Miracle Cure

by William Rosen

  What the story of chloramphenicol’s rise and ultimate decline (at least as an antibiotic prescribed millions of times annually) revealed was that safety couldn’t be measured in a vacuum. Evaluating the danger of any new therapy demanded context—its efficacy, as balanced against its risks. The only candidate to do this was the FDA, but the Food, Drug, and Cosmetic Act only empowered the agency to measure safety, not effectiveness.

  That was about to change.

  NINE

  “Disturbing Proportions”

  The inaugural issue of the Saturday Review of Literature arrived on newsstands in August 1924, and for the next eighteen years the magazine was edited by Henry Seidel Canby, a professor at Yale University. Canby assembled an impressive group of literary critics to produce the weekly magazine, including the essayist and novelist Christopher Morley, and Mark Twain’s biographer Bernard DeVoto. But the Saturday Review is best remembered today as the brainchild of Norman Cousins, who took over as editor in 1942. The Cousins era, which lasted until his departure in 1971, represented the magazine’s high-water mark in circulation and influence, when it was the voice most attended to by America’s midcentury, middlebrow households.

  Cousins regularly urged his staff to remember, “There is a need for writers who can restore to writing its powerful tradition of leadership in crisis,” and to that end, he and the magazine tirelessly advocated for the entire catalog of largely unreachable liberal objectives, from world government to nuclear disarmament. For actual impact on current events, though, the Saturday Review never exhibited a more significant bit of leadership-in-crisis writing than in a series that began in its January 3, 1959, issue.

  The cover featured a photograph of Arthur Schlesinger, Jr., whose latest book, The Coming of the New Deal, was reviewed. The lead article, written by the magazine’s science editor, John Lear, was “Taking the Miracle Out of Miracle Drugs.” Its first line read, “Prescription of antibiotics without a specific cause for such treatment has reached disturbing proportions.”

  The causes of that disturbance, as enumerated by one of Lear’s interviewees, Dr. Henry Kempe, head of pediatrics at the University of Colorado Medical School, were several. First was that reflexive prescription of antibiotics often hid the real disease from diagnosticians; during the ten days required for most antibiotic treatments, the patient would frequently grow worse, as the true cause of disease went unaddressed. Second, despite the generally well-tolerated character of most antibiotics, when millions of people are given them every day, thousands will exhibit symptoms of antibiotic poisoning—everything from vomiting to skin rashes. Third, antibiotics, as antagonists to all sorts of bacteria, often caused gastrointestinal upset by killing the “good” bacteria residing in the digestive tract.

  But the biggest problem with the miracle drugs was that prescribing them for everything from head colds to migraines was breeding antibiotic resistance. Lear, writing that antibiotic-resistant strains of pathogens had been “known to medicine for almost five years,” actually understated the case significantly. Alexander Fleming, in his 1945 Nobel Prize Lecture, had warned, “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them,” and it wasn’t exactly a newsworthy observation even then. Between 1954 and 1958, as Lear documented, hospitals in the United States had experienced five hundred outbreaks of diseases caused by antibiotic-resistant pathogens—outbreaks that spread fast enough that they met the formal definition of local epidemics: disease episodes in which the daily number of new infections exceeds the number of cases resolved (though, being local, such epidemics were typically not the stuff of newspaper headlines).

  The real point of interest, to Lear, was why the epidemics were appearing at all. Since physicians knew (or should have known) that antibiotics were next to useless against viruses, why did they persist in prescribing them for viral diseases? Although it’s possible that some physicians knew that most antibiotic activity occurred by disrupting the bacterial cell walls—walls that viruses, which are essentially free-floating bits of DNA, neither have nor need—did they fail to realize that this made viral disease essentially invulnerable to antibiotic treatment? Though doctors had been overshooting the mark on treating patients for decades—Oliver Wendell Holmes, in the same speech in which he recommended consigning the whole materia medica to the seafloor, recognized that “part of the blame of over-medication must, I fear, rest with the profession, for yielding to the tendency to self-delusion which seems inseparable from the practice of the art of healing”—Lear thought the answer was more obvious, and scandalous: advertising. “Established ethical drug companies, traditionally cautious in advancing claims for their medicines, are being jostled and jolted competitively in antibiotic sales by the Madison Avenue ‘hard sell’ of bulk chemical makers. . . .”

  Lear wasn’t lacking for specifics. In a section of the article entitled “The Case of the Invisible Physicians,” he described a brochure produced by Pfizer, intended for doctors, promoting “the antibiotic formulation with the greatest potential value and the least probable risk . . . Sigmamycin . . . the antibiotic therapy of choice.” The promotional piece featured photos of eight business cards, each with the name of a physician. One was from Massachusetts, another from Oregon. The others—including a dermatologist, a urologist, and a pediatrician, in case the message about Sigmamycin’s wide range of effectiveness wasn’t getting through—practiced in Florida, Arizona, California, Illinois, Pennsylvania, and New York, where each one was an enthusiastic endorser of the drug.

  Since the business cards included addresses and phone numbers, Lear tried to contact them. What he found were nonworking phone numbers and addresses from which his letters had been returned, either marked address, or addressee, unknown. The doctors and their testimonials were purest fiction, the “Madison Avenue ‘hard sell’” invention of a creative copywriter in the William Douglas McAdams agency.

  Lear’s piece generated a huge number of letters to the Saturday Review, both admiring—“the most factual and intelligent article written on the subject to date”—and critical: “I don’t know a single physician who pays the slightest attention to drug ads.” Pfizer’s president, John McKeen, visited the magazine’s editorial offices, where he admitted that the brochure could have been misleading, and that the company had initiated procedures to prevent a recurrence. But the first article had been only a ranging shot. Lear’s second would be dead on target. “The Certification of Antibiotics” was the cover story of Saturday Review’s February 7 issue (in what was surely a coincidence, it appeared just underneath an article by Adlai Stevenson entitled “Politics and Morality”). Its subject was the same senior official in the Food and Drug Administration who had been visited by Albe Watkins in 1952, a bacteriologist named Henry Welch.

  Welch had joined the FDA in 1938, as part of the agency’s expansion after the passage of the Food, Drug, and Cosmetic Act, and had risen through the ranks fairly quickly. In 1943, he was named to direct the Division of Penicillin Control and Immunology, and in 1951 was appointed director of the Division of Antibiotics, where he was responsible for the approval of new drugs.

  At almost precisely the same time Welch took on his new responsibilities at the FDA, he was introduced to a Spanish psychiatrist named Félix Martí-Ibáñez. Martí-Ibáñez had been his country’s undersecretary of health and social service until 1939, when the nationalist victory in the Spanish civil war forced him to find other employment. He spent the 1940s working in the United States for a number of pharmaceutical companies, including Hoffmann-La Roche (where he served as medical advisor for international sales), Winthrop, and Squibb. The émigré psychiatrist therefore had a ringside seat for the antibiotic revolution, which he correctly viewed as a huge opportunity: not for creating research, but retailing it. The discovery of antibiotic therapy wasn’t just transforming the practice of medicine, but also the practice
of medical communication. An unprecedented explosion in useful therapeutic knowledge—it’s worth remembering that penicillin, streptomycin, the various versions of tetracycline, chloramphenicol, and erythromycin had all been introduced between 1941 and 1948—was occurring at a rate that made existing channels far too slow. An organization that could promise rapid diffusion to the largest number of clinicians in the shortest amount of time would be supplying something of enormous value.

  From the late 1950s on, most academic physicians regarded Martí-Ibáñez as a bit of a huckster, and his reputation hasn’t improved very much since. One thing he can’t be accused of, however, is hypocrisy. The Spanish psychiatrist made it clear in speeches and articles that the ideal source for financing the organization and diffusion of therapeutic knowledge was the pharmaceutical firms themselves. “Who better than the pharmaceutical industry,” he wrote, “could organize, coordinate, and integrate on an international scale the vast and increasing knowledge on antibiotics?”

  Martí-Ibáñez had a business plan. In 1951, he put it into action. He and Welch joined forces to found a new journal, entitled Antibiotics and Chemotherapy, with an editorial board that included a who’s who of antibiotic research, including Florey, Waksman, and Alexander Fleming. Martí-Ibáñez, as president of MD Publications, would run the business side; Welch would be the editor.

  Antibiotics and Chemotherapy was an immediate success with medical researchers, but its content was virtually all bench science, which limited its appeal. To serve the much larger audience interested in the clinical application of the new drugs, in 1955 Welch and Martí-Ibáñez launched another journal, which they named Antibiotic Medicine, changing the title a year later to Antibiotic Medicine and Clinical Therapy. The new journal was circulated free to physicians and other health professionals, as Martí-Ibáñez and Welch reasoned that delivering to that particular audience would make the publication an attractive place for pharmaceutical company advertising. It seems not to have occurred to anyone at the FDA that allowing their antibiotic division’s director to work for a for-profit journal supported entirely by the same pharmaceutical companies whose applications he was responsible for endorsing or rejecting was the very definition of a conflict of interest.

  For John Lear, alarm bells sounded. When he interviewed Welch for his February 1959 article and asked him to confirm or deny the rumor that he derived substantial income from the journals, Welch replied, “Where my income comes from is my own business [but] I have no financial interest in MD Publications. . . . My only connection is as editor, for which I receive an honorarium.”

  It would be some months before the size of that honorarium was fully understood. Antibiotic Medicine and Clinical Therapy paid Henry Welch 7.5 percent of all advertising revenue, and 50 percent of all sales of article reprints. In the four years between the journal’s introduction and John Lear’s exposé in Saturday Review, the two “honoraria” had paid Henry Welch nearly $250,000, about $2.24 million today. Welch, it was later learned, had told a number of colleagues that his FDA salary—$17,500 a year—was barely enough to pay his income tax. They thought he was kidding.

  There is little evidence that Welch was, in the classic sense, corrupted by this. But whether or not he agreed to approve antibiotics produced by journal advertisers, pharmaceutical companies adopted a grateful, and generous, attitude toward MD Publications generally, and Welch personally. Parke-Davis, to mention only a single example, wrote a check for $100,000 for prepaid advertising in Antibiotic Medicine and Clinical Therapy during its first year of publication. When the journal folded in 1961, it still had $38,000 of Parke-Davis’s money, which the company graciously agreed to write off as a goodwill gesture. Half of the money still in the cash register, $19,000, was paid directly to Henry Welch.

  Between 1955 and 1960, Pfizer paid $171,000 for reprints, earning Henry Welch more than $85,000. Even more incriminating: Lear discovered letters to Pfizer’s director of advertising in which Welch and Martí-Ibáñez pleaded with him to continue supporting Antibiotics and Chemotherapy. The money quote included the following: “The February issue of this publication will include an editorial by Dr. Welch reappraising the use of Nystatin [an antifungal drug derived from yet another of the fecund Streptomyces, which Bristol-Myers Squibb was promoting heavily] in conjunction with broad-spectrum antibiotics. This paper will furnish your people with excellent ammunition with which to counteract the exaggerated claims made for Nystatin” [emphasis added]. The quid pro quo—Antibiotics and Chemotherapy was about to criticize Nystatin in print; Nystatin’s competitor could pay to share that seemingly disinterested criticism with its sales force, and through them with America’s physicians—was implied, but clear.

  It was an era that was no stranger to outrage over disgraceful behavior, as both the “payola scheme,” in which record companies paid disc jockeys for airplay, and the TV quiz show scandals were huge stories in 1959. Henry Welch was, to most people, small potatoes. But that didn’t mean no one noticed. As a direct result of John Lear’s articles, Congressman Emanuel Celler of New York insisted that Welch should be fired, and soon enough, Dr. Arthur Flemming, the secretary of the Department of Health, Education, and Welfare, demanded his resignation. Welch, who had already applied for disability retirement (and who had a very comfortable retirement, funded by his publishing empire, to look forward to), complied.

  To this day, Henry Welch, even more than Félix Martí-Ibáñez, remains a poster boy for the dangers of corruption by pharmaceutical companies, so much so that Web sites with a conspiratorial tinge continue to invoke him as the original “shill for big pharma.” They have a point, but they miss the far more significant aspect of Welch’s importance to pharmaceutical development in the late 1950s.

  Welch and Martí-Ibáñez sincerely believed in the broadest possible use of antibiotics, often in combination not just with other antibiotics, but with vitamins—in a typical example, Pfizer created a compound consisting of Terramycin and “stress formula” vitamins—to both treat and prevent infectious diseases. More to the point, Pfizer had researched, developed, and manufactured Sigmamycin, the combination of 167 milligrams of tetracycline and 83 milligrams of oleandomycin (a close relative of erythromycin) that had been endorsed by the eight nonexistent doctors John Lear had exposed in his January article.

  By the mid-1950s, all of the most popular antibiotic therapies were “fixed-dose combination drugs”—mixed cocktails of erythromycin and penicillin, for example. The idea behind them was, on the surface, plausible enough, a long-standing belief in the synergistic combination of two therapies. As far back as 1913, Paul Ehrlich himself had recommended “a simultaneous and varied attack . . . directed at the parasites, in accordance with the military maxim, march in detachments, fight as a unit.” Forty-five years later, pharmaceutical companies had taken Ehrlich’s “if some is good, more must be better” recommendation to heart, and were producing no fewer than sixty-one fixed-dose combination antibiotics. Four of them contained five antibiotics apiece, eight had four, twenty used three, and “only” twenty-nine were humble enough to combine a mere two. When the drugs in combination were truly synergistic, this therapy worked fine. Sometimes, as with PAS and streptomycin, they were. And sometimes they weren’t. Two or more antibiotics could be antagonistic, as was already known to be the case with penicillin and Aureomycin.

  Synergistic or not, fixed-dose combinations remained attractive to pharmaceutical companies. Working in a marketplace in which every competitor could sell generic versions of tetracycline or penicillin, even the most innovative firms saw the advantage in differentiating their branded products one from the other. And if they hadn’t yet figured it out on their own, Félix Martí-Ibáñez had been eager to educate them. In 1956, he wrote:

  [I]t is particularly important to seek specialties which combine antibiotics with other drugs. Such combinations, if they can be justified medically, are a defense against the current price tre
nd in penicillin and streptomycin. The broad spectrum antibiotics [i.e., the tetracyclines and chloramphenicol] may eventually suffer the same fate. This is the time, therefore, to seek products combining such drugs as Terramycin and Aureomycin with other useful therapeutic agents. . . .

  The recipient of the letter wasn’t a clinician or researcher. It was Martí-Ibáñez’s good friend and fellow psychiatrist, the advertising mastermind at William Douglas McAdams, Arthur Sackler.

  The challenge with fixed-dose combination antibiotics, however, was that while it was easy enough for an advertising copywriter to invent a catchy name and package for them, it was very hard indeed to convince physicians and hospitals that a particular fixed-dose combination wasn’t just different, but better. The rigor of well-designed randomized clinical trials made measuring the relative merits of each component of a two-part fixed-dose combination extremely uncertain. With three or more, it was virtually impossible. Further, unless the pathogen involved—and not just the bacterial species, but its biovar, or strain—was identified precisely, the fixed-dose combinations were as likely to harm as heal.

  Fixed-dose combination therapies were also a challenge to evaluate effectively using the double-blind randomized clinical trials pioneered by Bradford Hill. In what seems an almost willful return to the preantibiotic era, fixed-dose combinations could only be trumpeted using case studies and, especially, testimonials.

  Enter Henry Welch and Félix Martí-Ibáñez. In journal editorials and in speeches at the annual symposia on antibiotics that they hosted throughout the 1950s, they announced that the world had entered a “third era of antibiotic therapy” . . . (the first had been the narrow-spectrum antibiotics like penicillin; the second the broad-spectrum drugs like tetracycline). And if the only way to usher in the “third era”—neither of the two medical publishing innovators felt it necessary to note that the phrase had been provided by one of Arthur Sackler’s copywriters, who had coined it for the launch of Sigmamycin—was by replacing randomized clinical trials with personal experiences, then so much the worse for RCTs.