Altman, Lawrence K. "Experts See Bias In Drug Data," New York Times, 29 April 1997, pp.

 

Altman, Lawrence K. "Experts See Bias In Drug Data," New York Times, 29 April 1997, pp.
C1, C8.

Suppression of a university scientist's findings about a common thyroid drug by a company that
paid for the research has raised serious questions about how the growing link between industry
and academia affects the reliability of information provided to doctors and the public about drugs
and 0 their medical therapies.

In recent years, many medical leaders have expressed concern that the reluctance of scientists and
journal editors to publish studies that did not show any benefits from a drug or therapy
significantly skews the information available to doctors and the public. But the possible influence
of contracts between drug companies and academia in creating such biases has received little
attention.

Government, industry and academic experts said in interviews that it is difficult to get a clear
picture of what influences publication, but a top Food and Drug Administration official said that
the end result is that scientific journals present a much more positive picture. of new drugs than
the information the agency receives.

The thyroid drug case involved the Knoll Pharmaceutical Company of Mount Olive, N.J., the
manufacturer of Synthroid, the third most widely prescribed drug in the United States. Knoll is a
subsidiary of the BASF Group, a German manufacturer of chemicals, pharmaceuticals, cosmetics
and electronics.

For several years Knoll had prohibited a team led by Dr. Betty J. Dong at the University of
California at San Francisco from reporting a study showing that Synthroid was no more effective
than less expensive generic versions of the drug.

Dr. Dong signed a contract in 1987 giving Knoll's predecessor the right to veto any publication.
The study was completed in 1990, but the findings were reported in The Journal of the American
Medical Association on April 16 after Knoll relented.

Federal health officials and experts at universities, drug companies and scientific journals said
they considered the thyroid case unusual. And a spokeswoman for Knoll, Linda Mayer, said she
was not aware of other contracts between Knoll and academic institutions with clauses similar to
that in the contract with Dr. Dong.

Other experts said there was little information and few methods to determine how often
information was not reported because of restrictive clauses in contracts. Some said they
suspected that other cases similar to Dr. Dong's escape attention because academic scientists do
not seek publication in the first place.

Dr. Mary K. Pendergast, a Deputy Commissioner of Food and Drugs said that because the F.D.
A. "sees only the data and not the contracts," it has no way of knowing how often restrictive
clauses prevent academic investigators from publishing information that companies want
suppressed if they perceive it Will threaten their commercial interests.

But she said that it was "fair to say that whether it is because of this kind of contract or for other
reasons, the data set that the F.D.A. sees is often not consistent with the far rosier picture
portrayed in the published scientific literature."

Dr. Pendergast added, "Now whether it is because the companies have contracted with the
researchers to give the companies control, or whether because oftentimes the stuff that is not
published is negative data, or it is because journals were not interested in publishing it,
ultimately, from our perspective it has the same result that there is a discordance between the full
news about a new therapy and that which is published in the scientific literature in many cases."

The Federal drug agency is empowered to examine a much broader range of information about
drugs than journals. "So when thinking about drugs, drug approvals and drug development,
everyone has to remember that the journals provide a skewed subset of information" and
consumers should have a healthy skepticism about such reports, she said.

The problem that concerns experts is primarily not that harmful drugs will end up winning
F.D.A. approval, although drug safety is always a concern. Rather, experts said, their main worry
is that drugs that reach the market may be promoted beyond their value. Consumers might be
encouraged to spend more on drugs that offer no greater benefit than other, cheaper treatments.

"It is a very big issue," said Dr. Robert M. Califf of Duke University, an authority on conducting
independent clinical trials and the editor of The American Heart Journal.

He said, "There is an implicit contract that by volunteering to participate in an experiment in
which they take some risk, patients expect you to use that information to improve medical
knowledge." But he said that "if you were a company doing your own studies and you did five
studies that showed that your product was no good and one that showed that it was good, you
would only publish" the favorable one.

"Subtle pressure occurs in any contracting work, and when you work with government agencies
and you get a politically result, there can be a lot of pressure not to say it the way it came out," he
said.

A case in point involves a landmark, long-term study of heart disease in Framingham, Mass., that
the National Institutes of Health ran before Boston University assumed such responsibility.

In May, The Journal of Clinical Epidemiology win publish an article by Dr. Carl C. Seltzer, an
anthropologist and epidemiologist at Harvard University, detailing how in 1972 officials at the
institutes refused to allow him to submit for publication a paper showing that men who
consumed moderate amounts of alcohol had a lower risk of heart disease than those who did not
drink. The degree of protection appeared to correlate with the amount of alcohol consumed, and
it is believed to be the first time that link was made in a study. Since then, other studies have
shown the apparent benefit of alcohol on heart disease.
A memorandum from the N.I.H. at the time said that its main reason for blocking publication of
the article was that "an article which openly invites~the encouragement of undertaking drinking
with the implication of prevention of coronary heart disease would be scientifically misleading
and socially undesirable in view of the major health problem of alcoholism that already exists in
the country." Dr. Seltzer said.

Dr. Richard Horton, the editor of The Lancet, an international journal in London, said that "one
of the most important lessons to come out of the Betty Dong story is that journals need to be
more aware of the issue of who owns the data" and who the authors are.

Dr. Richard Smith, the editor of The British Medical Journal, which publishes studies from many
countries and who earned a degree in management at Stanford University, said that "getting
things published in journals is very important for drug companies in terms of marketing, ff it
comes out right,"

Dr. Smith added: "People ten drug companies they have an ethical obligation to publish all their
results. But if it is a negative, boring trial of the 23d drug in a class, they have enormous
difficulty getting it published in respectable journals because the editors say their readers are not
interested in it."

Dr. Frank Davidoff, editor of' The Annals of Internal Medicine, said he became concerned about
the issue in 1995 when his journal in Philadelphia was reviewing a web-conducted study about a
drug that he did not name. The journal's staff received several cans from the drug manufacturer's
marketing department, asking when the paper would be published because the company was
scheduling educational seminars.

When questioned, the authors made it clear that while the company did not have veto power over
the paper, they could not submit it until the company cleared it, Dr. Davidoff said.

Speaking of the paper that Dr. Dong withdrew just as it was scheduled to be published more than
two years ago and that led to public attention, Dr. Sidney M. Wolfe of Public Citizen's Health
Research Group, which is based in Washington, said, "There probably are a large number that get
suppressed at an earlier level, where there is no footprint."

In 1987, when Dr. Dong agreed to conduct the thyroid study, she believed that contracts
commonly included clauses restricting publication.

Over the last decade, many universities have tightened controls over their faculty members, and a
number have required faculty members to participate in workshops on managing grants so that
researcher. will not sign a contract without first going to the university. The experts said that the
relationship between academia and industry is generally positive.

However, Dr. Mildred K Cho, an ethicist at the University of Pennsylvania, last year reported a
study in The Annals of Internal Medicine that found that 98 percent, or 39 of 40, d rug-
company-sponsored articles published in several journals had outcomes favoring the drug of
interest, whereas 79 percent, or 89 of 112, without acknowledged drug company support favored
the drug of interest.

The findings suggested that suppression of negative data could be occurring, Dr. Cho said in an
Interview, but others contend that drug companies are more likely to support studies of drugs that
are likely to be beneficial.

Dr. Dong's case is "highly unusual," and similar cases today "would be very much at odds with
both our policy and our experience," said Donald R. Baldwin, assistant provost for research at
the University of Washington in Seattle.

But Dr. Susan E. Cullen, associate vice chancellor for research at Washington University in
St.Louis,. said that "in our experience, there is often trouble in terms of actuary negotiating
publication rights in" such contracts, "no question about that."

Nevertheless, both Dr. Culled and Mr. Baldwin said that ultimately their universities had not had
difficulty in gaining permission from industry for the right of faculty members to publish
findings from studies paid for by industry.

"It is very much against the career objectives of faculty to all veto power, because they are
absolutely wasting their time doing studies if publication is not an end pant," Dr. Cullen said.

Universities general. clauses in contracts that allow an industrial sponsor a period of up to three
months to review a manuscript for the purpose of filing patent applications and preserving a
company's confidential and proprietary technical information.

Another reason, Dr. Cullen said, is to allow companies to learn about adverse clinical events
before a manuscript is submitted for publication.

Dr. George D. Lundberg, editor of The Journal of the American Medical Association, speculated
tat a poll of an American medical schools would show that the top tier of academic institutions
are more likely to protect the academic freedom of faculty investigators "to report research
results no matter what they are and who funds them," than in the lower tier that "need the money
worse."

"My experience in academia ho shown me that the lower rung institutions tend to lag far behind
the leading ones, even on ethics," Dr. Lundberg said. "They just do not put in these policies as
rapidly as the top ones."