Chapter 1: How Do We Know? CHAPTER 1 How Do We Know? We have access to more information and evidence than ever, but facts seem to have lost their power. -- This Is Not Propaganda , a book about the Soviet Union In 2021, the Food and Drug Administration gave its approval to Aduhelm, a new drug for Alzheimer''s disease that didn''t work, could cause brain damage, and was poised to cost the nation each year a sum the size of NASA''s annual budget. How did the world''s once best prescription drug regulatory body fall so low? And how does this decline impact the medications that Americans take every day? We need to start by considering how a drug is evaluated to determine whether it works, and what we even mean by "working." It took us over a century to learn how to rethink this question; knowing about that journey is key to understanding where we''ve ended up, and to contemplate the more primitive approach to which we may be returning. Before 1906 anybody could put anything they wanted in a bottle and call it a medicine, without even having to reveal what was in it. A manufacturer could then make any claims it wanted about the product''s effectiveness for any condition. They were called "patent medicines," even though they were generally not patented. Many of them did no good at all, and some were downright dangerous.

Pills and elixirs promoted to treat pain, depression, cancer, "female troubles," liver disease, and a host of other complaints filled store shelves and mail-order catalogues. Many were physiologically inert, but some contained hefty amounts of alcohol, opium, cocaine, or a combination of them. Yes, sick babies given narcotic or alcohol elixirs did seem to become more comfortable, stopped crying, and slept better. Many of them also stopped breathing. On the picker-upper side of the medicine cabinet, it''s widely known that Coca-Cola got its name because the active ingredient in the original formulation was cocaine. Apart from its substantial addictive potential, this explains why so many people believed that things really did go better with Coke. That ingredient was removed in the early 1900s. A Uniquely American Condition? Around the same time, the Rexall company introduced its "Americanitis Elixir" to treat the ills caused by a rapidly industrializing society.

The product was "as necessary as food and drink," its ads proclaimed, continuing, This unique medical discovery strengthens and tones the nerves. It supplies to the body phosphorous in soluble form--a thing never before considered possible. Rexall Americanitis has accomplished wonderful results all over the country and its merits are now universally recognized. The part about phosphorus was utterly meaningless; the product''s real active ingredients appear to have been 15 percent alcohol and some chloroform, explaining the ad''s tagline "Note how quickly that feeling of nervous strain disappears." Companion advertisements for the product were directed at "nervous, over-worked, and run-down women," noting that the product "acts directly on the nerves." (Yes, alcohol and chloroform will do that.) The ad for women continued, Rexall Americanitis Elixir is the only remedy of its kind in existence. As its name implies, it''s a specific for the peculiar exhausted nervous conditions resulting from the continuous rush and tension under which Americans live.

This remedy fills an important gap in the line of medicines. Other promotion in the early 1900s from the Bayer company touted its two recently invented compounds: Aspirin for fevers (that''s worked out well over the years), and Heroin for cough (not so much). Both drugs had been created by the same chemist during the same period in 1897. Bayer''s Aspirin found its way into nearly every home medicine cabinet, while Bayer''s Heroin helped set the stage for a crippling epidemic of addiction, discussed more fully in chapter 20. This was before the invention of the categories of controlled substances or prescription-only drugs, so any doctor could recommend any substance to any patient. Nor was a doctor even needed: such substances could be bought directly by the consumer, with no requirement or guarantee that any of them be either safe or effective. It wasn''t until the Progressive Era at the start of the twentieth century that the nation began to wonder whether government should do something about this chaotic abundance of sometimes-toxic choices. The nation''s first attempt at drug regulation simply proposed that manufacturers should be required to label what was in their products, which would be helpful for people trying to limit their inadvertent intake of opioids, cocaine, or alcohol.

As modest as the requirement was, like all attempts to regulate medications over the decades it was met with charges of government overreach encroaching on the rights of citizens. But cooler if still timid heads prevailed, and in 1906 Congress passed the first Pure Food and Drug Act, creating the Food and Drug Administration. This small step did nothing to ensure that any of these products worked, or even were safe: manufacturers just needed to state what was inside the bottle or tablet. The country still was not ready for something as modest as a law requiring that medicines not be poisonous; that didn''t fall into place until over three decades later, in 1938 (see chapter 5). And then, for another quarter century after that, drugmakers still didn''t have to prove that their products really worked. That revolutionary concept was proposed in legislation introduced in 1961 by Senator Estes Kefauver, a Democrat from Tennessee. Along with other proposed laws that dealt with the high prices of medicines--a recurring theme in American history--he introduced the radical idea that a manufacturer should be required to show that its product helped patients before it could be sold or promoted. No other country required that; at the time, this idea was seen as far too liberal, and the initiative seemed headed for certain defeat.

The proposed reforms were met with the usual objections, this time put forward by an increasingly powerful pharmaceutical industry: the new rules would impose excessive government control, limiting the rights of doctors to prescribe whatever they chose and of patients to ingest anything they wanted. Furthermore, the argument went, it would harm the capacity of drugmakers to discover new products. A Golden Era for Drug Evaluation In one of those accidents of history that no one saw coming, the early-1960s Kefauver amendments were implausibly rescued at the last minute by the thalidomide tragedy, in which thousands of babies worldwide were born with congenital defects caused by a drug their mothers took during pregnancy (see chapter 5). Although a central goal of the Kefauver amendments was the containment of high drug prices and the thalidomide tragedy concerned drug safety, the birth defect debacle led to the passage of his legislative package and gave the government new powers in yet a third domain: medication effectiveness. The new 1962 law required a manufacturer to provide the FDA with credible evidence that a new product actually worked before it could be sold. Nothing like that had been put into place anywhere: it changed everything about how people think about and use medications, both in the U.S. and eventually around the world.

This evidence would have to come from what the law defined as "well-conducted studies"; that usually meant randomized controlled trials (RCTs) in patients. The logic behind the RCT is as powerful as it is simple. Many diseases wax and wane on their own. Enthusiastic doctors may attribute any improvement to something they had done, and patients often perceive benefit from ingesting compounds with no biologic effect at all. The RCT handles these problems elegantly through a remarkably simple approach: take a large group of patients with a given disease and randomly allocate some to get the drug being studied, and some to get a comparison treatment--often an inert substance, the placebo. The approach makes vivid use of the concept "all things being equal." If a large group is assigned to get treatment A or treatment B by the flip of a coin (or a computer random number generator), all things other than the treatment really are rendered equal across the two groups. It''s also important that neither the patient nor the doctor to know who got what.

That key feature has traditionally been known as "double-blinding," but in deference to visually impaired people and their advocates, some now prefer the term "double-masking." At the end of the trial the data are unblinded (unmasked?); if the randomization worked well and the sample size is good enough to make a chance finding unlikely, then any differences that are seen in the group that got the drug are extremely likely to have been caused by the medication and nothing else. This simple approach, which wasn''t in routine use until after World War II, utterly transformed our ability to know what works and what doesn''t in medicine. For the same reasons, it also proved useful for understanding the frequency and severity of side effects, as described in chapter 6: patients sometimes develop symptoms they attribute to placebos, known as the "nocebo" effect, from the Latin root for "noxious." Randomization and double-blinding/masking help take care of that as well. The RCT became the mainstay of drug evaluation relatively recently, in the second half of the twentieth century. Before that, respected authorities would decide what drugs worked based primarily on their own clinical experience (often an unreliable indicator), or assumptions about mechanisms of physiology and pharmacology.