Original article

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(16): 279-85; DOI: 10.3238/arztebl.2010.0279

Schott, G; Pachl, H; Limbach, U; Gundert-Remy, U; Ludwig, W; Lieb, K

Background: In recent years, a number of studies have shown that clinical drug trials financed by pharmaceutical companies yield favorable results for company products more often than independent trials do. Moreover, pharmaceutical companies have been found to influence drug trials in various ways. This paper provides an overview of the findings of current, systematic studies on this topic.
Methods: Publications retrieved from a systematic Medline search on this topic from 1 November 2002 to 16 December 2009 were independently evaluated and selected by two of the authors. These publications were supplemented by further ones found in their references sections.
Results: 57 publications were included for evaluation in Parts 1 and 2 of this article. Published drug trials that were financed by pharmaceutical companies, or whose authors declared a financial conflict of interest, were found to yield favorable results for the drug manufacturer more frequently than independently financed trials whose authors had no such conflicts. The results were also interpreted favorably more often than in independently financed trials. Furthermore, there was evidence that pharmaceutical companies influenced study protocols in a way that was favorable to themselves. The methodological quality of trials financed by pharmaceutical companies was not found to be any worse than that of trials financed in other ways.
Conclusion: Published drug trials that are financed by pharmaceutical companies may present a distorted picture. This cannot be explained by any difference in methodological quality between such trials and trials financed in other ways.
Clinical drug trials funded by pharmaceutical companies yield favorable results for the sponsor’s products more often than independent trials do. This has been demonstrated by a number of studies in recent years (14). Various ways have been described in which pharmaceutical concerns exert influence on the protocol and conduct of drug trials, as well as on the interpretation and publication of their results (1, 3, 5, 6).

Two important reviews on this topic were published in 2003 (7, 8):

Bekelman et al. carried out a quantitative analysis of 37 studies to investigate the extent and the relevance of financial links between biomedical companies on one hand and academic institutions and scientists on the other (7). This systematic review showed widespread conflicts of interest in the shape of financial connections between scientists, academic institutions, and the pharmaceutical industry. Around one quarter of academic staff and two thirds of academic institutions had financial relationships with industry. Analysis of 8 review articles embracing a total of 1140 original articles (including randomized controlled trials [RCT], economic analyses, and retrospective cohort studies) revealed a statistically significant association between funding by biomedical companies and conclusions favorable to the pharmaceutical industry (summarized odds ratio [OR] 3.6, 95% confidence interval [CI] 2.6–4.9). Industry financing was also connected with limitations of publication rights and constraints on access to trial data.

In the second review, a systematic analysis of 30 publications, Lexchin et al. showed that drug trials financed by pharmaceutical companies are less likely to be published, but that those published more frequently yield positive results for the sponsors’ products than do independently funded studies (8). The quality of the methods employed (analyzed in 13 publications) in trials financed by pharmaceutical companies was not inferior to that in studies with other sources of funding.

Influence on many different aspects of a clinical drug trial can affect the results, from the purpose via the planning and conduct of the study all the way to its evaluation and publication (5).

The authors of the present systematic review set out to assess whether recently published studies reveal a connection between financing of drug trials by pharmaceutical companies and results favorable to these companies’ products. Part 1 investigates whether and, if so, how the type of funding affects study protocol and quality. Part 2 identifies and depicts the aspects of clinical drug trials that can be influenced by financial support from the pharmaceutical industry.

Methods
Systematic literature review
The criteria for the selection of systematic investigations into the effects of financing on study results were oriented on the above-mentioned reviews (7, 8). The literature search was carried out in the PubMed database. The most important MeSH terms and search terms, combined by means of Boolean operators, were “conflict of interest”, research support as topic”, clinical trials as topic”, “commerce”, “drug industry”, “authorship”, “publication bias”, and “financial support”.

The following limits, among others, were imposed: “publication date”, “clinical trial”, “meta-analysis”, and “randomized controlled trial”.

Searches were carried out on 26 May 2008 (for the period 1 November 2002 to 26 May 2008), 4 December 2008 (for 26 May 2008 to 3 December 2008), and 16 December 2009 (for 1 October 2008 to 16 December 2009).
Publications in all languages were included. Two of the authors (G. Schott, U. Limbach) independently selected suitable studies on the basis of the inclusion and exclusion criteria (see below). In the case of disagreement, consensus was achieved by discussion with a third author (K. Lieb). The reference lists of all selected articles were inspected for further relevant publications (9).

Inclusion and exclusion criteria
The criteria for inclusion were:

• Publication between 1 November 2002 and 16 December 2009 (i.e., directly following on from the period analyzed by Bekelman et al. [7])
• Description of the methods employed
• Provision of empirical data as to whether and how financing by pharmaceutical companies affects various aspects of clinical trials (e.g., protocol, conduct, results, conclusions, or publication).

Commentaries, editorials, and abstracts were excluded.

Some studies were found to combine clinical drug trials and analyses of, for example, surgical interventions, medical devices, or preclinical investigations. In such cases the study was included as long as the results of clinical drug testing were described separately.

Evaluation of the literature
The basic characteristics, purpose, and principal findings of each of the studies reviewed were recorded (eTable gif ppt). The quality of the studies’ methods was not systematically evaluated, because there is no validated, reliable instrument for quality assessment that can be applied to all of the various study designs (including systematic reviews, meta-analyses, case studies, and cross-sectional studies).

In the effort to ensure comprehensive portrayal of the various ways in which influence could be exerted, a descriptive approach was chosen; no hypotheses were advanced or statistical analyses performed. The studies were arranged by topic according to their results.

Results
The search of the PubMed database yielded 1705 publications. After inspection of reference lists, 57 publications that satisfied the inclusion and exclusion criteria were evaluated (Figure gif ppt). The results of this evaluation are described in Parts 1 and 2 of the present study.

The publications included were primarily studies performed with the expressed goal of comparing clinical trials funded by pharmaceutical companies with clinical trials that had not received financial support from such companies, e.g., with regard to the results or conclusions. These studies were accompanied by a number of publications that investigated the consequences of financing of a study by pharmaceutical companies. These included, for example, articles in which information from the files of the US licensing authority (Food and Drug Administration, FDA) was compared with data from publications in medical journals, and case studies on individual substances.

Two systematic reviews carried out for much the same reason as the present review were excluded on the grounds that their principal primary studies had already been included (10, 11). The results of the publications covered in the present review are based largely on clinical drug trials conducted principally in the Anglo-American countries. A few publications also analyzed studies performed in Germany. The most recent studies whose data were taken into account in the papers covered were published in November 2008. The publications evaluated concern various areas of medicine, but it cannot be completely ruled out that original data from a small number of drug trials were included more than once. A few studies dealt with several aspects.

Connection between type of funding and results of drug trials
Twenty-six of the 57 publications analyzed sought to ascertain whether the results and/or conclusions of drug trials depended on the type of funding or on financial conflicts of interest on the part of the authors (eTable).

These investigations dealt with various medical topics and disciplines (among them oncology [e1, e2], cardiovascular diseases [e3], and psychiatry [e4]) and featured different study designs (e.g., systematic review, meta-analysis, case study).

Altogether, 23 of these 26 studies came to the conclusion that there was a positive correlation between the financing of a study by pharmaceutical companies and/or conflicts of interest on the part of the authors and results or conclusions that were favorable to the sponsor. The statistical significance of this finding was investigated in 22 cases and confirmed in 20.

In 4 cases it was apparent that the findings were interpreted favorably towards the pharmaceutical concern that had funded the study, independent of the results (e5e8).

In 3 investigations there was no clear association between the funding of a study by pharmaceutical companies and findings that favored the sponsors (e9e11). In one of these, a urological study (e11), very few publications were analyzed (n = 24); furthermore, the author disclosed “Speakers’ Bureau—Pfizer” as a conflict of interest. Another study investigated the connection between the conclusions and the source of financial support in clinical trials that had appeared in 5 influential medical journals over a period of 20 years (e10). Most trials yielded positive results for the drug in question regardless of the funding source, but this study also revealed a trend over the course of time towards more positive findings in industrially financed trials than in trials supported by non-profit organizations (e10). The third study compared the results (but not the interpretations or conclusions) of clinical trials of drugs used in pain management, some of them long available as generics (e9).

Study protocol
Five of the 57 studies analyzed investigated whether funding by pharmaceutical companies affected the design of the study protocol (Table 1 gif ppt). The use of placebos was shown to be significantly more common in RCTs of drugs for psoriasis that were financed by such companies than in those with funding from other sources (e12). Moreover, several studies of treatment for premature ejaculation that were sponsored by a pharmaceutical company were found to have disregarded the relevant objective endpoint (e13). In an investigation of inhaled corticosteroids, significant differences in the frequency of adverse drug reactions (ADR) between the probands and the control group occurred only half as often when the study had been funded by the manufacturers (see also Part 2). The differences could be attributed wholly to the study design. For example, studies financed by pharmaceutical companies used lower dosages.

A further study revealed that an RCT of rofecoxib was a “seeding trial,” i.e., a clinical study that claims to be testing a scientific hypothesis but in reality has the purpose of making the drug known to prescribing physicians and thus increasing sales (e14). Examination of confidential internal documents that became public in the context of legal proceedings revealed that the study had been designed and conducted by the marketing department of the pharmaceutical company concerned. However, there were also signs of other irregularities. The target group of prescribers (family doctors) was determined at the outset, and only then was the study protocol formulated. Neither ethics committees nor participants were informed of the true goal of the study, namely promotion of the drug. To make this marketing as successful as possible and pitch the product to a large number of doctors, the study was carried out in 600 centers. Such a high number of centers would not have been required for the official purpose of the study (comparison of the gastrointestinal tolerability of rofecoxib and naproxen). Indications of increased cardiovascular morbidity among those taking rofecoxib were not pursued. The article describing the study was written by employees of the manufacturer of rofecoxib, but appeared under another researcher’s name. This was thus a case of guest authorship (see Part 2). The pharmaceutical company concerned investigated the marketing effect of the study, finding that participating physicians did indeed prescribe rofecoxib significantly more often than non-participants in its first 6 months on the market.

In contrast, differences in study protocol among investigations of atypical antipsychotics could not be attributed to the type of funding (e15). The protocols of 3 pharmaceutical companies and of studies not supported by the pharmaceutical industry were compared. Blinding, placebo controls, and use of an atypical antipsychotic for comparison were found more frequently in the protocols of two of the pharmaceutical companies than in those of the third company or the studies without industrial financing.

Connection between type of funding and quality of study methods
Altogether, 4 publications concerned themselves with the methodological quality of drug trials in relation to financial support (Table 2 gif ppt). Various instruments were employed to assess quality: for RCTs the Jadad scale (12) and a scale based on the CONSORT Statement (e16), both of which ask, for example, about blinding and randomization; for systematic reviews, the Oxman and Guyatt index, which for instance asks about search strategies and avoidance of selection bias (13).

In 2 investigations the quality of the methods of the clinical trials financed by pharmaceutical companies was comparable to or even better than when funding came from a sponsor without commercial interests (e16, e17), and in only one study did it tend to be worse (e18). Comparison of industrially financed meta-analyses and Cochrane Reviews showed that the latter displayed higher quality (e6); search strategies and randomization methods were described more often, for example, and literature searches were more comprehensive.

Discussion
The results of clinical drug trials that are funded by pharmaceutical companies or whose authors have financial conflicts of interest are favorable to the products of the sponsoring company far more frequently than studies whose funding comes from other sources. Furthermore, interpretation of the data in the conclusions of industrially financed trials more often favors the sponsor. This was shown by the present systematic review and analysis of investigations, published between 1 November 2002 and 16 December 2009, into various diseases, study types (e.g., RCTs and observational studies), and drugs. The results confirm the conclusions of 2 systematic reviews, both published in 2003, conducted with similar intent (7, 8). The principle of equipoise, i.e., uncertainty which of the alternative approaches benefits the patient most, forms the ethical foundation of clinical studies in which the probands receive various treatments (14). This principle seems to be violated in many studies funded by pharmaceutical companies.

There are numerous reasons why studies financed by pharmaceutical manufacturers more often yield positive results. Four investigations found evidence that pharmaceutical companies influence the study protocol to their advantage (e12e14, e19), e.g., by more frequent use of placebos in control groups than in independently funded studies (e12). Although the responsible authorities sometimes demand placebo-controlled trials as a condition of licensing, they also request active controls (15). Further factors leading to higher frequency of results favorable to the sponsor in trials funded by pharmaceutical companies are described in Part 2 of this review.

Trials financed by pharmaceutical concerns displayed no signs of poorer methodological quality. On the contrary, two studies showed superior quality (e16, e17). It must be taken into account, however, that some factors that serve to assess the quality of the instruments used in a study were not determined, among them the clinical relevance of the target parameters. In oncology, for instance, there are currently major defects in the protocols of industrially sponsored clinical trials, e.g., deficiencies in the definition of patient-relevant endpoints and in the selection of suitable substances for the control arm of RCTs (1619). Moreover, clinical trials in oncology are often discontinued after preliminary analysis (20), with the result that only a short time after the licensing of a drug its additional benefits and the safety of new substances can frequently no longer be evaluated, preventing any benefit/risk analysis (21).

This work was supported by funds from the Initiative for Health Services Research (Förderinitiative Versorgungsforschung) of the German Medical Association (Bundesärztekammer, BÄK). The 110th German Medical Assembly tasked the BÄK with investigating, in the framework of the Initiative for Health Services Research, the influence of sponsors on the scientific results of drug trials.

Conflict of interest statement
The authors declare that no conflict of interest exists according to the guidelines of the International Committee of Medical Journal Editors.

Manuscript received on 29 May 2009, revised version accepted on
23 February 2010.

Translated from the original German by David Roseveare.


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


@For e-references please refer to:
www.aerzteblatt-international.de/ref1610
eTable available at:
www.aerzteblatt-international.de/article10m0279
1.
Djulbegovic B, Lacevic M, Cantor A, Fields KK, Bennett CL, Adams JR, et al.: The uncertainty principle and industry-sponsored research. Lancet 2000; 356: 635–8. MEDLINE
2.
Friedberg M, Saffran B, Stinson TJ, Nelson W, Bennett CL: Evaluation of conflict of interest in economic analyses of new drugs used in oncology. JAMA 1999; 282: 1453–7. MEDLINE
3.
Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, Minaker KL, et al.: A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med 1994; 154: 157–63. MEDLINE
4.
Yaphe J, Edman R, Knishkowy B, Herman J: The association between funding by commercial interests and study outcome in randomized controlled drug trials. Fam Pract 2001; 18: 565–8. MEDLINE
5.
Bero LA, Rennie D: Influences on the quality of published drug studies. Int J Technol Assess Health Care 1996; 12: 209–37. MEDLINE
6.
Flanagin A, Carey LA, Fontanarosa PB, Phillips SG, Pace BP, Lundberg GD, et al.: Prevalence of articles with honorary authors and ghost authors in peer-reviewed medical journals. JAMA 1998; 280: 222–4. MEDLINE
7.
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. MEDLINE
8.
Lexchin J, Bero LA, Djulbegovic B, Clark O: Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70. MEDLINE
9.
Ressing M, Blettner M, Klug SJ: Systematic literature reviews and meta-analyses: part 6 of a series on evaluation of scientific publications [Systematische Übersichtsarbeiten und Metaanalysen: Teil 6 der Serie zur Bewertung wissenschaftlicher Publikationen]. Dtsch Arztebl Int 2009; 106: 456–63. VOLLTEXT
10.
Sismondo S: Pharmaceutical company funding and its consequences: a qualitative systematic review. Contemp Clin Trials 2008; 29: 109–13. MEDLINE
11.
Golder S, Loke YK: Is there evidence for biased reporting of published adverse effects data in pharmaceutical industry-funded studies? Br J Clin Pharmacol 2008; 66: 767–73. MEDLINE
12.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al.: Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12. MEDLINE
13.
Oxman AD, Guyatt GH: Validation of an index of the quality of review articles. J Clin Epidemiol 1991; 44: 1271–8. MEDLINE
14.
Freedman B: Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141–5. MEDLINE
15.
EMA, CHMP: Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man (CPMP/EWP/205/95 Rev. 3) on haematological malignancies. London, 20. November 2008; Doc. Ref. EMEA/CHMP/EWP/520088/2008. Zuletzt geprüft: 8. Februar 2010.
16.
Apolone G, Joppi R, Bertele’ V, Garattini S: Ten years of marketing approvals of anticancer drugs in Europe: regulatory policy and guidance documents need to find a balance between different pressures. Br J Cancer 2005; 93: 504–9. MEDLINE
17.
Bertele’ V, Banzi R, Capasso F, Tafuri G, Trotta F, Apolone G, et al.: Haematological anticancer drugs in Europe: any added value at the time of approval? Eur J Clin Pharmacol 2007; 63: 713–9. MEDLINE
18.
Johnson JR, Williams G, Pazdur R: End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 2003; 21: 1404–11. MEDLINE
19.
van Luijn JC, Gribnau FW, Leufkens HG: Availability of comparative trials for the assessment of new medicines in the European Union at the moment of market authorization. Br J Clin Pharmacol 2007; 63: 159–62. MEDLINE
20.
Trotta F, Apolone G, Garattini S, Tafuri G: Stopping a trial early in oncology: for patients or for industry? Ann Oncol 2008; 19: 1347–53. MEDLINE
21.
Ludwig W-D, Fetscher S, Schildmann J: Teure Innovationen in der Onkologie – für alle? Der Onkologe 2009; 15: 1004–14.
e1.
Peppercorn J, Blood E, Winer E, Partridge A: Association between pharmaceutical involvement and outcomes in breast cancer clinical trials. Cancer 2007; 109: 1239–46. MEDLINE
e2.
Booth CM, Cescon DW, Wang L, Tannock IF, Krzyzanowska MK: Evolution of the randomized controlled trial in oncology over three decades. J Clin Oncol 2008; 26: 5458–64. MEDLINE
e3.
Ridker PM, Torres J: Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000–2005. JAMA 2006; 295: 2270–4. MEDLINE
e4.
Tungaraza T, Poole R: Influence of drug company authorship and sponsorship on drug trial outcomes. Br J Psychiatry 2007; 191: 82–3. MEDLINE
e5.
Als-Nielsen B, Chen W, Gluud C, Kjaergard LL: Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA 2003; 290: 921–8. MEDLINE
e6.
Jorgensen AW, Hilden J, Gotzsche PC: Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review. BMJ 2006; 333: 782–5. MEDLINE
e7.
Yank V, Rennie D, Bero LA: Financial ties and concordance between results and conclusions in meta-analyses: retrospective cohort study. BMJ 2007; 335: 1202–5. MEDLINE
e8.
Gilstad JR, Finucane TE: Results, rhetoric, and randomized trials: the case of donepezil. J Am Geriatr Soc 2008; 56: 1556–62. MEDLINE
e9.
Barden J, Derry S, McQuay HJ, Moore RA: Bias from industry trial funding? A framework, a suggested approach, and a negative result. Pain 2006; 121: 207–18. MEDLINE
e10.
Buchkowsky SS, Jewesson PJ: Industry sponsorship and authorship of clinical trials over 20 years. Ann Pharmacother 2004; 38: 579–85. MEDLINE
e11.
Tulikangas PK, Ayers A, O’Sullivan DM: A meta-analysis comparing trials of antimuscarinic medications funded by industry or not. BJU Int 2006; 98: 377–80. MEDLINE
e12.
Katz KA, Karlawish JH, Chiang DS, Bognet RA, Propert KJ, Margolis DJ: Prevalence and factors associated with use of placebo control groups in randomized controlled trials in psoriasis: a cross-sectional study. J Am Acad Dermatol 2006; 55: 814–22. MEDLINE
e13.
Waldinger MD, Schweitzer DH: Premature ejaculation and pharmaceutical company-based medicine: the dapoxetine case. J Sex Med 2008; 5: 966–97. MEDLINE
e14.
Hill KP, Ross JS, Egilman DS, Krumholz HM: The ADVANTAGE seeding trial: a review of internal documents. Ann Intern Med 2008; 149: 251–8. MEDLINE
e15.
Procyshyn RM, Chau A, Fortin P, Jenkins W: Prevalence and outcomes of pharmaceutical industry-sponsored clinical trials involving clozapine, risperidone, or olanzapine. Can J Psychiatry 2004; 49: 601–6. MEDLINE
e16.
Yuen SY, Pope JE: Learning from past mistakes: assessing trial quality, power and eligibility in non-renal systemic lupus erythematosus randomized controlled trials. Rheumatology (Oxford) 2008; 47: 1367–72. MEDLINE
e17.
Perlis CS, Harwood M, Perlis RH: Extent and impact of industry sponsorship conflicts of interest in dermatology research. J Am Acad Dermatol 2005; 52: 967–71. MEDLINE
e18.
Montgomery JH, Byerly M, Carmody T, Li B, Miller DR, Varghese F et al.: An analysis of the effect of funding source in randomized clinical trials of second generation antipsychotics for the treatment of schizophrenia. Control Clin Trials 2004; 25: 598–612. MEDLINE
e19.
Nieto A, Mazon A, Pamies R, Linana JJ, Lanuza A, Jimenez FO, et al.: Adverse effects of inhaled corticosteroids in funded and nonfunded studies. Arch Intern Med 2007; 167: 2047–53. MEDLINE
e20.
Baker CB, Johnsrud MT, Crismon ML, Rosenheck RA, Woods SW: Quantitative analysis of sponsorship bias in economic studies of antidepressants. Br J Psychiatry 2003; 183: 498–506. MEDLINE
e21.
Bero L, Oostvogel F, Bacchetti P, Lee K: Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med 2007; 4: e184. MEDLINE
e22.
Bhandari M, Busse JW, Jackowski D, Montori VM, Schunemann H, Sprague S, et al.: Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. CMAJ 2004; 170: 477–80. MEDLINE
e23.
Etter JF, Burri M, Stapleton J: The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation: a meta-analysis. Addiction 2007; 102: 815–22. MEDLINE
e24.
Finucane TE, Boult CE: Association of funding and findings of pharmaceutical research at a meeting of a medical professional society. Am J Med 2004; 117: 842–45. MEDLINE
e25.
Fries JF, Krishnan E: Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development. Arthritis Res Ther 2004; 6: R250-5. MEDLINE
e26.
Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S: Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry 2006; 163: 185–94. MEDLINE
e27.
Kelly RE, Jr., Cohen LJ, Semple RJ, Bialer P, Lau A, Bodenheimer A, et al.: Relationship between drug company funding and outcomes of clinical psychiatric research. Psychol Med 2006; 36: 1647–56. MEDLINE
e28.
Liss H: Publication bias in the pulmonary/allergy literature: effect of pharmaceutical company sponsorship. Isr Med Assoc J 2006; 8: 451–4. MEDLINE
e29.
Moncrieff J: Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination. Br J Psychiatry 2003; 183: 161–6. MEDLINE
e30.
Perlis RH, Perlis CS, Wu Y, Hwang C, Joseph M, Nierenberg AA: Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Am J Psychiatry 2005; 162: 1957–60. MEDLINE
e31.
Vlad SC, LaValley MP, McAlindon TE, Felson DT: Glucosamine for pain in osteoarthritis: why do trial results differ? Arthritis Rheum 2007; 56: 2267–77. MEDLINE
Arzneimittelkommission der deutschen Ärzteschaft, Berlin: Dr. med. Schott, Dipl.-Biol. Pachl, Prof. Dr. med. Gundert-Remy, Prof. Dr. med. Ludwig
Klinik für Hämatologie, Onkologie und Tumorimmunologie, HELIOS Klinikum Berlin-Buch:
Prof. Dr. med. Ludwig*
Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Mainz:
Cand. med. Limbach, Prof. Dr. med. Lieb*
* The authors Ludwig and Lieb have equally contributed to the manuscript.
1. Djulbegovic B, Lacevic M, Cantor A, Fields KK, Bennett CL, Adams JR, et al.: The uncertainty principle and industry-sponsored research. Lancet 2000; 356: 635–8. MEDLINE
2. Friedberg M, Saffran B, Stinson TJ, Nelson W, Bennett CL: Evaluation of conflict of interest in economic analyses of new drugs used in oncology. JAMA 1999; 282: 1453–7. MEDLINE
3. Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, Minaker KL, et al.: A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med 1994; 154: 157–63. MEDLINE
4. Yaphe J, Edman R, Knishkowy B, Herman J: The association between funding by commercial interests and study outcome in randomized controlled drug trials. Fam Pract 2001; 18: 565–8. MEDLINE
5. Bero LA, Rennie D: Influences on the quality of published drug studies. Int J Technol Assess Health Care 1996; 12: 209–37. MEDLINE
6. Flanagin A, Carey LA, Fontanarosa PB, Phillips SG, Pace BP, Lundberg GD, et al.: Prevalence of articles with honorary authors and ghost authors in peer-reviewed medical journals. JAMA 1998; 280: 222–4. MEDLINE
7. 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. MEDLINE
8. Lexchin J, Bero LA, Djulbegovic B, Clark O: Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70. MEDLINE
9. Ressing M, Blettner M, Klug SJ: Systematic literature reviews and meta-analyses: part 6 of a series on evaluation of scientific publications [Systematische Übersichtsarbeiten und Metaanalysen: Teil 6 der Serie zur Bewertung wissenschaftlicher Publikationen]. Dtsch Arztebl Int 2009; 106: 456–63. VOLLTEXT
10. Sismondo S: Pharmaceutical company funding and its consequences: a qualitative systematic review. Contemp Clin Trials 2008; 29: 109–13. MEDLINE
11. Golder S, Loke YK: Is there evidence for biased reporting of published adverse effects data in pharmaceutical industry-funded studies? Br J Clin Pharmacol 2008; 66: 767–73. MEDLINE
12. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al.: Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12. MEDLINE
13. Oxman AD, Guyatt GH: Validation of an index of the quality of review articles. J Clin Epidemiol 1991; 44: 1271–8. MEDLINE
14. Freedman B: Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141–5. MEDLINE
15. EMA, CHMP: Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man (CPMP/EWP/205/95 Rev. 3) on haematological malignancies. London, 20. November 2008; Doc. Ref. EMEA/CHMP/EWP/520088/2008. Zuletzt geprüft: 8. Februar 2010.
16. Apolone G, Joppi R, Bertele’ V, Garattini S: Ten years of marketing approvals of anticancer drugs in Europe: regulatory policy and guidance documents need to find a balance between different pressures. Br J Cancer 2005; 93: 504–9. MEDLINE
17. Bertele’ V, Banzi R, Capasso F, Tafuri G, Trotta F, Apolone G, et al.: Haematological anticancer drugs in Europe: any added value at the time of approval? Eur J Clin Pharmacol 2007; 63: 713–9. MEDLINE
18. Johnson JR, Williams G, Pazdur R: End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 2003; 21: 1404–11. MEDLINE
19. van Luijn JC, Gribnau FW, Leufkens HG: Availability of comparative trials for the assessment of new medicines in the European Union at the moment of market authorization. Br J Clin Pharmacol 2007; 63: 159–62. MEDLINE
20. Trotta F, Apolone G, Garattini S, Tafuri G: Stopping a trial early in oncology: for patients or for industry? Ann Oncol 2008; 19: 1347–53. MEDLINE
21. Ludwig W-D, Fetscher S, Schildmann J: Teure Innovationen in der Onkologie – für alle? Der Onkologe 2009; 15: 1004–14.
e1. Peppercorn J, Blood E, Winer E, Partridge A: Association between pharmaceutical involvement and outcomes in breast cancer clinical trials. Cancer 2007; 109: 1239–46. MEDLINE
e2. Booth CM, Cescon DW, Wang L, Tannock IF, Krzyzanowska MK: Evolution of the randomized controlled trial in oncology over three decades. J Clin Oncol 2008; 26: 5458–64. MEDLINE
e3. Ridker PM, Torres J: Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000–2005. JAMA 2006; 295: 2270–4. MEDLINE
e4. Tungaraza T, Poole R: Influence of drug company authorship and sponsorship on drug trial outcomes. Br J Psychiatry 2007; 191: 82–3. MEDLINE
e5. Als-Nielsen B, Chen W, Gluud C, Kjaergard LL: Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA 2003; 290: 921–8. MEDLINE
e6. Jorgensen AW, Hilden J, Gotzsche PC: Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review. BMJ 2006; 333: 782–5. MEDLINE
e7. Yank V, Rennie D, Bero LA: Financial ties and concordance between results and conclusions in meta-analyses: retrospective cohort study. BMJ 2007; 335: 1202–5. MEDLINE
e8. Gilstad JR, Finucane TE: Results, rhetoric, and randomized trials: the case of donepezil. J Am Geriatr Soc 2008; 56: 1556–62. MEDLINE
e9. Barden J, Derry S, McQuay HJ, Moore RA: Bias from industry trial funding? A framework, a suggested approach, and a negative result. Pain 2006; 121: 207–18. MEDLINE
e10. Buchkowsky SS, Jewesson PJ: Industry sponsorship and authorship of clinical trials over 20 years. Ann Pharmacother 2004; 38: 579–85. MEDLINE
e11. Tulikangas PK, Ayers A, O’Sullivan DM: A meta-analysis comparing trials of antimuscarinic medications funded by industry or not. BJU Int 2006; 98: 377–80. MEDLINE
e12. Katz KA, Karlawish JH, Chiang DS, Bognet RA, Propert KJ, Margolis DJ: Prevalence and factors associated with use of placebo control groups in randomized controlled trials in psoriasis: a cross-sectional study. J Am Acad Dermatol 2006; 55: 814–22. MEDLINE
e13. Waldinger MD, Schweitzer DH: Premature ejaculation and pharmaceutical company-based medicine: the dapoxetine case. J Sex Med 2008; 5: 966–97. MEDLINE
e14. Hill KP, Ross JS, Egilman DS, Krumholz HM: The ADVANTAGE seeding trial: a review of internal documents. Ann Intern Med 2008; 149: 251–8. MEDLINE
e15. Procyshyn RM, Chau A, Fortin P, Jenkins W: Prevalence and outcomes of pharmaceutical industry-sponsored clinical trials involving clozapine, risperidone, or olanzapine. Can J Psychiatry 2004; 49: 601–6. MEDLINE
e16. Yuen SY, Pope JE: Learning from past mistakes: assessing trial quality, power and eligibility in non-renal systemic lupus erythematosus randomized controlled trials. Rheumatology (Oxford) 2008; 47: 1367–72. MEDLINE
e17. Perlis CS, Harwood M, Perlis RH: Extent and impact of industry sponsorship conflicts of interest in dermatology research. J Am Acad Dermatol 2005; 52: 967–71. MEDLINE
e18. Montgomery JH, Byerly M, Carmody T, Li B, Miller DR, Varghese F et al.: An analysis of the effect of funding source in randomized clinical trials of second generation antipsychotics for the treatment of schizophrenia. Control Clin Trials 2004; 25: 598–612. MEDLINE
e19. Nieto A, Mazon A, Pamies R, Linana JJ, Lanuza A, Jimenez FO, et al.: Adverse effects of inhaled corticosteroids in funded and nonfunded studies. Arch Intern Med 2007; 167: 2047–53. MEDLINE
e20. Baker CB, Johnsrud MT, Crismon ML, Rosenheck RA, Woods SW: Quantitative analysis of sponsorship bias in economic studies of antidepressants. Br J Psychiatry 2003; 183: 498–506. MEDLINE
e21. Bero L, Oostvogel F, Bacchetti P, Lee K: Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med 2007; 4: e184. MEDLINE
e22. Bhandari M, Busse JW, Jackowski D, Montori VM, Schunemann H, Sprague S, et al.: Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. CMAJ 2004; 170: 477–80. MEDLINE
e23. Etter JF, Burri M, Stapleton J: The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation: a meta-analysis. Addiction 2007; 102: 815–22. MEDLINE
e24. Finucane TE, Boult CE: Association of funding and findings of pharmaceutical research at a meeting of a medical professional society. Am J Med 2004; 117: 842–45. MEDLINE
e25. Fries JF, Krishnan E: Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development. Arthritis Res Ther 2004; 6: R250-5. MEDLINE
e26. Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S: Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry 2006; 163: 185–94. MEDLINE
e27. Kelly RE, Jr., Cohen LJ, Semple RJ, Bialer P, Lau A, Bodenheimer A, et al.: Relationship between drug company funding and outcomes of clinical psychiatric research. Psychol Med 2006; 36: 1647–56. MEDLINE
e28. Liss H: Publication bias in the pulmonary/allergy literature: effect of pharmaceutical company sponsorship. Isr Med Assoc J 2006; 8: 451–4. MEDLINE
e29. Moncrieff J: Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination. Br J Psychiatry 2003; 183: 161–6. MEDLINE
e30. Perlis RH, Perlis CS, Wu Y, Hwang C, Joseph M, Nierenberg AA: Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Am J Psychiatry 2005; 162: 1957–60. MEDLINE
e31. Vlad SC, LaValley MP, McAlindon TE, Felson DT: Glucosamine for pain in osteoarthritis: why do trial results differ? Arthritis Rheum 2007; 56: 2267–77. MEDLINE

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