The development of the randomized controlled clinical trial (RCT) was one of the major scientific advances in clinical medicine. RCTs provide a major part of the evidence underlying evidence based medicine. RCTs provide a major source of data used by the US Food and Drug Administration, and similar agencies in other countries, to decide whether to approve drugs or devices to manage particular clinical problems. Unfortunately, with the rise of the RCT came a rise in attempts to suppress and manipulate clinical trials by those with vested interests, often in selling the products and services the trials can evaluate.
Many of the examples we have discussed were of attempts at manipulation or suppression of clinical trials originally done to provide evidence for product approval, or even ostensibly to advance clinical science. Yet a relatively new article covering evidence revealed from litigation about the drug gabapentin (Neurontin) originally made by Parke-Davis, first a part of Warner Lambert, now part of Pfizer suggests that many clinical trials may not be done to advance science, or even just to provide data to regulators, but only to market products.
The article is Vedula SS, Goldman PS, Rona IJ, Greene TM, and Dickersin K. Implementation of a publication strategy in the context of reporting biases: a case study based on new documents from the Neurontin litigation. Trials 2012; 13: 136. Link here.
Methods Summary
The article described a case study based on documents revealed in 2008 litigation. The purpose of the study was:
The study examined documents revealed through the 2008 litigation. It concentrated on documents relating to the marketing of Neurontin for four off-label indications, that is, for four potential reasons to use the drug which had not yet been approved by the US FDA. It focused on documents discussing strategies for marketing for these indications, and then documents about particular company sponsored RCTs done for these indications.
Strategies to Sell Drugs
The documents examined by the investigators showed that Parke-Davis prepared "marketing assessments" for four possible indications for Neurontin. The assessments discussed two possible strategies. The "indication strategy" would be to conduct trials for the purposes of providing data to the FDA in the hope that the FDA would then approve the new indication for the drug. The "marketing strategy" would be, in the words of an internal company memo quoted in the study, to conduct clinical trials and
In other words, the publication strategy involved using RCTs first for marketing, rather than scientific or regulatory purposes.
How the Trials were Controlled by Marketers
The publication strategy involved not simply doing trials and publicizing their results, but controlling the messages conveyed by the trials to make sure they primarily supported marketing. This was done by having the company's marketing department control the content of the trial reports.
The marketers controlled content by controlling those who wrote it.
Note that the control of publication by marketers describe above involved ghost-writing of articles by medical education and communications companies (MECCs). Later the article explained that these ghost writers were "not appropriately acknowledged" in the resulting published articles.
The Vedula et al study article provided examples of "spin" in the writing of again supposedly scholarly research publications used in fact to support marketing, and controlled if not composed by marketers.
Note that while most of these examples of spin involved manipulation of the dissemination of study results, that is, doubtful, biased or fallacious arguments based on apparently unbiased data, they also involved manipulation of the analyses (in italics).
The article also described manipulation of dissemination involving the timing of publication, including delaying publication of an article despite the wishes of the study's investigators because the results were not statistically significant, and hence not favorable for marketing.
Summary
Documents revealed by litigation about Neurontin in 2004 provided insights about how pharmaceutical and presumably other kinds of health care corporations may conduct systematic, deceptive stealth marketing campaigns to promote their products and services (look here). We noted that initial media coverage of documents revealed in the 2008 litigation also suggested the existence of a systematic "publication strategy" to control dissemination of results of particular trials, while suppressing trials whose results could not easily be spun to provide support of marketing objectives (look here).
Now the new paper by Verdula et al fill out our knowledge of this case. The paper suggests that randomized controlled clinical trials may be done not to advance science, or even convince regulators, but primarily to market their sponsors' products. Thus some significant proportion of the clinical research literature, the literature that physicians and other health professionals have relied upon to make evidence-based decisions for their patients, may exist mainly for marketing purposes. Even the most rigorous methods used by clinical epidemiologists to review research are meant to discover problems that arose from human error or the inevitable trade-offs made when research is done in the real world, but not deliberately introduced biases and defects meant to promote vested interests. Thus it is not clear that even the most "evidence-based" medical decisions are based on real scientific evidence rather than the spinning of marketers.
Thus health care professionals, policy makers, researchers, and the interested public need to be even more skeptical about arguments made to promote innovative treatments and other clinical interventions. However, it is not clear that even rigorous skepticism can defend the integrity of evidence based medicine from marketing disguised as clinical research.
Going forward, we must consider erecting an impregnable barrier between clinical research and those whose primary interest is to make money by selling health care goods and services. If we do not do that, we will forever need to worry that we really have no idea what "works in medicine," and whether any particular test, treatment, or program provides benefits that outweigh its harms.
Many of the examples we have discussed were of attempts at manipulation or suppression of clinical trials originally done to provide evidence for product approval, or even ostensibly to advance clinical science. Yet a relatively new article covering evidence revealed from litigation about the drug gabapentin (Neurontin) originally made by Parke-Davis, first a part of Warner Lambert, now part of Pfizer suggests that many clinical trials may not be done to advance science, or even just to provide data to regulators, but only to market products.
The article is Vedula SS, Goldman PS, Rona IJ, Greene TM, and Dickersin K. Implementation of a publication strategy in the context of reporting biases: a case study based on new documents from the Neurontin litigation. Trials 2012; 13: 136. Link here.
Methods Summary
The article described a case study based on documents revealed in 2008 litigation. The purpose of the study was:
to describe the implementation of a publication strategy for off-label marketing of gabapentin, within the context of reporting biases and spin of Pfizer and Parke-Davis’s clinical trial findings, for four off-label uses: migraine prophylaxis, treatment of bipolar disorders, neuropathic pain, and nociceptive pain.
The study examined documents revealed through the 2008 litigation. It concentrated on documents relating to the marketing of Neurontin for four off-label indications, that is, for four potential reasons to use the drug which had not yet been approved by the US FDA. It focused on documents discussing strategies for marketing for these indications, and then documents about particular company sponsored RCTs done for these indications.
Strategies to Sell Drugs
The documents examined by the investigators showed that Parke-Davis prepared "marketing assessments" for four possible indications for Neurontin. The assessments discussed two possible strategies. The "indication strategy" would be to conduct trials for the purposes of providing data to the FDA in the hope that the FDA would then approve the new indication for the drug. The "marketing strategy" would be, in the words of an internal company memo quoted in the study, to conduct clinical trials and
to disseminate the information as widely as possible through the world’s medical literature
In other words, the publication strategy involved using RCTs first for marketing, rather than scientific or regulatory purposes.
How the Trials were Controlled by Marketers
The publication strategy involved not simply doing trials and publicizing their results, but controlling the messages conveyed by the trials to make sure they primarily supported marketing. This was done by having the company's marketing department control the content of the trial reports.
A Neurontin Publications Subcommittee (NTN PSC) was formed within Pfizer and Parke-Davis to implement a publication plan. Minutes from meetings between the NTN PSC and Medical Action Communications (MAC), a medical writing company, indicate that a list of key messages, guiding the content of published reports related to the trials of gabapentin for off-label indications, was developed based on a branding guideThus it appeared to be that marketers, not physicians or scientists were in control of supposedly scholarly research publications appearing in medical journals.
The marketers controlled content by controlling those who wrote it.
A standard operating procedure related to publication of affiliate-driven manuscripts was identified in internal company documents dated October 16, 2002, and it sheds further light on the publication planning process (see Figure 3). (The term affiliate in this context refers to Pfizer’s foreign affiliates, that is, corporations related to Pfizer by either shareholdings or other means of control, including subsidiary, parent, or sibling corporations). According to the internal company documents, 'affiliate-driven manuscripts' were written for Pfizer and Parke-Davis by MAC and sent to the authors for approval. Each article was coordinated by a manuscript team, consisting of representatives from the medical and marketing divisions of the company. The documents also indicate that all affiliate-driven manuscripts should be forwarded to the NTN PSC for review. One of the objectives of manuscripts being reviewed by the NTN PSC was to ‘ensure that they are in-line with current product messages and areas of interest’Manipulating the Dissemination (and Analysis) of Research Results
Note that the control of publication by marketers describe above involved ghost-writing of articles by medical education and communications companies (MECCs). Later the article explained that these ghost writers were "not appropriately acknowledged" in the resulting published articles.
The Vedula et al study article provided examples of "spin" in the writing of again supposedly scholarly research publications used in fact to support marketing, and controlled if not composed by marketers.
We identified spin in publications related to 8/12 trials included in our analysis.... We classified the following as spin: emphasis in the published report on outcomes that were not specified in the study protocol (Study 879–201) ...; conclusions that did not match study findings described in the internal company research report (Study 945–220) ...; extensive rationale to explain away statistically non-significant (unfavorable to the sponsor) findings (Study 945–209; 945–291; No study number - Gorson) ...; conclusion of treatment effectiveness from an uncontrolled study (Study 945–250) ...; emphasis on statistically significant secondary outcomes despite negative findings for the primary outcome (Study 945–271) ...; and an explicit description of an attempt to spin study findings (as described in internal company emails) (Study 945–306).
Note that while most of these examples of spin involved manipulation of the dissemination of study results, that is, doubtful, biased or fallacious arguments based on apparently unbiased data, they also involved manipulation of the analyses (in italics).
The article also described manipulation of dissemination involving the timing of publication, including delaying publication of an article despite the wishes of the study's investigators because the results were not statistically significant, and hence not favorable for marketing.
Summary
Documents revealed by litigation about Neurontin in 2004 provided insights about how pharmaceutical and presumably other kinds of health care corporations may conduct systematic, deceptive stealth marketing campaigns to promote their products and services (look here). We noted that initial media coverage of documents revealed in the 2008 litigation also suggested the existence of a systematic "publication strategy" to control dissemination of results of particular trials, while suppressing trials whose results could not easily be spun to provide support of marketing objectives (look here).
Now the new paper by Verdula et al fill out our knowledge of this case. The paper suggests that randomized controlled clinical trials may be done not to advance science, or even convince regulators, but primarily to market their sponsors' products. Thus some significant proportion of the clinical research literature, the literature that physicians and other health professionals have relied upon to make evidence-based decisions for their patients, may exist mainly for marketing purposes. Even the most rigorous methods used by clinical epidemiologists to review research are meant to discover problems that arose from human error or the inevitable trade-offs made when research is done in the real world, but not deliberately introduced biases and defects meant to promote vested interests. Thus it is not clear that even the most "evidence-based" medical decisions are based on real scientific evidence rather than the spinning of marketers.
Thus health care professionals, policy makers, researchers, and the interested public need to be even more skeptical about arguments made to promote innovative treatments and other clinical interventions. However, it is not clear that even rigorous skepticism can defend the integrity of evidence based medicine from marketing disguised as clinical research.
Going forward, we must consider erecting an impregnable barrier between clinical research and those whose primary interest is to make money by selling health care goods and services. If we do not do that, we will forever need to worry that we really have no idea what "works in medicine," and whether any particular test, treatment, or program provides benefits that outweigh its harms.
Komentar
Posting Komentar