Special Article
Outcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use
N Engl J Med 2009; 361:1963-1971November 12, 2009
- Abstract
Background
There is good evidence of selective outcome reporting in published reports of randomized trials.
Methods
We examined reporting practices for trials of gabapentin funded by Pfizer and Warner-Lambert's subsidiary, Parke-Davis (hereafter referred to as Pfizer and Parke-Davis) for off-label indications (prophylaxis against migraine and treatment of bipolar disorders, neuropathic pain, and nociceptive pain), comparing internal company documents with published reports.
Results
We identified 20 clinical trials for which internal documents were available from Pfizer and Parke-Davis; of these trials, 12 were reported in publications. For 8 of the 12 reported trials, the primary outcome defined in the published report differed from that described in the protocol. Sources of disagreement included the introduction of a new primary outcome (in the case of 6 trials), failure to distinguish between primary and secondary outcomes (2 trials), relegation of primary outcomes to secondary outcomes (2 trials), and failure to report one or more protocol-defined primary outcomes (5 trials). Trials that presented findings that were not significant (P≥0.05) for the protocol-defined primary outcome in the internal documents either were not reported in full or were reported with a changed primary outcome. The primary outcome was changed in the case of 5 of 8 published trials for which statistically significant differences favoring gabapentin were reported. Of the 21 primary outcomes described in the protocols of the published trials, 6 were not reported at all and 4 were reported as secondary outcomes. Of 28 primary outcomes described in the published reports, 12 were newly introduced.
Conclusions
We identified selective outcome reporting for trials of off-label use of gabapentin. This practice threatens the validity of evidence for the effectiveness of off-label interventions.
Media in This Article
Figure 1
Number of Primary Outcomes in Research Protocols and Published Reports for 12 Clinical Trials of Off-Label Uses of Gabapentin.Figure 2
P Values for Primary Outcomes Reported in Published Reports, and Disagreement in the Definition of Primary Outcome in the Protocol as Compared with the Publication.Article Activity
- Article
The design of a clinical trial includes specification of primary and secondary outcomes.1 Although a change in the primary outcomes over the course of a trial can be legitimate, good research practice dictates that the decision-making procedure, the timing of the change, and the reason for the change be clearly documented in a formal protocol amendment and in the statistical analysis plan, and such changes should be described in published reports on the trial.2 Modifications that are made to the primary outcome after statistical testing has been completed constitute biased reporting if these changes were made to yield apparently positive results when analysis of the original outcome did not. Although reporting biases have been shown to occur regardless of the funding source,3-5 they appear to be more likely in studies funded by the pharmaceutical industry6,7 than in studies funded by other sponsors. Insight into the specifics of reporting biases has been provided by case studies using industry documents made public after legal challenges,8-10 new-drug applications to the Food and Drug Administration,11-13 clinical trial registries such as ClinicalTrials.gov,14 or a combination of these sources.14,15
We examined clinical trials of gabapentin (Neurontin, Pfizer) for off-label use for migraine prophylaxis, bipolar disorders, neuropathic pain, or nociceptive pain. Outcomes described in published reports were compared with those described in internal research documents from the industry sponsor.
Methods
Some but not all documents related to our study are available as a result of litigation against Pfizer and Parke-Davis in which the company admitted guilt for off-label marketing of its anticonvulsant drug gabapentin (Neurontin).8 For this article we also examined source documents obtained in more recent litigation against Pfizer and Parke-Davis related to trials that tested the drug's effectiveness for off-label use in migraine, bipolar disorders, neuropathic pain, and nociceptive pain. All study protocols, the internal company research reports, and published reports relating to clinical trials sponsored by Parke-Davis and Pfizer for the indications noted were obtained as part of the legal action or through the discovery process. Detailed information about the documents accessed can be found in the Supplementary Appendix (available with the full text of this article at NEJM.org).
The internal company research reports were standardized documents prepared by or for Pfizer and Parke-Davis at the conclusion of each clinical trial they sponsored. These reports consist of a description of the research conducted using a format similar to that of a scientific manuscript and may include appendices containing the study protocol and protocol amendments, a listing and description of adverse events, data analyses, and a statistical analysis plan (also called an inferential analysis plan or a report and analysis plan).
Data Extraction and Criteria for Assessment
Table 1Table 1
Primary-Outcome Data and Criteria for Disagreement between Protocol and Published Report. lists the data elements that were extracted from the study documents. These elements were extracted by one person and checked by another, and any discrepancies were resolved through discussion and reexamination of the original documents.For both the research protocols and the published reports, we counted all listed outcomes as primary outcomes if no distinction was made between primary and secondary outcomes. Since certain outcomes, such as quality of life, were described separately from primary and secondary outcomes in the protocol, we also counted them separately; pharmacokinetic outcomes were not counted. We considered protocol amendments and the statistical analysis plan to be part of the protocol when they were in the main body of the protocol or the appendices. Our main analyses used the primary outcome defined in the protocol, with sensitivity analyses conducted using the outcome defined by the statistical analysis plan when the two disagreed.
We determined the publication status of each trial (i.e., publication of a trial report or no evidence of publication) and whether the results reported were described as preliminary. For each trial, we selected one published report as the main study report, using the following order of priority: a full-length study report in a stand-alone article, a letter to the editor that reported study results, a nonsystematic review with pooled analysis using results from the included trial, and a conference abstract.
We documented a disagreement between the outcome as described in the protocol and the outcome specified in the main published report when at least one of four criteria was met (Table 1). (For examples, see the Box in the Supplementary Appendix.) Trials could be assigned more than one reason for disagreements on outcome. One author classified the descriptions of the outcome in the protocol and the published report as either in agreement or not in agreement and documented the reason for disagreement, if any, which was then verified by a second author.
If a published report was identified for a given trial, we looked for changes in primary and secondary outcomes from protocol to published report. To identify potential selective outcome reporting, we examined the statistical significance of the reported effect for the protocol-specified primary outcome according to publication status. In addition, we compared the statistical significance of the effect for the primary outcome specified in the protocol and as described in the internal company research report with that described for the primary outcome specified in the published report.
A P value of less than 0.05 was considered to indicate statistical significance. Findings were considered not to be statistically significant when the report stated this fact explicitly or when the primary-outcome results were presented with no indication of significance in conjunction with others characterized as significant. When the protocol was unavailable (in the case of two trials), we used the primary outcome (or outcomes) defined in the internal research report. (See Tables 2 and 3 and the sensitivity analysis in the Supplementary Appendix.)
Results
Reporting of Trials
We identified a total of 21 trials of gabapentin, which included 17 parallel-group, randomized trials; 2 randomized, crossover trials; and 2 open-label, uncontrolled studies (see Table 1 in the Supplementary Appendix). Three of the trials examined the use of gabapentin for migraine prophylaxis; the other 18 trials examined its use for the treatment of bipolar disorders (3 trials), neuropathic pain (9 trials), or nociceptive pain (6 trials). We also identified 2 ancillary studies — 1 each for nociceptive pain and neuropathic pain — and counted them as part of the main trials with which they were associated.
The study protocol was available for 18 of the 21 trials, and internal company research reports were available for 18 of the trials; for 1 trial there was neither a protocol nor a research report available. The results of 13 of the 21 trials were published16-36: 10 in full-length, stand-alone articles19-22,24,28,29,31,33,34; 1 in a letter to the editor36; 1 in a nonsystematic review, as part of a pooled analysis26; and 1 in abstract form as preliminary findings.16 We excluded 1 of these 13 published trials from subsequent analyses34 because we did not have access to the protocol or the internal research report, at least one of which was required for our purposes. Thus, we analyzed outcome reporting for a total of 12 published trials.
Changes in Primary and Secondary Outcomes
A total of 41 primary outcomes were described in 18 protocols and 2 research reports (used in place of 2 protocols that were not available). A total of 20 primary outcomes were described in the protocols of the 8 unpublished trials. Of the 21 primary outcomes described in the protocols of the 12 published trials, 6 were not included in the published report and 4 were reported as secondary outcomes (Figure 1Figure 1
Number of Primary Outcomes in Research Protocols and Published Reports for 12 Clinical Trials of Off-Label Uses of Gabapentin.); 11 outcomes were reported without change (i.e., the outcome described in the published report was consistent with that described in the protocol), with no distinction made between primary and secondary outcomes. A total of 12 outcomes that were reported as primary outcomes were newly introduced, and 5 were originally designated as secondary outcomes but were not distinguished from primary outcomes in the published report.For 8 of the 12 published trials, there was a disagreement between the definition of the primary outcome in the protocol and that in the published report (Figure 2Figure 2
P Values for Primary Outcomes Reported in Published Reports, and Disagreement in the Definition of Primary Outcome in the Protocol as Compared with the Publication. and Figure 3Figure 3
P Values for Protocol-Defined Primary Outcome in Internal Research Report and in Main Publication., and Table 2 in the Supplementary Appendix). Sources of disagreement included the introduction of an entirely new primary outcome in the published report (in the case of 6 trials); failure to distinguish between primary and secondary outcomes in the published report, even though the protocol did distinguish between them (2 trials); relegation of a primary outcome in the protocol to a secondary outcome in the published report (2 trials); and failure to include in the published report one or more primary outcomes specified in the protocol (5 trials). For 4 trials, the descriptions of the primary outcomes were consistent between the protocol and the published report.For only 1 of the 12 published trials24 that we included in our analysis were all the protocol-specified secondary outcomes included in the published report. Of the 180 secondary outcomes described in the protocols of the 12 published trials, 122 were never reported in the main publication (see the Figure in the Supplementary Appendix). At least 1 new secondary outcome was introduced in the published report for 4 of 12 trials. Of the 80 secondary outcomes included in published reports, 55 were unchanged from the protocol. None of the newly introduced outcomes were specified as post hoc in the published reports.
The protocol-defined primary and secondary outcomes we present in this article include information provided in protocol amendments, which we identified for 6 of the 12 published trials we analyzed. A statistical analysis plan was included in the internal company research report for 5 of the 12 published trials and for 7 of the 8 unpublished trials; the primary outcomes specified in the statistical analysis plan and in the internal company research report were in agreement for 11 of the 12 trials for which we had both these documents. We were unable to determine the date of the statistical-analysis plan relative to the protocol and research report for 3 of 5 published trials that had such a plan, so we cannot assess the timing of the changes from the protocol-defined outcomes that we observed. In the 2 remaining cases, the date on the statistical analysis plan precedes the date when the randomization code appears to have been broken.
Relationship of Study Results to Changed Outcomes and Selective Reporting
We wished to determine whether there was a relationship between a change in the primary outcome from protocol to published report and the failure to obtain a significant result that favored gabapentin when the protocol-specified primary outcome was used. For three of the four studies in which the primary outcome was unchanged, statistically significant results were reported. For the remaining study, with nonsignificant findings, the results were published as part of a pooled analysis. For five of the eight studies with a changed primary outcome, statistically significant findings were reported, and four of the five were published as full-length articles (Figure 2).
To examine the change in primary outcome between protocol and published report more thoroughly, we compared the statistical significance of the treatment effect for the protocol-specified primary outcome, as provided in the internal research report with that for the primary outcome stated in the published report (Figure 3, and Table 3 in the Supplementary Appendix). We found that both the P value and the primary outcome were consistent for only one of nine trials published in full (study 945-306). Results for the other eight trials are provided in the Supplementary Appendix.
Discussion
Our analysis compared study protocols for off-label use of gabapentin and the manufacturers' internal research reports with the published reports of study findings. The results of this analysis provide insight into changes made to prespecified study outcomes and the possible relation of these changes to the statistical significance of study results, as indicated by P values. More than half the clinical trials that we included in our analysis (11 of 20) were not published as full-length research articles. For 7 of the 9 trials that were published as full-length research articles, a statistically significant primary outcome was reported, and for more than half these trials, the outcome specified in the published report differed from the outcome originally described in the protocol. Three of the four trials with an unchanged primary outcome had statistically significant results for the protocol-specified primary outcome. Secondary outcomes also frequently differed between the protocol and the published report. Thus, trials with findings that were not statistically significant (P≥0.05) for the protocol-defined primary outcome, according to the internal documents, either were not published in full or were published with a changed primary outcome.
As shown in Figure 3, all the changes that took place between what was specified in the protocol, what was known before publication (as presented in the internal company research reports), and what was reported to the public led to a more favorable presentation in the medical literature of gabapentin's efficacy for unapproved indications. Of particular concern is our finding that the prespecified primary outcome — the most important measure of efficacy — was often reported inaccurately. Once the data are known, the addition or subtraction of primary outcomes can lead to the presentation of chance findings as evidence of a drug's effectiveness.
When investigators find it necessary to make legitimate changes in a trial's protocol while studies are ongoing, these changes should be clearly stated in protocol amendments, clinical trial registry records, and the statistical analysis plan.2 Furthermore, the published report should include a clear statement explaining the reason for the changes and their timing, potential biases that might have been introduced as a result, and the reasons for excluding outcomes from the analysis (if this was done).
Our study has several limitations. It is possible that we missed important information contained in unidentified, inaccessible, or unavailable documents, including protocols, statistical analysis plans, and research reports. For example, two trials did not have a protocol, so we used the primary outcome defined in the company's internal research report for our analysis. We considered this a conservative substitution, since the research reports were finalized after the trial had been completed. In another example, if changes to the primary outcome were made before the randomization code was broken, these changes could be justifiable. However, documents that might have provided useful information in this regard (e.g., the statistical analysis plan) were frequently not dated. In addition, our findings of selective outcome reporting may not be applicable to other drug trials performed for off-label indications, since the trials we reviewed were part of a legal action. However, selective reporting of primary outcomes has been shown across numerous drug categories.37
Our study is based on a relatively small number of trials undertaken to test a single drug manufactured by a single company and its successors. Furthermore, if a major purpose of the studies we examined was to promote off-label uses of gabapentin, the selective reporting we observed could be more extreme than that observed for studies conducted for other reasons. Previous studies in different settings have shown evidence of these same biases, however.3,37,38 Indeed, selective outcome reporting does not appear to be limited to studies funded by drug companies. Chan and colleagues examined published trials funded by the Canadian Institutes of Health Research and found that 40% of stated primary outcomes differed between the protocol and the published report.38 In addition, we cannot be certain that selective reporting was a decision made by employees of Pfizer and Parke-Davis, since the authors of the published reports included nonemployees. We did not systematically assess the methodologic quality of the included trials as described in the publications we examined. Previous research has indicated that quality scores are higher for trials conducted by the pharmaceutical industry than for trials conducted by not-for-profit entities,39 although reports from industry-sponsored trials have potentially distorted the scientific record because of other, less easily measured study factors.
We are concerned that the reporting practices observed in our analysis do not meet the ethical standards for clinical research or maintain the integrity of scientific knowledge. Fair and honest treatment of patients enrolled in clinical trials of any kind requires full, open, and unbiased reporting. Journal publication, a formalized platform for scientific discourse and dissemination of knowledge,40 should not be used as a marketing tool for off-label drug use.8,9
Reporting biases such as those we describe here increase the likelihood that interventions will appear to be effective when they are not.41,42 Such biases can lead to the omission of negative findings in systematic reviews of intervention effectiveness and in evidence-based guidelines. For example, the 2005 Cochrane systematic review regarding the effectiveness of gabapentin for acute and chronic pain concluded that it is effective on the basis of published findings43 and should now be updated with the inclusion of unpublished information made available through litigation.
Compulsory registration of clinical trials at inception or before the research ethics review has long been promoted as the best way to identify the full scope of trials undertaken, regardless of the findings or the funding source.44 Support by numerous organizations45,46 and U.S. legislation that mandates trials registration47,48 have been major steps toward improving the validity of currently available information. The World Health Organization International Clinical Trials Registry Platform requires identification of the primary outcome and “key secondary outcomes” (www.who.int/ictrp/network/trds/en/index.html), and the ClinicalTrials.gov registry includes “other key measures that will be used to evaluate the intervention(s)” (http://prsinfo.clinicaltrials.gov/definitions.html) for documenting outcomes. As our study shows, however, differences between the primary and other outcomes specified in the protocol and those described in the published report are often subtle but may lead to different interpretations of an intervention's effectiveness (Figure 3, and Table 2 in the Supplementary Appendix). To ensure that the research record is fully public, we believe that existing registration systems need to go further than they currently do and should include registration of the full study protocol and amendments.49
Dr. Vedula reports receiving fees from plaintiffs' lawyers in litigation concerning Neurontin. Dr. Dickersin reports serving as an expert witness in the litigation; funds from this effort were donated to Johns Hopkins to support academic scholarship in the area of reporting biases. No other potential conflict of interest relevant to this article was reported.
We thank Thomas M. Greene, the lead lawyer for class plaintiffs “In Re: Neurontin Marketing, Sales Practices, and Products Liability Litigation, United States District Court, District of Massachusetts,” and his colleagues Ilyas J. Rona and Dr. Palko S. Goldman, who provided assistance in collating, clarifying, and verifying information regarding the trials included in this study; and Drs. Janet Wittes, Jonathan Samet, and Robert Wise for their comments and suggestions.
Source Information
From the Center for Clinical Trials, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (S.S.V., R.W.S., K.D.); and the Department of Clinical Pharmacy and Institute for Health Policy Studies, University of California at San Francisco, San Francisco (L.B.).
Address reprint requests to Dr. Vedula at 615 N. Wolfe St., Baltimore, MD 21205, or at svedula@jhsph.edu.
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