Does the Pharmaceutical Industry Influence Guidelines? Two Examples From Germany
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Background: The recommendations in clinical guidelines are based on clinical trial findings and expert opinion. The influence of drug companies on these two factors is illustrated with two examples.
Methods: A judicially ordered expert review revealed that the market authorization holder (MAH) of gabapentin manipulated study data. Gabapentin was, therefore, chosen as an example for this article to analyze whether manipulated data serve as a basis for recommendations in German clinical guidelines. A search was carried out for manipulated publications on gabapentin that found their way into guidelines published by the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). To analyze the possible effects of financial ties between guideline authors and drug companies, the S3 guideline on the treatment of psoriasis vulgaris with efalizumab was compared with guidelines whose authors had no conflicts of interest. One of the authors of this article had noted variable prescribing practices for psoriasis among dermatologists while carrying out an economic assessment for a German state Association of Statutory Health Insurance Physicians.
Results: The data that had been manipulated by the MAH of gabapentin served as a basis for recommendations to prescribe gabapentin in guidelines that were published by the AWMF. Efalizumab was judged more favorably in the S3 guideline than in a guideline issued by the National Institute of Health and Care Excellence: for example, the evidence for it was judged as good, the use of efalizumab for induction and combination therapy in psoriasis vulgaris was recommended, and efalizumab was said to improve patients’ health-related quality of life.
Conclusion: Public access to all trial data must be ensured so that independent evaluations are possible. We take the view that the responsibility for creating guidelines should be borne by authors and organizations that do not have any conflicts of interest.
Clinical guidelines are systematically developed decision aids for the appropriate medical management of specific disease conditions. They can serve as a basis for physicians and patients to make well-informed joint decisions (1, 2). Guidelines are also consulted by payors in the health-care system in matters concerning reimbursement, and by lawyers in medical malpractice cases (e1).
Guidelines are usually issued by medical societies or government bodies. The Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) coordinates the development of guidelines by the individual medical societies (3). The guidelines whose methods are of the highest quality are called S3 guidelines: These are created after a systematic review of the literature by a representative group of guideline developers in a transparent consensus process (4). These guidelines’ recommendations on drug treatment are based on the findings of clinical trials and on the opinions of the participating experts (5).
The recommendations contained in guidelines are often not based on good evidence from clinical trials, but rather on expert opinion or “standards of care” (6). Especially when adequate trial data are unavailable, the personal opinions of members of the expert committee can influence the recommendations that appear in the guideline. It is entirely possible for identical data to be interpreted in opposite ways by different experts with or without conflicts of interest (7).
Conflicts of interest are defined as situations that create a risk of inappropriate influence by secondary interests on professional judgment or behavior that is supposed to serve a primary interest (8, 9). A conflict of interest is thus an extant condition, rather than an act on the part of an individual (10). Conflicts of interest arise when potential material or social advantages are at odds with the primary goals specified by medical ethics (9, 11).
Clinical trials that are paid for by drug companies are more likely to yield favorable results for the sponsor than independently performed trials. This fact has been demonstrated repeatedly in recent years (e2–e4, 12, 13).
There have been few publications to date analyzing the influence of drug companies on clinical guidelines, and very few in Germany (e5). There have been several studies reporting of the frequency with which guideline authors declare conflicts of interest: 80% to 100% of the guidelines studied contained no such information (e6–e9, 14), yet, when such information is given, as many as 90% of the authors turn out to have financial links to drug companies (e8–e15). The effect of conflicts of interest on the content of guidelines has only rarely been studied (e5).
In this article, we present two aspects of the influence of drug companies on guidelines, giving a concrete illustration of each. We investigate whether data that have been manipulated by drug companies find their way into guidelines published by the AWMF, and we also investigate whether potential effects of conflicts of interest among guideline authors are detectable in the guidelines’ recommendations.
The example of gabapentin vividly shows that drug companies sometimes provide manipulated and misleading information. In keeping with the practice of Deutsches Ärzteblatt International, no trade names will be given in this article.
Gabapentin was approved in 1995 as an antiepileptic drug (e16, e17). Since 2001, it has also been approved in many European countries, including Germany, for the treatment of peripheral neuropathic pain in adults, e.g., painful diabetic neuropathy and post-herpetic neuralgia. The United States Food and Drug Administration has not approved gabapentin as a medication to treat pain for any indication other than post-herpetic neuralgia (e16, e18).
The drug company that manufactures gabapentin was forced by an American court to make more than 8000 pages of internal documents publicly available. It acknowledged having used illegal marketing methods and paid a fine of $430 million (15, 16).
Publications regarding the efficacy of gabapentin were also found to have been manipulated (17, 18, e19). For example, primary endpoints were changed and unfavorable data were not reported in order to give the impression that gabapentin is effective for non-approved indications.
Kay Dickersin, the director of the US Cochrane Center and of the Center of Clinical Studies in Baltimore (Maryland, USA), gained access to internal company documents relating to gabapentin while serving as an expert for the judicial proceeding (19). Her report was highly critical of publications of trials conducted with drug-company support that concerned the use of gabapentin for the following indications (not approved in the USA): migraine, psychiatric/bipolar diseases, nociceptive pain, and neuropathic pain.
Dickersin found that these publications contained the following types of manipulation, among others:
- selective evaluation of patient data
- retrospective changes of primary endpoints
- inappropriately positive conclusions in relation to actual findings
- authorship of ghostwriters (19).
Because the judicial expert report demonstrated the manipulation of data on gabapentin by the market authorization holder (MAH), we have chosen gabapentin as an example to see whether publications that have been manipulated by drug companies find their way into guidelines published by the AWMF.
Guideline authors’ conflicts of interest
To study the potential effects of guideline authors’ financial links to drug companies, we compared the recommendations of the German S3 guideline on the treatment of psoriasis vulgaris (issued in 2006; see eBox 1) with those of contemporaneous guidelines written by authors without any such links. Moreover, the guideline authors’ declarations of conflicts of interest were analyzed and studied for completeness.
This particular guideline was selected because one of the authors of the present study had noted variable prescribing practices among dermatologists for efalizumab in the treatment of psoriasis while carrying out an economic assessment for a German state Association of Statutory Health Insurance Physicians. The dermatologists who prescribed efalizumab cited the S3 guideline as indicating that this was appropriate.
The S3 guideline on the treatment of psoriasis vulgaris was published in 2006 by the Division of Evidence Based Medicine of the Department of Dermatology, Venerology, and Allergology of the Charité – Universitätsmedizin Berlin, which had been commissioned to create the guideline by the German Dermatological Society (Deutsche Dermatologische Gesellschaft, DDG) and the Association of German Dermatologists (Berufsverband der Deutschen Dermatologen, BVDD) (20). The project was paid for by the DDG sponsors’ group; a number of drug companies were “content partners” of the DDG at that time. Active financial support was provided by the MAH of efalizumab (Serono GmbH), among others (21).
The creation of this S3 guideline was supported and moderated by the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der wissenschaftlichen medizinischen Fachgesellschaften, AWMF). It was carried out by a group of experts composed of five practice based and five hospital based dermatologists, who had been named by the BVDD and the DGG, respectively.
The guideline was revised after the European Medicines Agency recommended that the approval of efalizumab be suspended.
In Dickersin’s expert report, the manipulation of certain publications on the use of gabapentin for migraine, psychiatric/bipolar diseases, and nociceptive and neuropathic pain is described in detail (19). Two of the authors of the present review (Claudia Dünnweber and Gisela Schott) searched for these publications in pertinent guidelines downloaded from the AWMF website. They then examined the recommendations contained in the guidelines in the light of the underlying publications that had the defects described by Dickersin.
Guideline authors’ conflicts of interest
Guidelines that were roughly contemporaneous with the German S3 guideline (November 2006 ± 12 months), and that were written by persons who had no conflict of interest because of ties with drug companies, were sought in the database of the Guidelines International Network (www.g-i-n.net) and in the websites of the medical societies from various countries that can be accessed via www.leitlinien.de.
We looked for conflicts of interest among the S3 guideline authors by applying the multimodal screening technique described by Cosgrove et al. (22, e10) to the guideline homepage, with the aid of the Google search engine and the Medline database, in publications from the years 2004−2008.
The guidelines published by the AWMF on the treatment of migraine (23) and the treatment of neuropathic pain (24) contained recommendations based on publications that, according to Dickersin (19), were manipulated by the MAH (Table 1). Manipulated publications were also included in the Cochrane review that was cited as the basis for a recommendation in the guideline on the treatment of perioperative and post-traumatic pain (25, 26).
Moreover, data from trials that were not published by the MAH of gabapentin were not available for consideration by the authors of the guidelines on the treatment of neuropathic (24) and post-traumatic pain (25). For example, the drug company carried out five trials in which gabapentin was given together with other drugs to treat nociceptive pain after orthopedic surgery (and in other situations). None of these trials revealed any statistically significant benefit of the additional administration of gabapentin (19). None were published, and thus none were available for consideration in either the Cochrane review or the guideline on the treatment of perioperative and post-traumatic pain (25, 26).
Guideline authors’ conflicts of interest
Comparison of statements about efalizumab—The search for independently created guidelines on the treatment of psoriasis vulgaris with efalizumab, published within 12 months of November 2006, yielded two hits, one of which was used in the present study: a guideline by the National Institute for Health and Clinical Excellence (NICE) entitled “Etanercept and efalizumab for the treatment of adults with psoriasis” (27), which was published in July 2006 and is partly based on a Health Technology Assessment (HTA) report (28) financed by the National Health Service (NHS) of the United Kingdom. The authors of the HTA report and those of the guideline had no conflicts of interest (27, 28).
The second hit was excluded for a number of reasons, most importantly because it contained no explicit recommendations about pharmacotherapy (e20).
Various statements made in the NICE guideline and the German S3 guideline on the use of efalizumab in the treatment of psoriasis vulgaris are displayed and compared in Table 2 and eTable 1.
Clearly, multiple aspects of efalizumab and its use are judged more favorably in the S3 guideline than in the NICE guideline. For example, the S3 guideline states that there is good evidence for, and thus recommends, the use of efalizumab as induction and combination therapy for psoriasis vulgaris. The putative improvement of health-related quality of life under treatment with efalizumab is also emphasized in the S3 guideline but is not mentioned in the NICE guideline.
Information about conflicts of interest in the S3 guideline—Information about the guideline authors’ conflicts of interest were not given in the guideline itself but were available on the webpage of the guideline-writing group (21). Of the 15 voting participants in the consensus process by which the S3 guideline was generated, 10 had financial links (sometimes extensive ones) to as many as 11 different drug companies (eTable 2a, b).
All 10 participants declaring financial links to drug companies had received money from Serono GmbH, the drug company that obtained approval for efalizumab. These 10 included both of the authors of the section entitled “Biologics” in the S3 guideline, in which efalizumab was discussed. One of the two is a member of the advisory board of Serono GmbH.
For the five voting participants who declared no conflict of interest, further searching did not yield any evidence of financial links to pharmaceutical companies. It would thus appear that all conflicts of interest were appropriately declared.
The recommendations on drug treatment that are found in guidelines are based in large measure on the findings of clinical drug trials, but they also depend to some extent on the opinions of the experts who participate in the writing of the guideline.
This study shows that published data on gabapentin that were known to have been manipulated by the MAH of the drug found their way into the recommendations of guidelines that were published by the AWMF. Moreover, efalizumab for the treatment of psoriasis vulgaris was judged more favorably in the German S3 guideline than in the NICE guideline. Most of the authors of the S3 guideline had extensive conflicts of interest, particularly through financial links to the manufacturer of efalizumab; in contrast, authors with conflicts of interest were excluded from participation in the creation of the NICE guideline.
The case of gabapentin clearly illustrates that data manipulated by the drug companies serve as the basis of recommendations in German guidelines, and that biased publications are cited to support these recommendations. Manipulated evidence was also used as the basis for statements made about gabapentin in a certified CME publication (29, 30).
We do not direct our criticism at the authors of the guideline in question (or those of the CME publication just mentioned), but rather at the MAH of gabapentin. Internal company documents reveal that trial results were deliberately withheld. For example, the British director of a clinical trial comparing three different dosages of gabapentin for the treatment of neuropathic pain complained that his trial was not published. Employees of the drug company thereupon wrote each other multiple e-mails in which it was stated, for example, that “I don’t think we should be too hasty with this request” and that “...made it very clear that we should take care not to publish anything that damages neurontin’s marketing success” (19). [Neurontin is the manufacturer’s trade name for gabapentin—Ed.]
Guideline authors’ conflicts of interest
The potential effects of guideline authors’ conflicts of interest are illustrated by the present comparison of statements about efalizumab made in the S3 guideline, whose authors declared numerous conflicts of interest (20), and in the NICE guideline, none of whose authors had a conflict of interest (27). The lack of editorial independence of the S3 guideline was also criticized recently in an article on the quality of guidelines for the treatment of psoriasis vulgaris (31).
The assessment of efalizumab in the S3 and NICE guidelines is based on somewhat different groups of clinical trials, possibly because some trials were not published by their sponsors (e21–e23). The trials that were considered in both of the guidelines yielded similar findings (eTable1). Nonetheless, multiple aspects of efalizumab and its use are judged more favorably in the S3 guideline than in the NICE guideline. Without venturing to judge the correctness of the S3 guideline’s recommendations on the use of efalizumab, but simply note that they serve the interests of the manufacturer to a greater extent than the recommendations of the NICE guideline.
Possible effects of the favorable depiction of efalizumab in the S3 guideline may be seen in a doctoral dissertation about the prescribing behavior of practice-based dermatologists in the German federal states (Länder) of Berlin and Brandenburg (e24). An evaluation of 8500 patient visits to 49 dermatologists revealed that efalizumab was prescribed more often after publication of the S3 guideline, and that the study participants tended to overrate its effectiveness. For example, efalizumab was prescribed to patients with psoriasis and joint involvement, even though the drug has been found to be ineffective against psoriatic arthritis (e24). This pattern of prescribing behavior may have been caused by other factors aside from the S3 guideline, e.g., marketing by the manufacturer.
The comparative findings discussed in the present article merely document an association; they do not constitute proof that the authors’ conflicts of interest led to the more positive assessment of efalizumab in the S3 guideline. In the hierarchy of evidence grades, the present article reaches the low level of a case report. Case reports do, however, have a role to play in evidence-based medicine, as they can provide important clues (32).
Conclusions and recommendations
Intensive efforts are now underway in multiple countries to reform the process of guideline development. A call has been issued for guideline authors to declare transparently their conflicts of interest that arise from financial links to drug companies (33–35). A separate, and contrasting, call has been issued for the acceptance as guideline authors only of persons with no links to industry whatsoever (36, 37).
The Institute of Medicine (IOM), an advisory body that counsels the United States government, has recommended that
- persons with conflicts of interest should, in general, be excluded from the development of guidelines, and that
- the direct sponsoring of guideline creation by drug companies should be forbidden.
The procedure for determining what conflicts of interest are present should be just as transparent as the financing of the guideline (8). Detailed recommendations are given for the exceptional situations in which the participation of experts with conflicts of interest is unavoidable (8, 38). For example, the chairman of the guideline group should be an expert without any conflict of interest, and persons with conflicts of interest should never constitute a majority of the guideline-creating group. Furthermore, experts with conflicts of interest should not participate in decision-making processes.
In Germany, in April 2010, the presidium of the AWMF issued recommendations, based on those of the IOM, for handling conflicts of interest in medical societies, and particularly in the creation of guidelines (39). These rules should now be consistently followed by the participating medical societies and guideline authors, and violations of the rules should be dealt with appropriately.
The proof that drug companies manipulate drug trials for their own benefit has led to demands that drug trials should more often be carried out independently of the financial interests of drug companies. This will only be possible, however, if more money from public sources is made available for this purpose (12, 13). The creation of guidelines should also be in the hands of independent individuals and organizations.
This article is based on the findings of an expert assessment belonging to Part 2 of a project entitled “The Influence of Trial Sponsors on the Scientific Findings of Drug Trials” („Einflüsse der Auftraggeber auf die wissenschaftlichen Ergebnisse von Arzneimittelstudien“), which was sponsored by the German Medical Assembly (Deutscher Ärztetag) in the framework of an initiative to promote health services research (Förderinitiative Versorgungsforschung) of the German Medical Association (Bundesärzte-kammer). The full versions of the expert reports can be seen on the homepage of the German Medical Association at the following Internet address: www.baek.de/versorgungsforschung/expertisen
Some of the findings of this study were presented at the evidence-based medicine congress in 2011 and at the annual meeting of the DGPPN in 2012.
Conflict of interest statement
Dr. Schott is employed by Arzneimittelinformationsdienst AID e.V.
Ms. Dünnweber, M.P.H., has an employment relationship with the German Private Health Insurance Association (Verband der privaten Krankenversicherung).
Mr. Pachl, Dipl.-Biol., is employed by Arzneimittelinformationsdienst AID e.V.
Prof. Mühlbauer, Prof. Niebling, and Prof. Ludwig state that they have no conflicts of interest.
Manuscript submitted on 7 November 2012, revised version accepted on 29 April 2013.
Translated from the original German by Ethan Taub, M.D.
Dr. med. Gisela Schott
Arzneimittelkommission der deutschen Ärzteschaft
D-10623 Berlin, Germany
@For eReferences please refer to:
eBoxes and eTables:
Status: 21 Mai 2007, modified on 20 April 2009. Last accessed on 6 November 2012.
6 November 2012.
Doc. Ref. EMEA/487107/2009. Last accessed on 6 November 2012.
Dr. med. Schott, Dipl.-Biol. Pachl, Prof. Dr. med. Ludwig
Berlin School of Public Health, Charité, Universitätsmedizin Berlin: Dünnweber, MPH
Department of Pharmacology, Klinikum Bremen-Mitte gGmbH: Prof. Dr. med. Mühlbauer
Department of General Practice, University Hospital Freiburg, Germany: Prof. Dr. med. Niebling
Department of Hematology, Oncology, and Tumor Immunology, HELIOS Klinikum Berlin-Buch:
Prof. Dr. med. Ludwig
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