In 1986, six years after MST Continus went on sale in the U.K., it was still not available in the United States. Because its active ingredient, morphine, was a Schedule II controlled substance, it got extra attention at the FDA. An even slower than normal approval process occurred. Raymond and Mortimer Sackler privately griped about the snail’s pace. What bothered them was something common to all pharma executives: the time spent getting a drug to the market cut into its exclusive patent protection.1 Before the 1962 Kefauver Amendments had required significantly more rigorous clinical trials, more than 90 percent of all drugs got approved in under a year after submission to the FDA. Since a patent’s monopoly started ticking at the time of the invention, valuable years of sales were sometimes lost in the FDA’s approval bureaucracy.I2
By the 1980s, it took on average between six and eight years for a drug to be approved from its date of invention.3 Research and development cost several hundred million dollars.4 Traditional pharmaceutical firms argued it was counterproductive to spend so much money and sometimes get so little exclusivity for selling new drugs.5 Studies showed that once a drug patent expired, up to 80 percent of the top brand-name sales disappeared within twelve months.6 A decade later, Pfizer’s cholesterol-lowering blockbuster, Lipitor, became the most cited example: it dropped from $5.3 billion in sales in its last year of patent protection to $932 million the year after.7
Pharma companies had tried speeding up the time from the lab to the market. Among the largest dozen drug firms, half had spent billions on new R&D technologies in combinational chemistry and genomics, both of which promised much faster drug discovery.8 Instead of rebuilding their R&D from scratch, the other six companies scooped up biotech start-ups. It was the early days of what would become a decade-long pharmaceutical merger and acquisition boom.9
Spending billions on new research and development or acquiring biotech firms at inflated prices to get drugs out of the lab faster were not options for smaller drug companies such as Purdue. It is not surprising that they found ways—used by Big Pharma also—to extend the patent monopoly on their best-selling drugs. Instead of big expenditures on developing new medications, they simply recycled old ones. They could usually get patent extensions by changing how a drug was administered, the chemical composition of its coating, even its molecular makeup.
The nontherapeutic modifications were eligible for a three- to five-year patent extension, and occasionally pharma companies succeeded in convincing doctors and patients that it was worth paying a premium for those minor changes. However, winning a new patent and resetting the selling monopoly to day one required more than nontherapeutic alterations. It entailed demonstrating a “secondary medical use,” evidence of its efficacy for a different therapy than the one for which it was approved originally.
The research divisions of pharmaceutical companies were always on the lookout for additional therapeutic uses for their existing product line. Surprisingly few, however, were discovered in the laboratory. Instead, most of the breakthroughs were the result of the unregulated power of doctors to dispense a company’s drugs off-label. Physicians are presumed under the law to have enough expertise to use drugs as they deem fit. They can change the approved dosing, prescribe one approved drug to be taken in combination with others, or use it for conditions unrelated to the clinical testing for safety and efficacy conducted by the drug company.10
Estimates are that between a quarter to half of all prescriptions dispensed annually in the U.S. are for off-label use.11 Doctors who prescribe drugs off-label are in effect conducting their own informal clinical trials. There is no requirement that physicians inform their patients that they are using a medication off-label. The AMA and other professional medical associations have made such disclosure discretionary, fearing that requiring it would make many patients skittish.12
At the very least, off-label seems an extraordinary circumvention of the FDA’s power to examine drug safety and efficacy before patients use them.13 Two Harvard Medical School professors who studied off-label dispensing in The New England Journal of Medicine noted that it bypasses all the “arduous testing required of drug companies” and “clinical trials… [to] determine whether a drug is safe and effective for an intended use.”14
When doctors were empowered with off-label dispensing authority in 1938, there were fewer than twenty prescription drugs for sale in America. Entire classes of drugs—antibiotics, tranquilizers, hypertension meds—were yet to be invented. Drugs were not complicated, certainly nothing remotely like the later generations of biotech medications. Since 1938, the FDA has approved some 1,500 drugs.15 In the far more complicated and fast-paced world of today’s medical and pharmaceutical industries, the Harvard researchers warn that without the FDA “manufacturers could potentially bury physicians and patients in an avalanche of ‘information’ to promote drugs.” While no single piece of data might be “technically fraudulent,” the overall presentation might create a false appearance of safety or therapeutic benefit. No practicing physician has the time to independently verify the accuracy and context of the tsunami of information.16
The same unfettered discretion given to physicians, however, is strictly regulated when it comes to drug companies. It is a criminal violation for any pharma company or its employees to suggest any use of a drug that deviates from the strict terms of the FDA approval. Drug firms must submit a Supplemental New Drug Application and provide evidence of efficacy and safety before the FDA approves any changes.
Doctors, meanwhile, do not have to give any reason for their off-label dispensing. Oncologists often use chemotherapies off-label since one approved for a single type of cancer might show promise in treating other types of tumors. Cardiologists sometimes treat congestive heart failure and even anxiety with drugs approved for hypertension. And there is a disproportionate off-label dispensing of antipsychotic drugs to elderly patients, particularly those in long-term-care facilities.17
It does not matter to a firm’s bottom line if a hit drug was prescribed 10 million times annually to treat the condition for which the FDA had originally approved it, or if half the sales were off-label. When the off-label prescribing reaches a tipping point, pharma companies then apply for “another medical use” to the FDA.
Many pharmaceutical companies have stories about how off-label dispensing led to hit drugs. Two hypertension drugs unexpectedly turned into popular “lifestyle” medications after doctors noticed patient side effects. The FDA approved Upjohn’s Loniten (minoxidil) in 1979 to control high blood pressure. At the University of Colorado, a first-year resident asked the chief of dermatology to check on a patient in her forties with an odd skin reaction. Loniten had lowered her high blood pressure, but she had hair growth on her legs, arms, and along the hairline. The dermatology chief, only partly in jest, said, “Boy, this would be great stuff if we could apply it to the top of our heads.”18 Word that a possible hair growth medication was available spread. Balding men began asking their doctors about how they could get it. Starting in the early 1980s, the nation’s dermatologists wrote on average twice as many Loniten prescriptions off-label than did cardiologists for hypertension. Several dozen “hair restoration” clinics sprang up across the country. When Upjohn had trouble keeping up with the demand, American doctors ordered it from foreign distributors.19 It took Upjohn until 1988 before it got FDA approval for a totally reformulated prescription liquid called Rogaine.
A year after Rogaine hit the market, British Pfizer scientists discovered Rivatio (sildenafil citrate), a treatment for pulmonary arterial hypertension, a condition where blood pressure in the lungs is too high and causes shortness of breath, fatigue, and chest pain. It did not take treating physicians long to notice that male patients “did not want to give back the unused medication.” A nurse later recalled that when she went to check on a patient’s blood pressure during a clinical trial, all the men in the clinic were lying on their stomachs. Only then did she discover sildenafil’s side effect was that it caused erections.
Pfizer could not ignore that the off-label prescribing for “enhanced sexual performance” boomed. It took off early on because a rumor went viral in the pre-internet world: many men mistakenly thought it increased penis size.20 It also was in demand from recreational drug users, especially circuit parties where it was mixed with the club drug ecstasy and dubbed “sextasy.” It took Pfizer until 1998 to obtain FDA approval for Viagra to treat the newly minted condition of “erectile dysfunction.”21 II 22
Ortho-McNeil learned its Tri-Cyclen birth control pill had another use when doctors at Stanford reported that female students arrived at the campus clinic asking for “The pills that cure acne.” The FDA allowed Barr Pharma to sell its Seasonale birth control to women who wanted fewer menstrual cycles (“menstrual suppression).” And extensive off-label dispensing allowed Bayer to get FDA approval for its oral contraceptive, Yaz, not only to treat acne but also for a premenstrual dysphoric disorder, a supercharged type of PMS that was identified only in 1987 as a stand-alone condition.
Allergan was mostly an ocular care company when it paid $8 million in 1991 to buy Oculinum, a drug developed by a San Francisco ophthalmologist.23 III 24 The FDA had approved it in 1990 to treat two rare disorders, benign essential blepharospasm (BEB), a progressive neurological disorder that results in eyelid spasms, and strabismus, a misalignment of the eyes that causes them to wander and can lead to vision loss.25 It was not long before doctors noticed that the drug, renamed Botox (short for BOtulinum TOXin), improved the appearance of wrinkles at the injection sites near the eyes. Botox took off. Dermatologists and cosmetic surgeons had trouble keeping up with baby boomers hoping to turn back the aging clock (10 percent of the users were men, leading to the nickname Brotox). Samantha Jones, the self-consumed publicist played by Kim Cattrall in the hit HBO series Sex and the City, helped make it part of the culture: “I don’t really believe in marriage. Now, Botox on the other hand, that works every time.”26
Most of that happened in the first decade while the drug was dispensed only off-label. It is unlikely that the hundreds of thousands of patients who paid $400 to $500 per session to lessen temporarily the appearance of their facial wrinkles were aware that it was not FDA approved for cosmetic treatment. Nor did they probably know that the CDC and military bioterrorism experts listed its active ingredient, botulinum toxin, as one of the world’s deadliest nerve agents. When the San Francisco ophthalmologist had conducted his lab studies in the 1970s, he had to obtain the toxin from the military’s biological warfare facility at Fort Detrick, Maryland. It was the same poisonous toxin that thrives in defectively canned food. When consumed it can cause paralysis and death.27
There was no better test case than Botox to demonstrate the inviolable natural right of U.S. doctors to prescribe drugs off-label. The FDA did not object to injections of the toxin around the eyes and in the forehead. There were no tests then about whether it could migrate into the central nervous system, where it would cause havoc. Was there a possibility the body might produce its own antibodies to a foreign toxin and over time use it to attack other cells spontaneously? Did injections every four to six months weaken the body’s immune system?
Some other popular off-label drugs had proved disastrous.28 Thalidomide had been approved in Europe in the late 1950s as a nonaddictive sleep aid. Doctors prescribed it off-label to control morning sickness for pregnant women. It was that unapproved use that led to the horrible birth deformities that became thalidomide’s legacy.29 Fenfluramine was a drug approved for weight loss for the morbidly obese. For off-label use it was often combined with a related drug, phentermine, and nicknamed fen-phen. It was dispensed not only to the morbidly obese but to two million patients who wanted a simple fix to shedding some extra pounds. It was pulled from the market after two years of accumulating reports that it caused a spike in cardiac valve disease and severe pulmonary hypertension.30 Wyeth had to halt all off-label dispensing of its hormone replacement, Prempro, as “protective against heart disease,” when a massive, multiyear study revealed it resulted in a significantly higher risk of breast cancer.
Allergan, in 2002, would finally get FDA approval for Botox for the “temporary improvement in the appearance of moderate to severe glabellar lines in adults aged 65 or younger.” It was the first drug ever approved for a strictly cosmetic purpose. Botox, which was used in fewer than fifty thousand nonsurgical cosmetic treatments in 2001, broke four million annually in 2010. Its sales did not slow at all when the FDA ordered it to have a black box label warning about rare but potentially life-threatening complications (two children had died during trials for treatment of cerebral palsy). Since Botox was only dispensed at clinics or doctors’ offices, patients never saw the warning on the box in which the vials were shipped. And few if any treating physicians mentioned it. Botox was, by the time of its black box warning, entrenched as Allergan’s best-selling drug, a position it held for fifteen years. It consistently averages about 20 percent of the company’s annual revenues ($3.2 billion in 2018).
Pfizer’s Lyrica was approved originally for epilepsy and severe anxiety but was widely dispensed by doctors to treat spinal cord injury and diabetic nerve pain. Before its patent expired, Pfizer got the FDA’s okay for it to treat those conditions.31 That merely expanded the off-label uses for Lyrica, and its generic Pfizer cousin gabapentin. They are among the most widely used drugs for many types of pain, chronic cough, menopausal hot flashes, and even depression. A March 2019 New England Journal of Medicine review by two University of South Carolina doctors concluded that in “many well-controlled studies” Lyrica was little better than a placebo in treating pain.32
One of the researchers, Christopher Goodman, told The New York Times’s Jane Brody, “Patients and physicians should understand that the drugs have limited evidence to support their use for many conditions, and there can be some harmful side effects, like somnolence, dizziness and difficulty walking.”33
Those caveats did not slow Lyrica’s sales. Since 2011, off-label dispensing has provided about half of its annual revenues. During those eight years, Lyrica was mostly at or near the top ten selling drugs worldwide, and brought in $37.5 billion to Pfizer.34
The Sacklers had no such hopes that some enterprising doctors might find off-label uses for MST Continus and turn it into a blockbuster. The single restriction for off-label prescribing is that it is banned for all controlled substances.35 Purdue had to concentrate on less ambitious ways of extending its patent. Together with Mundipharma, Napp, Bard, and other Sackler companies, Purdue researched how to alter MST Continus just enough to qualify for an extension. Lab technicians tested dozens of different sustained release coatings in the hope of converting dosing from twice to once daily. Researchers examined dispersion methods to better control the drug’s peak plasma level. That would allow custom-tuning of the pill to the patient’s physical ailments. Suspension technology, the ability to dissolve the drug in a powdered form, was another line of research.
A ten-year study found that 80 percent of the top one hundred best-selling drugs had gotten at least one patent extension by using a “new and improved” application. More than half had multiple extensions.36 (Purdue ultimately received thirteen new patents for its best-selling opioid painkiller OxyContin, released in 1996 and its exclusive sales rights extended through 2030).
Purdue and the Sacklers had backed the Pharmaceutical Manufacturers Association’s efforts to get Congress to pass a seven-year extension for all patents. At twenty-four years it would have provided the world’s longest patent protection and would save small drug companies like Purdue all the hard work and cost of developing “new and improved” versions. The PMA’s thirty-five directors had lobbied for the longer patent at every legislative session since 1980. Congress nearly passed a PMA-drafted bill in 1982 but objections from generic drug manufacturers led to the vote’s postponement. They contended that any agreement extending the exclusive time to sell a drug for traditional pharma firms should be part of more sweeping legislation that made generics more readily available.37 Just as mainstream drug firms griped about how the Kefauver Amendments had made the FDA approval process torturous, generic drug companies grumbled about how that same law made it difficult for them to get their medications to market.38
After the thalidomide disaster, the Kefauver Amendments had concentrated on safety. That was the reason for the much more intensive clinical testing requirements for new drugs. All the safety and efficacy data were treated as if they were the proprietary information of the drug company that submitted it. Some shared it by publishing articles in scientific journals, but others kept it private. Except for antibiotics, which were exempted, that created a problem for generic manufacturers. The Kefauver statute required generic makers to submit a voluminous application with enough scientific literature to demonstrate convincingly that their copy was safe and effective. If they could not do that, their remaining option was to conduct their own costly clinical trials. Adding to the problems for generic manufacturers was that the FDA was so swamped with branded-name drug applications that it often pushed generic ones to the bottom of the pile.39 The FDA, described by The New York Times as “the Federal Government’s most criticized, demoralized and fractionalized agency,” could not keep pace with the expanded powers it had gotten in the 1970s.40
Senator Ted Kennedy spearheaded an effort under the Carter administration to address shortcomings in the drug approval process. The result was the Drug Regulation Reform Act of 1978, which among other provisions gave the FDA more discretion to quickly approve a lifesaving breakthrough drug before the clinical trials were completed. It also expanded the agency’s power to regulate pharma manufacturing processes as well as to require firms to conduct post-marketing studies of how their drugs were performing. And, spurred by a patient advocacy group for Huntington’s disease, a fatal genetic brain disorder, Kennedy included in the new statute the creation of a National Center for Clinical Pharmacology. One of its missions was to address the dearth of research and development for so-called orphaned drugs.
The new law did not address how to speed up approvals for drug applications at the FDA.IV41 Most generics remained stuck in the slow lane. And there was not much the FDA could do to process drugs faster. Ronald Reagan had followed through on his campaign promise to cut the size of government agencies. During his first term, the FDA’s budget was slashed, and it cut six hundred employees.42 Drug approvals were not the only important understaffed division. Patient advocacy groups, backed by the Abuse and Mental Health Services Administration and the Department of Health and Human Services, had implored the FDA for several years to take action against Quaaludes (methaqualone), a barbiturate-type sleep aid. Rorer, the company whose most famous pre-Quaaludes product was the over-the-counter antacid Maalox, had started selling them in 1972. Before the end of the decade, the little white pills were one of the most popular and widely abused recreational club drugs. Pill mills that passed themselves off as “stress clinics” diverted tens of millions of tablets. By 1980, fewer than a dozen pill mills accounted for more than three fourths of all annually prescribed Quaaludes.43 Ludes, disco biscuits, or quads, as they were called, led to an explosion in hospital admissions, date rapes, even lethal overdoses. The FDA never managed to put in place the dispensing restrictions that might have made a difference, instead only ordering some changes to the label that had little impact.
The Drug Enforcement Administration pushed the Food and Drug Administration out of the equation in 1984 by listing Quaaludes on Schedule I of the Controlled Substances Act, making their sale illegal in the U.S.44
That same year California congressman Henry Waxman and Utah senator Orrin Hatch brought the Generic Trade Association and the Pharmaceutical Manufacturers Association to the negotiating table. By the time they met, many generic manufacturers had given up on trying to make copies, even of a successful drug whose patent had expired. By 1984, there were nearly 150 brand-name medications that had come off patent and for which no generic version had FDA approval.45 The few generic makers that tried going against the grain ran into the obstacles posed by Big Pharma legal departments. In 1984, Hoffmann-La Roche prevailed in a high-profile patent infringement suit against a generic firm, Bolar. The D.C. Circuit Court enjoined Bolar from even conducting its bioequivalence testing before Roche’s patents expired. The court expressed sympathy for Bolar’s contention that there should be an “experimental use” exemption to allow it and other generic companies to develop drugs that were ready for submission to the FDA the moment the patent expired on the brand-name medication. That was, the court ruled, a “legislative activity proper only for the Congress.”46
The cost of such restricted generic competition was that patients paid anywhere from double to ten times more for brand-name drugs.47 Waxman and Hatch hoped they could find common ground so a deal might benefit patients with more drug choices and competition.
In early talks, the standoff between the pharma companies and the generic makers seemed unbreakable. The momentum shifted to the generics after the FDA issued a report that estimated that more generics would save consumers about $1 billion over a decade.48 Waxman and Hatch used the study to offer a compromise. Generics would only have to demonstrate to the FDA that they were the bioequivalent of the brand-name drug, meaning their copies offered the same strength, concentration, release pattern, and purity. They no longer would have to demonstrate efficacy but instead could rely on the studies provided in the original application for the brand they were copying. The Generic Trade Association enthusiastically endorsed the proposal. A lot of major drug companies thought it woefully insufficient.49
To appease the traditional drugmakers, the lawmakers offered extensions for drug patents, up to five years depending on a somewhat abstruse formula. The statute calls it “patent term restoration,” and it can add a maximum of five years to make up for the time in regulatory review and half the period used for clinical trials. (In 1997, the FDA initiated a rule that allowed a six-month extension to any patent on which the drug company tested its product for pediatric use; two hundred companies have gotten that credit.)
Over a series of rancorous board meetings, the thirty-five directors of the Pharmaceutical Manufacturers Association debated an issue they knew was fundamental to the industry’s future. The winning argument was that there was a real risk that Congress might pass the legislation even if the industry group presented a unified opposition. The groundswell of public support, combined with the lobbying by many “rare disease” patient groups, had brought the generics bill close to cracking the bipartisan support levels it needed to pass. If the drug industry was seen as only obstructive, protecting its own interests rather than focusing on what was best for patients, it might result in an even more punishing bill.
The vote by the drug reps was 22–12 in favor of the Hatch-Waxman compromise. Those voting against it included some of pharma’s biggest names, including Hoffmann-La Roche, Merck, Schering-Plough, Johnson & Johnson, Squibb, Ciba-Geigy, Bristol-Myers, A. H. Robins, American Cyanamid, and American Home Products.50 They were not standing on principle for the industry but focused on the impact the proposed law would have on their bottom lines. Ayerst Laboratories, a division of American Home Products, had a $300-million-a-year heart drug, Inderal, that was set to come off patent at the end of 1984. Roche’s patent on Valium, still selling more than $250 million annually, was set to expire in 1985 (Roche offset the impact of losing Valium’s patent by making a deal with Britain’s Glaxo to help market the ulcer treatment Zantac. It became the world’s biggest-selling drug.)51 More than half of the country’s top fifty selling drugs were set to come off patent in the coming decade.52
Upjohn thought that discounting a hit drug might scare away generic competitors. Its Motrin (ibuprofen) was the world’s top selling nonaspirin and nonsteroidal anti-inflammatory and was scheduled to come off patent the following spring.V Motrin was responsible for ten percent of Upjohn’s $2 billion in annual revenue and 40 percent of its profits. In July, Upjohn tried preempting any discounters by cutting its wholesale price for Motrin by 35 percent. The results were not good. In the short term, the stock market pummeled Upjohn’s shares.53
A last-ditch lobbying effort by those opposed to the law failed. In September 1984, Congress passed comprehensive legislation that “created the modern US generic drug industry.” That law, The Drug Price Competition and Patent Term Restoration Act, was informally known as the Hatch-Waxman Act.54 The companies that had opposed the statute watched to see if the maneuvering by Upjohn in decreasing the price of Motrin, and directing its sales force to redouble its efforts to have pharmacies keep it as their first nonsteroidal anti-inflammatory drug, paid off. It did not. Rivals were prepared. The FDA had increased its Generic Division from thirty-two to fifty-four employees. It quickly approved several lower-strength over-the-counter versions. The shelves at local drugstores were soon stocked with Advil from American Home Products, Nuprin by Bristol-Myers, Thompson’s Ibuprin, and Johnson & Johnson’s Medipren. Motrin’s sales plummeted 40 percent.
As for Inderal, Ayerst Labs’ hypertension drug, within a year of it coming off patent in 1984, twenty generic versions had FDA approval. Some sold at half of Inderal’s list price. Ayerst waged an aggressive multipronged campaign against the FDA-licensed copiers. It concentrated on doctors, since polls indicated that 80 percent thought that generics would fall short on delivering the same quality and efficacy as the brand-name medication.55
Ayerst paid for a dozen academic researchers to write articles for medical journals emphasizing the potential health risks of generics (only one disclosed Ayerst’s backing). The company also sponsored a study in JAMA that picked a few outlying examples to conclude that the cost savings were negligible. It sent out “Dear Pharmacist” letters warning that if there were any quality problems with the copies of Inderal, druggists might be responsible for lawsuits by patients who had heart attacks as a result of switching medications.56 And it offered free airline tickets anywhere in the U.S. for physicians who switched full-time to prescribing only Inderal Long-Acting, a less popular extended release formula on which it still had a patent for another two years. Finally, Ayerst disseminated information that the FDA standards under Waxman-Hatch only required that the statistical variation between the efficacy of the brand-name drug and the generic be no more than 30 percent. Was it worth possibly saving a few dollars on a prescription to run the risk that the bargain medication could be close to one-third less effective? (The FDA tightened its standard to a 20 percent deviation in early 1987, although in practice the variation is often closer to 5 percent.)57
Despite Ayerst’s campaign, in the two years following its patent expiration, Inderal sales were slashed by a third.58
The Waxman-Hatch Act had made generic manufacturers a force. The failure of Ayerst and other traditional companies to defend their off-patent best-selling brand drugs was evident in the industry’s sales numbers. Before Waxman-Hatch, generics accounted for $1.5 billion of the $21 billion in annual drug sales. Two years after the legislation, generics had more than tripled to $5.1 billion, capturing 23 percent of the market.59 That success was despite the lobbying efforts of the Pharmaceutical Manufacturers Association to enlist allies to raise questions about their safety and efficacy.60
Arthur Sackler thought Hatch-Waxman was a terrible development. Of course he had a personal stake in the outcome, since his McAdams advertising agency made its money from hundreds of millions spent on promotional campaigns for brand-name drugs, and generic manufacturers then did little advertising. Sackler tried to help his Big Pharma clients by publishing a series of articles in several of his most widely circulated medical journals, all passing along some supposedly terrible incidents about generics. One that received wide attention was “Schizophrenics ‘Wild’ on Weak Generic.” It ran in the September 25, 1985, edition of Medical Tribune, distributed free to the nation’s physicians. According to the article, when the psychiatric intensive care unit of the Charlie Norwood Veterans Administration hospital in Athens, Georgia, switched from the brand-name tranquilizer Thorazine to a generic, “11 previously stabilized patients ran amok and needed increased dosages until the hospital went back to Thorazine” a month later.61 At that point, the patients returned to their previous calm states “as if a switch had been flipped.”
When the FDA investigated, it discovered that half the patients had not received either tranquilizer. The other half did exhibit some behavioral problems, but not nearly as dramatic as the retelling in Medical Tribune. Moreover, those patients were on the generic for six months before there were any adverse indications, not the one month “as if a switch had been flipped” in the version Sackler published.
In that sensational article, the only person quoted about what supposedly had happened at the VA was the clinic’s chief psychiatrist, Dr. Richard Borison. The FDA concluded in its probe that Borison had acted in good faith but the study lacked “the rigor of a truly scientific investigation.” No one at the FDA put together that Borison and Arthur Sackler had long had professional ties. Not even Sackler could have imagined that a decade later a Georgia grand jury would issue a 172-count indictment against Borison and a colleague for having “developed and executed a scheme through which they systematically stole in excess of $10 million” and that they “routinely lied to conceal their crimes and endangered the safety of the patients and study participants they were employed to serve, protect and heal.”62 A CBS 48 Hours report said the pair had “turned human drug trials into their personal money machine.” One of the biggest scams, according to the indictment, involved AstraZeneca’s antipsychotic Seroquel. They certified it as an effective pharmaceutical fix for post-traumatic stress disorder, although their clinical studies had demonstrated nothing of the kind.63 Borison was ultimately convicted, sentenced to fifteen years in prison, fined $4.2 million, and stripped of his medical license.64
Long before Borison was brought to justice, Sackler cut back on publishing the “generics are dangerous” stories. It was tilting at windmills, he told a colleague. “Generics are here to stay.” (Today they account for 80 percent of all prescription drugs dispensed.)65
I. The United States was the last country that used the FTI (first to invent) standard for a patent. It was measured usually when the inventor filed a patent/trademark or copyright or sometimes by other evidence of when the invention was created. It did not matter if someone else filed for the patent. So long as an inventor could demonstrate they had the idea first, they would get the patent rights. In 2011, President Obama signed the America Invents Act, which converted the U.S. to the international standard of FTF (first to file). For patents filed prior to June 8, 1995, the term of the patent is twenty years from the first filing date or seventeen years from the issue date, whichever is longer. There are also different patent periods for biologics (twelve years) and small molecule drugs (usually pills with a simple organic composition, five to seven years).
II. Rogaine’s sales never lived up to the pre-release expectations; widespread media stories had touted it as a cure for baldness but its sales disappointed Upjohn after patients reported the results were slow and less dramatic. It was responsible only for $11 million of Upjohn’s $776 million in revenues in the first six months it was on the market. Viagra, on the other hand, was an instant hit. On the first day of sales, March 27, 1998, pharmacists ran out of stock across the nation. Rivals called it the “Pfizer Riser.” It went on to become a $2 billion drug for Pfizer over a decade and created a new drug category. Eli Lilly’s erectile dysfunction drug, Cialis, shot right to the top after its 2003 release.
III. Dr. Alan Scott, the ophthalmologist, had been searching for a cure for crossed eyes. He noticed that injections of the drug near the eyes of experiment monkeys had a side effect: it reduced forehead wrinkles. Decades later Scott told a reporter, “I really wasn’t tuned into the practical, and valuable, aspect of that.… I was a pretty good doctor and not a bad lab worker, but I was not a great businessperson.”
IV. What did help beginning in 1992 was that drug companies agreed to pay the FDA special fees for “Accelerated Approval” or “Priority Review.”
V. Motrin holds the title as the biggest-selling nonnarcotic prescription painkiller brand name in pharma history. More than half its sales were in the decade before the FDA approved an over-the-counter version at a lower strength.