Secrecy has always been the norm in the pharmaceutical arena, but over the past decade it has taken on even greater significance as the funding of medical research has swung from something that was done to improve public health to something that is done for commercial gain.
In the United States 70% of the $5.56 billion that goes into funding for clinical research comes from the biopharmaceutical industry, with an additional 20% generated by the makers of medical devices. Similar figures are not available for Canada, but the pharmaceutical industry spends about as much on clinical research as the entire budget of the Canadian Institutes for Health Research.
As the source of funding changes, so do the obligations to share and publicly disclose research results. When research is done to advance the public welfare, then the premise is that everyone should share in the benefits, but when it takes on a commercial flavour, it is being done to produce a commodity--and commodities are by their nature private. Research is kept secret to ensure that companies derive the maximum value from their investment.
Of course, the state could compensate for increased funding from commercial interests by also increasing the amount that it devotes to medical research, thereby helping to ensure that there is a substantial amount of publicly available research. However, there has been a paradigm shift in the thinking of the Canadian government in this area. The government collects user fees from industry to cover about 50% of the cost of running the Therapeutic Products Directorate (TPD), the agency that approves new drugs, and over the past decade since user fees were instituted the TPD has adopted many of the industry’s priorities, including more emphasis on rapid drug approvals.
The apparent reorientation of the TPD in favour of business interests is further reflected in its Business Transformation Strategy (BTS) that is being implemented. The BTS was introduced in early 2003 and “builds on the commitments made by the Government of Canada to ‘speed up the regulatory process for drug approvals,’ to move forward with a smart regulations strategy to accelerate reforms in key areas to promote health and sustainability, to contribute to innovation and economic growth, and to reduce the administrative burden on business.”
One of the key phrases in the BTS is “smart regulation.” This means that Canada should “regulate in a way that enhances the climate for investment and trust in the markets.” While health is not ignored, the emphasis is clearly on creating a business-friendly environment. The shift from the precautionary principle to risk management is subtle but unmistakable. Realigning regulation to conform to the principles of smart regulation would not totally abandon the concept of precaution, but it seems to imply that there would have to be a threat of serious or irreversible damage before it would come into play.
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A survey of a representative group of life science companies in the United States conducting or sponsoring research in academic institutions found that 56% reported that companies sometimes or often kept the resulting information confidential for more than six months, well beyond the time needed to file a patent. A lack of communication among researchers for prolonged periods can damage science in a number of ways–including forcing the unnecessary repetition of research, thereby exposing patients to potential risks that have already been uncovered, using up scarce resources, and causing the discontinuation of projects because of the unavailability of information.
A recent survey of 107 U.S. medical schools documents the extent of the culture of secrecy that results from industry funding. On some measures the results are reassuring--93% prohibit the sponsor from deciding whether or not the results should be published--but 62% permit the sponsor to alter the study design after an agreement has been executed, and 80% allow the sponsor to own the data.
As bad as it is within the academic community, the situation is likely to be even worse in the broader community sector where there is no culture of academic freedom. Research funding has moved dramatically out of academia and into the community. In the U.S., in 1994, 63% of corporate funding for clinical research went to the academic community, but by 2004 that share was down to only 26%. Here in Canada, between 1997 and 2004, the percent of trials conducted in the community setting went from 47% to 60%.
Receiving money from commercial sources can lead to either a suppression of or a delay in the publication of research results. Nearly one-quarter (24%) of faculty involved in university-industry research relationships responded affirmatively to the question: “Have you personally conducted any research at your university the results of which are the property of the sponsor and cannot be published without their consent?” Only 5% reported they were not involved in such relationships.
Unpublished studies can bias the results of meta-analyses, especially if the trials being withheld are negative. A meta-analysis of trials on the use of selective serotonin reuptake inhibitors (SSRIs) in children with depression illustrates the dangers in withholding publication. Published trials suggested a favourable risk-benefit profile for some SSRIs, but when data from the unpublished trials was added, the conclusion was that, except for fluoxetine (Prozac™), the possibility of harms outweighed that of benefits.
GlaxoSmithKline did not publish results that showed that paroxetine (Paxil™) was ineffective for the treatment of depression in children and adolescents because, according to an internal company memo, “It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.”
Almost one-third of academic scientists who received gifts from industry (biomaterials, discretionary funds, research equipment, trips to meetings, support for students, and other research-related items) reported that the companies making the donations wanted pre-publication review of any articles or reports stemming from their use of the gift. An article in the New England Journal of Medicine presents six vignettes based on interviews with investigators where publication was stopped or the content of articles was altered by the funding company.
Authors with financial relationships with industry are unlikely to report these relationships. Although 26 out of 70 authors studying calcium channel blockers, a class of drugs used to treat heart disease and high blood pressure, had received funding from manufacturers of these products, only two of them reported any type of potential conflict of interest in the resulting publications.
An investigation by the internationally known general science journal Nature looked at more than 200 sets of clinical practice guidelines (CPGs) that outline how doctors should diagnose and treat particular medical problems. Only 90 contained details about individual authors’ conflicts of interest, and of those only 31 were free of industry influence. More than a third of the panels that developed the CPGs included at least one member who gave seminars on behalf of a company whose products were being recommended, and 10% had someone who owned stock in a company with products being considered.
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The introduction of the COX-2 inhibitors, a new class of medications for pain and inflammation that included Vioxx™, was hailed by many in the medical and patient communities because they were suppose to cause much less stomach bleeding. The CLASS study published in the Journal of the American Medical Association (JAMA) in 2000 appeared to confirm the protective effects of another one of these drugs, celecoxib (Celebrex™), over traditional non-steroidal anti-inflammatory (NSAID) medications after six months of treatment. However, material on the website of the U.S. Food and Drug Administration (FDA) revealed a number of discrepancies between the data as published in JAMA and as submitted to the FDA.
What the authors of the CLASS study and the companies marketing Celebrex™didn’t tell anyone was that the published trial actually combined the results of two trials, one that continued for 12 months and another that ran for 16 months. At the 12-16-month time, there was no difference in gastrointestinal adverse effects between those patients who used Celebrex™ and those using the traditional NSAID.
Drug companies are also hiding the authorship of articles through a practice known as ghostwriting, using a professional medical writer to produce an article favourable to one of their products and then seeking a well-known clinician to sign the article. Dr. Adriane Fugh-Berman from the Georgetown University School of Medicine in Washington D.C. recounts her experience with an article describing interactions between herbal preparations and drugs that “thin” the blood. In the summer of 2004, she was approached by a medical communications company, representing a drug firm, asking her if she would write an article about interactions between warfarin, one of these blood thinners, and herbs. Before agreeing, she asked the communications company for further information and a few months later received a draft article, complete with a title page containing her name. Although the sponsoring drug company did not make any blood thinners at that time, it was planning to introduce one shortly and in order to enhance the market for its new product wanted to point out problems with existing medications. To make sure that the point about the potential dangers of warfarin were sufficiently prominent, it had hired the communications company to write the article. Fugh-Berman’s job was to sign off on the piece if she agreed with its contents.
Dr. David Healy, a psychiatrist from Wales, shows how Current Medical Directions, another medical communications company, produced favourable articles about the antidepressant sertraline (Zoloft™) for its maker Pfizer and then went about searching for well-known academics who would agree to be authors.
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Drug regulation in Canada is shrouded in secrecy. Even the names of drugs in the approval process are not disclosed, and all of the information that industry submits, including clinical trial data on safety and effectiveness, is deemed confidential and can only be released with the permission of the company--even with an Access to Information request.
There is no good evidence to show that the interests of companies would be harmed by the disclosure of information about safety and effectiveness; specifically, confidentiality about this information is not necessary to foster research and innovation, but disclosure definitely has the potential to enhance safety through disclosing all of the known relevant information about a new drug. On the other hand, non-disclosure has serious disadvantages for the TPD, health professionals, and the public. If information submitted to regulatory agencies is never disclosed, then these data will never enter the normal peer review channels and are therefore not subject to scrutiny by independent scientists.
Without this type of feedback, TPD reviewers may be more prone to misjudge the accuracy or usefulness of the data submitted; the scientific atmosphere in the agency may be stifled, and the professional growth of its staff severely inhibited. Deprived of any independent access to information, health professionals have to accept the TPD’s judgment about the safety and effectiveness of products.
A recent Health Canada document on increasing transparency favourably refers to the European Public Assessment Report (EPAR), which is a document produced by European Medicines Agency (EMEA), the equivalent of the TPD, after a drug has been approved. EPARs are supposed to reflect the assessment file submitted by the manufacturer, its analysis by the EMEA’s scientific advisory body, and the reasons underlying that body’s opinion.
The International Society of Drug Bulletins (ISDB), an international organization of independent drug bulletins, undertook an analysis of 9 EPARs issued between September 1996 and August 1997. The most striking finding was a lack of standard presentation of information: for instance, the Scientific Discussion section did not always have epidemiological data, and in some EPARs the mechanism of action of the drug was not fully presented. The reporting of clinical trials was not always clear and none of the nine EPARs mentioned references to published trials. Expert opinions on the drugs, along with their doubts and final positions, were of variable quality. The ISDB subsequently extended its analysis to cover all EPARs published in 1999 and 2000. The results were still very negative: the EPARs were not harmonized, reliable, or correctly updated.
La revue Prescrire, an independent French drug bulletin that does not take any pharmaceutical company advertising, considers that “in many cases, analysis of EPARs suggests that these documents are totally or mainly written by the firms themselves, or edited by copying and pasting from the firm’s application.” The level of secrecy in the TPD has been criticized a number of times, including by Health Canada’s own scientific advisory board in February 2000, headed at that time by Roberta Bondar, and later in early 2004 by the House of Commons Standing Committee on Health. In response, the TPD announced a new initiative termed the Summary Basis of Decision (SBD), modelled heavily on the EPARs. When a new drug or medical device is approved, the SBD would outline the scientific and benefit/risk-based reasons for the TPD’s decision to grant market authorization for a product.
The key part of the SBD of importance to prescribers and consumers is the clinical information on drug effectiveness and safety. Is enough information provided to allow for safe and rational use of new medications or the new uses for previously approved drugs? In the past couple of years, there have been several cases where an examination of the data submitted to drug regulators has allowed the identification of information that was either unavailable or misrepresented within the published literature. These same discoveries would not have been possible using the new SBDs because they lack crucial information: the study protocol behind the research is unavailable; there is no information about baseline characteristics of trial participants, the number of participants who withdrew and reasons for their withdrawal; and the data are presented in such a way as to make it very hard to determine how safe and beneficial the new drug truly is.
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The pharmaceutical industry is the major funder of medical research in developed countries, and with that position it has been able to impose its agenda of commercial secrecy on the research that it funds. As a result, researchers are increasingly refusing to share data, potentially jeopardizing one of the fundamental bedrocks for the advancement of science. While the situation in academia is a cause for grave concern, there are strong grounds for believing that the situation in the broader community sector, where funding is increasingly being directed, is even worse.
In order to protect sales, companies suppress negative results, either by refusing to submit them for publication or by trying to intimidate people who publicize these unwanted findings. The relationship between industry and researchers and authors is not revealed, so that the conflicts-of-interest that such a relationship generates remains below ground and does not threaten the legitimacy of the research. When research is published, it is often presented in a biased way that distorts the truth in favour of commercial interests.
Finally, the TPD, the body which is suppose to be protecting the public interest, colludes with industry in keeping research into the effectiveness and safety or drugs from public view. In doing so, it not only damages its own credibility, but it also sets the stage for the misuse of drugs to the detriment of doctors, other health care workers, and the people who take the medications.
In order to challenge this cult of secrecy, it will be necessary to challenge the corporate ethic that has allowed industry to become the natural funder of medical research.
(Joel Lexchin, MD is an associate professor at the School of Health Policy and Management at York University and the Department of Family and Community Medicine at the University of Toronto. This article was adapted from a longer paper by Dr. Lexchin on pharmaceutical secrecy. The full text, footnoted and fully referenced, can be obtained on request.)