The Betty Dong Affair

Excerpted from Blaming the Brain, by Elliot Valenstein.  The Free Press, 1998.  Pages 276-279 of the hardcover edition (from the section of footnotes to chapter 6).

A recent example of the pressure that may be exerted by a pharmaceutical company concerns Synthroid, a synthetic thyroid hormone pill.  The Boots Company, Britain's largest drug retailer, owned the rights to Synthroid, which has the greatest share of the over $600 million annual sales of synthetic thyroid hormone in the United States.  It is estimated that over 8 million people take Synthroid daily to correct hypothyroid conditions.

In recent years, competing pharmaceutical companies have tried to get a larger share of the market by claiming that their pills are bioequivalent and much less expensive.  The Boots Company awarded a $250,000 contract to Dr. Betty Dong, a clinical pharmacist at the University of California at San Francisco (UCSF), to study the bioequivalency of Synthroid and three other synthetic thyroid drugs on the market.  Dr. Dong must have appeared to the Boots Company to be an ideal person to do this study for them, as she had previously published articles reporting a risk in switching patients from brand-name thyroid pills to generic versions.

Much to the concern of the Boots Company, when the study was nearing completion at the end of 1990 and the results were analyzed, the data indicated that the four synthetic thyroid drugs tested were bioequivalent.  When the Boots Company learned of the unfavorable results, it tried to persuade Dr. Dong to water the conclusions down.  When this failed, Boots began to discredit the study, pulling out all stops in an effort to block publication of the manuscript. Letters were written to the head of Dr. Dong's academic unit raising objections to the way the study was executed and asserting that “we believe this study, because of its many difficulties, should be terminated.”  Boots also sent letters to the chancellor and vice-chancellor of the university and to several other department heads.  The letters charged that there were all kinds of methodological, procedural, and also possibly ethical problems with the study, even though the company had approved the research protocol in advance.  Two university investigations, however, found only extremely minor flaws in the study and they concluded that Boots was trying to harass them and Dr. Dong.

Dr. Dong and her collaborators made several changes in the manuscript, trying unsuccessfully to satisfy Boots without compromising the study.  Finally, not wanting to waste all the time and effort invested in the study, they submitted an article to The Journal of the American Medical Association (JAMA) in April 1994.  Dr. Dong and her colleagues included a covering letter with their manuscript stating that the study had been funded by Boots, which remained critical of the study despite numerous meetings with the authors, and the letter indicated that copies of all the data and the manuscript had been sent to the company.  The article received favorable reviews from five outside consultants and was scheduled for publication.  In fact, page proofs were already at the printer.  In the meantime, the Boots Company had hired consultants, many of whom were people who had previously received fees from the company for lectures or for serving on their Thyroid Research Advisory Council.  The information the consultants received about the study and about what had transpired between Boots and Dr. Dong was supplied only by the company.  Dr. Dong had no input. The conclusion of the consultants was that the study was seriously flawed and Boots's research director wrote to the editors of JAMA citing the conclusions of the consultants and requesting that the study not be published because of its alleged flaws.  Moreover, the Boots Company had included a clause in the contract that forbade any publication of the results without the written consent of the company.  Dr. Dong had apparently signed the contract thinking that the statement would have no consequences.

The threat of a lawsuit by the company was effective in eliminating virtually all of Dr. Dong's support at her university.  Earlier, the UCSF administration planned to back Dr. Dong, but as the threat of an expensive lawsuit became more of a reality, the dean of the Pharmacy School, George Kenyon, explained that while the university considered academic freedom a critical value, “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.”  A university attorney warned Dr. Dong and her coauthors that they would have to defend themselves in court without any support from the university.  The legal costs would have been prohibitive, and after consulting with her coauthors, Dr. Dong telephoned the editors of JAMA and instructed them to pull the article.  Carter Eckert, a Boots executive, commented at the time that he had “stopped a flawed study that would have put millions of patients at risk.”  However, others, including Leslie Benet, chairman of UCSF's Pharmaceutical Sciences Department, scoffed at this claim, declaring that “the Boots people did everything they could to make sure this study didn't get published because it was detrimental to their company.”  Other, “noninvolved” scientists, described the “flaws” as minor, not affecting the outcome, and they stated that it was “extreme hyperbole to question the scientific merit of the study on the basis of those deficiencies.”

In March 1995, Boots was taken over by BASF A.G., a German chemical and pharmaceutical company.  BASF then started marketing Synthroid through its subsidiary Knoll Pharmaceutical.  In May 1995, JAMA received a letter from Gilbert Mayor, formerly of Boots and then of Knoll, which was highly critical of Dr. Dong's study.  Similar letters were written to the editors of other journals.  The letter to JAMA stated that the journal should “be concerned about publishing [the paper].”  Gilbert Mayor, along with some of his associates, then wrote a sixteen-page critique in which they appropriated Dr. Dong's data and reanalyzed it to argue that the other synthetic thyroid drugs were not equivalent to Synthroid.  This was just the opposite of what Dr. Dong and her colleagues had concluded.  Gilbert Mayor's critique was published in the American Journal of Therapeutics, where he was an associate editor.

Due to a carefully researched article in The Wall Street Journal, Knoll began to receive a lot of criticism, and the FDA started looking into the matter.  Facing increasing criticism, the president of Knoll, along with some of the company's board members, met in November 1996 with officials of the University of California at San Francisco, including the university chancellor.  At this meeting, Knoll agreed that it would not attempt to stop the study from being published, but the company officials continued to insist that the study was flawed.  One can only wonder how many flaws would have been found if Dr. Dong and her colleagues had concluded that the other drugs were not as effective as Synthroid.  The study was finally published in JAMA in April 1997.  It has been estimated that if other, less expensive, synthetic thyroid drugs had been used instead of Synthroid, $356 million would have been saved annually.  On 29 April 1997, a lawsuit was filed against BASF A.G. and Knoll Pharmaceutical in the federal court of San Francisco, accusing them of suppressing a medical study in an effort to control the American market for thyroid drugs.  An excellent account of this whole incident was written by King, R. T., Jr., “Bitter Pill:  How a Drug Firm Paid for University Study, Then Undermined It,” The Wall Street Journal, 12 April 1996, pp. 1 and 6.

See also “A Cautionary Tale”, Science, 1996, 273, p. 411;  Rennie, D., editorial, “The thyroid storm,” JAMA, 1997, 277, 1238-43;  Altman, L. K., “Drug Firm, Relenting, Allows Unflattering Study to Appear,” The New York Times, 16 April 1997, pp. Al and A12;  Mayor, G. H., Orlando, T., and Kurtz, N. M., “Limitations of levothyroxine bioequivalence evaluation:  analysis of an attempted study”, Am. J. Therapeutics. 1995, 2, 417-32;  Dong, B. J., “Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism,” JAMA, 1997, 277, 1205-13.