NIH sponsored hypertension trial incites controversy: COI

Thu, 21 Nov 2002

Controversy has erupted around the research disclosure process of a government sponsored, clinical trial that gave drug companies the manuscript of the report 30 days prior to its submission for publication in the Journal of the American Medical Association. Questions will surely be raised about whether the results may have been altered–especially because the authors have been kept in the dark.

The trial was the first ever to compare the efficacy of 4 treatment regimens for hypertension–a diuretic, an ACE inhibitor, a calcium blocker and an alpha blocker, in 40,000 patients. It should establish which, if any, is superior in preventing cardiovascular complications of hypertension. The financial stakes are enormous.

But the integrity of the research findings and reporting process–the lack of control by the investigators–have been called into question. Scientists question why the results will not be released at next week’s meeting of the American Heart Association, “the premier meeting of the cardiovascular community and would seem the ideal place to announce the results of what could be the most important trial ever conducted in the hypertension field,” but rather at a press conference in mid- December.

Several clinical trial investigators expressed concern about industry’s influence. Even the Chair of the ALLHAT steering committee, Dr Curt Furberg (Wake Forest University), is quoted saying he is “uncomfortable” “about the decision to give industry such advance notice of the results, but that this had been incorporated into a contract between the NIH and the companies donating the drugs and had “nothing to do” with the steering committee.”

The case demonstrates how marketing controls medical research and it demonstrates complicity by NIH which sponsored the trial, but deferred to industry.

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http://www.theheart.org/lite.cfm?DGEGFBD

THE HEART ORG

Nov 15, 2002

ALLHAT: Government trial incites disclosure controversy

EXCERPT:

Bethesda MD – The results of the landmark US government hypertension trial, the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which are not being presented until mid-December, have been disclosed to the companies donating drugs to the trial, which has led to some concern among the scientific community.

ALLHAT is the first-ever trial to directly compare the effect of 4 treatment regimens for hypertension a diuretic, an ACE inhibitor, a calcium blocker and an alpha blocker on hard clinical end points. With 40 000 patients, it should establish which, if any, is superior in preventing cardiovascular complications of hypertension. It therefore has enormous commercial implications. The trial is also testing the lipid-lowering treatment pravastatin vs placebo in a subgroup of patients.

The doxazosin arm of the antihypertensive portion of the trial was stopped prematurely because of significantly less benefit in patients in this group compared with the reference diuretic arm. The rest of the trial continued to its end earlier this year. The data have now been analyzed and submitted for publication in the Journal of the American Medical Association. The plans are to announce the results at a press conference in mid-December in Washington DC, which has been timed to coincide with publication of the paper.

Companies sent prepublication manuscript

While members of the steering committee obviously know the results, as they have written the paper, the hundreds of investigators have not yet been informed of the outcome, but 3 companies that donated drugs to the trial (1 of which also gave some financial support) were sent draft copies of the final-results paper 1 month before submission for publication and were given the opportunity to submit comments for consideration by the writing committee of the trial. The companies involved are Pfizer, which paid for the alpha-blocker arm of the trial and donated both doxazosin and amlodipine, and BMS/Sankyo, which donated pravastatin but did not give any financial support. Chlorthalidone and lisinopril were both paid for by the NIH.

Several clinical trialists have expressed surprise and concern that these companies have been given such advance notice of the results and have been allowed to submit comments to the writing committee.

Dr Harvey White

Dr Harvey White (Green Lane Hospital, Auckland, New Zealand) said he was “staggered” by this decision. “Even in trials that are completely sponsored by industry, only a few people should see the results, and then only a few days before presentation so that they can work out implications for their company. In an industrial-sponsored trial there needs to be a bit of flexibility as the company usually has a major input to the design of the trial, but this seems very generous, especially as it is an NIH-conducted trial, most of which has been funded by the government.”

Dr Paul Armstrong

Dr Paul Armstrong (University of Alberta, Edmonton) agrees. “If the trial is mainly funded by the NIH, it does seem peculiar to me that industry would have special access prior to presentation and publication,” he commented to heartwire. Furberg “uncomfortable”

Dr Curt Furberg

Chair of the ALLHAT steering committee, Dr Curt Furberg (Wake Forest University), says he is “uncomfortable” about the decision to give industry such advance notice of the results, but that this had been incorporated into a contract between the NIH and the companies donating the drugs and had “nothing to do” with the steering committee.

He commented to heartwire that the NIH was doing what some academic groups would do in a sponsored trial situation, where a company is funding the whole trial. “But many academic groups would object to these conditions in a sponsored trial, and it is even more questionable in an NIH-conducted trial,” he said.

Furberg noted that in situations where the results are positive for the companies involved the fact that they have prior access may not matter much, but the situation becomes more difficult if the results are negative. “If they are pleased with the result, they tend to be comfortable in the back seat. But when the results are not what they want, the companies may try to influence the writing committee and plan for damage control, and advance knowledge is therefore very important to them.” He says a strong steering committee should be able to stand up to the companies in this respect, but that sometimes there can be some commercial influence exerted. Many academic groups would object to these conditions in a sponsored trial, and it is even more questionable in an NIH-conducted trial.

In the case of ALLHAT, Furberg says the writing committee of the trial has complete power to decide whether any comments submitted by the companies are valid enough for inclusion in the paper. “The companies have no veto power. The writing committee can take or leave their comments,” but he adds that the very fact they are given the opportunity to make comments could influence the committee a little.

Shouldn’t the investigators know first? Another reason not to inform the companies first is that the investigators themselves have not been told the results. “There are 600 sites in this trial, so that is a lot of investigators. I would have liked to have informed them before the companies,” Furberg says.

White, who was a member of the ISIS and GUSTO clinical trial groups, agrees. “The ISIS committee would have been appalled if the sponsors had heard a month before the investigators, and in GUSTO-1, we limited the sponsor from knowing the results until about 1 week before presentation. And these were all industry-funded trials. For an NIH trial, there should be no need to tell the companies involved before the results are presented to investigators.” Confidentiality problem

Another problem with allowing companies access to the results is confidentiality. The more people who know the results in advance, the more likely it is that they will be leaked before official presentation, which in the case of ALLHAT does seem to have occurred: rumors of the outcome are circulating among the cardiology community. The . . . committee would have been appalled if the sponsors had heard . . . before the investigators.

The contract between the NIH and these companies states that the companies “will limit disclosure of any such prepublication manuscripts to a minimal number of scientific/clinical/patent staff connected with the study,” although it adds that immediately before publication more extensive distribution of the results is allowed within the company to avoid it being “blindsided.”

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