While the debate in Britain was about end-of-life care, in the U.S., FDA commissioner James Goddard caused angst among the nation’s big tobacco companies as he tried expanding his agency’s authority to regulate their product. The surgeon general’s report warning that smoking caused lung cancer had been released only eighteen months earlier (January 1964). In a country where 40 percent of adults were regular smokers, Congress had responded only by requiring that all cigarette packs include a generic warning label.1 As with alcohol before Prohibition, lawmakers were reticent to do anything that might too severely crimp the huge tobacco tax revenues. They added more than $8 billion annually to the federal government, about 6 percent of its entire budget (another $3 billion went to states and cities with their own cigarette taxes).2 Goddard contended the FDA should have jurisdiction over cigarettes since they had become a health issue. But without the science that unequivocally established nicotine’s addictiveness, he could not make a winning case (it took forty-four years before the FDA got the authority to regulate tobacco).3
Although he failed to get control of tobacco, he cited it in staff meetings as proof of his intent to put an end to what he called the FDA’s era of subservience. The agency had all the legal powers it needed, he said, but time and again had failed to use them. FDA general counsel William Goodrich thought Goddard was dramatically different from his predecessors. He was “very gung-ho,” inspired by “the public interest movement,” and “prepared to beat on the [pharma] industry.”4
Word soon spread in Washington about the fiery new commissioner. The New York Times described him as “a wild-eyed crusader with a battle-ax flailing boldly.”5 Inside the agency his staff dubbed him “Go-Go Goddard.”6
Goddard was not satisfied merely with picking a fight with the tobacco industry or with Roche and its blockbuster benzos. A few months into his tenure he delivered an unprecedented broadside to the Pharmaceutical Manufacturers Association, the industry’s leading trade group, at its annual convention.
“Too many drug manufacturers,” he said, “have obscured the prime mission of their industry: to help people get well.”7 While he was not against profits, he warned that the companies should stop trying “to slip something by us” in new drug filings. During his brief FDA tenure, he had been “shocked” at how many drug applications were shoddy and unprofessional. He promised to personally ensure that “amateur and unprofessional” submissions would be rejected. The FDA would no longer tolerate the “constant, direct, [and] personal pressure” the firms had long exerted on the review division.8
Goddard’s frank and adversarial tone stunned those at the Pharmaceutical Manufacturers Association. He had cherry-picked a few bad examples, they contended, in order to smear the entire industry. Most left the convention convinced that Goddard was bad for business. They were abuzz about his final warning: if the industry did not try to resolve the problems he raised, pharma would be “altered beyond your present fear.”9
Goddard turned out to be as much action as he was talk. Upon returning to Washington, he restarted his predecessor’s recall of antibiotic combination cold remedies. Soon, the FDA expanded the number of drugs it wanted off the market from several dozen to 300.10 Pharma got another jolt when Goddard created the Scientific Investigations Staff to examine “the work of clinical investigators suspected of performing improper research.”11 Adding to the industry’s angst, he promoted Frances Kelsey, whom he considered “a sacred cow” for her role in preventing the sale of thalidomide in the U.S., to become the division’s first director. And Goddard put a fright into pharma when he proposed that new drugs should be tested in clinical trials against meds in the same category that were already on the market. He contended that could ensure new medications were better than what was available already.
He did not get everything on his wish list. Drug companies quickly blocked his idea of testing new versus old drugs. Proving efficacy was enough of a hurdle for them to satisfy.12 He was also frustrated he could not hold medical journals legally responsible if they ran drug ads that later turned out to be misleading.13 JAMA had published an article citing thirty-five cases of birth defects from a Parke-Davis drug, and subsequently ran three months of advertisements that did not mention that (the ads were the handiwork of Bill Frohlich).14
And he failed to require clinical researchers to obtain detailed signed consent forms from all drug trial participants. It had been included in a draft of the Kefauver Amendments but deleted before it became law. Pharma had protested that full disclosure of all risks in experimental trials would frighten volunteers. Goddard’s interest was because of a scandal eighteen months earlier. It concerned whether full disclosure had been made to hundreds of patients, most with cancer, who had been injected with live cancer cells to check immune response to new tumors.15 The research was no secret. A team of cancer specialists, led by a leading authority, Dr. Chester Southam, had conducted the work for a decade at New York’s prestigious Sloan Kettering. Many researchers on the team had given lectures or led symposiums about their work, and their results had been published over the years in eighteen peer-reviewed medical journals.16 Beyond those patients at Sloan Kettering, the team had injected live cancer cells into patients at New York’s Memorial Hospital, Brooklyn’s Jewish Chronic Disease Hospital, and inmates who had apparently volunteered at Ohio State Penitentiary. What put the research on the front pages of the New York papers was that three doctors at the Jewish Chronic Disease Hospital refused to participate when they discovered that the informed consent form signed by the patients did not disclose that the injections contained live malignant cancer cells. Nor did it include anything about the risks. The three dissenting physicians, along with a hospital board director, resigned in protest when Southam went ahead anyway. “I don’t want Nazi practices of using human beings as experimental guinea pigs,” one said on departing. New York tabloids covered the story as if it was an American remake of the Nuremberg trials.17
An investigation by the New York State attorney general led to the state’s Board of Regents finding Southam guilty of deceit, fraud, and unprofessional conduct. His license was suspended for a year.18 Many of his colleagues thought he had been unfairly pilloried for the reason that the drug lobby fought Goddard’s attempt at full disclosure: patients might have been scared away at words like “living malignant cells” or told about every risk, even the ones that were possible but unlikely. The best evidence that most in the medical establishment did not consider Southam’s ethical violations egregious is that when he was again permitted to practice medicine in 1964, the American Cancer Society elected him their executive vice president.19
In the final regulations issued by the FDA the following year the agency made no mention of Goddard’s desire for stricter and more transparent guidelines to protect research volunteers.20 (It took the disclosure six years later of the shocking 1930s Tuskegee syphilis experiments on poor African Americans to force a meaningful revision of the informed consent rules.)
Although Goddard had an ambitious to-do list, he recognized that one matter took precedence: starting the ambitious review mandated by the Kefauver Amendments of the effectiveness of thousands of drugs approved between 1938 and 1962. The endeavor was beyond the FDA’s capability, especially since he wanted the agency to devote more resources to expanded enforcement of existing regulations. Only a couple of months after becoming commissioner, he reached out for help to the National Academy of Sciences (NAS) and National Research Council (NRC). They struck an agreement, dubbed the Drug Efficacy Study, in June 1966. In exchange for $834,000 from the FDA, the NAS/NRC assigned their Division of Medical Sciences to undertake a broad evaluation of all the pre-1962 drugs. They divided the drugs into categories such as antibiotics, hormones, sulfas, and tranquilizers. Thirty panels composed of 185 scientific and medical experts would judge the drugs’ efficacy.21
Harvard’s Max Finland estimated that if the experts used Kefauver’s standard of “substantial evidence,” the panels would take twenty-five to fifty years to finish their work.22 Goddard was a realist. He agreed to a more lenient standard of “the informed judgment and experience” of the medical experts.23 Instead of requiring new and independent research, the panels would analyze every drug’s published studies and data. Two hundred and forty pharma firms sent truckloads of information on over four thousand drugs to the reviewers.24 The panels ranked each—effective, probably effective, possibly effective, and clearly ineffective—as to how it delivered on its therapeutic claims. Drugs deemed ineffective would be banned from the market unless the pharma company reformulated it and proved anew its efficacy.25
Fixed-dose combination antibiotics, introduced by the Pfizer-made/Sackler-promoted Sigmamycin, were the most controversial. Twenty percent of all medications under review were combinations.26 In the ensuing debate the review panels added an additional finding: “ineffective as a fixed combination.” That meant there was no evidence that the combined drugs were any more effective than each of the meds on their own.27
As Goddard waited for the Drug Efficacy Study to return with its final recommendations, the FDA’s examiners in the administrative hearings on the mild tranquilizers returned in April 1967 with a partial judgment.28 Relying on the 1965 Drug Abuse Control Amendments, both Miltown and Equanil met the definition of “potential for abuse” and should be subject to controls similar to those on amphetamines and barbiturates.29 Drugmakers Carter and Wyeth had been prepared for an adverse ruling and immediately sued the FDA in federal court.
The FDA’s hearings on Librium and Valium, meanwhile, were far from over. Roche was only halfway through presenting its defense. It had a long list of expert witnesses, mostly prominent researchers and noted psychopharmacologists. They testified that if the two benzos were used as intended, they did not produce debilitating or life-threatening side effects, were not addictive, and did not lead to an increase in suicide. Roche’s attorneys dismissed the FDA’s patient accounts of painful withdrawals from the drug as rare and not evidence of an underlying problem.30
The following month Goddard refocused on medical advertising. He had failed to interest a single pharma company with a proposal to replace all medical advertising with an annual FDA-produced compendium that included full labeling information.31 Goddard wanted pharma to subsidize the cost. Drug executives thought it preposterous that they pay for a government-sponsored encyclopedia at the expense of abandoning their own advertisements.32
On May 17, the FDA issued a new set of regulations under the “fair balance” requirement for promotion. No drug could be advertised as superior to another unless the FDA approved the claim after the presentation of “substantial evidence.” That rule was sparked by two instances in which companies advertised their birth control pills as safer (Mead Johnson) or that they caused less weight gain (Lilly), when neither was true.33 The FDA also instituted a tougher requirement for listing side effects in an ad. They would have to be displayed in the promotional copy itself, not buried in a barely discernible font at the bottom.34
Finally, Goddard introduced measures to prevent a redux of what Sackler and Frohlich had done with Achrocidin, Lederle’s fixed-dose antibiotic cold drug. In promoting that drug, Sackler and Frohlich had cited a 1933 clinical study to puff up the medication’s supposed benefits, while ignoring twenty newer, more comprehensive studies indicating the exact opposite. Among a rash of new “dos and don’ts,” obsolete data could no longer be used in promotion, published reports of side effects could not be ignored, and animal studies could not be cited as having any clinical significance.35
Pharma forcefully opposed the new rules. The president of Sackler’s McAdams ad agency spoke for many on Medicine Avenue when he said the proposals “jeopardized freedom of the press.”36 Goddard did not budge. The FDA instead seized shipments of some medications in which it judged the ads misleading. Warner-Lambert’s Peritrate, used for chest pain relief, was the first. The company had incorrectly relied on studies to boast about efficacy beyond what it had proved to the FDA.37 The use of seizures was controversial and brought a howl of protest from drug companies who charged that under Goddard, the FDA’s role had crossed from protecting the public to an abusive use of power.
Goddard created problems for pharma beyond simply the scope of FDA authority. He persuaded Lyndon Johnson that a stronger federal role was needed in keeping tabs on the drug industry. In 1967 LBJ endorsed legislation to restrict the $100 million that pharma spent on free samples to doctors annually. The final version of the Food and Drugs Safety Act passed that year was not as expansive, however, as Goddard had hoped. While the new law barred pharma from sending unsolicited drug samples through the mail, there was no limit on how many detail teams could distribute.38 And to make up for losing the right to mail unsolicited samples, drug firms began adopting a wide range of new ways to provide doctors with perks, everything from weekend trips to the Bahamas to golf tournaments and cocktail parties.39
Not even the president could get all the legislation he wanted when it came to pharma. Two years earlier, Congress had passed the first ever government-sponsored health care programs, Medicare and Medicaid.40 Both were part of LBJ’s Great Society reforms. Medicare removed everyone over sixty-five from the individual health care insurance market. It focused on covering the costs of hospitalization. A prescription drug benefit was included in an early draft bill but dropped before the final vote “on the grounds of unpredictable and potentially high costs.”41 Eligibility for Medicaid, on the other hand, was not dependent on age. It was intended for Americans with limited incomes, defined as those living at or below the federal poverty line. Medicaid did cover prescription drugs.42
The Johnson administration was alarmed by the rapid increase in drug costs and how much pharmaceuticals exceeded what the government had budgeted. To control runaway prices, one LBJ-backed bill would have instituted “reasonable costs” as a pricing standard. Another would have mandated the government only buy generic medications.43
Those proposals set the drug industry on fire. The AMA joined in, arguing they would infringe on physician autonomy to decide which medication was best for a patient.44 The Pharmaceutical Manufacturers Association flooded congressional offices with booklets warning generics were not safe.45 Both bills died before making it out of their committees. In response, Lyndon Johnson appointed a Task Force on Prescription Drugs to determine whether drug coverage should be added to Medicare.I
Goddard, meanwhile, had the ear of some prescription-reform-minded Democratic senators, Wisconsin’s Gaylord Nelson, Louisiana’s Russell Long, and New Mexico’s Joseph Montoya. Nelson had succeeded Estes Kefauver as the chairman of the Antitrust and Monopoly Subcommittee. Goddard repeatedly urged him to pick up where Kefauver stopped. Beginning in May 1967, Nelson opened an investigation—Competitive Problems in the Drug Industry—that focused on “the health and pocketbook of American citizens.”46 It was the first of what would be a record-setting thirty-four hearings over twelve years (generating seventeen thousand pages of final reports).47 Nelson tried half a dozen times in the coming decade to enact some variation of compulsory generic drug legislation; pharma defeated it every time.
In January 1968, the Drug Efficacy Study panels finally reported their conclusions to the FDA. They had reviewed over 16,500 therapeutic claims for 4,000 pre-1962 drugs. Only 434, about 12 percent of those examined, delivered on all their promised claims.48 Seven hundred and sixty-nine were marked as “ineffective”; that included most of the fixed-dose combination antibiotics.49 Psychotropics were hit hard, with more than half marked as not working for the condition for which they were dispensed.50 The biggest drug companies—Upjohn, Pfizer, Lederle, Lilly, Wyeth, and Merck—had the highest number of products judged “ineffective.”51
The information in the final reports was so voluminous that Goddard established a Drug Efficacy Study Implementation (DESI) task force inside his Bureau of Drugs.52 Its task was to recommend which drugs the FDA should decertify. It was also responsible for reviewing additional evidence drugmakers submitted to appeal the ratings, particularly the nearly 1,800 drugs marked as “possibly ineffective.” Ultimately, the DESI task force upgraded to “effective” only an eighth of those.53
The failure of so many drugs to get passing marks from the scientific review panels was bad news for tens of millions of the drug-taking public. While many people had come to believe that pharma put profits above public health, a further shadow was cast over the industry’s vaunted reputation for excellent research. Some national newspapers printed full-page summaries of the “ineffective” drugs.54 How good was it if over half of all the therapeutic claims made for all pre-1962 drugs were not supportable? Few had known until those rankings that the “scientific evidence” many drug companies touted in ads were simply paid testimonials.
While the DESI was under way, Goddard was antagonizing pharma on new fronts. That February, during Senate hearings about the booming diet pill industry, he testified “there are no drugs which can safely control the problem of obesity.”55 That was a direct challenge to some five thousand physicians who specialized in treating obesity with diet pills. By the time of the Senate probe, Americans were spending $250 million annually on those doctors and another $120 million on so-called rainbow pills, named after the brightly colored tablets that had become a hallmark of weight loss clinics.56 Goddard announced during his testimony that he had ordered the FDA to seize 43 million tablets from a dozen manufacturers.57 The rainbow pill he targeted was a wildly popular combination of a desiccated form of the thyroid hormone mixed with the heart drug digitalis.
The drug in Goddard’s crosshairs had been on the market for decades, but the FDA had only recently linked several deaths to it. “It is incomprehensible,” said the president of Texas-based Lanpar, a manufacturer from whom federal agents seized $500,000 in pills, “that a product that has been marketed successfully for 30 years overnight becomes the target of the FDA.”58 Those drugs were lethal hazards, the commissioner told the Senate panel. And he cited the rainbow medications as a key reason why the FDA’s review of which pre-1962 combination drugs should be recalled was vitally important.59
Goddard’s rainbow pills seizures were front-page news. Many in the industry thought he was grandstanding. Life sent a thin reporter undercover to ten weight loss clinics, and while a couple told her she did not need to lose weight, the rest prescribed 1,500 amphetamine-based pills in two weeks.60 While the manufacturers of rainbow pills were a handful of smaller firms that had been founded just for that purpose (New Jersey’s Clark & Clark, Dallas’s Lanpar Company, Denver’s Western Research Laboratories, and St. Louis’s Mills Pharmaceuticals), the seizures tarnished the entire industry.61 News that March of the deaths of twelve Maryland women from rainbow pills prompted Senator Gaylord Nelson to add diet pills to his ongoing pharmaceutical inquiry.62
All of pharma agreed on one matter: they had to get rid of Goddard. For more than a year they had engaged in a whisper campaign designed to disparage him and undermine his support in Congress. They characterized him as driven by insatiable ambition, only interested in accumulating power as opposed to doing what was best for the public and drug industry. Business-friendly Barron’s warned that the “FDA Has Become a Threat to U.S. Health and Welfare.” The problem, according to Barron’s, was that the agency was in “the doctrinaire hands of its Commissioner, James L. Goddard.” His policies had so suppressed the development of lifesaving drugs in the country’s pharmaceutical research labs, that “the medicine men of FDA, all unwittingly perhaps, are angels of death.”63
Goddard unintentionally helped his enemies by saying things that weakened the support he had inside the Johnson administration. He irritated law enforcement officials in his 1968 testimony before a House subcommittee that was weighing whether to criminalize LSD. Goddard was the only administration voice to oppose the law, preferring instead to fund public education about the perils of drugs and treatments for addicts. His contention that local drugstores were not competitive and would one day be extinct irked one of his most ardent supporters, former pharmacist Vice President Hubert Humphrey.64
In May 1968, the embattled Goddard submitted his resignation. According to The New York Times, his departure was “because of differences with the Administration over his policing of the purity of foods and the safety and efficacy of drugs.… He antagonized pharmaceutical manufacturers and many physicians.”65 Pharma was jubilant. Goddard’s replacement, Dr. Herbert Ley Jr., the chairman of the Harvard School of Public Health’s Epidemiology and Microbiology Department, started in July.II66 But the celebration over Goddard’s departure was short-lived as Ley disabused the industry that he would return to the less aggressive Larrick-era approach. He made it clear inside the agency as well that he was determined to follow through with most of Goddard’s ambitious agenda, including the DESI recommendations regarding the pre-1962 drugs.
Thirty members of the National Academy of Sciences, all of whom had served on the drug panels, shared with Ley a draft of a scholarly article they wrote concluding that the FDA should decertify all fixed-dose combination antibiotic medications. They were almost never better than each of the constituent drugs alone, and in some cases demonstrably worse.67 Drug companies used the combination meds to extend patents on expiring medications, or sometimes to develop combo products for which they charged considerably more than each drug on its own.68 JAMA refused to publish the article, believing that removing the drugs cut the power of physicians. (The NEJM published it but not until the following year.)69
The chief target of the academic experts was Upjohn’s Panalba, a patented combination of two generic antibiotics, tetracycline and novobiocin.70 It had been a major success for Upjohn. With more than 750 million prescriptions in the decade since its release, it provided 20 percent of the company’s American gross income.71 The Drug Efficacy Study had concluded that Panalba was actually less effective than either stand-alone antibiotic because the duo often counteracted each other. As for side effects, Panalba was more toxic than just tetracycline, and one in five patients were allergic to novobiocin.72 A dozen patients had died of Panalba complications.73 And it had cost consumers at least $12 million more than if they simply had used just-as-effective tetracycline. What few knew was that Upjohn’s internal testing had revealed the drug was dangerous, capable of causing blood disorders and even liver damage.74
The reason for Panalba’s success? Since its inception its promotion had been the brainchild of Arthur Sackler and his McAdams agency. Sackler had already gotten in trouble before the Kefauver subcommittee for his misleading campaign on Upjohn’s corticosteroid.
With Panalba, Sackler developed something he dubbed the “rational approach to prescribing antibiotics.” It was, as medical historian Scott Podolsky says, a “shoot first and ask questions later” philosophy. The ads urged doctors to use “Panalba promptly to gain precious therapeutic hours.” Since taking a tissue culture to confirm whether an infection was bacterial was not always practical, “a rational clinical alternative is to launch therapy at once with Panalba, the antibiotic that provides the best odds for success.” Sackler coined the description that Panalba was an “antibiotic-reinforced antibiotic” (the addition of novobiocin helped “protect against resistant staph”).75
On Christmas Eve 1968, Commissioner Ley relied on the recommendation of his DESI task force and announced the FDA’s intention to decertify Panalba. Ley knew if the agency was successful stopping the sale of the most successful fixed-dose combo antibiotic, it could move against the hundreds of others on the market. Ley provided thirty days for comments or input. Upjohn requested a full hearing to contest the decision, the same as Carter and Wyeth had done when they fought the Miltown/Equanil controls a few years earlier.
Ley said no. If every pharmaceutical company got a hearing to relitigate the merits of the DESI decisions, the agency would be bogged down for years. He was certain that the Kefauver Amendments’ grant of power for reviewing the pre-1962 drugs was so broad that pharma would have to abide by whatever decision the agency reached. That proved a miscalculation. Panalba became the test case for the entire industry and turned into a much bigger fight than Ley had imagined. It sparked a Senate investigation (that ultimately judged fixed-dose antibiotics as useless and sometimes dangerous).76 Upjohn filed a federal lawsuit contending the FDA ruling violated the doctors’ constitutional free speech and exceeded its statutory authority. Upjohn insisted that the courts should in fairness order the FDA to hold administrative hearings for every drug it wanted to withdraw from public sale. Meanwhile, Panalba stayed on the market as the litigation wound its way to the Supreme Court. Some of Upjohn’s rivals had by then filed their own lawsuits or briefs in support of the effort to quash the FDA’s ability to demand effectiveness evidence for the pre-1962 drugs.
The battle over whether Congress intended the FDA to have such broad administrative powers in recalling drugs worked its way through the federal courts. The Supreme Court did not settle the matter for four years in a quartet of decisions. Justice William Douglas delivered the unanimous opinion in the main Panalba case.77 It was a milestone for the FDA, a full-throated endorsement of the agency’s powers. The court concluded that Congress meant exactly what it said in the 1962 law: it intended to give the FDA broad authority to remove drugs it considered ineffective, not just those deemed unsafe. When any drug is recalled, the court ruled it applied automatically to all the me-too versions. As for the question of whether the agency could use “administrative summary judgment” to withdraw drugs “for the protection of the public,” the court ruled it did. All the FDA had to do was to “provide a formal hearing” in those instances when the company’s newly submitted evidence met the agency’s standard of “rigorous proof.”78 The Supreme Court’s ruling in favor of the FDA’s expansive power set the foundation for the FDA’s gigantic second phase of the Drug Efficacy Study for 300,000 over-the-counter medications (which took twenty years to complete).79 It also, concluded Edward Shorter, a social historian of medicine, transformed the FDA “from a sleepy little cop agency into a bureaucratic powerhouse.”80
Many in the pharmaceutical industry, as had happened after the passage of every major previous drug law, warned that the court decision would cripple research and innovation. The problem for the drug companies was that they had lost their credibility on the “sky-is-falling” complaint. For every drug removed from the market in the U.S., manufacturers continued selling them for years in Latin America, Asia, Europe, and Africa.81
I. That LBJ commission did not deliver its report for almost two years, during the first months of the Nixon administration. It recommended that Medicare should include a drug benefit program; Nixon relegated the idea to death by neglect. Adding drug coverage to Medicare would not be seriously considered again for thirty years.
II. Goddard had enough of government service. After leaving the FDA he initially took a job in Atlanta-based EOP Technology, a private data processing firm. He later moved to the Ford Foundation, and even did some consulting work for drug companies.