Altman, Lawrence K. "Drug Firm, Relenting, Allows Unflattering Study to Appear," New York

 

Altman, Lawrence K. "Drug Firm, Relenting, Allows Unflattering Study to Appear," New York
Times, 16 April 1997, pp. 1, A16.

Concluding a dispute that raised questions of academic integrity, a pharmaceutical company has
permitted publication of a long-suppressed study that showed its widely used thyroid drug was no
more effective than less expensive generic versions of the drug.

The findings are being published today in The Journal of the American Medical Association after
the company, which had financed the study in the hopes that its drug would be proven superior,
said it would no longer object.

The study compared four versions of levothyroxine, a hormone replacement given to about eight
million Americans with underactive thyroids. One of the four was the company's brand-name
version, Synthroid, which is the third most widely prescribed drug in the United States.

The researchers at the University of California at San Francisco found that for most patients the
less costly generic forms of the drug worked just as well as Synthroid and another brand-name
version, Levoxyl or Levoxine, which is similar in price to the generic drugs.

More than $350 million might be saved each year if doctors prescribed generic instead of
brandname forms of levothyroxine, said the authors of the study, which was led by Dr. Betty J.
Dong, a pharmacy professor at the university. For some patients, however, brand-name thyroid
drugs may be better than generic forms, Dr. Dong's team said.

An editorial in the journal said the company that financed the study had waged an energetic
campaign to discredit the work and had refused permission for Dr. Dong to publish the findings.
The editorial chided the university for failing to defend academic freedom in the dispute between
researcher and sponsor.

Boots Pharmaceuticals Inc., a forerunner of the Knoll Pharmaceutical Company of Mount Olive,
N.J. which makes Synthroid, gave Dr Dong's team a $250,000 grant in 1987 to carry out the
study. The finding were a surprise to both the drug company and Dr. Dong. Both had expected
the study to show that Synthroid was superior.

When Dr. Dong received the grant, she signed an agreement not to publish the findings without
the drug company's explicit permission. Dr. Dong told editors of the journal that she had
assumed that academic researchers signed such clauses. Indeed, the journal said, the practice was
common at Dr. Dong's university until 1993, when it began requiring centralized review of such
contracts.

Dr. Dong and Dr. Joseph B. Martin, the university's chancellor, declined to be interviewed or to
comment beyond what they had published in the journal.

The journal's editorial, written by its deputy editor, Dr. Drummond Rennie, who also is a faculty
member of the University of California at San Francisco, directed its harshest criticism at the
university's administration and faculty, but it also criticized Knoll, the Food and Drug
Administration and professional societies.

The journal also published a letter from Carter H. Eckert, the president of Knoll, who apologized
for blocking publication of Dr. Dong's paper, saying it was "contrary to our normal practice." He
expressed "regret that our decision was interpreted as lack of support for academic freedom."

Mr. Eckert said in an interview that he was confident that debate among scientists about the
findings would vindicate Knoll's view that "the study was significantly flawed" and that
switching from Synthroid to other forms of levothyroxine could put millions of patients at risk.
Knoll, Mr. Eckert said, "has been attempting to get this information out into the open, in a
balanced view with all the facts on the table, for some time."

The F.D.A. came under attack in the editorial for not setting specific standards for determining
the amounts of levothyroxine that reach the blood, which can help clarify whether generic forms
of the drug are working as well as brand names.

Professional societies such as the American Thyroid Association were criticized for not imposing
limits on thelr entanglement with Industry. Knoll has provided more than 60 percent of the
association's commercial sponsorship, though the group has taken steps to make Itself more
independent from corporate sponsorship, the journal said. The journal also said It had difficulty
finding experts to review Dr. Dong's paper who did not have financial ties to Knoll.

Strongly objecting to the editorial's criticism of the American Thyroid Association, its president,
Dr. E. Chester Ridgway, of the University Colorado Health Sciences Center, said the support
from Knoll was 20 percentnt. That support did not weaken the association's moral authority as
the editorial contended, Dr. Ridgway said. He added that "the Idea that a society or individuals
who accept support for a meeting or a lecture necessarily loses moral ground is ridiculous and
completely unsubstantiated."

Disclosure that "its faculty can be bullied and kept quiet by their sponsor" has tarnished the
reputation of the University of California at San Francisco, the editorial said. In recent years,
Industry has been paying for more research In academic medical centers. But Dr. Rennie said
faculty "should not assume that such sponsors will encourage publication of unfavorable results
and should never allow sponsors veto power."

"The problem would never have arisen had the university set up a system to screen" out clauses
such as the one to which Dr. Dong agreed, Dr. Rennle said.

In a letter in the journal, Dr. Martin, the chancellor, said Dr. Dong's case was an "unfortunate
chapter in the annals of university-industry relations."

A spokesman for the university cited a news release it issued in February 1996 after The Wall
Journal published an article on the episode. The release said that "the difficulty here is weighing
the right to publish against a likely claim against the university for breach of contract and the
possibility of significant damages the company might claim by virtue of publication of the
article."

Dr. Dong's study began in 1987, when she signed a contract with Flint Laboratories, then the
manufacturer of Synthroid, to compare Synthroid and three other forms of levothyroxine among
22 women with underactive thyroid glands.

Dr. Dong's team tested four synthetic forms of levothyroxine. Two were brand-name drugs:
Synthroid, and Levoxyl or Levoxine, which is now made by Jones Medical Industries of St.
Louis. The other two were generic forms of levothyroxine.

When the study ended in 1990, Dr. Dong's team had found that all four products were similar,
and sent the findings to Boots Pharmaceuticals, which had taken over Flint. Boots later
complained to the university's top officials that the study was flawed. But two investigations by
committees appointed by the university found that the study was rigorously conducted in a way
that complied fully with the contract.

Over the next four years, Boots waged an energetic campaign to discredit Dr. Dong's study,
claiming it to was seriously flawed and preventing publication of the findings, the journal said.

When the university asked Boots to make specific allegations that the university could
investigate, Boots did not respond. In August 1994, the university told Boots that there was no
reason to suppress the manuscript and that to do so would be an unprecedented intrusion upon
academic freedom.

Earlier, in April 1994, concluding that Boots's concerns amounted to delaying tactics, Dr. Dong
sent the paper to the A.M.A. journal. After extensive review by five experts, the journal decided
to publish the paper in its issue of Jan. 25,1995.

But the night before Dr. Dong's article was to go to the printer, the University of California at
San Francisco called her and ordered her to withdraw it. Earlier, lawyers for the university
assured Dr. Dong that contracts like the one she had signed never prevented publication. But now
the university, concerned by the amount of money that could be at stake and with a new lawyer in
place, said It would not defend the authors if Boots sued. So Dr. Dong withdrew the paper.

The university should have "immediately and staunchly defended" academic freedom and backed
Its faculty on such a basic issue, "notwithstanding the language of the contract," the journal's
editorial said.

In May 1095, Dr. Gilbert H. Mayor of Knoll, which had been bought by BASF AG, wrote The
Journal of the American Medical Association and other journals disparaging Dr. Dong and her
study, saying the journals should "be concerned about publishing the paper."

In mid-1995, Dr. Mayor published the company's Interpretation of Dr. Dong's data in The
American Journal of Therapeutics without any acknowledgment to the scientists who conducted
It. The paper used Dr. Dong's data but analyzed It In a different way to reach the opposite
conclusion and cast doubt on Dr. Dong's work.

Dr. Sidney Wolfe of Public Citizen's Health Research Group in Washington said in an interview
that his organization had helped Dr. Dong find pro bono legal counsel after "the University of
California at San Francisco sold her out." Dr. Wolfe also said that "Americans have been bilked
of almost $800 million in extra costs for purchasing the Knoll version of thryoxine because of the
suppression of evidence that the other three versions are just as bioavailable."

In November 1996, Mr. Eckert met with Dr. Martin, and Knoll then agreed not to block
publication of Dr. Dong's paper, which the journal Is publishing without any changes In the
proof that was set two years ago.