Balancing Business and Science at ImClone

Artwork: Elena Lokshina, www.artblues.com John Mendelsohn had reached the pinnacle of his scientific career when he was called before US congressional investigators this autumn to answer questions about his role in ImClone Systems, the Manhattan technology company whose CEO, Sam Waksal, later pleaded guilty to fraud and conspiracy charges. The president of the University of Texas MD Anderson Cancer Center, Mendelsohn had led the once-ailing research institution through what The Houston Chronicle described as a "turnaround;" he was recognized as the developer of C225 (now Erbitux), a mono-clonal antibody still praised as promising in anticancer research.1 He had even been considered as a candidate for the directorship of the National Institutes of Health, according to the Chronicle. But that day, Oct. 10, members of the House Committee on Energy and Commerce skimmed over the details of Mendelsohn's public service and the decades of research that led to development of C225. Instead, they queried him about the clinical trials that led the US Food and Drug Administration to issue a "refusal to file letter" for Erbitux, which prompted the company's stock plunge. Mendelsohn, a member of the ImClone board of directors and scientific advisory panel, defended the company and his role in it in a tersely worded congressional testimony. "I joined and continue to work with ImClone because I believe its scientists have the vision, the desire, and the capability to get this new treatment to patients," he concluded. "My personal goal remains to do everything in my power to bring Erbitux through the approval process and to patients with cancer." Rep. Ernest Fletcher (R-Ky.) questioned what he termed "protocol violations" and "inadequate data collection." "Those are the very basic elements of research," he said, "and folks like you that have been in this business a long time know that throws out all of the research and makes it really lack credibility." Mendelsohn attempted to reply: "The protocol was developed with the advice of medical oncologists from some of the world's greatest institutions, 27 of which participated in carrying it out ..." But the committee suddenly recessed for a floor vote on Iraq, and Mendelsohn never got a chance to complete his rebuttal. Even if he had time to answer, he may not have been able to answer the question's subtext: How can biomedical investigators balance the pursuit of profits with the quest for honest science? "For the past several decades, conflicts have become much more evident as the worlds of commerce and academics have commingled," says Hamilton Moses, senior adviser and partner for the Boston Consulting Group, and a coauthor of a recent study of business-academic relations for the New England Journal of Medicine.2,3 "That has created a problem-- parallel with the opportunity." INVESTMENT IN IRONY Mendelsohn's work with ImClone could provide a primer both for properly managing a business-academic relationship, and for the perils of mixing profits and protocol. A review of 700 pages of documents indicates that he scrupulously followed the rules when he disclosed his financial interests in the monoclonal antibody C225 to the public and to the journals in which he published. Questions did arise because patients who received C225 from MD Anderson during trials were not, at first, informed that the institution's president had a financial stake in the drug. Mendolsohn personally apologized, and the institution faced no charges from the NIH Office of Research Protections. ImClone hired a clinical research organization to supervise the human trials, so Mendelsohn had no direct involvement in them, and, he has said, he never administered the drug to any patient. Mendelsohn also banned MD Anderson researchers from direct involvement with clinical trials on the drugs they helped develop. Mendelsohn would not comment for this article, but he has frequently asserted that his motivation for bringing C225 to approval, after nearly 20 years of research, was for patients in desperate need, and his efforts have rewarded him financially. He sold 20% of his shares in October 2001 for $6.3 million when Bristol-Myers Squibb bought into ImClone. Among colleagues, Mendelsohn has a reputation for forthrightness. Joseph V. Simone, chair of the National Cancer Policy Board, supervised Mendelsohn at Memorial Sloan-Kettering Cancer Center while Mendelsohn was chief of medicine there in the mid-1990s. "John is one of the straightest arrows you'll find anywhere," Simone says, adding that he has never owned stock in ImClone himself. "He's up front--I never had an iota of doubt about his integrity." Yet, not only has Mendelsohn faced grilling by Congress, he is also a codefendant in more than a dozen lawsuits filed by investors angered by their losses in ImClone. For Sheldon Krimsky, a professor at Tufts University and adjunct professor in family medicine and community health at the Medical School, Mendelsohn's experience is emblematic of corporate-sponsored science. "The deep involvement of scientists who are doing fundamental research [and] who are involved in equity in the company and marketing of the products will always have the appearance of conflict-of-interest, even if there are no contested issues with the product," Krimsky says. Krimsky acknowledges that some people can perform two roles and maintain the appearance of objectivity, as long as they do not have to decide between proceeding as dispassionate scientists or taking risks that could improve the standing of the corporation. But the scientist lands in jeopardy when marketing decisions are incorrect or made before the data are complete. "You cannot wear two separate hats," Krimsky says. "You can't just go to the laboratory and say, 'Right, here I am scientist; I am no longer a business person....Therefore, the appearance of conflict-of-interest will always be there." JUGGLING INTERESTS Such conflicts--and the biases that accompany them--arise not only in the mix of business and academia, but also when professors apply for grants, submit to publications, or seek tenure, says David Korn, senior vice president for biomedical and health science research for the Association of American Medical Colleges. Because of this potential for biased research, the AAMC encourages scientists and institutions to manage their conflicts of interest rather than ban them. The association's voluntary guidelines, published in December 2001, recommend full disclosure of financial conflicts as well as oversight by conflict-of-interest committees.4 "The important thing to be able to say is that we have been as scrupulous as is humanly possible in understanding what these interests were and that they existed, deciding whether the research should proceed in spite of those interests, and taking oversight steps to ensure research integrity, and the safety and well-being of the research subject," Korn explains. Both Krimsky and Korn say that disclosure can diminish animosity when conflicts arise, but it cannot guarantee exoneration. Mendelsohn's disclosure did not protect him from his public grilling or from investors' ire. "The suspicion will always be there, because most people understand you cannot have a divided self," Krimsky says. BASIC ETHICS The AAMC guidelines address research involving human subjects, but the pressure to overstate basic research results can also create conflicts: An important scientists' imprimatur can significantly influence how much money a biotechnology startup can raise, for example. A recently published study at the University of California, Los Angeles, reported that for every paper published in collaboration with a "star" scientist, the companies added about $1 million (US) to the proceeds of their initial public offerings.4 "The recurrent theme is that good intentions are not necessarily consciously diverted, but maybe unconsciously," Moses says. "The remedies for that and the protections against have to be very sophisticated." In their recent article, Moses and his coauthors recommended that faculty who are clearly identified with companies either take leaves of absence or take part-time appointments to clearly separate academic and company roles. Such separation, however, cannot erase biases inherent in a scientist's pursuit of a dream drug or therapy. Joe Thomas, associate dean of faculty at the Johnson School of Business at Cornell University, says a scientist's commitment in itself to a discovery can blur business reasoning--for example, when the researcher determines whom to hire or how long to pursue an avenue of research. "When it comes to a product that they have worked on for twenty years, there is no objectivity about this as a business," Thomas says. "It's like their child. If you put twenty years into something, you feel emotionally attached." UNBLEMISHED CAREER The congressional committee didn't ask Mendelsohn how he, or anyone, could work as a dispassionate scientist, while also promoting a drug that he believes might cure a deadly disease, and helping run a business. Though ethicists Moses and Korn urge scientists in business to weigh the risks, they also hail the benefits of mixing business and science. "I would encourage the young researcher to look at industry and academic labs as both viable career options," Moses says. Indeed, Mendelsohn's reputation has outweighed any questions. Last May, as investigators scrutinized ImClone, the American Society of Clinical Oncologists gave Mendelsohn the David A. Karnofsky Memorial Award for his work with anti-EGF receptors and his service as a clinical oncologist. Katharine Uraneck (kuraneck1@nyc.rr.com) is a physician and freelance writer in New York City. References 1. M. Sit-Duvall, "Hospital heal thyself; formerly ailing M.D. Anderson finds prescription for a turnaround," The Houston Chronicle, June 10, 2001. 2. H. Moses et al., "Collaborating with industry--Choices for the academic medical center," New England Journal of Medicine, 347:1371-5, Oct. 24, 2002. 3. M.R. Darby, L.G. Zucker, "Going public when you can in biotechnology," working paper, National Bureau of Economic Research, 2002, available online at www.nber.org/papers/w8954. 4. Task Force on Financial Conflicts of Interest in Clinical Research, Protecting Subjects, Preserving Trust, Promoting Progress: Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research, Association of American Medical Colleges, 2001, available online at www.aamc.org/members/coitf/firstreport.pdf.

Balancing Business and Science at ImClone

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