Elizabeth Loder on academic-industry interactions

Elizabeth Loder It was a Boston day so cold that my morning assortment of emails included a message suggesting that hospital employees should be on the lookout for indoor puddles that might indicate frozen, burst water pipes. As I walked across the medical school campus towards the Tosteson Medical Education Center, I did not anticipate that this year’s 69th Annual Soma Weiss Student Research Day at Harvard Medical School (HMS) would be as well attended as it was. Nevertheless, the auditorium was soon respectably full, the audience no doubt drawn in part by the panel discussion that was to precede the four oral presentations and poster discussions of student research.

The staid title of the panel discussion – “Industry Interactions as a component of an academic career” – hinted to those in the know of excitement and controversy. Medical school faculties everywhere have been preoccupied by attempts to define and monitor the interactions of their faculty with pharmaceutical and device companies, and HMS recently has had more than its share of attention-drawing cases of alleged conflicts of interest.

Alas, the excitement was not to be. In his introductory remarks, discussion moderator and HMS Dean Jeffrey Flier moved quickly to lower expectations of a fireworks-filled debate. This, he said, would not be a discussion of the HMS conflict of interest policy, or the propriety of academic-industry partnerships, but rather a chance to hear how five HMS faculty members have combined their academic careers with industry relationships. With that, he invited each of the five panel members to describe their research and interactions with industry.

George Church, PhD, HMS Professor of Genetics, said that most of his funding comes from government grants. Many, he said, actually urge or require industry connections. A National Science Foundation (NSF) grant that he has, for example, stipulates corporate involvement “from year 1” and specifies transition of the project to no NSF funding after 15 years. The Bayh-Dole Act of 1980, he reminded us, encourages patenting and licensing of research findings.

The alternative is trade secrets, which are good for no one. He noted that when technology is developed, it is unlikely it will make it to the marketplace without a company to handle its clinical development and marketing phases. His area of interest has been DNA sequencing and he has worked with a number of companies that have entered the market. The result is that instead of the original single company that sequenced DNA at high cost, there are now about 15 companies and the cost has come down dramatically.

Lewis Cantley, PhD, the William Bosworth Castle Professor of Medicine at HMS, described his work as basic science focused on how cells communicate and respond to growth factor. He has filed some patents over the years and occasionally these have been licensed. He has formed “a few companies” along the way, but does not find conflict of interest a problem. Companies have problems understanding how to use the drugs they develop, and he believes it is helpful for scientists to consult with them on those matters. In his view, an important scientific mission is the application of basic science discoveries, and that is impossible without companies. He is careful to avoid exclusive consulting arrangements. He remarked that Harvard does not allow companies owned by faculty researchers to fund research in their laboratories. Not all institutions are so strict, but he views this restriction as wise. Otherwise, he suggested, it is not difficult to imagine that research beneficial to the faculty member’s company might take precedence over other projects in the laboratory.

Laurie Glimcher, MD, the Irene Heinz Given Professor of Immunology at the Harvard School of Public Health, and Professor of Medicine at HMS, is trained as a physician. Her laboratory, though, does mostly pre-clinical research focused on the identification of regulatory genes involved in rheumatologic and other inflammatory disorders. The majority of her laboratory funding comes from the National Institutes of Health (NIH) or nonprofit foundations. She has, however, served for a decade on the Board of Directors of the pharmaceutical company Bristol-Myers Squibb. She acknowledged the controversy over academics serving on such boards, but said that in the end she decided it was important to have physician-scientist involvement in the board. Her tenure as a board member has been interesting and educational; she has encouraged the company to focus on areas of unmet medical need. Her impression of the company’s management and scientists is positive. She noted that developing drugs is difficult and costly. Recently she has entered into a sponsored research agreement with Merck that involves funding for her laboratory to identify genes involved in bone formation and resorption. The identified targets will inform high throughput screening aimed at the identification of promising small molecules.

Elliott Antman, MD, Professor of Medicine at HMS and director of the Brigham and Women’s Hospital Coronary Care Unit, noted that most of his research is clinical. He discussed his work on new antithrombotic treatments and treatments for heart failure and atrial fibrillation. His clinical work regularly reminds him that some patients are not helped by existing treatments. He described his research on a new drug designed to improve on current antithrombotic treatments. He and fellow academic investigators met with the Food and Drug Administration and designed the trial, completed it, and found that the new drug was indeed more effective than the old drug. They reported their findings meticulously, acknowledging that the price of this improved efficacy was a higher risk of bleeding.

The investigators had access to a complete copy of the raw information database and case report forms and performed their own independent analyses. He pointed to this as an example that relationships with industry can occur on a “high moral ground”.

Jerome Avorn, Professor of Medicine at HMS and Chief of the Division of Pharmacoepidemiology and Pharmacoeconomics in the Department of Medicine at Brigham and Women’s Hospital, spoke last. His work evaluates what happens once drugs are on the market, how they get used, and their cost-effectiveness. This perspective is different from that of basic science. With basic science, he noted, the relationship between industry and scientists is usually characterized by shared incentives and goals, a “win-win” situation because the better the science, the better the resulting product. With clinical trials, though, the interests of researchers and industry can diverge if the drug proves less effective than the company would like. The “third piece” of drug development, post-marketing evaluation, is particularly challenging, since honest evaluations of the safety and comparative efficacy of a drug can create “win-lose” situations that do not occur at the basic science level.

As evidence of the way in which scientific and company interests can diverge at this stage, Dr. Avorn pointed to a study published in a recent issue of the New England Journal of Medicine, that demonstrates an increased risk of sudden cardiac death with antipsychotic drugs. This potential harm does not mean, he said, that such drugs should be avoided. Their benefits might well outweigh the risk in cases of serious psychosis. It did, he suggested, call into question their use in populations where there is not strong evidence of benefit, but such restraint is not always in a company’s economic interests once a drug has been marketed. He called attention to the recent legal judgment against Eli Lilly for encouraging off-label, unapproved uses of their antipsychotic zyprexa.

From this and other similar cases, Dr Avorn does not conclude that doctors and researchers should avoid engagements with industry. Rather, he says, we should not be naive. What worries him is that we need to pay more attention to the pitfalls, the greater potential for “non-win-win” situations once drugs reach clinical testing or are marketed. He noted that most of his division funding comes from NIH.

In the absence of a US equivalent of the National Institute for Clinical Effectiveness (NICE), Dr. Avorn said that it is sometimes necessary to work with industry if one is interested in researching drug effects. While this can go well, it can also go badly, and he gave an example of each outcome. In the first case, he recounted how Pfizer representatives approached him and described their worry about a possible side effect of one of their Parkinson’s drugs. They enlisted his aid to investigate this problem, which, it turned out, was related to the drug in question but also occurred with other drugs in the class. The company used this information to devise guidance and warnings for patients and doctors. A similar project with Merck, however, did not go so well.

After signing an agreement that allowed Dr Avorn and colleagues access to the rofecoxib database, Merck attempted to discredit the resulting research that suggested harms. The details of this now-infamous case are a cautionary tale, well covered elsewhere.

In the subsequent question and answer session, Dr Antman said that third-party payers such as insurance companies represent an almost untapped source of research funding. One large health insurer, Aetna, is currently funding a study to see if providing patients with three years of free medication following a myocardial infarction cuts down on later hospitalizations and thus costs. Dr Glimcher said that a systematic approach to phase four trials is essential, and that in her view companies should be funding these. Dr Avorn said that public funding is needed for some of these endeavors. Knowledge, he observed, is a public good but in the US there has been a dearth of public funding for post-marketing research. He did not think one could really expect a company to be able to look at thinks dispassionately. They are advocates for the product, while academicians are advocates for science. Academics, Dr Avorn suggested, are the “canaries in the coalmine” regarding drug safety, and to do that job most effectively they should not have to depend on drug companies for funding.

He recommended researchers ask themselves “Is what I’m studying being driven by the availability of corporate funding or do I really think this is a question that needs to be answered?”

He recounted a discussion he had with a researcher studying the appropriateness of chemotherapy use. The researcher described efforts to identify patients who should be getting chemotherapy but were not. All well and good, Dr Avorn told him, but asked whether he was also planning to evaluate overuse of chemotherapy. No, came the answer, the company funding the research was principally interested in underuse.

Elizabeth Loder is clinical editor (secondary care), BMJ