A UC San Francisco study suppressed for seven years by the drug company that sponsored the research on thyroid medications is finally being published today after a delay that may have cost U.S. consumers more than $2 billion. A separate report in the same journal suggests that the incident, though an extreme case, is far from an isolated occurrence in the world of pharmaceutical research.
Dr. Betty J. Dong and her colleagues at UC San Francisco report in the Journal of the American Medical Assn. that inexpensive generic formulations of the drug levothyroxine, used to treat insufficient output of thyroid hormones, work just as well as Synthroid, the brand-name product that dominates the market.
If only half of the 15 million prescriptions for levothyroxine filled every year were for the generic form, the team estimated, consumers would save $356 million annually.
The study's sponsor, Boots Pharmaceuticals Inc., which has since merged with Knoll Pharmaceutical Co., objected to the finding when the study was concluded in 1990 and ultimately invoked an obscure clause in the contract to halt publication.
In letters also published in the journal today, Knoll officials apologized for suppressing the information, but argued that the study was poorly designed--even though company scientists played a major role in planning it.
"We've done the right thing from the beginning," Knoll President Carter Eckert said Tuesday. "Everything we have done is with the idea of making a balanced scientific debate take place so that patients are not put on the wrong drugs."
But a commentary by Dr. Drummond Rennie of UC San Francisco, West Coast editor of the journal, noted that "this is a good study carried out by highly competent workers following a sensible design. . . . It is hard to believe that the sponsors would have made such extraordinary efforts to delay and block publication of the study for such a very long time and for such an extraordinary number of specious reasons if the results had shown Synthroid to be better."
Neither Dong nor anyone else from the university was willing to comment on the articles or the controversy. "We believe the work speaks for itself," said UC San Francisco spokesman Bill Gordon.
It is not immediately clear if publication of Dong's results will change prescribing habits, experts said Tuesday.
"Because there is still some doubt about the equivalence of the drugs . . . I would recommend that patients stay on the preparation they are now taking," said Dr. John Nicoloff of USC. "No one would argue with that."
But in California and other states where HMOs are prevalent, the study could have "a huge effect," said Dr. Andre J. Van Herley of UCLA. "In the setting of cost containment, this is something that is going to have an impact. . . . HMOs themselves can make a decision and issue a warning to physicians to use only the generic versions."
In a separate study in the journal, nearly 20% of 2,167 researchers surveyed said they had had publication of a paper delayed six months or longer to allow time for patent applications, to protect the proprietary value of results, to slow dissemination of undesired findings or to resolve disputes over intellectual property. But none reported interference as egregious as in the UC San Francisco case, said Dr. David Blumenthal of Massachusetts General Hospital, that study's lead author.
Delays in publication are "going to become more and more of a problem," Rennie said, as government funding is reduced and industry takes on a larger role.
More than 8 million Americans fail to naturally produce enough thyroid hormone, suffering such symptoms as lethargy, stiffness and low tolerance for cold. The condition is treated with the hormone, called levothyroxine.
Synthroid, the first synthetic version of levothyroxine, was introduced in 1958. Synthroid now controls 84% of the market.
As other manufacturers began producing levothyroxine, many said that their versions were "bioequivalent" to Synthroid--that is, that the same amount of the hormone entered the bloodstream. But because no comparative clinical trials had ever been conducted on such drugs, the Food and Drug Administration would not allow them to claim equivalence on package inserts and in advertising, and their sales suffered.
Anecdotal evidence and a preliminary study by Dong, in fact, suggested that the drugs were not bioequivalent. Boots gave Dong $250,000 to study Synthroid and three other formulations, obviously expecting her to find significant differences.
The UC San Francisco team studied 22 women with hypothyroidism, giving them each of the four products for six-week periods in random order. They observed small differences in effectiveness of the drugs, they wrote, but "these differences are not statistically significant and therefore probably not clinically significant in the majority of users."
Boots executives and researchers immediately began disputing Dong's findings, challenging her methodology and analysis of the data. This squabbling went on for four years. The university appointed independent researchers to examine the study, and all reported that it was well designed and appropriately conducted.
Meanwhile, in 1994, Boots researcher Gilbert Mayor, who had been highly critical of the study, published a devastating critique in a new journal, the American Journal of Therapeutics, of which he was an associate editor.
Frustrated by her inability to resolve the conflict with Boots, Dong submitted her finished article to the Journal of the American Medical Assn., advising of Boots' opposition. The journal submitted it to an unusually large number of reviewers, all of whom found it well done. It was scheduled for publication Jan. 25, 1995.
At that time, however, Boots was in the process of selling its pharmaceutical division to the West German company BASF AG. Publication of the paper could have adversely affected the sale. (The sale eventually went through for $1.4 billion. BASF then merged the company with its Knoll subsidiary.)
At that point, Boots executives invoked the clause that allowed them to formally block publication. UC San Francisco attorneys advised Dong that the contract she had signed with the company was legal and notified her that the university would not defend Dong and her colleagues if they were sued. She withdrew the paper 13 days before it was to appear.
Under pressure from the FDA and the negative public perception created by the ongoing incident, Knoll's Eckert met with the UC San Francisco chancellor last November. Knoll ultimately agreed not to block publication of the paper, while still insisting that its conclusions were not supported by the data.
Several lessons should be learned from the episode, Rennie says. Dong was naive in signing the contract, but the university--which had a policy forbidding such clauses in research contracts--should have examined it more aggressively. All universities should establish policies to forbid such clauses, he said, and set up a system to screen them out.
Moreover, he wrote, "An academic principle of the highest priority was at stake . . . and this principle should have been immediately and staunchly defended, not withstanding the language of the contract." Had the university done so, he speculated, no suit would probably have been filed.