Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (43 page)

• The psychiatrist Roland Kuhn presented his findings on a new tricyclic antidepressant (imipramine) at the Second International Congress of Psychiatry in Zurich in September 1957 to an audience of barely a dozen people.

• Robert Noble found himself presenting his findings on vinca alkaloids as cancer chemotherapy at
midnight before a small cluster of scientists at a meeting of the New York Academy of Sciences in 1958.

• Australian Barry Marshall, rebuffed by gastroenterologists, sought an infectious disease conference in Brussels in 1983 to present his observations on bacterial association with stomach ulcers.

Nevertheless, each of these discoveries eventually transformed the world.

The same flawed peer review process also controls what is deemed worthy of publication in scientific journals. In a similar vein, there are some striking examples of prestigious journals rejecting for publication core papers outlining the results of groundbreaking studies:
⁸

• Rosalyn Yalow was so bitter over her letter of rejection from a prestigious American journal regarding her path-breaking original submission, which would lead to radioimmunoassay, that she even reproduced it in her 1977 Nobel Prize lecture twenty-two years later.
⁹

• Paul Lauterbur's landmark report in
Nature,
the leading British scientific journal, establishing a new principle of magnetic resonance image (MRI) formation was initially rejected. Lauterbur rewrote it, including a general statement that “these techniques should find many useful applications in studies of the internal structures,” surely one of the great understatements in the scientific literature. After a few further revisions were required, it was finally published.
¹⁰

• Barry Marshall persisted for ten years against long-held dogma regarding the causation of peptic ulcer disease before his revolutionary concepts were widely accepted. A report first submitted by him to the
New England Journal of Medicine
was rejected and then published in the
Lancet.

• Judah Folkman has persevered for more than forty years in delineating the role of angiogenesis in tumor growth and spread, finding difficulty in the early years in having his work published.

Hungarian Humor

Arbiters of the scientific literature demand declarative sentences of no uncertainty or ambiguity. A case in point is the experience of Albert Szent-Györgyi, a Hungarian biochemist working at Cambridge University in England. In 1928 he extracted a compound from a cow's adrenal gland, not yet recognizing it as vitamin C. Thinking he had isolated a new sugarlike hormone, he named it “ignose,” the suffix
-ose
being used by chemists for sugars or carbohydrates (like gluc
ose
and fruct
ose
) and the
igno-
part indicating he was ignorant of the substance's structure. The editor of the
Biochemical Journal
did not share his humor and rejected the submitted manuscript. When Szent-Györgyi's second suggestion for a name, “Godnose,” was similarly rejected, he settled upon the name hexuronic acid, based upon the known six carbon atoms in the formula. He subsequently identified it as ascorbic acid, or vitamin C, for which he was awarded the Nobel Prize in 1937.

Peers are, almost by definition, part of the established order and typically mired in traditional thinking. They are also human beings with their own agendas and priorities. What it comes down to is this: Who on a review committee is the peer of a maverick?
¹¹

T
HE
D
RUG
P
USHERS

The dearth of scientific innovation is systemic, and government grants and peer reviews are not the only culprits. The other major offender is
the pharmaceutical-industrial complex, a behemoth that has become more of a marketing machine than a fountainhead of research and development. Since the mid-1980s, the industry has shown a striking decline in innovation and productivity, even while its profits have soared. The number of new drugs approved by the Food and Drug Administration (FDA) fell especially sharply in the ten-year period from 1996 to 2005, from 53 in 1996 to only 20 in 2005, despite record-high research spending by the industry, averaging more than $38 billion a year during that time.

Why did the industry have so few major breakthroughs in such a free-spending period? Because it has progressively shifted the core of its business away from the unpredictable and increasingly expensive task of creating drugs and toward the steadier business of marketing them. Most drug makers now spend twice as much marketing medicines as they do researching them. They compensate for dramatically diminished productivity and loss of patent protection by raising prices, maneuvering to extend patents, engaging in direct-to-consumer advertising, and developing and marketing more and more “me-too” and lifestyle drugs that do not enhance health and longevity. Hope has been largely replaced by hype.

Since the FDA lifted limits on direct-to-consumer (DTC) advertising of drugs in 1997, this form of marketing grew into a $4.2 billion business. (Only one other country, New Zealand—with a population of less than 4 million—allows such advertising.) The ensuing onslaught of ads, mostly on television, that urged you to “ask your doctor about” the drug being advertised was so effective that patients began demanding prescriptions from their doctors, who often obliged even if the new drugs were considerably more expensive and no better than existing drugs.
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Indeed, this compliance on the part of doctors is part of the problem. The average number of prescriptions they wrote for each American rose from seven in 1993 to twelve in 2004.
¹³
American doctors wrote some 3 billion prescriptions in 2005. In the same year, prescription drug sales soared to about $250 billion in the U.S. and an astronomical $500 billion worldwide. In a typical year, the fifty most heavily advertised drugs account for nearly half the increase in spending on
prescription drugs.
¹⁴
(In their better moments, most doctors express feelings of discomfort about their acquiescence. A 1997 survey reported that more than 80 percent of physicians had negative feelings about drug advertising to the consumer.
¹⁵
And at the American Medical Association meeting in June 2005, six separate resolutions were introduced advocating for limitations or outright bans on DTC marketing of prescription drugs.)

In an even more insidious practice that is part and parcel of consumer-oriented advertising, pharmaceutical companies are widening the very definition of “illness” to create new markets for drugs. As documented in the book
Selling Sickness,
old conditions are expanded, new ones are created, common complaints are labeled “medical conditions,” and people's “unmet needs” are taken advantage of as markets for medications to grow ever larger.
¹⁶
Under such a system, premenstrual syndrome (PMS) became a psychiatric illness with the imposing name of premenstrual dysphoric disorder (PMDD), and for the very bad moods some women suffer before their periods, Eli Lilly repackaged its aging antidepressant Prozac in a lavender pill dubbed Sarafem. Hyperactive children all have attention deficit disorder (ADD), and there are now maladies called female sexual dysfunction (FSD) and social anxiety disorder (Glaxo advertised its antidepressant Paxil for this newly noted “disorder”). By 2006, nearly 4 million people—adults and children—were taking drugs to treat attention deficit disorder and hyperactivity.

Perhaps the biggest reason the pharmaceutical industry is so profitable and yet so unproductive is its current obsession with “metoo” drugs, the insider term for variants of existing drugs that contain virtually the same ingredients as previously approved ones. Instead of looking for truly innovative medicines to succeed those slated to lose patent protection, the industry focuses most of its research efforts on developing and producing drugs that are either minor variations or outright duplicates of drugs already on the market. Of the ten top-selling drugs in the world, half offer almost no benefit over drugs marketed previously.
¹⁷

An especially egregious example is Nexium, the “purple pill” for heartburn that was the nation's most widely advertised prescription
drug in 2006. When British company AstraZeneca's patent on Prilosec, a blockbuster prescription drug for heartburn that reached astronomical sales of $6 billion in 2000, was due to expire in 2001, the company simply extracted the active half of its molecule, which the Patent Office then recognized as a separate invention called Nexium. In clinical trials, it had a 90 percent healing rate in erosive esophagitis compared to Prilosec's 87 percent. Approved by the FDA, it became one of the best-selling drugs in America, retailing for more than $5 a pill. The company continued to market Prilosec over the counter for a fraction of the cost, a maneuver that knocked out the usage of its generic drug, omeprazole.
¹⁸
Furthermore, the industry continues to launch an increasing number of “lifestyle” drugs—such as the trinity of impotence relievers Viagra, Levitra, and Cialis; Pfizer's and Merck's baldness remedies; and Bristol-Myers's drug to eliminate women's facial hair—whose sales largely depend on inducing consumers to ask doctors for them. These are indicative of the fact that the drug companies are motivated purely by profit and not by any desire to find cures for serious illnesses for their own sake. Relatively rare diseases, for example, with a small potential market are not on their accountants’ agenda. The story of the drug Gleevec is a case in point. Academic research uncovered a localized genetic flaw underlying a rare fatal type of leukemia called chronic myeloid leukemia. Novartis had patented the molecule that inactivated the gene's enzyme, but the company showed little interest in committing resources to the drug's development, even after Brian Druker, an NIH-funded university researcher, showed its usefulness. As Jerry Avorn tells it in his book
Powerful Medicines,
“cancer researchers had to resort to the bizarre tactic of sending a petition to the company's CEO, signed by scientists in the Leukemia and Lymphoma Society of America, imploring him to make more of the drug available for clinical studies.” The FDA approved the drug within two years.
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Novartis now not only charges $27,000 for a year's supply of Gleevec, it also uses it as the poster child for drug company innovation.

To take other examples, even after genetic fingerprinting by the Human Genome Project and Craig Venter's privately funded gene research of diseases such as sickle cell anemia, cystic fibrosis, and Huntington's
disease, little progress toward curing or treating the diseases resulted. Researchers and Big Pharma generally disregard “niche” diseases, those affecting so few people that a breakthrough treatment would not lead to glory or profit.

In one major instance, it was the very pursuit of a cure for a rare disease that led to a conceptual breakthrough that eventually brought both glory and profit. Michael Brown and Joseph Goldstein's discovery of the mechanism of cholesterol metabolism through their study of the rare inherited disease known as familial hypercholesterolemia led to the widespread use of statins for the treatment of high cholesterol.

One oft-quoted estimate is that the industry as a whole invests up to 40 percent of its revenue in promotional efforts. Without a doubt, it spends far more on salesmen than on scientists. An army of more than 90,000 pharmaceutical sales representatives (“detailmen” and “drug reps”) in the United States costs well over $7.5 billion a year. And, unfortunately, neither doctors nor patients have the time, knowledge, or inclination to pay close attention to the scientific sophistry behind many of the new drugs coming on the market.

Hair Today, Gone Tomorrow

In 1980 a Pennsylvania physician was treating a bald man for high blood pressure with the oral drug minoxidil. The doctor was surprised to note new follicles growing on the patient's scalp, and this hair-raising experience soon led to a commercial product. Approved by the FDA for men in 1988 and for women in 1991, it is now sold over the counter in the form of a lotion called Rogaine. It is believed to work by inducing dilation of scalp blood vessels. Balding American men spent $96 million on Rogaine in 2005.

Two other drugs related to remedying the problems of either not enough or too much hair were also discovered unexpectedly. Propecia was originally approved to treat benign prostatic hyper-plasia, an enlargement of the prostate gland, by blocking a testosterone. This hormone has long been known to be associated with
baldness. A drug in pill form was approved in 1997 only for men because it may cause birth defects in women of childbearing age.

The drug eflornithine, which in 1979 was found useful in treating African sleeping sickness, was later discovered to suppress the enzyme that causes facial hair to grow. It is now marketed as a cream, Vaniqa, for the removal of unwanted facial hair.

The first step in modern drug development is identifying the molecule a drug could potentially attach itself to, called the target. The raw statistics are daunting. For every 5,000 compounds the industry screens as potential new medicines, 250 promising ones make it to the next stage: testing in animals. This stage of discovery and preclinical research typically takes six to seven years. Of the 250, five compounds survive to be tested in people in clinical trials. Phase I, investigating the drug's safety on 20 to 100 volunteers, may take one and a half years. Phase II, testing efficacy and side effects in 100 to 500 patients who are candidates for the drug, may take up to two years. Phase III, confirming the drug's usefulness and studying its long-term toxicity in 1,000 to 5,000 patients, generally requires another three to four years. Then, over perhaps a year and a half, the FDA reviews the evidence and decides if the drug is safe and effective enough to approve. At the end of the pipeline, only one out of the five drugs that went into clinical trials eventually emerges as approved for sale.