Published on Sunday, February 20, 2000 in the New York Times
Biomedicine Is Receiving New Scrutiny As Scientists Become Entrepreneurs
by Sheryl Gay Stolberg
 

Dr. H. Kirk Hammond, a cardiologist at the University of California in San Diego, never envisioned himself an entrepreneur. "I'm a blue jeans-wearing, tieless character," he said.

But when he invented a gene therapy technique to treat heart disease, he did what any self-respecting academic scientist does these days: he started a biotechnology company.

Today, he has one foot in academia and the other in industry. On campus, he trains doctors and runs a gene therapy lab, financed in part by his company, Collateral Therapeutics. As its chief scientist, he has drummed up support for a public offering of stock, and helped design clinical trials for his therapy.

But there is one bright line that Dr. Hammond says he will not cross: He will not treat patients who are enrolled in studies of his invention. "I think it would look bad for me to be involved in any direct way," he says.

With the biomedical revolution in full swing, academic scientists who lack industry ties have become as rare as giant pandas in the wild. But as Congress begins to investigate lapses in federal oversight of gene therapy experiments, lawmakers, bioethics experts and federal regulators say they are troubled that so many researchers have a financial stake in companies testing their discoveries -- companies whose fortunes, with those of the scientist, can rise and fall on a single product.

The fear is that the lure of profit could color scientific integrity, prompting researchers to withhold information about potentially dangerous side effects or push for experiments that might not be quite safe.

Of particular concern are doctors who enroll and treat patients in clinical studies that are paid for by the companies they own, a practice that the Food and Drug Administration says is growing in gene therapy.

Some universities, including the University of California at San Diego, simply do not allow it. Even if Dr. Hammond wanted to test his own invention, he could not do so and keep his university job. But the rules are not the same across the board.

Dr. Ronald G. Crystal, a gene therapy researcher at Cornell University's Weill Medical College, has treated patients in small studies paid for by the company he founded, Gen-Vec. So has Dr. Jeffrey M. Isner, a scientist at St. Elizabeth's Medical Center in Boston. Dr. Isner, along with the medical center and two other partners, founded a company called Vascular Genetics, of which he owns 20 percent. Both doctors declined to be interviewed for this article.

But both have drawn the attention of members of the Recombinant DNA Advisory Committee, the National Institutes of Health panel that oversees gene therapy research. Dr. Crystal was criticized for asking the panel not to disclose that a heart disease patient had died of an underlying illness during a gene therapy experiment. And before the panel learned that most gene therapy researchers were failing to comply with its guidelines to report patient side effects, Dr. Isner was singled out for failing to do so.

Dr. Ruth Macklin, a member of the advisory panel and professor of bioethics at Albert Einstein College of Medicine in the Bronx, said she worried that researchers with financial conflicts would try to keep information about risks a secret for fear it would hurt investment in their companies.

Dr. Macklin said she would like the panel to require doctors who own stock or have other financial interests in companies to disclose those interests on the consent forms distributed to patients.

Others, like Dr. David Blumenthal, who directs the Institute for Health Policy at the Massachusetts General Hospital, would ban the practice outright. "I'm not comfortable with scientists' owning substantial equity in small firms that are sponsoring their clinical research," Dr. Blumenthal said. "I think it creates a conflict of interest, and the conflict is particularly difficult to justify in cases where patients' welfare may be affected."

Food and Drug Administration officials are also uncomfortable. Dr. Jesse Goodman, deputy director of the agency's Center for Biologics Evaluation and Research, said that in a typical clinical trial sponsored by a large drug company, the company served as a check on the researcher, ensuring that information about side effects was properly disclosed and that patients were given clear information about the benefits and risks.

But when the company and the researcher are one and the same, he said, that check is absent. He said the agency was trying to decide whether additional oversight was needed to protect patients in such studies.

Yet the issue of just what is a conflict can get murky. A case in point is the University of Pennsylvania, where an 18-year-old patient, Jesse Gelsinger, died in a gene therapy experiment last fall, bringing the current wave of scrutiny. The principal investigator of the study was Dr. James Wilson, director of the university's Institute for Human Gene Therapy. He is also the founder of a biotechnology company, Genovo, in which both he and the university hold stock.

The relationship is so entangled, said Peter Erichsen, the university's general counsel, that it set up two committees to oversee it. Dr. Wilson cannot sit on Genovo's scientific advisory board and his work as a company consultant is unpaid. He may not participate in clinical studies paid for by the company.

In an interview shortly after Mr. Gelsinger's death, Dr. Wilson said he agreed with the restrictions. "I think it gets a little bit concerning when the person who has responsibility for enrolling patients is the scientist who is driving" the research, he said then. "I think that's a conflict."

But Genovo contributes one-fifth of the $25 million annual budget at the gene therapy institute, and in return has exclusive rights to develop Dr. Wilson's discoveries into commercial products.

So while the company did not pay for the study that cost Mr. Gelsinger his life -- it was financed by the National Institutes of Health -- Genovo does have an indirect interest in all of Dr. Wilson's work. Indeed, Dr. Wilson was required to disclose his connection to Genovo on the "informed consent" document that explained the study's benefits and risks to patients.

What effect, if any, such relationships have on the outcome of clinical studies is difficult to evaluate, said Dr. Mildred Cho, a bioethicist at Stanford University who has studied conflict-of-interest policies at the 100 largest research institutions in the country. "There is almost never a smoking gun," she said. "You can't say Jesse Gelsinger died because Jim Wilson had stock in Genovo."

Evidence is beginning to emerge, however, that industry ties do color scientific judgment. In a 1996 analysis of 789 articles in medical journals, Dr. Sheldon Krimsky, a professor of urban and environmental policy at Tufts University, found that 34 percent of the authors had a financial interest -- most frequently a patent pending -- in the subject matter being studied.

In a later study, Dr. Krimsky interviewed the authors of articles in medical journals about calcium channel blockers, commonly prescribed for high blood pressure and chest pain from angina. Among those who supported the use of the drugs, 96 percent had a relationship with the pharmaceutical industry, compared with 60 percent who were neutral toward the drugs and 37 percent who were critical of them.

No federal regulations govern the specifics of scientists' relationships to the companies they create. The National Institutes of Health require universities to set their own policies, but experts say the rules vary widely. Some researchers can sit on the scientific advisory boards of their own companies; others must maintain a greater distance. Some can have only a small investment. Others can have a significant equity stake. Dr. Hammond owns 15 percent of Collateral Therapeutics. Dr. Wilson's equity in Genovo is not public, but Mr. Erichsen, the university lawyer, said that Dr. Wilson and his family could own no more than 30 percent of the company, and Dr. Wilson said half of his holdings were in a blind trust for his children.

Twenty years ago, before the revolution in genetics, academia was academia and industry was industry, and rarely was there any overlap.

Now, so many university scientists have started their own companies that deans of medical schools no longer talk about eliminating conflict of interest; the current buzzword for dealing with conflicts is "management." The primary management tool, university officials say, is disclosure. But that means disclosure to supervisors -- not to the public.

Congress has helped fuel the trend of scientists' starting their own companies. In 1980, it passed the Bayh-Dole Act, a law designed to speed up the commercialization of academic discoveries. It encouraged universities to patent inventions, and then assign the rights to those patents to private companies that could develop them into products. Instead of relying on existing companies, scientists like Dr. Hammond began raising venture capital and starting businesses of their own.

Universities like the Bayh-Dole Act because it generates income from licensing fees and royalties, and because it gives their best scientists incentive to stay in academia. Scientists like it because it helps them carry discoveries from the laboratory to the bedside, and because they no longer have to leave the prestige of academia to earn the money available in industry.

For some, it has been quite lucrative. Dr. William Haseltine, the chief executive of Human Genome Sciences in Rockville, Md., founded seven biotech companies while a professor at Harvard University. "I don't even know how many millions I've made," Dr. Haseltine said. But, he insisted, "the motivation was not primarily money."

"The motivation was the joy of conceiving ideas and reducing them to practical reality to make a difference in people's lives," he said.

That, said Dr. Hammond of the University of California at San Diego, was precisely why he started Collateral Therapeutics. In the late 1980's, he said, he began looking at patients with heart disease whose bodies had grown new blood vessels to do the work of the blocked ones. It struck him that there must be a gene that would promote this beneficial blood vessel growth, and that "it would be really nice just to be able to put those genes into patients."

By 1993, he said, he had figured out how to do it. "Back then, I was completely ignorant of business, and to be honest, quite alienated by business," he said. "But I had two young daughters and not a lot of money, a retirement in my future and I had sense enough to know that what I had discovered was important."

The patent was filed in 1995, but the university could not get any companies interested in licensing it. So Dr. Hammond met with some venture capitalists and started Collateral Therapeutics, which quickly licensed the patent rights. Within months, the company was working with a German pharmaceutical firm, Schering A.G., which began human tests of Dr. Hammond's technique in May 1998.

Even without participating in the clinical trial, the arrangement has been a delicate balancing act for Dr. Hammond. He takes unpaid leave from his university job when he is traveling on company business. He accepts payment as a consultant, but his job as vice president for research is unpaid. Although Collateral Therapeutics provides research money for his laboratory, he said, the company does not hold exclusive rights to commercialize his discoveries, as is the case with Genovo and Dr. Wilson at the University of Pennsylvania. And Dr. Hammond cannot sell his shares in Collateral while human testing is under way, he said, because the Securities and Exchange Commission prohibits it.

"It's theoretical money; I can't do anything with it because I'm an insider," he said. "The university would love me to sell all of it. They think that makes me less contaminated in some way. I think that's nonsense."

###

Copyright 2000 The New York Times Company