Time for a Drug Test Registry_Marcia Angell_Why NIH is Not Up to the Task

Time for a Drug Test Registry_Marcia Angell_Why NIH is Not Up to the Task

Fri, 13 Aug 2004

The uncovering of concealed, unpublished evidence showing that children suffered harm in antidepressant drug trials, has led to a rude public awakening. Selective reporting of clinical trial data has become “standard practice” and the scientific literature has been corrupted by biased medical reports.

Caught in the cross-fire, the American Medical Association and the International Committee of Medical Journal Editors recommended establishing a clinical trial registry. Slapped with a lawsuit by NYS Attorney General, GlaxoSmithKline put some of its Paxil pediatric trial data on its website. Eli Lilly and other drug companies stated their intention to do even better. But voluntary disclosure is no longer an option.

Dr. Marcia Angell, former editor of The New England Journal, doesn’t just call for a clinical trial registry, she enumerates essential conditions for a meaningful clinical trial registry in a Washington Post Op Ed:

1. The registry should contain all trials, not just those that the companies want to include, and it should be administered by a publicly accountable agency, such as the National Institutes of Health.

2. Clinical trials should be registered at inception, not after they are completed.

3. The registry should identify the main researchers and disclose any financial ties they have to the companies whose drugs they are studying.

The Alliance for Human Research Protection has but one disagreement with Dr. Angell’s recommendations-entrusting oversight responsibility to the National Institutes of Health (NIH). We believe that in light of NIH’s unseemly track record involving system wide conflicts of interest, NIH cannot possibly serve as a credible public agency to guard against industry’s influence on overseeing clinical trial data.

In addition to its failure to enforce federal conflicts of interest rules, NIH has failed to follow and enforce existing ethical standards in clinical trials conducted at NIH or funded by NIH–in accordance with 45 CFR 46.

In the wake of an unending stream of revelations about hidden, ongoing conflicts of interest by top NIH scientists and directors, NIH’s standing and credibility have been badly compromised. These conflicts first came to light in an investigative report by David Willman of The Los Angeles Times [1], then confirmed by an 8-month investigation by the House subcommittee on Oversight and Investigations. [2, 3, 4, 5]

A recent report by the Office of Government Ethics (OGE) is yet another stinging indictment of the agency’s “permissive attitude toward outside activities [which] played a major role” in encouraging industry’s penetration and influence on NIH research. The OGE deemed Dr. Zerhouni’s proposals for dealing with conflicts of interest ineffectual, calling his proposal to expand financial disclosure “not a substitute for appropriate substantive standards of ethical conduct.” [6]

Instead, Marilyn Glynn, director of the OGE called for firm, across-the-board restrictions, necessary to restore public confidence in the nation’s preeminent medical-research agency. [7, 8] The OGE report made 10 recommendations to rout out conflicts of interest both within the agency (restricting intramural scientists) and scientists funded by NIH who work off campus (extramural).

In a show of fraternal solidarity, the Federation of American Societies for Experimental Biology (FASEB) sided with Dr. Zerhouni, objecting to the restrictions on intramural scientists, calling them “punitive.” [9] But this argues for selective legitimizing of impropriety.

Glynn pointed out the fallacy of the NIH / FASEB partial approach to ethics, noting especially the safety of human subjects:

“probably the most compelling argument that can be made for any absolute prohibition on consulting with drug companies is that some NIH officials actually are involved in making clinical decisions affecting the health and safety of patients and other intramural research subjects, and those subjects need to be confident that decisions about their care are free from any potential influence from extraneous business connections.”

AHRP believes that there is a clear need for an independent agency to administer and oversee a public registry-and that agency should be accountable to Congress.

AHRP agrees with Dr. Angell’s call “to break the industry’s hold over the testing of its own products so that we will know whether new drugs are as effective as their makers claim. Talk of “miracles” and “innovation” is no substitute for evidence.”

However, given the record of egregious violations and abuse, there is a pressing need for sanctions to be imposed on researchers and institutions that fail to comply with the registry’s requirements.

Only when such a clinical trial registry is established will evidence-based medical practice become a reality.

References:

1. Willman, D. “Stealth merger: Drug companies and government medical research,” Los Angeles Times, December 7, 2003. p. A-1. http://www.latimes.com/news/nationworld/nation/la-na-nih7dec07.story http://www.latimes.com/news/nationworld/nation/la-na-nih6aug06,1,2647063.story?coll=la-headlines-nation

2. Willman,D. Lawmakers Assail NIH Conflict Rules. Los Angeles Times, May 13, 2004: http://www.latimes.com/news/nationworld/nation/la-na-nih13may13,1,3459920.story?coll=la-headlines-nation

3. AHRP Infomail. Lawmakers Accused Leaders of the NIH of Encouraging “the option of corruption.” May 18, 2004: http://www.ahrp.org/infomail/04/05/18.php

4. Wysocki, B. National Institutes of Health Is Under Fire; Longtime Favorite of Congress Grapples With Slim Funding Increases, Conflicts Inquiry. Wall Street Journal Jun 22, 2004 p. A.4

5. Weiss, R. NIH Scientists Broke Rules, Panel Says Deals With Companies Went Unreported, Probe of Potential Conflicts of Interest Finds. Washington Post, June 23, 2004; Page A19

6. Report of the NIH Blue Ribbon Panel on Conflicts of Interest: A Working Group of the Advisory Committee to the Director NIH, Jun 22, 2004: http://www.nih.gov/about/ethics_COI_panelreport.pdf (pdf file)

7. Weiss, R. NIH to Set Stiff Restrictions on Outside Consulting, Washington Post, August 4, 2004, Page A-1 http://www.washingtonpost.com/ac2/wp-dyn/A37841-2004Aug3?language=printer

8. Willman, D. NIH Is Pressured to Bar Drug Industry Stipends. Los Angeles Times, August 6, 2004, Page A-1: http://www.washingtonpost.com/ac2/wp-dyn/A37841-2004Aug3?language=printer

9. Agres, T. NIH ethics report draws critics. The Scientist. August 12, 2004. online at: http://www.biomedcentral.com/news/20040812/02

Contact: Vera Hassner Sharav
Tel: 212-595-8974

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http://www.washingtonpost.com/wp-dyn/articles/A61488-2004Aug12.html
THE WASHINGTON POST
Time for a Drug Test Registry
By Marcia Angell

Reports that the drug giant GlaxoSmithKline buried evidence that its top-selling antidepressant, Paxil, is not effective in children have stimulated calls for a public registry of company-sponsored research. It’s about time. You might imagine that this was an isolated case of corporate misbehavior, but in fact suppressing unfavorable research results is fairly standard practice in the pharmaceutical industry.

Before drug companies are allowed to bring a new drug to market, they are required by the Food and Drug Administration to conduct clinical trials to show that the drug is safe and effective. They are supposed to provide the agency with the results of all the trials, not just some. But they don’t have to publish or otherwise make the results available, and neither does the FDA. Moreover, the FDA may approve a drug on the basis of a few trials that make it look good, even though other trials may indicate it is not effective. The companies selectively publicize the most positive results, and legions of sales representatives then visit doctors to tout the positive findings.

Just as troubling as the outright suppression of unfavorable research is the bias in the research that is published. Clinical trials can be set up to make drugs look good, and that, too, has become common. Companies can, for example, enroll only young people as human subjects, even if the drug is likely to be used by older patients — thereby lessening the chance that side effects will show up. Or they can compare a new drug with an older drug administered at too low a dose, which means the new drug is bound to look better.

Sometimes they sift through the results of a trial and select just the positive findings for publication — a practice known as “data dredging.” For instance, a trial of the effect of a drug on heart attacks may be converted to a trial of the drug’s effect on blood pressure, if it begins to look as if the drug isn’t much good for heart attacks. Or a one-year trial may be converted to a six-month trial if the drug looks good only in the first half of the study.

Researchers, even in our best universities, often go along with this sort of thing, because sponsors insist on it. A public registry of clinical trials would help eliminate many of these abuses, but only if it met the following three conditions:

First, it should contain all trials, not just those that the companies want to include, and it should be administered by a publicly accountable agency, such as the National Institutes of Health. Registration should be a condition of enrolling human subjects in research, since volunteers expect their participation to contribute to scientific knowledge and the public has a right to accountability. The argument that listing trials might reveal important proprietary secrets is not persuasive, because by the time drugs enter clinical trials, they are already patented and largely developed.

Second, it is crucial that trials be registered at inception, not after they are completed. The initial information should include a brief description of the design of the trial, including the kinds of patients to be enrolled, the drugs and doses to be tested, what the new drug will be compared with, the duration of the trial, the endpoints that will be measured, and the methods of measurement. That way any bias in the design of the study would be immediately apparent, and sponsors could not shift the endpoints as the trial progressed. At completion, the salient results should be reported. Not all trials are worth publishing in medical journals, but companies will still want their best studies to gain the added prestige and attention afforded by publication in a good peer-reviewed journal. That is fair only if information about all of the trials is available in the registry.

Third, the registry should identify the main researchers and disclose any financial ties they have to the companies whose drugs they are studying. Since drug companies don’t have direct access to patients, they depend on academic researchers and private doctors to supply human subjects and collect the data. Identifying them in the registry would hold them responsible for the quality of the research they perform.

The evidence of bias in medical reports is undeniable. It’s time to break the industry’s hold over the testing of its own products so that we will know whether new drugs are as effective as their makers claim. Talk of “miracles” and “innovation” is no substitute for evidence. The establishment of a government registry of clinical trials is a good way to begin, but it must be done right.

The writer is a former editor in chief of the New England Journal of Medicine and author of the forthcoming book, “The Truth About the Drug Companies.”

C 2004 The Washington Post Company

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