhance your well being in any number of ways.
Many people are familiar with the first three stages of drug approval in which a drug must clear hurdles of safety and efficacy. In some cases, drug companies are granted accelerated approval for their cancer drugs in exchange for a promise that they will complete follow-up studies to ensure that these medicines actually work. Unfortunately, pharma companies are often either late in doing these confirmatory studies, or they don’t do them at all. A 2005 study showed that follow-up data was submitted in only 9 cases out of 26 accelerated approvals for cancer drugs, some of which were shown to have serious side effects after they were approved for sale. And when drug companies do generate the data, it sometimes shows that the drug does not have a survival benefit. This happened with AstraZeneca’s non-small cell lung cancer drug gefitinib (Iressa), which led the FDA to restrict access to this medicine in 2005.
Takeda Pharmaceuticals recently announced that it is pulling its drug serrapeptase (Dazen) off the market after selling it for 40 years in Japan. The reason? Tests of the drug in 2009 revealed that it was completely ineffective; there was no difference ina patient’s symptoms whether or not the drug was given. Sales figures for 2009 were nearly $13 million. If you think that’s a lot of wasted money, just imagine about how many yen the company earned over the 40-year period they sold the drug. Pfizer’s gemtuzumab (Mylotarg) was withdrawn from the market in 2010: it failed to demonstrate any benefits to patients in follow-up studies, and patients taking it were actually dying in greater numbers than those who didn’t.
Another dangerous drug that was pulled from the market was Regulin, as recounted in John Abramson’s excellent “Overdo$ed America: The Broken Promise of American Medicine.” The initial FDA reviewer was of the opinion that the drug should not be approved because it offered no significant advantages over existing medicines, and it appeared to cause liver inflammation. The reviewer was removed, however, and Regulin wound up being approved by the FDA for treating diabetes. However, after mounting reports of liver damage and liver failure, the drug was finally pulled off the market three years and $1.8 billion in sales later. It was suspected of killing nearly 400 people and damaging the livers of many more.
Off-label marketing of drugs for indications for which they have not been approved has resulted in some billions of dollars in profits and billions of dollars in fines for pharma companies in recent years. These fines are widely considered a cost of doing business in the industry. Why is off-label marketing forbidden? Because it results in drugs being used for ailments for which they have not been shown to be either safe or effective, potentially costing consumers their money and possibly their lives.
Many people would classify homeopathy, naturopathy, and similar treatments as modern day snake oil. In his book “Snake Oil Science: The Truth About Complementary and Alternative Medicine,” author R. Barker Bausell convincingly illustrates how rigorous scientific evidence does not support the effectiveness of these therapies, and people using them, while possibly benefiting from the placebo effect, are simply wasting their money.
Pressure on the FDA to approve new medicines increased markedly after the pharmaceutical industry began footing much of the bill for drug approvals as a result of passage of the Prescription Drug User Fee Act (PDUFA) in 1992. The number of drugs approved by the FDA but later withdrawn due to safety reasons more than tripled (from 1.6 percent to 5.3 percent) in 1997-2000 compared to 1993-1996.
I don’t disagree with the viewpoint that says that regulations make it more difficult to get drugs approved. But isn’t this a process that we want to be (at least somewhat) difficult? Shouldn’t there be clear and convincing evidence that the drugs that we (and the government) pay for are both safe and effective? As stated above, I readily concede that the FDA isn’t perfect and could function better in providing clear and timely guidance to the drug industry. However, I am happy that they stand between you and I and the people who would sell us modern versions of snake oil to make a buck.
It is widely agreed that new classes of antibiotics are needed to combat the growing number of drug-resistant microbes. The problem facing the pharma and biotech industry isn’t excessive regulation; it’s a lack of inducements in the midst of a drought of innovation. Let’s create significant new incentives that will reward companies for generating new drugs to combat the problem. Among the possibilities are significant tax breaks, longer patents, and guaranteed pricing tied to effectiveness. Maybe this will help redirect money that the industry is presently committing to acquisitions or biosimilars into new and novel medicines that will someday save millions of lives.
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