The Danger Within Us

by Jeanne Lenzer

  But as the decades passed, things began to change for Braunwald, as they did for the entire healthcare system. The new alliance between academia, industry, and venture capitalists had a dual impact on Braunwald’s work. On the one hand, it became far more lucrative. * On the other hand, for the first time in his career, his work began to be plagued by scandal and questionable science. Unlike Braunwald’s earlier research, a number of his contributions during this period would not withstand the test of time.

  As we’ve seen, one of the factors obscuring the truth about medical devices is the increasing scarcity of non-commercial research. In 1977, industry sponsorship of medical research comprised 29 percent of funding. By 2009, that figure had increased to 60 percent, and by 2014, 86 percent of clinical trials were funded by industry.319 As with other features of the medical-industrial complex, this problem has a complicated history that stretches back several decades.

  Back in the 1960s, there was a powerful movement afoot to insulate university-based research from corporate pressures. The unpopularity of the Vietnam War led to massive campus protests against the power of the military-industrial complex. Students and politically engaged citizens, including many academics, demanded that universities distance themselves from doing research for corporate entities. But politicians—themselves often the recipients of funding from the military-industrial complex—fought back fiercely. They not only wanted universities to conduct military research, they also wanted the US to be the global leader in scientific and technological innovation. To do that, they believed that universities had to strengthen their ties to industry.

  In the 1980s, President Ronald Reagan and his science adviser, George Keyworth, threw their weight behind “technology transfer”—the movement of ideas from academia to the marketplace.320 A key tool for promoting technology transfer was the Bayh-Dole Act, which promoted university-industry partnerships by allowing universities and their individual researchers to claim patent rights for their innovations. This opened a new funding stream for academia never before possible. The opportunities for profits were dazzling—and medical science was on the front line.

  The now defunct Office of Technology Assessment (OTA) warned against mingling academic research with commercial interests, saying that doing so could “adversely affect the academic environment of universities by inhibiting free exchange of scientific information, undermining interdepartmental cooperation, creating conflict among peers, or delaying or impeding publication of research results.”320 The OTA also cautioned that important research “with no commercial payoff” (such as public health initiatives and basic science) might be abandoned in favor of research that could deliver profits. These warnings were largely ignored in the rush to support university research with potential commercial value.

  Congress passed the Bayh-Dole Act on December 12, 1980. Support for the act increased on the heels of a Supreme Court decision, Diamond v. Chakrabarty (1980), which ruled that researchers could patent life forms, turning on its head the long-standing assumption that living things could not be covered by patent law. When genetic engineer Ananda Mohan Chakrabarty developed a genetically modified bacterium, the court ruled that he could patent not only the process of developing the bacterium but also the actual bacterium itself. In the words of Sheldon Krimsky, professor of urban and environmental policy and planning at Tufts University:320

  This ruling opened the floodgates for the patenting of cell lines, DNA, genes, animals, and any other living organism that has been sufficiently modified by humans to qualify as “products of manufacture.” With this ruling by the Supreme Court, university scientists who sequenced genes had intellectual property that they could license to a company or that could serve as the catalyst for forming their own company.

  The Chakrabarty ruling electrified academics and cash-strapped universities. The allure of cashing in on their research was irresistible.

  Eugene Braunwald jumped on the Bayh-Dole bandwagon early. As we’ve seen, Braunwald was deeply committed to the value of scientific medical research, and he was undoubtedly excited by the availability of funding from industry to support vast new fields of such research. He was also a true believer in the power of academic and business partnerships to promote medical innovation.

  In 1978, in what may be one of Braunwald’s earliest investigations cosponsored by industry,* Braunwald and his coauthors published the results of a study of eight heart failure patients treated with a new drug, amrinone.321 The study was sponsored jointly by the NIH and Sterling-Winthrop, the manufacturer of amrinone. Braunwald and his colleagues reported that the drug had a “substantial salutary” effect and was well tolerated.

  However, British cardiologist Peter Wilmshurst also studied the drug and found that amrinone not only didn’t improve heart failure but also “frequently caused life-threatening side effects.”322 When he showed Sterling-Winthrop his results, obtained from a study that used four times the number of patients reported by Braunwald, the company pressured him to exclude certain patients from his analysis. Wilmshurst refused. To do so, he said, would suggest “an apparent but spurious” benefit for patients in heart failure. When Wilmshurst refused to change his analysis, the company threatened him with a lawsuit.323

  Wilmshurst didn’t back down, so Sterling-Winthrop took another tack: it ended Wilmshurst’s research on amrinone by removing the drug from the hospital pharmacy and research institute where Wilmshurst conducted his study.324, 325

  Wilmshurst wondered about Braunwald’s glowing review of the drug and looked into the financial interests of Braunwald and his colleagues. He discovered that not only was the study cosponsored by the manufacturer, as had been reported, but of the five authors who were listed as “employed by the Cardiology Department at Harvard Medical School,” two were full-time employees of Sterling-Winthrop and had never worked at Harvard and “[t]wo of the three that worked at Harvard were also paid consultants to the company.”326, 327

  Braunwald was on the editorial board of the New England Journal of Medicine, which published his claims, but when Wilmshurst submitted his own findings to the journal for publication, his paper was refused. Although Braunwald may not have played an active role in the publication decision, reputational power may have. Eventually, although some small, uncontrolled studies reported the benefits of amrinone, subsequent controlled studies found that the drug offered no apparent benefit and was associated with significant harms.328, 329

  Wilmshurst turned over numerous documents to the British newspaper The Guardian chronicling the entire affair, including some documents revealing the ruses used by Sterling-Winthrop to suppress negative outcomes related to amrinone.330, 331 The true profile of amrinone’s safety and efficacy remains distorted to this day.

  Wilmshurst received the HealthWatch annual award for his work on amrinone, and he was praised for his spine and good humor by Richard Smith, former editor of The BMJ.323

  The amrinone affair was the first apparent crack in Braunwald’s credibility. But it was soon followed by other questions about the reliability of his research claims.

  In 1981, John Darsee, a researcher in Braunwald’s lab, confessed to a single instance of data forgery, but later investigations of his more than one hundred publications revealed that over a period of twelve years he had fabricated much of the data used in those publications. Some eighty-two articles and abstracts were eventually retracted.332 Thirty of his papers were published while he was at Harvard working with Braunwald.333 Four of six articles he coauthored with Braunwald had to be retracted.

  Darsee’s coworkers had repeatedly voiced their suspicions to their immediate supervisor, Robert Kloner, who notified Braunwald that Darsee was thought to be fabricating data. Braunwald said he conducted an internal investigation and, other than a single episode in which Darsee admitted to faking dates on a report, found no wrongdoing. However, Braunwald didn’t report the charges to the NIH, which had funded the research.334 Darsee’s coworkers believed he was so favo
red by Braunwald that he was essentially untouchable. It was only when coworkers found discarded data in a trash can that they discovered the hard evidence needed to show that Darsee had indeed made up data.332

  Eventually the NIH was notified and sent investigators to look into the charges against Darsee. They reportedly discovered “a massive fraud”: the data for a number of Darsee’s published experiments did not exist. This was particularly awkward for Harvard and Braunwald because they had maintained up to that point that during their investigations they had reviewed the data fully.335

  Two NIH scientists, Walter W. Stewart and Ned Feder, independently got wind of the scandal and decided to examine it further. They wanted to know whether Darsee’s forty-seven coauthors—including Braunwald—should have realized that Darsee had fabricated data.336 When Stewart and Feder eventually published the results of their investigation, they couched their findings in careful language, but the implications were clear: Braunwald had been incautious at best, and at worst he had turned a blind eye to fraud.

  Braunwald wasn’t about to take the charges lying down. When Stewart and Feder submitted a draft version of their article to Braunwald for his comments, he came out swinging. Bancroft Littlefield Jr., Braunwald’s attorney, told Stewart and Feder that their article was “defamatory” and “libelous” and that he would encourage Braunwald to “take appropriate legal action” if they published the article.

  Braunwald’s threats worked—for a while. As the targets of Braunwald’s wrath, Stewart and Feder were unable to publish their findings for more than three years. Littlefield sent a similarly threatening letter to John Maddox, editor in chief of Nature, indicating that the journal, which initially expressed interest in publishing the article, would also be subject to a potential lawsuit. Nature backed away.337

  At least fifteen journals also turned Stewart and Feder’s paper down—some explicitly citing the threat of lawsuit.336 Eventually, however, in 1987, after more than a three-year delay, Nature went ahead and published the article.338 Still, Braunwald’s formidable influence was apparent: the article was published with a highly unusual disclaimer. A statement from the Nature editors at the end of the article read: “Some editorial changes have been made in this manuscript without the consent of the authors. A reply from Braunwald follows.”338, 339 The publishers appended a lengthy defense by Braunwald in which he said he was “staggered” by the extent of Darsee’s fraud but denied Stewart and Feder’s charge that Darsee’s articles contained “an abundance of errors,” inconsistencies, and “lapses from standards” that should have alerted his coauthors.338 Braunwald dismissed virtually all Stewart and Feder’s findings, saying that “allegations involving the papers from Harvard—all of which were retracted in 1982—are insubstantial or simply wrong and have nothing to do with scientific misconduct.”339

  However, in defending his work with Darsee, Braunwald implicitly admitted to a duplicitous presentation of his research with Darsee and Kloner. The trio claimed to have used computer-generated randomization in a study involving the salvage of heart muscle in dogs, but they mixed in historical data to the control group, undermining the authors’ claim of scientific rigor. Braunwald acknowledged that they did not reveal the use of historical data in the article but defended their actions, saying they did so to spare the “sacrifice of animals” even though some animals were sacrificed.340

  Although he denied wrongdoing, certain damage had been done. Braunwald’s research claims, once considered golden, were thought by some to be misleading or worse.

  Yet many in the world of medicine continued to revere Braunwald, whose research empire was delivering the gold and whose power and influence were spreading around the globe. But the amrinone and Darsee imbroglios were just harbingers of things to come. Although Braunwald conducted industry-sponsored or cosponsored research prior to 1984, in that year he increased his ties to industry by several orders of magnitude when he founded the Thrombolysis in Myocardial Infarction (TIMI) Study Group, which rapidly grew into a multibillion-dollar multinational organization. TIMI studies focused on the use of a clot-buster drug, tPA, which Braunwald studied first as a treatment for blood clots in the lungs, then as a treatment for heart attacks, and subsequently as a treatment for strokes. The drug was the brainchild of Genentech, the world’s first biotech company. Braunwald and Genentech would be intimately connected for many years. And despite the early tussles over his research, this was still the 1980s and not a time for skeptics. The entire world was agog with the marvels of modern medicine and the rise of the newest technology: the biotech industry. It was all so hopeful.

  * * *

  On November 13, 1987, spectators watched fireworks explode on the ground while controllers at the San Francisco International Airport halted overhead air traffic for ten minutes. A perplexed pilot observed, “They don’t close airports unless it’s for God or Air Force One.” But neither God nor Air Force One was arriving at the San Francisco airport that day. The cause for celebration was, incredibly, a drug. As Fortune magazine recounted, the big event was the Food and Drug Administration’s approval of tPA.341 San Francisco, home of Genentech, the biotech company that developed tPA, was set to share in the windfall to come. So it was indeed time for fireworks and celebration. Genentech cofounder and venture capitalist Robert A. Swanson was ecstatic.

  Swanson wasn’t the only one celebrating. Doctors across the nation had already proclaimed the drug as lifesaving—impressed that a figure no less than Eugene Braunwald, the father of modern cardiology, was hailing tPA as “penicillin of the heart”—a discovery as historic as the advent of antibiotics.342 Braunwald would play a significant role in promoting tPA as a treatment for heart attacks over an older, cheaper drug, streptokinase.

  But tPA’s road to FDA approval was not easy. Without Braunwald’s backing, it’s possible the drug would never have made it to market. Braunwald’s cousin Eugene Kleiner was the head of a venture capital firm that invested seed money in Genentech. Braunwald says his cousin played no role in his subsequent involvement with the study of Genentech’s clot buster, but introductions weren’t necessary; Genentech jumped at the opportunity to have the world’s leading cardiologist on its side. It was a relationship that would form the basis for much of Braunwald’s research—and the growth of Braunwald’s TIMI Study Group. Although initial funding for TIMI came from the National Institutes of Health, it quickly attracted funding from big pharma, device manufacturers, and the biotech industry—particularly from Genentech, which produced TIMI’s chief initial drug of study, tPA—though neither Braunwald nor Genentech would reveal the amount of the funding.343

  Braunwald’s partisanship was evident throughout the process of bringing tPA to market. Insider trading rules and clinical-trial ethics rules prohibited Braunwald from telling Genentech (or any outside entity) about the early findings of the TIMI study comparing the clot busters tPA and streptokinase in the treatment of heart attacks. But Genentech was desperate to know; a good deal of money was at stake.

  Elliott Grossbard, Genentech’s director of clinical research, describes how Braunwald and Genentech got around the prohibition.342 Braunwald called Grossbard and asked him to come to Boston. Grossbard flew in and met with Braunwald, who peppered Grossbard with questions about how quickly Genentech could produce more tPA. Grossbard interpreted Braunwald’s queries as a way of telegraphing the preliminary results to him without doing so directly. Grossbard said, “Braunwald basically leaks to me that the difference [between tPA and streptokinase] is pretty overwhelming in terms of opening up the arteries. I was ecstatic.”342 Grossbard knew that tPA had to be performing well in the TIMI trial or there would be no need to ramp up production.

  Braunwald gives a different account of his conversations with Grossbard. He says he simply “needed to understand more about this totally new drug,” adding, “If Grossbard thought I was ‘telegraphing’ anything, he was mistaken…” In fact, says Braunwald, he couldn’t have telegraphed the results
of the study to Grossbard because he didn’t know the results until the trial was stopped early by the board that monitored the study.

  Despite Grossbard’s excitement after his visit with Braunwald, not everything would go smoothly. At one point, the FDA ordered Genentech to stop testing the drug immediately. The agency discovered that the company was using Chinese hamster ovary cells to produce tPA, and fragments of tumor-causing viruses had been discovered in the cell line.

  The timing couldn’t have been worse. Other companies were working on competitor products. If Genentech didn’t manage to win FDA approval before other companies, it could be left out in the cold. Grossbard flew to Washington, DC, to plead his case with the FDA. He told the agency that an NIH trial—the one conducted by Braunwald—was under way. Grossbard said, “Because it was the NIH and it was this big operation, they backed off,” adding, “We had this tremendous gift of being able to dodge bullets.”342

  Genentech was able to keep producing tPA. But the scientific results needed for approval were not forthcoming. The company knew that it was not well positioned going into FDA hearings on May 29, 1987. Streptokinase, an older and far cheaper drug, had been shown to reduce overall deaths by about 20 percent.344 Genentech and TIMI had only conducted tests of tPA’s effect on surrogate markers, such as “time to open vessel,” rather than its effect on mortality.

  However, Genentech and tPA enthusiasts weren’t about to let weak science stand in the way. They somehow managed to persuade Wall Street Journal editors to publish, on the day before the FDA advisory meeting, a commentary insisting that tPA should be approved. One of the FDA officers passed out a copy of the editorial at the advisory meeting, saying drily, “Well, it looks like we don’t have anything else to do.”342