The medical profession shake up this week

Those who’ve been following the medical news this week know about the editorial in the Journal of the American Medical Association calling for the medical profession to clean up its act in regards to conflicts of interest. This issue of the publication is already being called history-in-the-making. Its articles and the major proposals for overhauling medicine made by the editors, Dr. Catherine D. DeAngelis, M.D., MPH; and Dr. Phil B. Fontanarosa, M.D., MBA, are being well covered by others, but one point hasn’t yet been raised.

Briefly, for those who haven’t read this JAMA issue, it has two articles (full text and relevant documents have been made available free to nonsubscribers) written by authors predominately involved in the Vioxx lawsuits against Merck & Co.

The first article reviewed 250 court documents and found that journal articles had been ghost-written by Merck authors, and academic scientists had been paid for the use of their names ($750-$2,500) listed as first or second authors before the articles were submitted for publication, apparently trying to conceal company involvement. Neither the ghostwriters nor Merck’s sponsorship had been disclosed in half of the published clinical trial articles.

The second article compared the published articles reporting on drug trials with internal company records (Merck had control of the clinical trial data) which suggested that in both the published articles and the information submitted to the FDA, Merck had downplayed the actual heart disease deaths, including a 4.43-fold increased risk for all-cause mortality. The article also found: “In December 2001, when the FDA raised safety questions about the submitted safety data, the sponsor did not bring these issues to an institutional review board for review and revealed that there was no data and safety monitoring board for the protocol study.” It raised questions about how allowing a sponsor to control and analyze the data in a clinical trial harms the integrity of the scientific process and the protection of human research participants.

When companies prepare a clinical trial report, the results are spun more positively, said Dr. Joseph Ross, M.D., MHS of Mount Sinai. For the academic authors, publication of large studies in major medical journals is prestigious and often opens doors for other roles, including lucrative consulting.

Ghost writers

Ghostwritten medical papers was discussed here last year when an investigation compared the full trial protocols for industry-initiated clinical trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg during 1994–1995, with what was published, and discovered evidence that 75% had been ghost written. Organizations have been calling for protocols for disclosing all parties who’ve been involved in a study, including the roles of medical writers, editors and statisticians, but implementing them has proven difficult, the investigators said, partly because of the far-reaching roles medical writers play in the industry. It is very common for professional medical writers to compose trial reports, reviews, and other papers for the pharmaceutical industry, but their part isn’t revealed.

Organizations, such as the International Committee of Medical Journal Editors, have established criteria for the citations of authorship in journals, to distinguish their contributions from other contributors. According to their guidelines:

Authorship credit should be based on 1) substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically for important intellectual content; and 3) final approval of the version to be published. Authors should meet conditions 1, 2, and 3.

As the Danish investigators noted, medical writers who are actually ghost-writing the initial drafts work behind the scenes. The medical writers hired by companies or medical writing subcontracting companies rarely have final approval of an article but, instead, do the grunt work and first draft for the company or academic scientists who do. In the hiring process, such medical writers are screened and those who are retained are ‘team players’ and members of the club, so to speak, who will please clients by writing favorably about the drug or device. Certainly, there are authors who accurately and objectively present a study’s finding and its limitations and strengths. But most medical writers who want jobs or assignments must go-along-to-get-along and keep quiet about serious critiques or concerns. According to the ICMJE guidelines, these ghostwriters wouldn’t be recognized as authors but, instead should be listed as contributors in the acknowledgements along with disclosures of their financial support. But seldom are.

In the JAMA editorial, Drs. DeAngelis and Fontanarosa wrote that failing to disclose ghost writers gives the false assumption to readers that the principal investigator was involved in writing the manuscript from the beginning, where experienced authors know that the initial draft (as paid for by Merck in this issue’s examples) sets the tone for a manuscript.

JAMA editorial lessons

The JAMA editors’ lengthy editorial, “Impugning the Integrity of Medical Science — The Adverse Effects of Industry Influence,” opened by saying:

The profession of medicine, in every aspect—clinical, education, and research—has been inundated with profound influence from the pharmaceutical and medical device industries. This has occurred because physicians have allowed it to happen, and it is time to stop... The direct influence of for-profit companies on education and clinical practice has been well documented, so this Editorial deals primarily with clinical research.

After reviewing the two investigations exampling Merck published in this issue of JAMA, they identified three lessons learned:

First, manipulation of studies and misrepresentation of study results could not occur without the cooperation (active and tacit) of clinical researchers, other authors, journal editors, peer reviewers and the FDA. Second, public trust for clinical research is in great jeopardy especially when the extent of how widespread such practices have become is unknown. Although we truly believe that the vast majority of researchers and other authors are honest and have the highest scientific integrity, manipulation of studies and publications by the pharmaceutical and medical device industries is either increasing or there has been more exposure of these practices. Third, in addition to clinical research, clinical practice and medical education also are greatly influenced by for-profit companies. Drastic action is essential, and cooperation of everyone involved in medical research, medical editing, medical education and clinical practice is required for meaningful change to occur.

They go on to make eleven proposals for all of those involved in medical research, publication and education to preserve and strengthen the integrity of medical science:

1. All clinical trials listed in registries accepted by the International Committee of Medical Journal Editors prior to patient enrollment, with the name(s) of the principal investigator(s) required as part of the trial registration.

2. All those meeting authorship criteria be listed; journals mandate each author report his/her specific contribution; all others involved with the manuscript or study must be named in the acknowledgment section, including their affiliations.

3. “All journals must disclose all pertinent relationships of all authors with any for-profit companies, and must publish all funding sources for each article.”

4. Funding sources and author disclosures should included in journal editors’ decisions of accepting a paper for publication.

5. “For-profit companies that sponsor biomedical research studies should not be solely or primarily involved in collecting and monitoring of data, in conducting the data analysis, and in preparing the manuscript reporting study results. These responsibilities should primarily or solely be performed by academic investigators who are not employed by the company sponsoring the research.”

6. Requirement for an independent statistical analysis of clinical trial data.

7. “Any author who fails to disclose financial relationships or other conflicts of interest, or who allows his or her name to be used for work that he or she did not actually perform, must be reported to the appropriate authority or appropriate oversight body....”

8. Sanctions for any peer reviewer who provides confidential information to any third parties, such as for-profit companies, or who engages in other similar unethical behavior.

9. “Any editor who knowingly allows (or is party to allowing) for-profit companies to manipulate his or her journal must be relieved of the editorship.”

10. “To maintain a healthy distance from industry influence, professional organizations and providers of continuing medical education courses should not condone or tolerate for-profit companies having any input into the content of educational materials or providing funding or sponsorship for medical education programs.”

11. “Individual physicians must be free of financial influences of pharmaceutical and medical device companies including serving on speaker's bureaus or accepting gifts.” [emphasis added]

“It can be argued that merely disclosing relationships with for-profit companies and identifying who actually writes articles for publication does little to stop the practices for cases in which the relationships are unethical or in which the sponsor has inappropriate influence over the data or control over the manuscript,” they wrote. “However, disclosure does provide readers with information that can be used in deciding about the credibility of the article—at least as interpreted by the reader.”

While their recommendations are debated over upcoming months, it benefits us to recognize that “for-profit” pharmaceutical and medical device companies are not the only sources of conflicts of interest. Nonprofit organizations and foundations are equally important disclosures. These large, influential entities route vast amounts of pharmaceutical and special interests moneys and are growing sources of research funding and financing of professional organizations. Political ideologies can, and as we’ve seen, have, similarly influenced the integrity of research, clinical guidelines and health policies published in medical literature.

Capital Research Center’s June 2002 report noted that the number of nonprofits in the U.S. has grown from 138,000 in 1990 to 218,000 in 1998. Among the ten wealthiest are “President & Fellows of Harvard College ($15.3 billion), the Howard Hughes Medical Institute ($13.0 billion), Yale University ($7.3 billion), the Shriners Hospitals for Children ($7.2 billion), the Kaiser Foundation Hospitals ($7.1 billion), Stanford University Board of Trustees ($6.0 billion), and the Trustees of the University of Pennsylvania ($5.9 billion).”

For example, one of the largest health foundations in the country is, of course, Robert Wood Johnson Foundation (with 60% of its assets invested in Johnson & Johnson). Among the research it has supported includes the research efforts of nonprofits such as the American Lung Association, American Cancer Society and American Heart Association; the American Medical Association, and numerous research universities for anti-tobacco research and lobbying. Among its grants for 1998, for example, was $13.2 million to Columbia University, $1.3 to the University of Kentucky Research Foundation, and awards of $100,000-$350,000 apiece for 31 university research centers for research on substance abuse. It has awarded $3 million in 2006 to fund 14 universities and research organizations for its Healthy Eating Research program, based at the University of Minnesota, with another $11 million earmarked for the next five years for research to support its childhood obesity initiatives. This is just a fraction of the $500 million it has earmarked for obesity CME education, research and lobbying. A second round of grants totaling $16 million for its Healthy Eating Research program went out in 2007, as part of that year’s $487.87 million grants and contracts to 829 grantees. RWJF’s influence in research, clinical guidelines and public policies is pervasive, yet largely unrecognized in medical literature.

Disclosures are not only appropriate for pharmaceutical and medical device companies. Kaiser Permanente’s Division of Research, for example, has funded more than $30 million in research, contributed more than 220 scientific articles to medical and public health literature in 2006, and has published over 2000 articles. Kaiser health plan says its eight research centers comprise one of the largest research programs in the U.S. Since 2002, it has collaborated with Robert Wood Johnson Foundation, the CDC, American Association of Health Plans, Health Partners, and the National Business Group, to develop the national anti-obesity agenda, including research, clinical guidelines for doctors, and education for children and healthcare professionals. As the JAMA editors said, disclosures might at least help readers better understand the reliability of published information.

Dr. Roy M. Poses M.D. wrote in an article entitled “Ghosts come home to roost:”

We on Health Care Renewal have been talking for years now about how clinical research and medical education have been influenced and manipulated to promote vested interests. It now appears that a substantial portion of the clinical evidence base and a substantial amount of medical education have been so undermined.

Dr. DeAngelis is right. We have given up medicine and now we have got to get it back. If we don't, we will be left with unimaginably expensive health care that does little good except to the pocket books of the well connected.