Original article

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(17): 295-301; DOI: 10.3238/arztebl.2010.0295

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

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 overview of current, systematic studies on this topic is intended to identify and characterize the particular aspects of the performance of a drug trial that can be affected by financial support from a pharmaceutical company.
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. A number of studies revealed that many trials financed by pharmaceutical companies—in some cases, as many as half of all such trials—are never published. Moreover, multiple publications of the same findings were found, and some reports were found to include selectively published data. Further studies revealed evidence of other problems including incomplete trial registration, constraints on publishing rights, withheld knowledge of adverse drug reactions, and the use of ghostwriters who were supplied by the pharmaceutical companies.
Conclusion: Financial support from a pharmaceutical company influences multiple aspects of the performance of drug trials and often leads to a favorable result for the corporate sponsor of the trial. Public access to trial protocols and results must be ensured. Moreover, more effort should be made to carry out drug trials independently, without the financial support of pharmaceutical companies.
Anumber of studies in recent years have shown that clinical drug trials financed by pharmaceutical companies yield favorable results for the company’s product more often than independent trials do (1, 2). The authors’ own systematic review of investigations -published between 1 November 2002 and 16 December 2009 comes to the same conclusion (Part 1 of this article [3]). The results of a drug trial can be influenced at many different stages of the study (Figure gif ppt). For some of these areas there is clear evidence of influence exerted by pharmaceutical companies (1, 2, 4). In Part 1 the authors presented, for example, findings showing that pharmaceutical companies influence results to their advantage through the design of the study protocol, e.g., the selection of dosage, control groups, or endpoints (e1e3).

Execution of the study according to plan and objective depiction of the results can also be influenced, e.g., by contractual stipulations that grant the pharmaceutical company access to the trial data or give it the power to prevent the publication of results. Moreover, the presentation of results can be manipulated by ghostwriters and guest authors. The word “ghostwriter” is used to describe a person who is not mentioned in the publication despite an essential role in performing the study or writing the manuscript. This includes statisticians who analyze the results. The term “guest author” describes someone who is listed as an author of a publication although he or she does not fulfill the recognized criteria for authorship (as outlined for example in [5]) (e4, e5). Typically, a well-known opinion former is invited to be guest author in order to underline the importance of the study results. The withholding of negative and statistically non-significant findings can result in so-called publication bias, leading to a distorted perception of the therapeutic value of the drug concerned (6).

The present investigation sets out to spotlight the different stages and aspects of drug trials that are—as shown by recent systematic reviews—influenced by funding from the pharmaceutical industry.

Methods
The methods are presented in detail in Part 1 (3). Suitable studies identified by a Medline search (1 November 2002 to 16 December 2009) were independently evaluated and selected by two of the authors (G. Schott, U. Limbach), who also added relevant publications from the reference lists.

Results
Types of influence
Investigations into the types of influence that pharmaceutical companies exert on drug trials are summarized in the Table and the eTable (gif ppt).

Incomplete registration
With the aim of facilitating public access to clinical trial data and preventing pharmaceutical companies from influencing the publication of results, in 2004 the International Committee of Medical Journal Editors (ICMJE) made registration a condition for publication in any of the 11 leading medical journals (7): new trials had to be registered by 1 July 2005; those already under way, by 13 September 2005. Meanwhile several registers fulfill the ICMJE standards.

In January 2005 major pharmaceutical organizations, among them the Pharmaceutical Research and Manufacturers of America (PhRMA) and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), implemented guidelines that obliged their members to enter trials prospectively in publicly accessible registers (8, 9).

Despite this, two of the 57 studies included in the present investigation contain data suggesting that pharmaceutical companies are still not registering important information on clinical drug trials.

One study in 2005 showed that although the introduction of the ICMJE rules was followed by an overall sharp increase in registrations at ClinicalTrials.gov, the companies’ information regarding particular aspects of their trials, e.g., primary endpoints, remained imprecise or was absent altogether (e6).

The results of the other study, published in 2006, indicate that manufacturers of pharmaceuticals used in dermatology were not registering all their studies. For several companies it remained unclear what guidelines were being applied to the registration of drug trials (e7).

Concealment of adverse drug reactions
Seven of the studies investigated concerned themselves with adverse drug reactions (ADRs) in industrially supported drug trials (Table gif ppt).

Severe ADRs led to cerivastatin and rofecoxib being taken off the market 4 and 5 years, respectively, after licensing (10). In the course of subsequent legal proceedings, internal documents of the manufacturers were made public. Analysis of these documents re-vealed that relevant data on ADRs had not been provided to the public or to the American licensing body (Food and Drug Administration, FDA) at the appropriate time (e8, e9). In the case of cerivastatin, the manufacturer was aware of data indicating an interaction with gemfibrozil, leading to increased occurrence of rhabdomyolysis, around 100 days after their product was launched on the market; it was 18 months, however, before this was added to the contraindications in the product information (e8). As for rofecoxib, data pointing to increased mortality after intake in patients with Alzheimer's dementia were communicated neither to the FDA nor to the general public in good time (e9); trial data on the occurrence of cardiovascular ADRs were inadequately evaluated (e10, e11).

In the case of the selective serotonin reuptake inhibitor (SSRI) paroxetine, deficient analysis of available data is the reason why well-known ADRs, e.g., paresthesia and nervousness, are still not mentioned in the product information (e12).

Exertion of influence by pharmaceutical manufacturers was also evident in studies on inhaled corticosteroids (e3). In trials financed by pharmaceutical companies, statistically significant differences in ADR occurrence between drug and control groups were significantly less common and the authors of these publications (e3) designated the drug safe for use more frequently than in trials with other sources of funding (see Part 1).

One planned analysis of the statistical power of pharmacoepidemiological studies on ADRs of antiretroviral drugs depending on the sponsor could not be carried out because too few studies were funded by pharmaceutical companies (e13).

Publication bias
Of the 57 studies included in this investigation, 14 analyzed the connection between the type of funding of a trial and publication bias.

Licensing studies, which are particularly important for the assessment of new drugs, are carried out almost exclusively by pharmaceutical companies. Comparisons of data provided to the FDA with articles published in medical journals have shown that around 25% to 50% of these studies remain unpublished (e14e16). Positive or significant results are published more often than negative or non-significant findings (e14e17). The authors of two studies tested and confirmed the statistical significance of this statement (e14, e15). Furthermore, negative results were portrayed as positive (e15, e16).

A study on trials of SSRIs revealed that those with significant results were more likely to be published, sometimes more than once, whereas trials with non-significant results or findings unfavorable to the drug under investigation (intention-to-treat analyses versus per-protocol analyses) were not published (e17). Another study showed how efficacy of gabapentin for unlicensed (“off-label”) indications was feigned by alteration of the primary endpoint and non-publication of unfavorable data (e18).

Comparison of published and unpublished data from pharmaceutical companies showed that published data on SSRIs suggested a positive benefit/risk balance, but risk predominated when unpublished data were taken into account (e19). The strengths of effect of 12 different antidepressives as stated in published data were frequently greater than those derived from information supplied to the licensing authorities (e16).

There are varying data on whether the type of funding of a trial influences the likelihood of publication. While an investigation of protocols provided to an ethics committee showed that funding independent of pharmaceutical companies is associated with a greater likelihood of publication (e20), two studies in oncology (e21, e22) and an investigation of the protocols supplied to a different ethics committee (e23) revealed that trials funded by pharmaceutical companies were published more often (e22, e23) or more quickly (e21). A further investigation of publications of registered trials showed that low publication rates are not limited to particular sponsors of a trial; rather, they are a problem with both industry-funded and state-financed trials (e24).

Two investigations, one of cardiovascular research studies (e25) and the other of studies on the efficacy of influenza vaccines (e26) found evidence that results of clinical trials funded by pharmaceutical companies are cited more often. Pharmaceutically sponsored studies on the efficacy of influenza vaccines were also published in higher ranking journals. An analysis of pharmaceutical companies’ press releases on clinical trials showed that key data were provided but there was often no mention of study limitations and no quantification of the results (e27).

Rights over trial data and restricted publication rights
Two investigations on this topic were identified. Both an analysis of the protocols of all studies initiated and published by pharmaceutical companies in a particular region of Denmark in 1994 and 1995 (e28) and a questionnaire survey of medical specialists in Australia (e29) indicated that in some trials pharmaceutical companies secure the rights over the data and place constraints on publication rights.

Ghostwriters and guest authors
A case study on rofecoxib (e5) and an investigation into the above-mentioned studies in Denmark both found evidence of frequent resort to ghostwriters and guest authors in industry-funded publications. The Denmark investigation showed that statisticians employed by pharmaceutical companies are frequently not mentioned in the published articles (e4).

Discussion
Drug trials financed by the pharmaceutical industry yield results favorable to the funding company much more often than studies with other sources of support. This has been shown by the present systematic review (Part 1 [3]) and in other comparable investigations (1, 2).

This finding may be explained by various factors, some of them supported by systematic investigations. Publication bias, from selective publication of positive results or withholding of negative findings (e15e20), probably goes a long way to explaining the predominance of positive results in studies funded by pharmaceutical companies. Non-publication of results constitutes scientific malpractice and can ultimately lead to patients receiving inadequate treatment. Besides the companies and organizations that fund studies, scientists, ethics committees, and journal editors must also take responsibility for publication of all study results, whether they be positive or negative (11).

Publication bias may be favored by the fact that some pharmaceutical companies still do not give complete information when registering their trials, despite their commitment to do so (8, 9, 12). This is indicated by the results of two studies, albeit published as early as 2005 and 2006 (e6, e7). Given that study results are often published incompletely, in distorted form, or not in accordance with the study protocol (e15e19, e30), all planned drug trials should be registered and their protocols be made publicly available before conclusion of the investigations.

Furthermore, there were indications that pharmaceutical companies use ghostwriters (frequently staff statisticians) (e4, e5) and that knowledge of ADRs is withheld (e8e10, e12, e13). The gravity of the potential consequences of this concealment is illustrated by the withholding of mortality data on rofecoxib (e9).

Some aspects of pharmaceutical companies’ influence on the results and publication of drug trials have not been systematically investigated. For instance, Richard Smith, long-serving editor of the British Medical Journal, drew attention to the fact that many medical journals derive a substantial income from the pharmaceutical industry, e.g., from advertisements and reprints. He discerned therein a risk to the independence of journals and postulated that they often serve as extensions of the marketing departments of pharmaceutical companies (e31, 13). Medical journals should therefore publish their income on a regular basis, e.g., annually. This demand is a logical consequence of an investigation which showed that industry-funded studies on the efficacy of influenza vaccines were published in higher-ranking journals than studies with other sources of financing (e26).

The present investigation has various limitations. One of them—also described by Lexchin et al. (2)—is the difficulty in identifying the relevant literature. The authors’ PubMed search yielded only 38 of the 57 studies covered; the remaining 19 were found on inspection of the reference lists or were the subject of personal communications. Moreover, there was no assessment of the quality of the studies included, one of the preconditions for quantitative analysis. Furthermore, publications were included in which the terms “conflict of interest” and “funding by the pharmaceutical industry” were defined in different ways. Both served the goal of this qualitative study, namely comprehensive portrayal of the various ways in which influence can be exerted.

Conclusion
This systematic review clearly shows that clinical trials with the involvement of pharmaceutical companies often present the therapeutic benefit of a drug in too positive a light and also fail to mention risks. Clinical studies are increasingly being funded by pharmaceutical companies (e32e35). Professional medical bodies construct evidence-based guidelines on the basis of published trial results, so their recommendations may be flawed. This contributes to excessive prescription of expensive new drugs whose efficacy is overestimated and risks underestimated. Moreover, because the evidence is distorted patients do not receive adequate information (14).

In the past few years measures have been taken worldwide to deal with the problems described here. Laws have been enacted, for example, with the intention of securing public access to research data (1518). In the USA, for instance, a law of 27 September 2008 prescribes the registration and publication of the results of clinical trials in a register accessible on the internet (15, 19). In the European Union, directive 2001/20/EC requires registration of all clinical studies (16). A guideline implemented in 2008 lays down what classes of information from the EudraCT database—accessible only to governmental authorities—should be made available in the publicly accessible EudraPharm drug database, which thus remains incomplete (17, 18).

Pharmaceutical organizations have implemented recommendations that are intended to ensure comprehensive publication of research findings, whether positive or negative (9, 12, 20). This initiative on the part of the pharmaceutical industry is welcome; however, the present investigation shows that negative results are still not being published in timely fashion and control mechanisms have failed.

Official regulatory measures to guarantee public access to study protocols and results and prevent the withholding of information about dangerous ADRs are urgently required. This would also give independent drug bulletins and bodies representing physicians, e.g., the Drug Commission of the German Medical Association, the opportunity to obtain detailed, unbiased information about new drugs. Furthermore, it should be obligatory to prove that a new drug provides additional benefit compared with existing pharmacological and non-pharmacological forms of treatment. More public funding should be made available for independent studies (21, 22).

Measures must be taken at many levels to ensure that commercial interests do not undermine the knowledge of scientifically correct study planning, study execution, and publication (4, 5, e15, 15, 2325, e36, e37). A large number of physicians are involved in the planning and conduct of drug trials. For the benefit of their patients, they should assume greater responsibility and work to counteract the economic self-interest of pharmaceutical companies in research and clinical practice.

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 clinical 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::
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eTable available at:
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Equator network website. Zuletzt geprüft: 8. Februar 2010
Arzneimittelkommission der deutschen Ärzteschaft, Berlin: Dr. med. Schott, MPH, Dipl.-Biol. Pachl, Prof. Dr. med. Gundert-Remy, Prof. Dr. med. Ludwig
Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Mainz: Cand. med. Limbach, Prof. Dr. med. Lieb*
Klinik für Hämatologie, Onkologie und Tumorimmunologie, HELIOS Klinikum Berlin-Buch: Prof. Dr. med. Ludwig*
* The authors Lieb and Ludwig have equally contributed to the manuscript.
1. 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
2. Lexchin J, Bero LA, Djulbegovic B, Clark O: Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70. MEDLINE
3. 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 [Finanzierung von Arzneimittelstudien durch pharmazeutische Unternehmen und die Folgen – Teil 1: Qualitative systematische Literaturübersicht zu Einfluss auf Studienergebnisse, -protokoll und -qualität]. Dtsch Arztebl Int 2010; 107 (16): 279–85. VOLLTEXT
4. Bero LA, Rennie D: Influences on the quality of published drug studies. Int J Technol Assess Health Care 1996; 12: 209–37. MEDLINE
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