Science for sale

A Harvard researcher stands to profit from a product he 'independently' reviewed for the National Institutes of Health. The scientific community, heavily funded by corporate money, has no clear way to handle such conflicts.

by Tinker Ready

On a frigid January morning, a group of young Harvard scientists gathered at Massachusetts General Hospital to share their latest findings. In a small meeting room, they chatted in clusters and gestured toward the scientific papers and brain-scan images posted on nearby bulletin boards.

Every year, the Massachusetts Alzheimer's Disease Research Center, a network of Harvard Medical School faculty members, holds this "poster session," a time-honored form of scientific show-and-tell. At this year's meeting, scientist Dennis Selkoe -- graying but trim and youthful -- moved through the room like a celebrity, looking very Brooks Brothers in a sea of rumpled L.L. Bean. In the small national community of Alzheimer's researchers, Selkoe is a star, the man responsible for shedding much light on the mysterious biochemical breakdowns that destroy the brains of Alzheimer's patients.

Selkoe is more than just a top-level scientist, though. He's one of a new breed of university-based entrepreneurs who have found a way to move their work out of the lab and onto Wall Street. As one of the founders and major shareholders of a California-based company called Athena Neurosciences, he's earned millions by linking his scientific fortunes with the pharmaceutical industry.

Now a Harvard review panel is trying to determine whether Selkoe has let his corporate interests interfere with his scientific judgment. Last year, he added his name to a National Institutes of Health (NIH) report endorsing a controversial blood test for Alzheimer's. What he neglected to mention in the report is that Athena Neurosciences -- the company he helped found -- manufactures the test and stands to profit from the NIH's endorsement.

An anonymous complaint filed in December with the Harvard Medical School dean's office charges Selkoe and another Harvard neurologist with conflict of interest for their role on the NIH panel that produced the report. The complaint also suggests that the report played down research that was critical of Athena's Alzheimer's test. In hindsight, Selkoe himself says that he should have made sure the published version of the report noted his corporate affiliation. "Otherwise," he says, "I stand by the accuracy and validity of the statements in the report."

But not everyone agrees that this is a simple case of poor judgment. Susan de la Monte, a Harvard pathologist who helped develop another, competing Alzheimer's test, says "it's about time" Harvard dealt with the conflicts surrounding Selkoe's roles as academic scientist and drug-company consultant. "I have conflicts too," she says. "But I don't sit on a committee telling people to use the test."

It's not just a problem at Harvard. The issue is a national one: increasingly, the turf of academic science overlaps with that of pharmaceutical marketing. As it stands, there's no national requirement for scientists to disclose their corporate ties. Schools such as Harvard have their private rules for dealing with the issue, but even if a scientist's work turns out to be compromised, there's no guarantee that doctors or patients will ever know.

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If you think science is neatly split between independent research in university labs and companies that produce products for profit, you're about 20 years behind the times. In the past, most campus scientists paid their bills with grants from the federally funded NIH. The agency still funds most university research, but a growing percentage of campus labs are now linked to a pharmaceutical or biotech company. Some companies will pay to fund a single study. Others pay the bills for an entire university lab in exchange for access to all their findings. Scientists often sell the rights to their discoveries -- everything from disease-linked genes to potential new drugs -- and share the spoils with the university. And, increasingly, university-based scientists are starting their own companies to cash in on their findings.

Some of these links have allowed important discoveries to move off the lab shelf and into the medicine chest. Emory University scientists discovered 3TC, an important element in anti-AIDS drug regimens. They licensed it to drug giant Glaxo Welcome, which had something Emory didn't -- the capacity to manufacture and market the drug. Harvard researchers developed the technology behind a form of artificial skin for burn victims, which is now made and sold by Cambridge-based Genzyme. Academic scientists have also worked with industry to produce childhood vaccines and the first effective treatment for SCID, the immune-system failure known as the "bubble boy" disease.

But consumer groups and health ethicists worry that without proper safeguards, bias may creep into the work of scientists who stand to make money off their findings. They fear, too, that scientists concerned about patent rights may be less willing to share important findings with other researchers, who could challenge or build on their work.

Many researchers take umbrage at the suggestion that corporate sponsorship could influence their science, but it happens all the time. In 1997, the University of California at Irvine shut down a cancer-research lab after finding that scientists had invested in a company that hoped to sell the drugs they were testing -- and then had failed to report side effects and had used experimental drugs without FDA approval. In 1998, researchers at the University of Toronto looked at a series of heart-drug studies and found that researchers with funding from companies that make the drugs were far more likely than independent scientists to produce studies supporting their use. A full 96 percent of the articles endorsing the drugs were penned by company-sponsored researchers, compared to 37 percent of the articles written by researchers without company ties. Since then, findings have come out questioning the drugs' safety. The Toronto data "support complete disclosure of relationships with pharmaceutical manufacturers for clinicians and researchers who write articles examining pharmaceutical products," the study's authors wrote.

Sheldon Krimsky, a soft-spoken and slightly disheveled academic, has been making that argument for years. A professor in the innocuous-sounding urban-studies department at Tufts University, Krimsky has made something of a second career as a research watchdog. Sitting at his desk in his Medford office with a folder of reports and news clippings on his lap, he shakes his head. He's disgusted by a recent deal struck between the University of California and a Swiss drug company called Novartis. In exchange for $25 million, Novartis will have first dibs on all Berkeley's discoveries in plant genetics.

"You have an entire department at Berkeley that is being bought off by Novartis," he says.

Krimsky predicts that a private company will probably buy an entire university someday. In the meantime, in his mind, companies are just buying them one professor at a time. "There's no question in any reasonable person's mind that who you get the funding from affects your work," he says. So there is a pressing need, he says, for a system that would require scientists to acknowledge their corporate affiliations whenever they publish a study, speak at a conference, or sit on a review panel. It's not enough that the administrators and editors know; the researchers' colleagues and the public also need to know where their loyalties lie, Krimsky says.

"Readers should have the opportunity to form their own opinions on whether conflict of interest exists," he says.

But Krimsky has found that they rarely do. Two years ago he looked at 800 scientific papers and found that in 34 percent of the articles, the authors owned stock, served as company consultants, or had some financial stake in the findings. Last year, he looked at 62,000 scientific papers to find out how many scientists had footnoted their corporate affiliations. Only one-half of 1 percent of the articles included disclosure statements.

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The Athena Alzheimer's test is a classic case of how the lack of disclosure allows the pharmaceutical industry to dress up marketing and call it academic research.

There is little question that a huge demand exists for tests and drugs for Alzheimer's disease. A crippling, incurable condition, the disease affects about four million people in the US, most of them elderly. The first signs are muddled language, confusion, and memory loss. Faced with the prospect of a gradual yet complete neurological shutdown, Alzheimer's patients and their families are desperate for a cure. There is none, but testing can offer hope for some. Patients suffering from memory loss would like a way to know whether the problem stems from Alzheimer's or some other cause, such as drug interactions or minor strokes. Those who don't have the disease would get to relax; those who do could make plans for their future. But there is no blood test or brain scan that offers a definitive diagnosis. Most doctors rely instead on a combination of MRIs, memory tests, and gut instincts.

In 1993, scientists at Duke University discovered an Alzheimer's-related gene. Two years later, Selkoe's company, Athena, bought from Duke the right to use the discovery to develop a diagnostic test for the disease. The result was the ADmark test, which hit the market in 1996. The test, however, is less than perfect: even if you have the form of the gene discovered at Duke, it's not certain you'll get Alzheimer's. And some people who have Alzheimer's don't have the gene. In 1997, another company -- Quebec-based Nymox Corporation -- began marketing a different test, this one based on Susan de la Monte's discovery of a protein found in high levels in the blood of Alzheimer's patients.

Since both tests are new and neither is definitive (they both promise 80 to 90 percent accuracy), insurance companies won't pay for them until they have more of a track record. Without insurance coverage or complete reliability, many doctors continue to diagnose Alzheimer's the old-fashioned way: memory tests, brain scans, and instinct.

Athena thus found itself with a hard sale, some new competition, and a high level of skepticism among the doctors who represented its potential customer base. So -- following the "nine-out-of-ten-doctors-recommend" approach -- it decided to get some expert endorsements. In 1997, Athena gave the nonprofit Alzheimer's Association a $100,000 grant to organize a panel to look at the usefulness of Alzheimer's tests. The nonprofit group then asked the highly respected National Institutes of Health to host the panel and lend its name to the final report. Athena's role was thus veiled behind two layers of nonprofit credibility. The Alzheimer's Association rounded up a team of experts on Alzheimer's to conduct the research; among the experts was Harvard's Dennis Selkoe. Another was Alan Roses, the Duke scientist who discovered the technology behind the Athena tests. (Roses personally collects only a fraction of the Duke patent-license fees on the test; most of the money goes to a Duke scholarship fund.)

When the panel's final report was published last April in The Neurobiology of Aging, one of the field's more prestigious journals, it endorsed the Athena test. The article noted Athena Neurosciences's "sponsorship" of the study, but nowhere did it mention that Selkoe co-founded Athena, or that Roses held the patent on the Athena blood test.

The panel's endorsement of the Athena test was somewhat subtle. The scientists evaluated not products but the relevance of "biomarkers" -- physical signs that tests look for. But it did single out the technology behind the Athena test, calling it the only one that "can add confidence" to the conventional diagnostic techniques of memory testing and brain scans. They called de la Monte's protein test "promising" but said it would "require further study."

Then, in December, the Wall Street Journal came out with an article headlined DID TIES TO ALZHEIMER'S TEST MAKER SWAY NIH REPORT? The article pointed out both Selkoe's and Roses's links to the company whose test they were endorsing. A week later, Harvard Medical School dean Joseph Martin received an anonymous complaint charging Selkoe and another Harvard Alzheimer's researcher -- John Growdon, who chaired the panel -- with violating the university's conflict-of-interest rules.

Selkoe, informed of the complaint, declined to be interviewed in person, but offered a written statement via e-mail. He says he suggested to Growdon that he should disclose his corporate affiliation, but that Growdon thought it unnecessary.

"However," Selkoe wrote, "it should be considered that my affiliation with Athena was already very widely known in the Alzheimer's disease field and was included in published articles in the past."

Well, not always. In 1992, Science magazine reported that Selkoe routinely wrote about Alzheimer's disease without mentioning his corporate affiliation. And a random check of eight studies published in 1996 and 1997 that included Selkoe as an author found no mention of his relationship with Athena, a relationship that has paid off richly. When Athena went public in 1993, Selkoe owned 255,000 shares worth $3 million, according to the Science article. In 1996, when Elan Corp PLC, an Irish biotech company, bought Athena, Selkoe had a $50,000-per-year consulting contract with Athena and sat on the company's board, according to Securities and Exchange Commission documents. He now sits on Elan's board of directors.

Committee chairman Growdon, for his part, declined to return repeated phone calls from the Phoenix. He did tell the Wall Street Journal that he knew about Selkoe's ties to Athena and thought they were "irrelevant."

Not every doctor agrees. Neil W. Kowall, the director of the BU Alzheimer's center, says he doesn't find that he needs the tests. He also notes that the manufacturers of the tests "have prominent scientists as stockholders and/or consultants who profit from their success."

"The Nymox [de la Monte's] test, in my opinion, is of dubious value," says Kowall. "It is unclear whether the Athena test is useful in daily practice. I don't use either."

Still, according to the Wall Street Journal article, Athena reported that sales of its ADmark test jumped by 28 percent last year. The marketing material distributed with the test makes note of the NIH panel's endorsement, but nowhere does it mention that panel members had links to the manufacturer. It simply doesn't have to.

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So who's minding the store? With so much money at stake, the scientific community tends to dance around the conflict-of-interest issue and has been unable to reach a consensus. As it stands now, universities police themselves. The system of oversight is a patchwork, varying from school to school and operating primarily behind closed doors.

The problem isn't new. Congress paved the way for the "academic entrepreneur" by passing a law in 1980 that made it easier for federally funded scientists to patent and profit from their findings. Soon scientists became stockholders, board members, and consultants for companies making the very drugs they were testing.

Ten years ago, the NIH, aware of the growing problem, took a stab at cracking down. The NIH, which dispenses $15 billion in annual research grants, is one of the few agencies -- if not the only one -- with the clout to hold scientists accountable. In 1989 it asked researchers to begin reporting their corporate links when applying for NIH funding. The response was fast and fierce. Professors and administrators flooded the agency with angry letters calling the plan an attack on academic freedom.

So the NIH backed off. Instead, the agency asked research universities to set up their own rules requiring professors to report corporate ties.

Part of the problem with this approach is that the entire process -- from the reports to the reviews -- remains secret. Mildred K. Cho, a professor at Stanford University's Center for Biomedical Ethics, thinks this defeats the whole purpose of disclosure. "The disclosure is not a true disclosure if it is not public," she says. "Most of these disclosures never really see the light of day, except within the institutions."

Because the schools collect a share of every professor's royalty check, they have their own conflicts as well, according to Cho. These days, universities encourage what they call "technology transfer," their term for research that is sold or licensed to a private company. On its Web site, a Harvard Business School program that assists professors in this process promises "fame, fortune [and] funding." The schools get a bit of that fortune themselves, since they collect a share of the licensing fees and royalties. And at Harvard and MIT, that share is growing. In 1997, MIT earned $21.2 million in royalties and from the sale of stock in startup companies. That was up from $10.2 million in 1996. In 1997, Harvard filed 61 patent applications, signed 67 licensing agreements, and collected $16.5 million from existing licensing contracts. That was up from $7.6 million in 1996.

Sheldon Krimsky, the Tufts-based watchdog, says this arrangement leaves him with little faith in academia's willingness to police its own. "The universities protect their turf," he says.

The Dennis Selkoe case is interesting because Harvard is known for having a particularly strict policy. At the time the policy was created, in 1990, the university was still smarting from the case of a Mass Eye and Ear Hospital doctor who tested a questionable eye drug on hundreds of patients. The drug turned out to be useless, but not before the doctor earned $1 million by selling stock in the company that made it. So, while some universities allow faculty to test their own companies' drugs if they disclose their interest to the school, Harvard forbids such tests. Their rules on publishing, however, are a bit more vague. Harvard researchers must get permission from a faculty committee if they want to present research results on a subject without disclosing relevant financial interests.

No one really knows just how effective that policy is. Harvard scientists publish thousands of articles each year and, according to one administration source, the school has no way of monitoring them. Usually they wait until complaints arise and then handle them quietly.

Harvard officials say they're looking into the complaint against Selkoe but have not yet decided whether a full investigation will be necessary. The case has been referred to the university's select committee on conflict of interest, which met in early April and made a recommendation to Dean Joseph Martin, according to Medical School spokeswoman Peta Gillyatt. As of last week, she said, Martin had not had a chance to review their report. Even when he does, however, the committee has no obligation to report its findings to the public or to the scientific community.

On a national level, the result of this sort of university policy is that neither patients nor their doctors find out about these conflicts unless a colleague or a competitor blows the whistle.

Drummond Rennie, the West Coast editor for the Journal of the American Medical Association, has begun speaking out for change. In a speech at a recent MIT conference titled "Secrecy in Science: Exploring University, Industry, and Government Relations," Rennie called on scientists and universities to support efforts to make disclosure of corporate financing routine and public. "Disclosure is only good if you disclose to everyone," Rennie said after his talk.

In the Selkoe case, Rennie didn't think mere disclosure was appropriate for the Athena-linked scientists. "They should have been excluded from the panel," he said.

But they weren't. And now the marketing material Athena distributes with its ADmark test makes note of the NIH study along with other scientific studies of the test's value. Doctors who haven't been reading the newspaper will remain unaware of its author's links to the company.

Meanwhile, Alzheimer's research remains intensely competitive. From the corporate standpoint, diagnostic tests such as ADmark -- however profitable -- represent only a pit stop in the race to discover a drug that can actually prevent or cure Alzheimer's. Dennis Selkoe's current research is focused on a theory that fatty substances that build up in the brain -- known as "amyloid plaques" -- hold the key to the cause of the disease. His lab recently unraveled the role of an enzyme that helps produce these substances --an enzyme that Selkoe described on a Harvard Web page report as "a promising target for drug discovery."

Athena is reportedly trying to develop a drug that would dissolve these plaques. The stakes are enormous. If the drug could stop Alzheimer's short, it would be a lifesaver for patients. Selkoe would be able to take credit for producing the first effective treatment for the disease. And Athena would have a blockbuster on its hands, according to an article in Signals, an online magazine about the biotech industry. "Barring scientific progress, about 14 million will have [Alzheimer's] by the middle of the next century," the article states. "Clearly, any drug that could truly alter the syndrome's course would be an instant multi-billion-dollar hit."

Athena reportedly will be ready to ask the Food and Drug Administration for permission to begin human tests on its drug sometime this year.

When Selkoe's team published their recent work in the April 8 issue of the journal Nature, there was no disclosure. The journal doesn't require it, says Krimsky. And he hasn't seen any mention of Selkoe's corporate ties in news reports on the discovery.

"My guess is, if the drug does not pan out -- that's when people will begin looking at the conflicts of interest," Krimsky says. "If it's successful, the attitude will be that the scientists deserve the windfall."

Still, even if the drug is successful, it's unlikely to be perfect. It may work for some patients but not others, or it may simply slow the disease's progress. It is likely to have side effects that doctors will have to weigh against the benefits. And if Athena is the first out of the gate, it will quickly face competition. And at least 20 other Alzheimer's drugs are currently under study. Once they all hit the market, scientists will be asked to help patients decide whether they're any good. And unless those researchers disclose their industry links, no one will know whether they speak for the science or for the company.

As a consumer as well as a scientist, JAMA's Rennie says, such conflicts worry him. "The patient in me," he says, "sees that as a real threat."

Tinker Ready, a freelance journalist in Cambridge, has written for Health News, Heart Watch, Harvard Public Health Review, Southern Exposure, and the Boston Globe. She can be reached at tinkerr@mediaone.net.