Kefauver soon had more on his mind than Sackler. After the last witness testified in February 1962, the proposed legislation went to the Judiciary Committee for review. According to Kefauver, at “a secret meeting” with some other senators, the pharma industry “just about knocked the bill right out of the ring.”1
The drug industry’s lobbying was effective because few politicians feared voter backlash if they failed to control drug prices. The lack of public outcry over the hearings had emboldened the industry. The revised bill that emerged from the Judiciary Committee was “a mere shadow of” the original, Kefauver lamented.2 Gone were key revisions of the patent law. Kefauver’s two-and-a-half-year quest to change the way the pharmaceutical industry priced its drugs was on the verge of being scuttled.
Everything abruptly changed in mid-July. “ ‘Heroine’ of FDA Keeps Bad Drug off Market,” ran the front-page headline in The Washington Post.3 It was the story of “how [the] skepticism and stubbornness of a government physician… a bureaucratic nitpicker… prevented what could have been an appalling American tragedy.” The doctor was Frances Oldham Kelsey, an FDA approval officer. Merrell, the same firm that had faked studies for its MER/29 cholesterol drug, pressured Kelsey to approve thalidomide, a sedative sold over the counter throughout Europe as a nonaddictive sleep aid and a morning sickness treatment for expectant mothers.4 At that time, a drug was automatically approved if the FDA took no action within sixty days of an application. Kelsey, however, had delayed the process by peppering Merrell with many requests for more information.5 Despite the company’s arguments, she was not convinced of the drug’s safety.6
By the time of the Washington Post story, there was evidence of its dangers with some reports of horrible birth deformities in mothers who had taken the drug. (Eventually, thalidomide was blamed for more than ten thousand infants worldwide born with extreme underdevelopment of the arms or feet. Two thousand died of complications.)7 I 8
The tremendous fright caused by the thalidomide disaster revived overnight Kefauver’s moribund legislation. The outcry sparked a bipartisan rush by politicians all wanting to take some credit for drug reform. A nationwide poll showed that 76 percent of those queried about “government control over drugs” thought it should be “more strict.”9 Kefauver embraced the newfound support even though he realized it meant abandoning his campaign to foster more competition and control pricing in favor of crafting a bill that focused on consumer safety.
Pharma was now on the defensive. It did not want to be cast as the villain by opposing a bill now framed as providing necessary safeguards to prevent the next thalidomide tragedy. The industry’s main lobbying group, the Pharmaceutical Manufacturers Association, begrudgingly embraced some provisions that enhanced drug safety while resisting efforts to revive any of the antitrust and patent revisions.10
Adding to pharma’s problems was a book published during the Senate hearings. Biologist Rachel Carson’s Silent Spring indicted the dangers of unfettered pesticides in the environment and food chain. She warned about many health dangers, including possibly cancer.II 11 Carson’s revelations about how American chemical companies often put profits ahead of people and the planet amplified similar concerns around thalidomide.12 Polls showed it shook confidence in the post–World War II faith in science and medicine. Many Americans had faith in DuPont’s slogan, “Better Living Through Chemistry.” And an equal number had clung to a good opinion of pharmaceutical companies, believing that their mission of discovering cures somehow made them more altruistic.13
The public’s anger emboldened the FDA’s Young Turks, junior grade officials who believed the agency was hobbled by its insufficient powers. They lobbied Kefauver to include in his bill sufficient regulatory tools for the FDA to better keep tabs on the drug industry and its products. Kefauver offered to abandon his efforts to limit patents in order to get a few wavering senators to commit to giving the FDA significantly more authority.14
The legislation that had seemed dead only a few months earlier was passed unanimously by the Senate and House. President Kennedy signed it into law on October 10. It was the first major reform of the nation’s drug laws since the 1938 Food, Drug, and Cosmetic Act and it marked the end to the hundred-year experiment in which the industry had policed itself and the public self-medicated. Consumer advocates hailed the law’s safeguards.
The Kefauver Amendments marked the first time that all drug manufacturers had to register with the FDA, satisfy quality control standards, and agree to regular on-site inspections. The sixty-day time limit for an FDA examiner to respond to a new drug application was abolished. The FDA got the power to recall drugs it judged “an imminent hazard to the public health” or that failed to deliver their therapeutic claims.15 The agency no longer had to wait until there was a trail of injured or dead patients for proof of a drug’s danger. The statute also empowered the FDA, much to the consternation of Medicine Avenue, to ensure that advertisements to doctors struck a “fair balance” between promotional hyperbole and scientific accuracy.16 The law did not define “fair balance,” but left it to the FDA to figure out.17
While those changes were important, they paled in comparison to a few key provisions that made the Kefauver Amendments landmark legislation. Before the law, in order for a pharma firm to get its drug approved by the FDA, it only had to show the medication was reasonably safe. The FDA had no authority to consider whether the drug worked for what it was intended.18 The focus only on safety resulted in therapeutically useless medications hitting the market. The technical distinction about the FDA’s power was never clear to the public, which assumed that government approval meant a drug was safe and effective. All drugs now had to establish “substantial evidence” of efficacy based on “adequate and well-controlled studies.” Each pharma firm had the burden of proof to demonstrate its drug “will have the effect it purports or is represented to have.” The law did not define “adequate and well-controlled studies,” again leaving the specifics to the FDA.19
If the intent of the Kefauver Amendments was to ensure that all future drugs actually worked, what about the more than nine thousand medications the FDA had approved between 1938 and 1962 when efficacy was not considered?20 Some four thousand were still on the market, including a couple of hundred me-too drugs that had been approved with only an FDA advisory letter.21 The Kefauver Amendments required that those pre-1962 medications had to also be examined for effectiveness. It gave two years for the pharma companies to assemble the evidence for the effectiveness of their early drugs.
Meeting the goals of the new law meant substantially more work for the FDA. That was not easy given its limited resources: the agency’s budget allowed it to inspect drug factories on average only every five and a half years.22 As an initial step, the FDA split its Division of New Drugs into five separate departments: the Investigational Drug Branch (evaluating the clinical studies pharma submitted); Controls Evaluation (reviewing product controls at research labs and manufacturing plants); Medical Evaluation (judging the safety and efficacy data in the New Drug Application forms); New Drug Status (working with manufacturers on the correct dosing levels); and New Drug Surveillance (compiling side effect reports).
Pharma companies feared that the law would make the drug approval process much longer, costlier, and more complex.23 Pharma’s apprehension soon turned to alarm. Frances Kelsey, the FDA medical officer who had refused to approve the sale of thalidomide in the U.S., was appointed the chief of the new Investigational Drug Branch.24 Kelsey was a certified national hero. President Kennedy had awarded her the Distinguished Civilian Service Award, the highest honor for a government employee. Dozens of newspapers and half a dozen national magazines had published glowing profiles that made her the most recognizable face in FDA history.25
In January 1963, to eliminate ambiguity over the law’s undefined “adequate and well-controlled studies,” Kelsey announced a detailed protocol that every pharma company had to follow to demonstrate the efficacy of their proposed new drugs. Under Kelsey’s rules, firms could not start human trials until they first convinced the Investigational Drug Branch that the proposed medication had no serious adverse effects and demonstrated therapeutic effectiveness in animal testing. Only then could they start the first of three phases for the human trials. The Kefauver Amendments gave the FDA the final say over the qualifications of the researchers and facilities chosen for those trials. The first phase, composed of several dozen volunteers, focused on safety. The second phase tested for therapeutic effectiveness on a minimum of several hundred patients. Kelsey’s final stage was a backbreaker for pharma. It required randomized comparative testing against a similar drug or a placebo, using thousands of patients in many different locations. Kelsey made it evident that the FDA would give the most credence to double-blind trials, those in which neither the investigator nor the volunteer knew who received the drug and who got the placebo.26 The 1963 rules would remain virtually intact for more than fifty years.
Pharma firms immediately withdrew about a quarter of the pending drug applications at the FDA, those that had not been approved before the Kefauver Amendments became law. They were medications judged to have a “low commercial priority” because they addressed rare illnesses and small numbers of patients. They did not seem profitable given the expense and time of the new clinical study requirements. Harry Shirkey, a leading pediatrician and chairman of the AMA’s Council on Drugs, dubbed those medications “pharmaceutical orphans.”27 (Decades later the government would create a statute to revive them, turning the orphaned drugs from an abandoned category into the highest-priced sliver of the industry.)
The rigorous testing also had an unintended consequence that only became evident years later. It marked the beginning of the end for the era where individual researchers filtered tens of thousands of soil samples searching for antibacterial microbes or screening hundreds of compounds for signs of psychopharmacological activity. It was, of course, still possible for a lone scientist in a small lab to get lucky and discover an unknown and promising drug. And that did occasionally happen. But completing the FDA’s three stages of clinical trials was incredibly more complex and took several years on average. Every company knew that no matter how promising a compound looked in a lab, it might be quite different when administered to patients. The high failure rate for innovative drugs was a reason why many pharma firms turned out me-too drugs.28 Since 1960, the average pharma company put about 25 percent of its R&D budget into research for an entirely new class of drugs and 75 percent into developing me-too drugs.29 Risk taking—starting—became an ever-rarer commodity in American pharma in the coming decades.30
It was not feasible to apply Kelsey’s strict benchmarks for new drug approval to the four thousand pre-1962 medications still on the market. Research scientists estimated that reviewing all the published clinical information for those drugs would take between twenty-five and fifty years. Minnesota senator Hubert Humphrey, himself a pharmacist by trade, held hearings that summer about how federal agencies could better cooperate in regulating drugs.31 One of the committee’s final recommendations was that the AMA’s Council on Drugs should take a more proactive role in providing unbiased drug information to doctors.32 The Council on Drugs was game, but it had trouble keeping up even with just those drugs recently approved by the FDA. It managed on average to analyze only one of every three new medications fully. By the time doctors got the AMA information, it was often so late that newer drugs had replaced the ones the AMA had studied.33 No matter how strong an exhortation the AMA received from Congress, it was evident the country’s largest medical association could not keep up with the flood of drugs coming out of pharma labs.
The same was true at the FDA where the agency lacked the skilled staff and know-how to fully carry out its expanded powers.34 Its annual budget was less than what some companies spent on introducing a single major drug.35
Pharma, meanwhile, complained publicly that the onerous regulations would stifle innovation. Privately they carped about how clinical testing would slow their products getting to the market and increase their costs. Pharma encouraged its allies to rally against the Kefauver Amendments in the hope that a future Congress might rein in some of the broader powers it granted to the FDA. At a midsummer 1963 international symposium in Chicago, many prestigious academicians, pharmacologists, and scientists expressed serious concerns about whether the new regulations would “snuff out the life of clinical pharmacology.” A survey of medical school researchers that year revealed that 75 percent said the law had made them disinclined to finish their current projects and less likely to start new ones.
The International Business and Financial Weekly and other conservative financial publications ran editorials condemning the FDA’s expansive new powers and urged Congress to “clip their wings.”36 The era’s two leading libertarian economists, George Stigler and Milton Friedman, were adamant that only the free market should determine whether or not a product was effective. Drugs that did not work or were too expensive for the benefit they provided would lose out to more effective and lower-priced medications. The only role for the government, they declared, was to ensure that drugs were safe before they were sold to the public.37
Pharma had a superb confederate in the American Medical Association, which condemned the Kefauver Amendments for usurping the judgment of physicians. Just as Stigler and Friedman argued, the AMA contended the FDA’s only focus in approving drugs was safety. Questions of efficacy should be the exclusive province of dispensing doctors who had firsthand experience with patients. The Pharmaceutical Manufacturers Association added to the firestorm by denigrating the qualifications of some of the FDA’s newly hired medical officers when compared to renowned doctors. It was intended to raise doubts about the ability of the young government regulators, some just fresh from school, to pass judgment on drug effectiveness.38
Over time, pharma would point to a falloff in the number of annual drug approvals as evidence that the Kefauver Amendments had crimped innovation (the FDA’s counterargument was that the lower number of approvals simply represented “a more measured scientific pace”). The slower approval process was dubbed “drug lag,” and later kicked off a debate about whether the U.S. rules had allowed European pharma firms to surpass their American rivals.39
Drug industry executives shared a like-minded strategy, their belief that if the new regulations were onerous for pharma, they were crushing for the FDA. Their plan was simple. On every new drug application, they would bury the agency in dozens of three-ring binders crammed with information about clinical trials and laboratory minutiae.40 Records from Parke-Davis show that its application for an epinephrine product in 1938 totaled twenty-seven pages. A decade later, it submitted seventy-three pages when applying for approval on a new expectorant. Its largest submission to the FDA before the Kefauver Amendments had been 430 pages in 1958. After the law, its 1962 application for a contraceptive was 8,500 pages. For a new anesthetic in a few years, Parke-Davis sent to the FDA a backbreaking 167 volumes, consisting of 12,370 pages.41
Pharma planned to appeal FDA decisions they did not like. Hiring more lawyers and outside medical experts would be part of the price of doing business in the post-Kefauver world. The FDA, however, was not naive about pharma’s entrenched resistance. George Larrick, its commissioner, was a former senior federal food and drug inspector. Dwight Eisenhower had appointed him to run the FDA in 1954. He avoided the media and instead worked quietly during his tenure to build bipartisan support in Congress. Larrick’s discreet lobbying was one of the chief reasons that Congress felt comfortable putting the enhanced drug enforcement powers of the Kefauver Amendments under the FDA. In 1954, when he took charge, there were 950 employees and the agency had a $6 million annual budget. Before Larrick left the FDA in 1965, its budget had increased tenfold to $50 million, and it had more than four thousand employees. Many of the new hires had medical degrees or doctorates in pharmacology.42
Larrick’s problem, however, was his poor public image. His quiet, behind-the-scenes arm-twisting may have benefited his agency, but it did not lend itself to good press coverage. To the extent the public knew him, it was as the man who had been duped for several years by Henry Welch, the disgraced chief of the antibiotics division who had been business partners with Martí-Ibáñez. And even though the FDA had prevented a disaster with thalidomide, that credit went to Frances Kelsey. Consumer advocates criticized Larrick for an open-door policy that allowed pharma to have considerable access to and influence over FDA regulators, including the examiners responsible for approving drugs. He was, according to a lead editorial in The Washington Post, “an indifferent steward of an important post.”43
Maybe the dismissive coverage was one of the reasons that Larrick decided to flex the FDA’s new powers. He did not go out of his way to pick a fight. Nor did he, however, shy away from one. Larrick settled on a class of medications he considered an easy target: drugs containing an antibiotic in combination with antihistamines, decongestants, or analgesics, marketed “for the relief of symptoms and prevention of complications of the common cold.”44
Medical studies in academic journals had overwhelmingly concluded those drugs were virtually worthless in fighting the viruses that caused colds. Arthur Sackler, however, had demonstrated that good promotion trumped the scholars when it came to sales. In 1955 he joined with his friend Bill Frohlich and took control of the campaign for Lederle’s Achrocidin, a combination of tetracycline, antihistamine, and an analgesic. Its sales were then an anemic seven thousand annual prescriptions. The duo devised a typically aggressive direct-to-physician mailer. Their ads featured a picture of an obviously ill patient under the words “It Started With A Cold,” noting that colds occasionally turned into upper respiratory infections. They cited a study that the odds were one in eight of developing a much more serious condition, such as pneumonia, bronchitis, sinusitis, and tonsillitis. They created the tagline “To protect and relieve the ‘cold’ patient: Achrocidin.”45
The advertisements did not disclose that the cited study was from 1933. Nor did it make any reference to the twenty far more up-to-date scholarly articles concluding the drug was useless for treating a cold. Lederle’s medical director was concerned the ads were misleading. Sackler and Frohlich had played with words and symptoms so that at a quick glance the product seemed a worthwhile remedy. Lederle’s medical director formally objected but was overridden. The company mailed the ads to 140,000 physicians. They also ran them extensively in medical journals. For physicians without the time or inclination to do their own research, those pitches—combined with free samples and visits by the Lederle detail men—proved persuasive.
The new promotion made sales pop from the minuscule seven thousand prescriptions to over four million in 1962. Lederle’s cold medication accounted for a remarkable 5 percent of all antibiotic sales in America.46 Sackler’s Medical Tribune later published the results of its own informal survey of doctors that supposedly ran ten to one in favor of prescribing antibiotics for the common cold.47
Larrick had watched intently when the Kefauver subcommittee investigated the Achrocidin ad campaign. The Senate panel had been frustrated since under the existing law, Sackler’s ad did not violate rules for how drug companies sold their products. That ad was no longer being run. So Larrick decided that under the new law, the FDA should go after the drug itself.
In August 1963, the FDA announced its intent to “decertify” Achrocidin and other prescription cold remedies. Simultaneously, the agency challenged the efficacy of thirty less frequently used antibiotics, some of which were sold in over-the-counter mouthwashes, throat lozenges, and nose sprays. Larrick relied on the recommendation of a group of leading science advisors the FDA had appointed in conjunction with the National Academy of Sciences. Their conclusion was that all the antibiotic drugs targeted for removal were of “no value in preventing or treating colds.”48 The New York Times listed another reason for the FDA’s move: “Frequent use can cause patients to develop resistance to the drugs, sometimes making them useless when the patient really needs them.”49 Those who opposed the move had thirty days to respond. The first battle in the post-Kefauver drug world had begun.
I. Although Kelsey had prevented thalidomide from going on sale in America, Merrell had distributed the drug for clinical safety trials to some twenty thousand patients in the United States. No one is certain how many of those patients were pregnant, but the FDA later concluded that seventeen babies with thalidomide deformities were born in the U.S. In South America and some Asian countries it continued to be sold by foreign drug companies for another decade under different product names that never disclosed any thalidomide content.
II. Carson’s main culprit was DuPont’s DDT, an insecticide often deployed by aerial spraying. It took activists a decade battling the chemical industry before the Environmental Protection Agency banned DDT in the U.S. The activist network spawned by Silent Spring was the driving force behind the 1970 creation of the Environmental Protection Agency.