19 THE $100 MILLION DRUG

Sackler and his Medicine Avenue colleagues had their own concerns about the Kefauver Amendments. The law threatened to turn medical advertising into one of the most regulated fields of commercial promotion.1 Labels and ads had to list all active ingredients and the drug’s generic name. (The Pharmaceutical Manufacturers Association and thirty-seven drug companies sued the following year to invalidate the requirement for listing the generic name every time the brand name was mentioned; the FDA agreed to withdraw that provision after the case reached the Supreme Court in 1967.)2 Even more irritating to Medicine Avenue was that the FDA would be the final arbiter of whether their promotions were “scientifically accurate.” Ads also had to include a “brief summary” of the warnings and side effects from the package insert. No one knew what a “brief summary” meant in practice.

Sackler urged restraint to both rivals and friends. The agency could now recall any drug if its advertisements violated the new standards. Sackler reasoned that if Medicine Avenue did not unnecessarily provoke the government’s only drug regulatory agency, it might not make advertising enforcement a top priority. There was little doubt the FDA had its hands full with approving new drugs and the fight to decertify fixed-dose cold remedies. The ad men hoped that all the new regulations would only affect future promotional campaigns, for drugs that were under development in laboratories.

To Medicine Avenue’s relief, there were few changes initially. In the meantime, ad campaigns for antibiotics continued to be the most lucrative moneymakers for the agencies. No one then knew that the golden age of antibiotic discovery was coming to an end. Half of all the ones used today had already been discovered.3

Arthur Sackler had made his reputation in medical advertising a decade earlier with his aggressive rollout for Pfizer’s Terramycin. Librium revealed what he would do next. Librium had become popular so fast that Hubert Humphrey’s 1963 Senate investigation had made it a stand-alone part of their review of federal drug oversight. The disclosures about Librium were largely lost in the nearly one-thousand-page final report. The report noted that Roche’s claims about Librium’s “remarkable effectiveness and versatility” were from “completely uncontrolled studies” where no effort was made “to observe any of the established disciplines” for reliable trials. And a slow but steadily growing list of side effects—vertigo, drowsiness, impaired thinking, slurred speech, confusion, and sometimes hallucinations—were documented.4 A study of thirty-six patients on high doses of Librium was the first to suggest it might cause dependence.5 Another reported that the car accident rate of daily Librium users was ten times greater than average.6

Few physicians kept abreast of ever-changing drug updates much less had incentive to tackle a six-inch-thick government report. Despite Librium’s spiking adverse effect profile, most doctors continued ranking it as one of the safest drugs on the market.7 A nationwide poll of physicians provided the best evidence of the impact of Sackler’s marketing: Librium was ranked as “one of the most significant advances in medical therapy.” It was the top physicians’ choice when asked “What drug is most useful in your own practice?” Librium also was the number one pick by doctors asked to select a drug that “was not used as primary therapy” but that “made the biggest contribution to easing the course of illness from the patient’s perspective.”8

Competitors worked furiously to create a rival drug. The results were more than a dozen me-too applications to the FDA, all chemical derivatives of Miltown.9 Unlocking the chemistry of benzodiazepines and creating a serious Librium competitor proved far more challenging. Even before the FDA’s 1960 approval of Librium, Roche had decided to protect its giant research lead in the new category by developing its own contender to its wonder drug. Leo Sternbach, the Roche scientist who discovered Librium, set about developing a successor. Sackler encouraged that strategy. He knew that every drug, no matter how indomitable it seemed when introduced, eventually lost market share to newer meds.10

This time, Sternbach’s laboratory quest was simpler. Instead of testing hundreds of compounds in the improbable hunt for a new class of therapeutic treatments, he focused on “changing the molecule without losing the tranquilizing activity.”11 Roche wanted a better me-too Librium.12

Only a small team at Roche knew that on October 26, 1959, three months before the FDA had given Librium its final approval, Sternbach had found his improved benzo. Never before had a pharmaceutical firm devoted so many resources to developing a competing drug to one of its own brands, before that first one was even on the market. Sternbach gave his new drug the generic name diazepam. Roche finally settled on Valium for the brand, from the Latin valere, “to be strong and powerful.”

Once again, Roche awarded Sternbach its $10,000 prize for an important discovery. He was only midway through a career that eventually garnered 241 drug patents (at one point, his discoveries accounted for a remarkable 40 percent of Roche’s international sales). “After I won that award three or four times,” Roche stopped giving it out every year.13 I 14

In its 1960 FDA submission, Roche claimed Valium to be more potent than Librium and with fewer side effects. Clinical testing confirmed that claim, demonstrating it was ten times stronger than Librium as an anticonvulsant and five times more powerful as a muscle relaxant and tranquilizer.15 Valium had an additional marketing advantage since it did not have Librium’s bitter aftertaste. Roche did not include that on its application since it was not required.

As opposed to Librium, which had been approved by the FDA before the 1962 Kefauver Amendments, Roche had to demonstrate “substantial evidence” of Valium’s efficacy. The FDA was inundated with voluminous pending me-too variations of Miltown, and it was handicapped in reviewing mind drugs, as it had only two psychiatrists in its drug division.16 It took three years before Valium was approved on November 15, 1963, ironically while the Senate hearings were under way about the undisclosed dangers of its chemical cousin, Librium.

The Senate scolding on Librium did not change Sackler’s grandiose plans for Valium’s rollout.17 “Without question, Valium was the biggest,” recalled Win Gerson, who had joined McAdams for the Librium campaign. “One of the great attributes of Valium was that it could be used by almost every specialty. There’s an anxiety component in literally every phase of medicine.”18

Roche had committed a record-setting $10 million for the drug’s promotion. “That was unheard of,” said Gerson. “Valium changed the way we communicated with physicians.” Four-page pullout ads became eight pages, direct mail to physicians included three-dimensional inserts, video specials ran on the closed-circuit TV systems at hospitals.19

Librium had featured the San Diego Zoo lynx and many of the ads were an emotional pitch about the need for a medication to keep at bay modern life’s insidious anxiety. For Valium, Sackler ditched the theatrics and concentrated on the drug’s robust therapeutic profile. “Stronger is better” was the core message. And he emphasized the science behind the new pill.20

Roche’s desire for an aggressive rollout aligned ideally with Sackler’s style. In the summer of 1963, six months before the drug went on sale, the FDA had summoned Roche’s chief of research, requesting that he bring the evidence to support its request to advertise Valium as a treatment for “nervousness.”21 Valium’s clinical trials were conducted before the Kefauver Amendments required much stricter standards for testing. Matthew Ellenhorn, the FDA chief for the Division of New Drugs, was not impressed with Roche’s trials. He suggested the company conduct more testing. Roche and Sackler ignored that advice. The first ad in JAMA that December touted Valium’s effectiveness in treating “incapacitating symptoms of insomnia, nervousness, agitation, tension, irritability, and associated physical symptoms.”22

The FDA called another meeting in which the New Drug Surveillance Branch asked Roche to remove one of Sackler’s most prominent ad lines, “No serious side effects.” The agency had received early reports that some patients developed ataxia, a loss of bodily functions. Roche said it would take the advice under consideration. Nothing changed in Sackler’s ads.

Roche was determined to make Valium a bigger success than its record-setting Librium. It spent lavishly on the detail team, dispatching them not just to pitch individual doctors, but to sell to medical institutions, hospitals, mental clinics, government health care facilities, and the military. It also increased the budget for free samples, something Sackler thought particularly useful for introducing a lifestyle drug. Roche distributed so many free samples—in one year in Canada it gave away 82 million pills just to hospitals—that health advocates complained the drug was dispensed to many people who did not need it. (It took a decade before Roche responded to the criticism and announced it would distribute free samples only if doctors requested them by returning a prepaid postcard the company provided. After that change, it still gave away on average about 15 million tablets every year.)23

Sackler personalized the promotion for Valium based on information from Bill Frohlich and his data collection firm, IMS. It cross-referenced the doctors who subscribed to medical journals with their prescribing habits. Sackler convinced Roche to organize physician focus groups to gauge their responses to different ads.24 The company also created a Sackler-inspired program explaining why benzodiazepines were the most effective drugs to counter the dangerous effects of too much stress. And it embraced Arthur’s then radical idea to use emerging video technology to promote the benzos as part of an accredited program by which physicians could earn continuing education credits. Roche created a three-hour closed-circuit television course and spent more than a million dollars on financing the Network for Continuing Medical Education (Sackler had by then started his own CME courses). There was also a consumer version for journalists specializing in health and medicine.25 Emphasizing Valium’s benefits for countering the bad effects of stress allowed Roche to suggest its wonder pill should be dispensed for everything from migraines to ulcers to diabetes to obesity.

The ads in journals for gynecologists, for instance, targeted menopause; obstetricians, controlling muscle contractions in early labor; orthopedists, muscle spasms; neurologists, how it helped with epilepsy and cerebral palsy; cardiologists, control of hypertension and as an aid in regulating arrhythmia; surgeons, its use as a preanesthetic; and substance abuse specialists, how it reduced the severity of withdrawal symptoms for alcoholics.26

Sackler had opted to skip most journals directed to psychiatrics since he assumed they were aware of the benefits of benzos.27 It worked. Although psychiatrists wrote large numbers of Valium and Librium prescriptions, most of Roche’s success was through an astonishing 97 percent of general practitioners who dispensed them.28

Valium set a new standard for what a scientist later called “choose your mood medications.”29 Doctors had written more than 50 million prescriptions in the peak year for the minor tranquilizers Miltown and Equanil. That was far more than all antipsychotics and antidepressants, only behind barbiturates and antibiotics.30 Librium’s sales left Miltown in the dust. It had topped 70 million prescriptions annually. And Valium was in a class of its own, with more than 100 million per year to American consumers.31

“Miltown and Librium had created the right atmosphere,” noted Gilbert Cant, Time magazine’s medical editor. “In the crassest of clichés, Valium represented an idea whose time had come.”32 Fortunately for Roche, Sackler had helped to make Valium fashionable.

“Executive Excedrin” or “Psychic Aspirin” were its Wall Street nicknames. The Rolling Stones sang about it in their 1966 hit “Mother’s Little Helper.” “Mother needs something today to calm her down. And though she’s not really ill, there’s a little yellow pill…”33 That same year novelist Jacqueline Susann called Valium “dolls” in her best-selling Valley of the Dolls.

Sackler’s campaign made Valium the pharmaceutical industry’s first $100 million drug.34 “Astronomical at the time, particularly in those days when prices were not increased as often as they are today,” said McAdams’s Gerson.35 Its success was so pervasive that for years its brand name was used in a broad sense to mean tranquilizer (the same as Xerox had in the 1950s and 1960s been used to mean photocopy).36

At Roche’s New Jersey manufacturing plant, three enormous pill-stamping machines churned out 30 million pills every fifteen hours.37 For what would become a record-setting stretch of thirteen years, as The New York Times noted, the world’s top selling drug “is not, as might be expected, a hopeful remedy for some life-threatening or fatal condition like cancer or heart disease or a crippler like arthritis. Instead, it is a white or pastel-colored tablet generally prescribed for an emotional state vaguely described as anxiety.”38 II 39

Roche had worried that every Valium prescription might replace one that would have been dispensed for Librium. Instead, Valium expanded the market for tranquilizers by adding upward of a million new patients. When Valium became the country’s top selling drug, Librium was still number three (the contraceptive pill was second). It had surpassed six billion total tablets in sales.40 The two blockbuster benzos averaged about 80 percent of the tranquilizer market and made Roche the most profitable drug firm on the planet.41

“Every publicly traded drug company worried about a huge spike in revenues and profits from a blockbuster,” recalls marketing executive Richard Sperber. “We all liked the success but not too much at once, it could not stay at that level forever. At some point, the year-over-year drop would look bad.” Sometimes companies diverted sales income into so-called opportunity spending, a catchall for ambitious future projects. Accountants worked magic to keep some of it off the revenue ledger.42

There were not enough accounting tricks or phantom programs to hide the flood of money that poured into Roche from benzos. The company’s stock peaked at a high of $73,000 a share, earning it the distinction as the most expensive publicly traded stock at that time. Fortune dubbed Valium “the greatest commercial success ever.”43

I. Several of Sternbach’s subsequent benzo derivative discoveries became major sellers, including the tranquilizer Rohypnol, later notorious as a date rape drug; the sedative/hypnotic Alodorm; and the anti-insomnia Mogadon. As for two others, the long-acting sleep sedative Dalmane, and the antianxiety Klonopin, Roche patented them in 1963 and 1964, respectively. However, Dalmane was not marketed until 1970 and Klonopin did not go on sale until 1975. Roche did not want to introduce them in the mid-1960s as additional rivals to the market that Librium and Valium then dominated.

II. For a decade after its introduction in 1963, Valium’s new prescriptions outnumbered refills. That was the best evidence of an expanding market. In 1974, refills held a three-to-two advantage over new scrips. The silver lining was that the overall number of Valium prescriptions had not decreased, only more were going to existing patients. Roche knew that patients were loyal and felt the drug worked; studies reported that 95 percent of patients reported Valium helped them, an astonishing result for any drug, much less one that had been on the market for ten years at that stage.