Industry Influence: FDA “Critical Path”/ Biased Research: BMJ / NIH: still smoke & mirrors

This Infomail deals with three interrelated issues:

1. A BMJ meta-analysis found pharmaceutical influence results in biased research reports:
The US government publication, HealthDay News, reports (below) that an independent authoritative analysis by the prestigious Cochrane Collaborative Center (in Denmark) concludes: "drug reviews that are supported by the pharmaceutical industry tend to be more biased and rate the drugs more favorably than independent reviews."

The meta-analysis was published in the BMJ (British Medical Journal):
" Industry supported reviews of drugs should be read with caution as they were less transparent, had few reservations about methodological limitations of the included trials, and had more favourable conclusions than the corresponding Cochrane reviews."  http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38973.444699.0Bv1?hrss=1

The authors found–as did other similar comparison evaluations–that: All seven of the industry-supported reviews recommended the drug in question without hesitation, while none of the Cochrane reviews did. In both cases, however, the estimated effect of the drug was similar. "This suggests that the main problem with industry-supported reviews lies in how conclusions are formulated." 

2. A report in the Los Angeles Times (below), the latest in an ongoing saga documenting ethics violations by high ranking government scientists at the National Institutes of Health.
The LAT reports the responses given by Dr. Elias Zerhouni, Director of NIH, to questions about  his agency’s staff failure to comply with his own conflict of interest rules.

His responses reveal that after a two year battle, NIH researchers at continue to refuse even to disclose their financial relationships to drug and biotech companies. 
"Question: How many government scientists at the NIH have taken consulting fees or stock awards or options from drug companies?
Answer: After six congressional hearings spanning more than two years, we still don’t know because not all of the financial arrangements have been revealed."

Their continued refusal to comply with Federal conflict of interest regulations is a demonstration of unmitigated arrogance and disrespect for both the integrity of science and their personal responsibility toward the American taxpayer who pays these government scientists’ salaries ranging from $132,000 to $200,000.  NIH scientists were shown to have published biased scientific findings that promoted their corporate backers’ products. See Congressional transcripts and the ongoing series in The Los Angeles Times.
 
These NIH rule breakers are operating under the delusion that they are–"masters of the universe"– and are therefore, entitled to privileges above and beyond what other high ranking federal employees are.  In point of fact the conduct of these scientists–as they continue to dodge NIH disclosure rules–is undermining our trust in the integrity of their reported research findings.
In so doing they are undermining the credibility of the entire Institute–and they should be ousted. 

Contrary to their inflated self-image, they are replaceable. There are plenty of honest scientists with untarnished expertise who would jump at the opportunity to work toward medical breakthroughs that will benefit the public–not their stock portfolios and those of their partners in industry.

We are reminded of  Senator Domenici’s verdict after witnessing the spectacle at a Congressional hearing in March 2004, in which some of the financial ties by NIH scientists were laid bare (e.g., copies of cancelled checks).  Sen. Domenici, who had for years been a staunch supporter of NIH told The Hill:  "I hate to say it, but the NIH [have] turned into pigs. You know, pigs! They can’t keep their oinks closed. They send a senator down there [to] argue [for increased budgets] as if they’re broke."  http://www.ahrp.org/infomail/04/03/18.php

3. These latest reports underscore the need for vigorous open, public debate such as took place at a two day conference that I attended at Hofstra University School of Law.
The battle lines were drawn between those who recognize the corrosive effect that the pharmaceutical industry is having on the safety and integrity of medicine and medical research, and the powerful stakeholders–the pharmaceutical-academic industrial complex–who profit from and wield inordinate influence on every facet of the business of medical research–including the very agency authorized to oversee and enforce safety standards.

Conference attendees learned about a range of problems besetting medical research under the influence of Big Pharma–in particular the multi-faceted Vioxx debacle. Thoughtful participants having different perspectives discussed and debated both the economic, public policy, and philosophical issues involved. http://www.ahrp.org/cms/content/view/354/55/ 

However, attendees also witnessed a display of arrogance, misrepresentation (of FDA’s performance over the last decade and a half), and denial of drug safety failures. Those who defend Big Pharma and its financial "support" of academia and the FDA (since 1992) deny there is a problem. Absent entirely from their perspective is a recognition that preventable human casualties are  evidence of a failed system that needs to be fixed. The defenders of PhRMA and the FDA are focused only on the number of new drugs brought to market–whether these drugs are helpful or harmful; and on sales statistics. They disregard the tens of thousands–no, hundreds of thousands–of preventable drug-related human casualties–as if these have no value.

One presentation verged on buffoonery.  Peter Barton Hutt, a former FDA chief Counsel, 1971-1975, began with blistering attacks on those who criticized Big Pharma and the performance of FDA. He vented his spleen by invecting against effective critics such as Dr. Marcia Angell (former editor of The New England Journal of Medicine) who was not present. He then proceeded to make unilateral absurd assertions as if he were Moses presenting the 10 Commandments.

Mr. Hutt asserted that: the FDA is the most powerful government agency in existence; FDA has supreme legal authority which has never been challenged by anyone successfully; industry shakes in terror of incurring FDA’s power to harm their marketing;  industry meekly accepts FDA directives so as not bring the wrath of FDA. And he asserted that no one can challenge or overrule the FDA. Although scheduled to participate in a round table debate between the defenders and critics, he took aim, fired, and fled.

A presentation by Dr. Rachel Behrman, FDA deputy director, Office of Medical Policy, Center for Drug Evaluation and Research (CDER), failed to acknowledge with a single word that FDA has repeatedly received failing grades for its drug safety monitoring. Numerous independent investigations of FDA’s performance—most recently by the Government Accountability Office (GAO) and the Institute of Medicine—have concluded that FDA’s poor performance in drug safety shows this crucial function of the agency to be dysfunctional. 

Had knowledgable critics who were familiar with the IOM report content, conference attendees would have thought the agency’s performance was distinguished, worthy of pride.

Dr. Behrman’s presentation and affect lent validity to the devastating evaluation the IOM report gave the CDER staff, noting its culture of arrogance and disregard for safety issues. Even as the agency has been severely criticized for its failure to protect the public from lethal drugs, the FDA has embarked on a radical new venture—Critical Path—to speed up the process of testing and bringing to market new classes of genetically engineered drugs and biologics. No mention whatsoever was made about any safeguards. Critical Path was designed by Dr. Janet Woodcock, CDER’s former director who now is in the Commissioner’s office. It was designed to help industry out of its developmental slump.  http://www.fda.gov/oc/initiatives/criticalpath/  

If this radical departure from current drug testing methods is implemented without meaningful enforceable safeguards or specified meaningful penalties to deter cost-cutting short cuts that endanger lives—as happened in the catastrophic, monoclonal antibody experiment, TGN1412, we fear the worst.  The near fatal TGN1412 experiment in which all 6 healthy volunteers were exposed (within the span of 12 minutes) to a drug-induced “cytokine storm” led to multi-organ failure that nearly killed all of them. http://www.ahrp.org/cms/index.php?searchword=tgn1412&option=com_search&Itemid=5

Without specified mandatory safeguards and the agency’s commitment to enforce those safeguards, as well as its willingness to impose severe penalties for violators, TGN1412 foreshadows the likelihood that similar safety infractions will result in preventable human casualties.

References:
1. Anders W Jørgensen , Jørgen Hilden , Peter C Gøtzsche.  Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review, BMJ,  6 October 2006

2. Earle G.  Domenici slams Specter and NIH ‘pigs’, THE HILL. March 17, 2004  www.hillnews.com/news/031704/domenici.aspx

Contact: Vera Hassner Sharav
veracare@ahrp.org
 
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http://www.healthfinder.gov/news/newsstory.asp?docid=535358
HealthDay News 
Industry-Supported Drug Research Called Into Question
Studies done by nonprofit groups tend to be less biased, review contends.
By Amanda Gardner

 FRIDAY, Oct. 6 (HealthDay News) — Drug reviews that are supported by the pharmaceutical industry tend to be more biased and rate the drugs more favorably than independent reviews, a new study contends.

 As a result, industry-supported reviews of existing drug research need to be taken with a grain of salt, said the authors of the study in the Oct. 7 issue of the British Medical Journal.

 "It comes as no surprise that certain methodological limitations and selection biases would emerge when a purely academic meta-analysis approach — or one driven by a pharmaceutical sponsor — was taken," said Dr. Mark Fendrick, a professor of health management and policy at the University of Michigan School of Public Health, and co-editor-in-chief of the American Journal of Managed Care.

 The new study corroborates a number of other recent studies that have shown that clinical trials of drugs funded by pharmaceutical companies and other for-profit entities were more likely to report positive findings than similar trials funded by nonprofit groups.

 At the same time, the drug industry is paying for more and more medical research, with a full half of studies now funded solely by the private sector, another study found.

 Independent reviews of drugs — such as those conducted by the Cochrane Collaboration, an independent body — can have a much-needed counterbalancing effect, said the authors of the new study, who are based at a Cochrane center in Denmark. Cochrane reviews collect and analyze existing data using a rigorous, standardized system, the researchers said.

 For the new study, the researchers compared 24 Cochrane reviews with other so-called meta-analyses, or studies of studies. Eight of the 24 reviews were supported by the pharmaceutical industry, nine had undeclared support, and seven had no support or were supported by non-industry sources.

 On a scale of 0 to 7, the median quality score for a Cochrane review was 7, but only 3 for the other reviews, the authors of the new study said.  Cochrane reviews more often considered the potential for bias within the review, compared with industry-supported reviews and reviews with undeclared support. And, in general, Cochrane reviews had fewer methodological problems, although they were not without problems altogether, the study authors said.

 All seven of the industry-supported reviews recommended the drug in question without hesitation, while none of the Cochrane reviews did. In both cases, however, the estimated effect of the drug was similar.   "This suggests that the main problem with industry-supported reviews lies in how conclusions are formulated," the authors stated.

 As one example, a meta-analysis funded by Merck & Co. concluded in 2001 that there was no increased risk for arterial thrombosis (blood clots within an artery) with the company’s now-withdrawn arthritis drug Vioxx. But another, non-industry-supported meta-analysis did show an increased risk for clots. That increased risk was evident in publications that were available to the authors of the first report, the authors of the new review said.

 In September 2004, Merck withdrew Vioxx from the market after studies found the painkiller increased the risk of heart attack and stroke.  In June, the New England Journal of Medicine issued a rare correction on an influential 2005 study on Vioxx. The correction involved a crucial point: That cardiovascular risks linked to the controversial cox-2 inhibitor kicked in at four months to six months of use, not after 18 months as had been reported in the article first published in 2005. The original article outlined the results of the so-called APPROVe study, which was funded by Merck.

 The authors of this week’s BMJ study found that, generally, drugs reviews with undeclared support, or not-for-profit support, or no support drew conclusions similar in cautiousness to the Cochrane reviews.  As a result of the new findings, the authors of the new study are calling for more transparency in industry-supported drug trials, including more information on the methodology used and the estimated effects of the drugs.

 "They’re not saying industry-supported meta-analyses should not be done or should not be published but, once again, the issue of sponsorship should be highlighted," Fendrick said. "Sponsorship of scientific research, whether a single study, a meta-analysis or anything else, should be emphasized to be sure that the potential for these biases are made immediately apparent."

 Asked to comment on the new study, Jeff Trewhitt, a spokesman for the Pharmaceutical Research and Manufacturers of America (PhRMA), a drug industry group, said, "We still need to study the report. But it is important to note that the vast majority of clinical studies that companies conduct are rigorously reviewed by regulators as part of the drug approval process. It’s in our interests to make sure that the studies are of the highest quality.

 "What’s more, PhRMA and its member companies are committed to accuracy and transparency in clinical trials. PhRMA, two years ago, launched www.ClinicalStudyResults.org and, so far, member companies have submitted data summaries covering nearly 300 medicines. The summaries cover positive and negative data. PhRMA also earlier this year urged companies to register clinical trials for all medicines and not just drugs for life-threatening diseases on www.clinicaltrials.gov at the National Institutes of Health," he added.

 More information
 For more on clinical trials, visit the U.S. National Institutes of Health <http://clinicaltrials.gov/ct/gui/info/resources;jsessionid=1722B877B4AB26C97025370C8CBDFE71> .

  (SOURCES: Mark Fendrick, M.D., professor, internal medicine, University of Michigan School of Medicine, Ann Arbor, professor of health management and policy, University of Michigan School of Pubic Health, Ann Arbor, and co-editor-in-chief, American Journal of Managed Care; Jeff Trewhitt, spokesman, the Pharmaceutical Research and Manufacturers of America, Washington, D.C.; Oct. 7, 2006, British Medical Journal)

 Copyright © 2006 ScoutNews, LLC All rights reserved.

 HealthDayNews articles are derived from various sources and do not reflect federal policy. healthfinder® does not endorse opinions, products, or services that may appear in news stories. For more information on health topics in the news, visit the healthfinder® health library <http://healthfinder.gov/library/> .
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http://www.latimes.com/news/nationworld/nation/la-na-nihqampa6oct06,1,6380351.story  
THE LOS ANGELES TIMES
QUESTIONS & ANSWERS / NATIONAL INSTITUTES OF HEALTH ETHICS RULES
Drug Companies’ Consulting Fees at Issue
By David Willman
October 6, 2006

WASHINGTON — Last month, the chairman of the House Energy and Commerce Committee called the National Institutes of Health an "ethical Potemkin village," where a facade of tough-sounding rules had shrouded permissive dealings with drug companies.

NIH ethics rules, tightened last year, prohibit employees from accepting any form of pharmaceutical company stock and most types of drug industry fees. But the agency’s director, Dr. Elias A. Zerhouni, recently said that NIH was assessing whether the stricter rules had driven away talented scientists. The assessment may determine whether rules are changed.

The payments from the drug companies to the federal scientists have raised questions about decisions surrounding which products make it into NIH clinical trials, as well as the scientists’ safety decisions and interpretation of results.

Question: How many government scientists at the NIH have taken consulting fees or stock awards or options from drug companies?
Answer: After six congressional hearings spanning more than two years, we still don’t know because not all of the financial arrangements have been revealed. When the Energy and Commerce Committee asked 21 drug companies for information about recent relationships with NIH scientists, scores of previously undisclosed arrangements were identified. And many drug companies were not contacted, so there may be additional undisclosed payments.

Q: For how many years did NIH scientists accept fees or stock from the drug companies?
A: This also is hard to know, although many veteran employees said they saw little or no consulting with the companies before the mid- to late 1980s.

Q: Did a single event open the door more widely?
A: Yes. In a November 1995 memo, then-NIH Director Harold E. Varmus informed directors of the agency’s 27 research institutes and centers that he was rescinding a policy that had barred them from accepting consulting fees and payments of company stock. Other conflict-of-interest rules that Varmus changed: For the first time, all NIH employees were allowed to accept industry stock or options. A limit of up to $25,000 per year in total outside income and a requirement that an employee not spend more than 500 hours a year on outside activities also were rescinded.

Q: Why have drug companies sought to hire NIH scientists as consultants?
A: Many companies say the scientists bring valuable expertise. In some instances, companies acknowledged that the luster of the NIH was seen as an asset in attracting investment capital.

Q: Why have NIH scientists sought paid consulting deals?
A: Some have said that working with industry gives them new perspectives on delivering a product or technology that could be used by the public. Varmus has acknowledged an additional motive for drug-company consulting among NIH scientists: money.

Q: How much does the NIH pay its scientists?
A: Among those who have reported industry consulting payments, annual federal salaries at the NIH have often ranged from $130,000 to $200,000.

Q: Aside from the now-banned paid arrangements, do NIH scientists still collaborate with industry on research?
A: Yes — these "official duty" activities are encouraged under federal law and often result in the NIH teaming with a company to test an experimental product.

Q: Of the 103 scientists who came under internal investigation, typically because their arrangements with drug companies had not been pre-approved, how many were fired?
A: None, although NIH administrators have recommended the terminations of two senior researchers. Decisions in those cases are pending. Six other scientists left the NIH before investigations were completed.

david.willman@latimes.com

Copyright 2006 Los Angeles

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