DÄ internationalArchive35-36/2013Does the Pharmaceutical Industry Influence Guidelines? Two Examples From Germany

Original article

Does the Pharmaceutical Industry Influence Guidelines? Two Examples From Germany

Dtsch Arztebl Int 2013; 110(35-36): 575-83. DOI: 10.3238/arztebl.2013.0575

Schott, G; Dünnweber, C; Mühlbauer, B; Niebling, W; Pachl, H; Ludwig, W

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.

LNSLNS

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 (e2e4, 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 (e6e9, 14), yet, when such information is given, as many as 90% of the authors turn out to have financial links to drug companies (e8e15). 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.

Manipulated data

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.

Efalizumab
Efalizumab
eBox 1
Efalizumab

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.

Methods

Manipulated data

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.

Results

Manipulated data

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).

Guidelines published by the AWMF with recommendations about gabapentin based on publications that were manipulated by drug companies
Guidelines published by the AWMF with recommendations about gabapentin based on publications that were manipulated by drug companies
Table 1
Guidelines published by the AWMF with recommendations about gabapentin based on publications that were manipulated by drug companies

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.

A comparison of statements about efalizumab in the NICE guideline and the S3 guideline
A comparison of statements about efalizumab in the NICE guideline and the S3 guideline
Table 2
A comparison of statements about efalizumab in the NICE guideline and the S3 guideline
Literature cited in the HTA report and in the S3 guideline concerning the efficacy of efalizumab
Literature cited in the HTA report and in the S3 guideline concerning the efficacy of efalizumab
eTable 1
Literature cited in the HTA report and in the S3 guideline concerning the efficacy of efalizumab

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).

Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
eTable 2a
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
eTable 2b
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris

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.

Discussion

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.

Manipulated evidence

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 (e21e23). 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 (3335). 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.

Corresponding author
Dr. med. Gisela Schott
Arznei­mittel­kommission der deutschen Ärzteschaft
Herbert-Lewin-Platz 1
D-10623 Berlin, Germany
gisela.schott@akdae.de

@For eReferences please refer to:
www.aerzteblatt-international.de/ref3513

eBoxes and eTables:
www.aerzteblatt-international.de/13m575

1.
Hart D: Ärztliche Leitlinien. In: Rieger H-J (ed): Lexikon des Arztrechts. 2nd edition, Heidelberg: Verlag C. F. Müller 2001.
2.
Lelgemann M, Lang B, Kunz R, Antes G: Leitlinien. Was haben Ärzte und Patienten davon. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2005; 48: 215–20. CrossRef MEDLINE
3.
Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.: AWMF online – das Portal der wissenschaftlichen Medizin: http://awmf.org/. Last accessed on 6 November 2012.
4.
Kopp I: Erstellung und Handhabung von Leitlinien aus Sicht der AWMF. MKG-Chirurg 2010; 2: 79–85.
5.
Schünemann H: Integrative Beurteilung der Evidenz im Gesundheitswesen: das GRADE System. Z Evid Fortbild Qual Gesundhwes 2009; 103: 261–8. CrossRef
6.
Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr.: Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009; 301: 831–41. CrossRef MEDLINE
7.
Wang AT, McCoy CP, Murad MH, Montori VM: Association between industry affiliation and position on cardiovascular risk with rosiglitazone: cross sectional systematic review. BMJ 2010; 340: c1344. CrossRef MEDLINE PubMed Central
8.
Committee on Conflict of Interest in Medical Research, Education, and Practice, Institute of Medicine: Lo B, Field MJ (eds): Conflict of Interest in Medical Research, Education, and Practice. 1th edition, Washington D.C.: National Academies Press 2009.
9.
Lieb K, Klemperer D, Ludwig W-D: Einleitung. In: Lieb K, Klemperer D, Ludwig WD (eds): Interessenskonflikte in der Medizin – Hintergründe und Lösungsmöglichkeiten. Berlin, Heidelberg, New York: Springer Medizin Verlag 2011; 3–9. CrossRef
10.
Thompson DF: Understanding financial conflicts of interest. N Engl J Med 1993; 329: 573–6. CrossRef MEDLINE
11.
Medical Professionalism Project: Medical professionalism in the new millennium: a physicians’ charter. Lancet 2002; 359: 520–2. CrossRef MEDLINE
12.
Schott G, Pachl H, Limbach U, Gundert-Remy U, Ludwig WD, Lieb K: The financing of drug trials by pharmaceutical companies and its consequences. Part 1: a qualitative, systematic review of the literature on possible influences on the findings, protocols, and quality of drug trials. Dtsch Arztebl Int 2010; 107: 279–85. VOLLTEXT
13.
Schott G, Pachl H, Limbach U, Gundert-Remy U, Lieb K, Ludwig WD: The financing of drug trials by pharmaceutical companies and its consequences. Part 2: a qualitative, systematic review of the literature on possible influences on authorship, access to trial data, and trial registration and publication. Dtsch Arztebl Int 2010; 107: 295–301. VOLLTEXT
14.
Langer T, Conrad S, Fishman L, Gerken M, Schwarz S, Weikert B, et al.: Conflicts of interest among authors of medical guidelines: an analysis of guidelines produced by german specialist societies. Dtsch Arztebl Int 2012; 109: 836–42. VOLLTEXT
15.
Steinman MA, Bero LA, Chren MM, Landefeld CS: Narrative review: the promotion of gabapentin: an analysis of internal industry documents. Ann Intern Med 2006; 145: 284–93. CrossRef MEDLINE
16.
Landefeld CS, Steinman MA: The Neurontin legacy – marketing through misinformation and manipulation. N Engl J Med 2009; 360: 103–6. CrossRef MEDLINE
17.
Vedula SS, Bero L, Scherer RW, Dickersin K: Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med 2009; 361: 1963–71. CrossRef MEDLINE
18.
Vedula SS, Li T, Dickersin K: Differences in reporting of analyses in internal company documents versus published trial reports: comparisons in industry-sponsored trials in off-label uses of gabapentin. PLoS Med 2013; 10: e1001378. CrossRef MEDLINE PubMed Central
19.
Dickersin K: Reporting and other biases in studies of Neurontin for migraine, psychiatric/bipolar disorders, nociceptive pain, and neuropathic pain: www.prescriptionaccess.org/docs/neurontin_exh_O.pdf. 10 August 2008. Last accessed on 6 November 2012.
20.
Nast A, Kopp IB, Augustin M, et al.: S3-Leitlinie zur Therapie der Psoriasis vulgaris. J Dtsch Dermatol Ges 2006; 4 Suppl 2: 1–126. CrossRef MEDLINE
21.
Dünnweber C: Einfluss pharmazeutischer Unternehmen auf die Empfehlung ärztlicher Leitlinien. Berlin School of Public Health an der Charité, Weiterbildender Masterstudiengang „Master of Public Health“. Master’s thesis submitted on 30 September 2010.
22.
Cosgrove L, Bursztajn HJ, Krimsky S, Anaya M, Walker J: Conflicts of interest and disclosure in the American Psychiatric Association’s Clinical Practice Guidelines. Psychother Psychosom 2009; 78: 228–32. CrossRef MEDLINE
23.
Therapie der Migräne. In: Kommission „Leitlinien der Deutschen Gesellschaft für Neurologie“ (ed): Leitlinien für Diagnostik und Therapie in der Neurologie. 4th edition, Stuttgart: Georg Thieme Verlag, 2008; 579–95.
24.
Therapie neuropathischer Schmerzen. In: Kommission „Leitlinien der Deutschen Gesellschaft für Neurologie“ (ed): Leitlinien für Diagnostik und Therapie in der Neurologie. 4th edition, Stuttgart: Georg Thieme Verlag, 2008; 630–9.
25.
Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) e.V.: S3-Leitlinie „Behandlung akuter perioperativer und posttraumatischer Schmerzen“: www.awmf.org/uploads/tx_ szleitlinien/041–001_S3_Behandlung_akuter_perioperativer_ und_posttraumatischer_Schmerzen_aktualisierte_Fassung_ 04–2009_05–2011.pdf. AWMF-Register Nr. 041/001;
Status: 21 Mai 2007, modified on 20 April 2009. Last accessed on 6 November 2012.
26.
Wiffen PJ, McQuay HJ, Edwards JE, Moore RA: Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2005; Issue 3: CD005452. MEDLINE
27.
National Institute for Health and Clinical Excellence: Etanercept and efalizumab for the treatment of adults with psoriasis: www.nice.org.uk/nicemedia/live/11580/33376/33376.pdf. NICE technology appraisal guidance 103. Issue date: July 2006, re-issued: December 2009. Last accessed on 6 November 2012.
28.
Woolacott N, Hawkins N, Mason A, et al.: Efalizumab and Etanercept for the Treatment of Psoriasis: www.nice.org.uk/nicemedia/live/11579/33369/33369.pdf. CRD/CHE Technology Assessment Group; Technology Assessment Report commissioned by the HTA Programme on behalf of The National Institute for Clinical Excellence, February 2005. Last accessed on 6 November 2012.
29.
Baron R: Diagnostik und Therapie neuropathischer Schmerzen: Dtsch Arztebl 2006; 103: A-2720–30. VOLLTEXT
30.
Diagnostik und Therapie neuropathischer Schmerzen. In: Kommission „Leitlinien der Deutschen Gesellschaft für Neurologie“ (ed): Leitlinien für Diagnostik und Therapie in der Neurologie. 3rd edition, Stuttgart: Georg Thieme Verlag, 2005; 531–44.
31.
Tan JK, Wolfe BJ, Bulatovic R, Jones EB, Lo AY: Critical appraisal of quality of clinical practice guidelines for treatment of psoriasis vulgaris, 2006–2009. J Invest Dermatol 2010; 130: 2389–95. CrossRef MEDLINE
32.
Hennekens CH, Buring JE: Descriptive Studies. In: Mayrent SL (ed): Epidemiology in Medicine. Bosten, Toronto: Little, Brown and Company, 1987; 101–31.
33.
Camilleri M, Cortese DA: Managing conflict of interest in clinical practice. Mayo Clin Proc 2007; 82: 607–14. CrossRef MEDLINE
34.
Lewis SZ: Building a better guideline: overcoming challenges and establishing transparency: www.guidelines.gov/expert/expert-commentary.aspx?id=16448. National Guideline Clearinghouse™ (NGC) Expert Commentary, April 2008. Last accessed on 6 November 2012.
35.
Schünemann HJ, Woodhead M, Anzueto A, Buist S, Macnee W, Rabe KF, et al.: A vision statement on guideline development for respiratory disease: the example of COPD. Lancet 2009; 373: 774–9. CrossRef MEDLINE
36.
Sniderman AD, Furberg CD: Why guideline-making requires reform. JAMA 2009; 301: 429–31. CrossRef MEDLINE
37.
Rothman DJ, McDonald WJ, Berkowitz CD, Chimonas SC, DeAngelis CD, Hale RW, et al.: Professional medical associations and their relationships with industry: a proposal for controlling conflict of interest. JAMA 2009; 301: 1367–72. CrossRef MEDLINE
38.
Steinbrook R: Controlling conflict of interest – proposals from the Institute of Medicine. N Engl J Med 2009; 360: 2160–3. CrossRef MEDLINE
39.
Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (AWMF): Empfehlungen der AWMF zum Umgang mit Interessenkonflikten bei Fachgesellschaften: www.awmf.org/fileadmin/user_upload/Leitlinien/Werkzeuge/empf-coi.pdf. Erarbeitet von einer Ad-hoc-Kommission der AWMF und verabschiedet vom Präsidium der AWMF am 23. April 2010. Last accessed on 6 November 2012.
e1.
Stöhr K: Leitlinien, Richtlinien und ärztliche Haftung. In: Müller GOE, Stein T (eds): Festschrift für Günther Hirsch. München: Verlag C. H. Beck 2011; 431–41.
e2.
Bekelman JE, Li Y, Gross CP: Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003; 289: 454–65. CrossRef MEDLINE
e3.
Bero LA, Rennie D: Influences on the quality of published drug studies. Int J Technol Assess Health Care 1996; 12: 209–37. CrossRef MEDLINE
e4.
Lexchin J, Bero LA, Djulbegovic B, Clark O: Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70. CrossRef MEDLINE PubMed Central
e5.
Arznei­mittel­kommission der deutschen Ärzteschaft: Der Einfluss pharmazeutischer Unternehmen auf ärztliche Leitlinien – Expertise: www.akdae.de/Stellungnahmen/Weitere/20120123.pdf. Berlin, Januar 2012. Zuletzt geprüft: 6. November 2012.
e6.
Buchan HA, Currie KC, Lourey EJ, Duggan GR: Australian clinical practice guidelines – a national study. Med J Aust 2010; 192: 490–4. MEDLINE
e7.
Papanikolaou GN, Baltogianni MS, Contopoulos-Ioannidis DG, Haidich AB, Giannakakis IA, Ioannidis JP: Reporting of conflicts of interest in guidelines of preventive and therapeutic interventions. BMC Med Res Methodol 2001; 1: 3. CrossRef PubMed Central
e8.
Cosgrove L, Bursztajn HJ, Krimsky S: Developing unbiased diagnostic and treatment guidelines in psychiatry. N Engl J Med 2009; 360: 2035–6. CrossRef MEDLINE
e9.
Choudhry NK, Stelfox HT, Detsky AS: Relationships between authors of clinical practice guidelines and the pharmaceutical industry. JAMA 2002; 287: 612–7. CrossRef MEDLINE
e10.
Cosgrove L, Krimsky S, Vijayaraghavan M, Schneider L: Financial ties between DSM-IV panel members and the pharmaceutical industry. Psychother Psychosom 2006; 75: 154–60. CrossRef MEDLINE
e11.
Holloway RG, Mooney CJ, Getchius TS, Edlund WS, Miyasaki JO: Invited article: conflicts of interest for authors of American Academy of Neurology clinical practice guidelines. Neurology 2008; 71: 57–63. CrossRef MEDLINE
e12.
Mendelson TB, Meltzer M, Campbell EG, Caplan AL, Kirkpatrick JN: Conflicts of interest in cardiovascular clinical practice guidelines. Arch Intern Med 2011; 171: 577–84. CrossRef MEDLINE
e13.
Neuman J, Korenstein D, Ross JS, Keyhani S: Prevalence of financial conflicts of interest among panel members producing clinical practice guidelines in Canada and United States: cross sectional study. BMJ 2011; 343: d5621. CrossRef MEDLINE PubMed Central
e14.
Taylor R, Giles J: Cash interests taint drug advice. Nature 2005; 437: 1070–1. CrossRef MEDLINE
e15.
Kung J, Miller RR, Mackowiak PA: Failure of clinical practice guidelines to meet Institute of Medicine standards: two more decades of little, if any, progress. Arch Intern Med 2012; 172: 1628–33. CrossRef MEDLINE
e16.
Schwabe U, Paffrath D (eds): Arzneiverordnungs-Report 2010. Berlin, Heidelberg: Springer Medizin Verlag, 2010.
e17.
Pfizer Pharma GmbH: Neurontin® 100/300/400 mg Hartkapseln. Stand: Juni 2011.
e18.
FDA: FDA Approved Drug Products: Neurontin: /www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search. Search_Drug_Name. FDA Center for Drug Evaluation and Research, Office of Communications, Division of Information Services. Last accessed on 6 November 2012.
e19.
Abramson J: Expert report of John Abramson, MD.: http://dida.library.ucsf.edu/pdf/oxx18v10. Neurontin Marketing and Sales Practices Litigation, MDL #1629, Docket #04–10981; 11 August 2008. Last accessed on 6 November 2012.
e20.
Claes C, Kulp W, Greiner W, Graf von der Schulenburg J-M, Werfel T: Deutsches Institut für Medizinische Dokumentation und Information (DIMDI) (eds): Therapie der mittelschweren und schweren Psoriasis. Bd. 34, Schriftenreihe Health Technology Assessment (HTA). Köln: DIMDI, 2006.
e21.
IMP24011. Phase III, randomised, double blind, placebo-controlled, multicentre study evaluating 12 weeks subcutaneous therapy with Genentech efalizumab in patients with moderate to severe psoriasis who are candidates for systemic therapy. In: Clinical and cost effectiveness of efalizumab (Raptiva) for moderate to severe psoriasis. [Industry submission]. Feltham: Serono Ltd., 2004.
e22.
ACD2600g. Phase IIIb, randomised, double-blind, parallel group, placebocontrolled, multicentre study evaluating 12 weeks therapy with subcutaneously administered Genentech efalizumab in adults with moderate to severe psoriasis who are candidates for systemic therapy. In: Clinical and cost effectiveness of efalizumab (Raptiva) for moderate to severe psoriasis. [Industry submission]. Feltham: Serono Ltd., 2004.
e23.
ACD2058g. Phase III, randomised double blind placebo-controlled study evaluating 12 weeks of therapy with XOMA1 efalizumab administered subcutaneously (SC), followed by either continued treatment for an additional 12 weeks or re-treatment for 12 weeks following a relapse. In: Clinical and cost effectiveness of efalizumab (Raptiva) for moderate to severe psoriasis. [Industry submission]. Feltham: Serono Ltd., 2004.
e24.
Hofelich V: Ergebnisse zur Evaluation der S3-Leitlinie zur Therapie der Psoriasis vulgaris in Deutschland: www.diss.fu-berlin.de/diss/servlets/MCRFileNodeServlet/FUDISS_derivate_000000006571/ Promotion_online.pdf. Dissertation; Klinik für Dermatologie, Venerologie und Allergologie der Medizinischen Fakultät Charité – Universitätsmedizin Berlin, Januar 2010. Last accessed on
6 November 2012.
e25.
Serono Europe Ltd.: Fachinformation „Raptiva®“. Status: September 2004.
e26.
EMA: Public statement on Raptiva (efalizumab): Withdrawel of the marketing authorisation in the European Union: www.ema.europa.eu/docs/en_GB/document_library/Public_statement/ 2009/11/WC500009129.pdf. London, 3 August 2009;
Doc. Ref. EMEA/487107/2009. Last accessed on 6 November 2012.
e27.
Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, et al.: Efficacy of gabapentin in migraine prophylaxis. Headache 2001; 41: 119–28. CrossRef MEDLINE
e28.
Serpell MG: Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain 2002; 99: 557–66. CrossRef
e29.
Backonja M, Beydoun A, Edwards KR, et al.: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280: 1831–6. CrossRef MEDLINE
e30.
Caraceni A, Zecca E, Bonezzi C, et al.: Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 2004; 22: 2909–17. CrossRef MEDLINE
e31.
Dallocchio C, Buffa C, Mazzarello P, Chiroli S: Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage 2000; 20: 280–5. CrossRef MEDLINE
e32.
Gorson KC, Schott C, Herman R, Ropper AH, Rand WM: Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry 1999; 66: 251–2. CrossRef MEDLINE PubMed Central
e33.
Wiffen PJ, McQuay HJ, Edwards J, Moore RA: WITHDRAWN: Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2011; Issue 3: CD005452. MEDLINE
e34.
Gottlieb AB, Gordon KB, Lebwohl MG, et al.: Extended efalizumab therapy sustains efficacy without increasing toxicity in patients with moderate to severe chronic plaque psoriasis. J Drugs Dermatol 2004; 3: 614–24. MEDLINE
e35.
Leonardi CL, Papp KA, Gordon KB, et al.: Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol 2005; 52: 425–33. CrossRef MEDLINE
e36.
Gordon KB, Papp KA, Hamilton TK, et al.: Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 2003; 290: 3073–80. CrossRef MEDLINE
e37.
Menter A, Kosinski M, Bresnahan BW, Papp KA, Ware JE Jr.: Impact of efalizumab on psoriasis-specific patient-reported outcomes. Results from three randomized, placebo-controlled clinical trials of moderate to severe plaque psoriasis. J Drugs Dermatol 2004; 3: 27–38. MEDLINE
e38.
Lebwohl M, Tyring SK, Hamilton TK, et al.: A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349: 2004–13. CrossRef MEDLINE
e39.
Menter A, Gordon K, Carey W, et al.: Efficacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis. Arch Dermatol 2005; 141: 31–8. CrossRef MEDLINE
e40.
Papp K, Bissonnette R, Krueger JG, et al.: The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody. J Am Acad Dermatol 2001; 45: 665–74. CrossRef MEDLINE
Drug Commission of the German Medical Association, Berlin:
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
Key messages
Guidelines published by the AWMF with recommendations about gabapentin based on publications that were manipulated by drug companies
Guidelines published by the AWMF with recommendations about gabapentin based on publications that were manipulated by drug companies
Table 1
Guidelines published by the AWMF with recommendations about gabapentin based on publications that were manipulated by drug companies
A comparison of statements about efalizumab in the NICE guideline and the S3 guideline
A comparison of statements about efalizumab in the NICE guideline and the S3 guideline
Table 2
A comparison of statements about efalizumab in the NICE guideline and the S3 guideline
Efalizumab
Efalizumab
eBox 1
Efalizumab
Literature cited in the HTA report and in the S3 guideline concerning the efficacy of efalizumab
Literature cited in the HTA report and in the S3 guideline concerning the efficacy of efalizumab
eTable 1
Literature cited in the HTA report and in the S3 guideline concerning the efficacy of efalizumab
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
eTable 2a
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
eTable 2b
Statements on conflicts of interest by authors of the S3 guideline on drugs for psoriasis vulgaris
1.Hart D: Ärztliche Leitlinien. In: Rieger H-J (ed): Lexikon des Arztrechts. 2nd edition, Heidelberg: Verlag C. F. Müller 2001.
2.Lelgemann M, Lang B, Kunz R, Antes G: Leitlinien. Was haben Ärzte und Patienten davon. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2005; 48: 215–20. CrossRef MEDLINE
3.Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.: AWMF online – das Portal der wissenschaftlichen Medizin: http://awmf.org/. Last accessed on 6 November 2012.
4.Kopp I: Erstellung und Handhabung von Leitlinien aus Sicht der AWMF. MKG-Chirurg 2010; 2: 79–85.
5.Schünemann H: Integrative Beurteilung der Evidenz im Gesundheitswesen: das GRADE System. Z Evid Fortbild Qual Gesundhwes 2009; 103: 261–8. CrossRef
6.Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr.: Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009; 301: 831–41. CrossRef MEDLINE
7.Wang AT, McCoy CP, Murad MH, Montori VM: Association between industry affiliation and position on cardiovascular risk with rosiglitazone: cross sectional systematic review. BMJ 2010; 340: c1344. CrossRef MEDLINE PubMed Central
8.Committee on Conflict of Interest in Medical Research, Education, and Practice, Institute of Medicine: Lo B, Field MJ (eds): Conflict of Interest in Medical Research, Education, and Practice. 1th edition, Washington D.C.: National Academies Press 2009.
9.Lieb K, Klemperer D, Ludwig W-D: Einleitung. In: Lieb K, Klemperer D, Ludwig WD (eds): Interessenskonflikte in der Medizin – Hintergründe und Lösungsmöglichkeiten. Berlin, Heidelberg, New York: Springer Medizin Verlag 2011; 3–9. CrossRef
10.Thompson DF: Understanding financial conflicts of interest. N Engl J Med 1993; 329: 573–6. CrossRef MEDLINE
11.Medical Professionalism Project: Medical professionalism in the new millennium: a physicians’ charter. Lancet 2002; 359: 520–2. CrossRef MEDLINE
12.Schott G, Pachl H, Limbach U, Gundert-Remy U, Ludwig WD, Lieb K: The financing of drug trials by pharmaceutical companies and its consequences. Part 1: a qualitative, systematic review of the literature on possible influences on the findings, protocols, and quality of drug trials. Dtsch Arztebl Int 2010; 107: 279–85. VOLLTEXT
13.Schott G, Pachl H, Limbach U, Gundert-Remy U, Lieb K, Ludwig WD: The financing of drug trials by pharmaceutical companies and its consequences. Part 2: a qualitative, systematic review of the literature on possible influences on authorship, access to trial data, and trial registration and publication. Dtsch Arztebl Int 2010; 107: 295–301. VOLLTEXT
14.Langer T, Conrad S, Fishman L, Gerken M, Schwarz S, Weikert B, et al.: Conflicts of interest among authors of medical guidelines: an analysis of guidelines produced by german specialist societies. Dtsch Arztebl Int 2012; 109: 836–42. VOLLTEXT
15.Steinman MA, Bero LA, Chren MM, Landefeld CS: Narrative review: the promotion of gabapentin: an analysis of internal industry documents. Ann Intern Med 2006; 145: 284–93. CrossRef MEDLINE
16.Landefeld CS, Steinman MA: The Neurontin legacy – marketing through misinformation and manipulation. N Engl J Med 2009; 360: 103–6. CrossRef MEDLINE
17.Vedula SS, Bero L, Scherer RW, Dickersin K: Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med 2009; 361: 1963–71. CrossRef MEDLINE
18.Vedula SS, Li T, Dickersin K: Differences in reporting of analyses in internal company documents versus published trial reports: comparisons in industry-sponsored trials in off-label uses of gabapentin. PLoS Med 2013; 10: e1001378. CrossRef MEDLINE PubMed Central
19.Dickersin K: Reporting and other biases in studies of Neurontin for migraine, psychiatric/bipolar disorders, nociceptive pain, and neuropathic pain: www.prescriptionaccess.org/docs/neurontin_exh_O.pdf. 10 August 2008. Last accessed on 6 November 2012.
20.Nast A, Kopp IB, Augustin M, et al.: S3-Leitlinie zur Therapie der Psoriasis vulgaris. J Dtsch Dermatol Ges 2006; 4 Suppl 2: 1–126. CrossRef MEDLINE
21. Dünnweber C: Einfluss pharmazeutischer Unternehmen auf die Empfehlung ärztlicher Leitlinien. Berlin School of Public Health an der Charité, Weiterbildender Masterstudiengang „Master of Public Health“. Master’s thesis submitted on 30 September 2010.
22.Cosgrove L, Bursztajn HJ, Krimsky S, Anaya M, Walker J: Conflicts of interest and disclosure in the American Psychiatric Association’s Clinical Practice Guidelines. Psychother Psychosom 2009; 78: 228–32. CrossRef MEDLINE
23.Therapie der Migräne. In: Kommission „Leitlinien der Deutschen Gesellschaft für Neurologie“ (ed): Leitlinien für Diagnostik und Therapie in der Neurologie. 4th edition, Stuttgart: Georg Thieme Verlag, 2008; 579–95.
24.Therapie neuropathischer Schmerzen. In: Kommission „Leitlinien der Deutschen Gesellschaft für Neurologie“ (ed): Leitlinien für Diagnostik und Therapie in der Neurologie. 4th edition, Stuttgart: Georg Thieme Verlag, 2008; 630–9.
25.Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) e.V.: S3-Leitlinie „Behandlung akuter perioperativer und posttraumatischer Schmerzen“: www.awmf.org/uploads/tx_ szleitlinien/041–001_S3_Behandlung_akuter_perioperativer_ und_posttraumatischer_Schmerzen_aktualisierte_Fassung_ 04–2009_05–2011.pdf. AWMF-Register Nr. 041/001;
Status: 21 Mai 2007, modified on 20 April 2009. Last accessed on 6 November 2012.
26.Wiffen PJ, McQuay HJ, Edwards JE, Moore RA: Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2005; Issue 3: CD005452. MEDLINE
27.National Institute for Health and Clinical Excellence: Etanercept and efalizumab for the treatment of adults with psoriasis: www.nice.org.uk/nicemedia/live/11580/33376/33376.pdf. NICE technology appraisal guidance 103. Issue date: July 2006, re-issued: December 2009. Last accessed on 6 November 2012.
28.Woolacott N, Hawkins N, Mason A, et al.: Efalizumab and Etanercept for the Treatment of Psoriasis: www.nice.org.uk/nicemedia/live/11579/33369/33369.pdf. CRD/CHE Technology Assessment Group; Technology Assessment Report commissioned by the HTA Programme on behalf of The National Institute for Clinical Excellence, February 2005. Last accessed on 6 November 2012.
29.Baron R: Diagnostik und Therapie neuropathischer Schmerzen: Dtsch Arztebl 2006; 103: A-2720–30. VOLLTEXT
30.Diagnostik und Therapie neuropathischer Schmerzen. In: Kommission „Leitlinien der Deutschen Gesellschaft für Neurologie“ (ed): Leitlinien für Diagnostik und Therapie in der Neurologie. 3rd edition, Stuttgart: Georg Thieme Verlag, 2005; 531–44.
31.Tan JK, Wolfe BJ, Bulatovic R, Jones EB, Lo AY: Critical appraisal of quality of clinical practice guidelines for treatment of psoriasis vulgaris, 2006–2009. J Invest Dermatol 2010; 130: 2389–95. CrossRef MEDLINE
32.Hennekens CH, Buring JE: Descriptive Studies. In: Mayrent SL (ed): Epidemiology in Medicine. Bosten, Toronto: Little, Brown and Company, 1987; 101–31.
33.Camilleri M, Cortese DA: Managing conflict of interest in clinical practice. Mayo Clin Proc 2007; 82: 607–14. CrossRef MEDLINE
34.Lewis SZ: Building a better guideline: overcoming challenges and establishing transparency: www.guidelines.gov/expert/expert-commentary.aspx?id=16448. National Guideline Clearinghouse™ (NGC) Expert Commentary, April 2008. Last accessed on 6 November 2012.
35.Schünemann HJ, Woodhead M, Anzueto A, Buist S, Macnee W, Rabe KF, et al.: A vision statement on guideline development for respiratory disease: the example of COPD. Lancet 2009; 373: 774–9. CrossRef MEDLINE
36.Sniderman AD, Furberg CD: Why guideline-making requires reform. JAMA 2009; 301: 429–31. CrossRef MEDLINE
37.Rothman DJ, McDonald WJ, Berkowitz CD, Chimonas SC, DeAngelis CD, Hale RW, et al.: Professional medical associations and their relationships with industry: a proposal for controlling conflict of interest. JAMA 2009; 301: 1367–72. CrossRef MEDLINE
38.Steinbrook R: Controlling conflict of interest – proposals from the Institute of Medicine. N Engl J Med 2009; 360: 2160–3. CrossRef MEDLINE
39.Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (AWMF): Empfehlungen der AWMF zum Umgang mit Interessenkonflikten bei Fachgesellschaften: www.awmf.org/fileadmin/user_upload/Leitlinien/Werkzeuge/empf-coi.pdf. Erarbeitet von einer Ad-hoc-Kommission der AWMF und verabschiedet vom Präsidium der AWMF am 23. April 2010. Last accessed on 6 November 2012.
e1.Stöhr K: Leitlinien, Richtlinien und ärztliche Haftung. In: Müller GOE, Stein T (eds): Festschrift für Günther Hirsch. München: Verlag C. H. Beck 2011; 431–41.
e2.Bekelman JE, Li Y, Gross CP: Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003; 289: 454–65. CrossRef MEDLINE
e3.Bero LA, Rennie D: Influences on the quality of published drug studies. Int J Technol Assess Health Care 1996; 12: 209–37. CrossRef MEDLINE
e4.Lexchin J, Bero LA, Djulbegovic B, Clark O: Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70. CrossRef MEDLINE PubMed Central
e5.Arznei­mittel­kommission der deutschen Ärzteschaft: Der Einfluss pharmazeutischer Unternehmen auf ärztliche Leitlinien – Expertise: www.akdae.de/Stellungnahmen/Weitere/20120123.pdf. Berlin, Januar 2012. Zuletzt geprüft: 6. November 2012.
e6.Buchan HA, Currie KC, Lourey EJ, Duggan GR: Australian clinical practice guidelines – a national study. Med J Aust 2010; 192: 490–4. MEDLINE
e7.Papanikolaou GN, Baltogianni MS, Contopoulos-Ioannidis DG, Haidich AB, Giannakakis IA, Ioannidis JP: Reporting of conflicts of interest in guidelines of preventive and therapeutic interventions. BMC Med Res Methodol 2001; 1: 3. CrossRef PubMed Central
e8.Cosgrove L, Bursztajn HJ, Krimsky S: Developing unbiased diagnostic and treatment guidelines in psychiatry. N Engl J Med 2009; 360: 2035–6. CrossRef MEDLINE
e9.Choudhry NK, Stelfox HT, Detsky AS: Relationships between authors of clinical practice guidelines and the pharmaceutical industry. JAMA 2002; 287: 612–7. CrossRef MEDLINE
e10.Cosgrove L, Krimsky S, Vijayaraghavan M, Schneider L: Financial ties between DSM-IV panel members and the pharmaceutical industry. Psychother Psychosom 2006; 75: 154–60. CrossRef MEDLINE
e11.Holloway RG, Mooney CJ, Getchius TS, Edlund WS, Miyasaki JO: Invited article: conflicts of interest for authors of American Academy of Neurology clinical practice guidelines. Neurology 2008; 71: 57–63. CrossRef MEDLINE
e12.Mendelson TB, Meltzer M, Campbell EG, Caplan AL, Kirkpatrick JN: Conflicts of interest in cardiovascular clinical practice guidelines. Arch Intern Med 2011; 171: 577–84. CrossRef MEDLINE
e13.Neuman J, Korenstein D, Ross JS, Keyhani S: Prevalence of financial conflicts of interest among panel members producing clinical practice guidelines in Canada and United States: cross sectional study. BMJ 2011; 343: d5621. CrossRef MEDLINE PubMed Central
e14.Taylor R, Giles J: Cash interests taint drug advice. Nature 2005; 437: 1070–1. CrossRef MEDLINE
e15.Kung J, Miller RR, Mackowiak PA: Failure of clinical practice guidelines to meet Institute of Medicine standards: two more decades of little, if any, progress. Arch Intern Med 2012; 172: 1628–33. CrossRef MEDLINE
e16.Schwabe U, Paffrath D (eds): Arzneiverordnungs-Report 2010. Berlin, Heidelberg: Springer Medizin Verlag, 2010.
e17.Pfizer Pharma GmbH: Neurontin® 100/300/400 mg Hartkapseln. Stand: Juni 2011.
e18.FDA: FDA Approved Drug Products: Neurontin: /www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search. Search_Drug_Name. FDA Center for Drug Evaluation and Research, Office of Communications, Division of Information Services. Last accessed on 6 November 2012.
e19.Abramson J: Expert report of John Abramson, MD.: http://dida.library.ucsf.edu/pdf/oxx18v10. Neurontin Marketing and Sales Practices Litigation, MDL #1629, Docket #04–10981; 11 August 2008. Last accessed on 6 November 2012.
e20.Claes C, Kulp W, Greiner W, Graf von der Schulenburg J-M, Werfel T: Deutsches Institut für Medizinische Dokumentation und Information (DIMDI) (eds): Therapie der mittelschweren und schweren Psoriasis. Bd. 34, Schriftenreihe Health Technology Assessment (HTA). Köln: DIMDI, 2006.
e21.IMP24011. Phase III, randomised, double blind, placebo-controlled, multicentre study evaluating 12 weeks subcutaneous therapy with Genentech efalizumab in patients with moderate to severe psoriasis who are candidates for systemic therapy. In: Clinical and cost effectiveness of efalizumab (Raptiva) for moderate to severe psoriasis. [Industry submission]. Feltham: Serono Ltd., 2004.
e22.ACD2600g. Phase IIIb, randomised, double-blind, parallel group, placebocontrolled, multicentre study evaluating 12 weeks therapy with subcutaneously administered Genentech efalizumab in adults with moderate to severe psoriasis who are candidates for systemic therapy. In: Clinical and cost effectiveness of efalizumab (Raptiva) for moderate to severe psoriasis. [Industry submission]. Feltham: Serono Ltd., 2004.
e23.ACD2058g. Phase III, randomised double blind placebo-controlled study evaluating 12 weeks of therapy with XOMA1 efalizumab administered subcutaneously (SC), followed by either continued treatment for an additional 12 weeks or re-treatment for 12 weeks following a relapse. In: Clinical and cost effectiveness of efalizumab (Raptiva) for moderate to severe psoriasis. [Industry submission]. Feltham: Serono Ltd., 2004.
e24.Hofelich V: Ergebnisse zur Evaluation der S3-Leitlinie zur Therapie der Psoriasis vulgaris in Deutschland: www.diss.fu-berlin.de/diss/servlets/MCRFileNodeServlet/FUDISS_derivate_000000006571/ Promotion_online.pdf. Dissertation; Klinik für Dermatologie, Venerologie und Allergologie der Medizinischen Fakultät Charité – Universitätsmedizin Berlin, Januar 2010. Last accessed on
6 November 2012.
e25.Serono Europe Ltd.: Fachinformation „Raptiva®“. Status: September 2004.
e26.EMA: Public statement on Raptiva (efalizumab): Withdrawel of the marketing authorisation in the European Union: www.ema.europa.eu/docs/en_GB/document_library/Public_statement/ 2009/11/WC500009129.pdf. London, 3 August 2009;
Doc. Ref. EMEA/487107/2009. Last accessed on 6 November 2012.
e27.Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, et al.: Efficacy of gabapentin in migraine prophylaxis. Headache 2001; 41: 119–28. CrossRef MEDLINE
e28.Serpell MG: Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain 2002; 99: 557–66. CrossRef
e29.Backonja M, Beydoun A, Edwards KR, et al.: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280: 1831–6. CrossRef MEDLINE
e30.Caraceni A, Zecca E, Bonezzi C, et al.: Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 2004; 22: 2909–17. CrossRef MEDLINE
e31.Dallocchio C, Buffa C, Mazzarello P, Chiroli S: Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage 2000; 20: 280–5. CrossRef MEDLINE
e32.Gorson KC, Schott C, Herman R, Ropper AH, Rand WM: Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry 1999; 66: 251–2. CrossRef MEDLINE PubMed Central
e33.Wiffen PJ, McQuay HJ, Edwards J, Moore RA: WITHDRAWN: Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2011; Issue 3: CD005452. MEDLINE
e34.Gottlieb AB, Gordon KB, Lebwohl MG, et al.: Extended efalizumab therapy sustains efficacy without increasing toxicity in patients with moderate to severe chronic plaque psoriasis. J Drugs Dermatol 2004; 3: 614–24. MEDLINE
e35.Leonardi CL, Papp KA, Gordon KB, et al.: Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol 2005; 52: 425–33. CrossRef MEDLINE
e36.Gordon KB, Papp KA, Hamilton TK, et al.: Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 2003; 290: 3073–80. CrossRef MEDLINE
e37.Menter A, Kosinski M, Bresnahan BW, Papp KA, Ware JE Jr.: Impact of efalizumab on psoriasis-specific patient-reported outcomes. Results from three randomized, placebo-controlled clinical trials of moderate to severe plaque psoriasis. J Drugs Dermatol 2004; 3: 27–38. MEDLINE
e38.Lebwohl M, Tyring SK, Hamilton TK, et al.: A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349: 2004–13. CrossRef MEDLINE
e39.Menter A, Gordon K, Carey W, et al.: Efficacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis. Arch Dermatol 2005; 141: 31–8. CrossRef MEDLINE
e40.Papp K, Bissonnette R, Krueger JG, et al.: The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody. J Am Acad Dermatol 2001; 45: 665–74. CrossRef MEDLINE