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2.  Reporting Bias in Drug Trials Submitted to the Food and Drug Administration: Review of Publication and Presentation 
PLoS Medicine  2008;5(11):e217.
Background
Previous studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favorable results. The objective of this study is to determine the publication rate of efficacy trials submitted to the Food and Drug Administration (FDA) in approved New Drug Applications (NDAs) and to compare the trial characteristics as reported by the FDA with those reported in publications.
Methods and Findings
This is an observational study of all efficacy trials found in approved NDAs for New Molecular Entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials corresponding to the trials within the NDAs. For each trial included in the NDA, we assessed its publication status, primary outcome(s) reported and their statistical significance, and conclusions. Seventy-eight percent (128/164) of efficacy trials contained in FDA reviews of NDAs were published. In a multivariate model, trials with favorable primary outcomes (OR = 4.7, 95% confidence interval [CI] 1.33–17.1, p = 0.018) and active controls (OR = 3.4, 95% CI 1.02–11.2, p = 0.047) were more likely to be published. Forty-one primary outcomes from the NDAs were omitted from the papers. Papers included 155 outcomes that were in the NDAs, 15 additional outcomes that favored the test drug, and two other neutral or unknown additional outcomes. Excluding outcomes with unknown significance, there were 43 outcomes in the NDAs that did not favor the NDA drug. Of these, 20 (47%) were not included in the papers. The statistical significance of five of the remaining 23 outcomes (22%) changed between the NDA and the paper, with four changing to favor the test drug in the paper (p = 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and papers, nine conclusions (9%) changed from the FDA review of the NDA to the paper, and all nine did so to favor the test drug (100%, 95% CI 72%–100%, p = 0.0039).
Conclusions
Many trials were still not published 5 y after FDA approval. Discrepancies between the trial information reviewed by the FDA and information found in published trials tended to lead to more favorable presentations of the NDA drugs in the publications. Thus, the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased.
Lisa Bero and colleagues review the publication status of all efficacy trials carried out in support of new drug approvals from 2001 and 2002, and find that a quarter of trials remain unpublished.
Editors' Summary
Background.
All health-care professionals want their patients to have the best available clinical care—but how can they identify the optimum drug or intervention? In the past, clinicians used their own experience or advice from colleagues to make treatment decisions. Nowadays, they rely on evidence-based medicine—the systematic review and appraisal of clinical research findings. So, for example, before a new drug is approved for the treatment of a specific disease in the United States and becomes available for doctors to prescribe, the drug's sponsors (usually a pharmaceutical company) must submit a “New Drug Application” (NDA) to the US Food and Drug Administration (FDA). The NDA tells the story of the drug's development from laboratory and animal studies through to clinical trials, including “efficacy” trials in which the efficacy and safety of the new drug and of a standard drug for the disease are compared by giving groups of patients the different drugs and measuring several key (primary) “outcomes.” FDA reviewers use this evidence to decide whether to approve a drug.
Why Was This Study Done?
Although the information in NDAs is publicly available, clinicians and patients usually learn about new drugs from articles published in medical journals after drug approval. Unfortunately, drug sponsors sometimes publish the results only of the trials in which their drug performed well and in which statistical analyses indicate that the drug's improved performance was a real effect rather than a lucky coincidence. Trials in which a drug did not show a “statistically significant benefit” or where the drug was found to have unwanted side effects often remain unpublished. This “publication bias” means that the scientific literature can contain an inaccurate picture of a drug's efficacy and safety relative to other therapies. This may lead to clinicians preferentially prescribing newer, more expensive drugs that are not necessarily better than older drugs. In this study, the researchers test the hypothesis that not all the trial results in NDAs are published in medical journals. They also investigate whether there are any discrepancies between the trial data included in NDAs and in published articles.
What Did the Researchers Do and Find?
The researchers identified all the efficacy trials included in NDAs for totally new drugs that were approved by the FDA in 2001 and 2002 and searched the scientific literature for publications between July 2006 and June 2007 relating to these trials. Only three-quarters of the efficacy trials in the NDAs were published; trials with favorable outcomes were nearly five times as likely to be published as those without favorable outcomes. Although 155 primary outcomes were in both the papers and the NDAs, 41 outcomes were only in the NDAs. Conversely, 17 outcomes were only in the papers; 15 of these favored the test drug. Of the 43 primary outcomes reported in the NDAs that showed no statistically significant benefit for the test drug, only half were included in the papers; for five of the reported primary outcomes, the statistical significance differed between the NDA and the paper and generally favored the test drug in the papers. Finally, nine out of 99 conclusions differed between the NDAs and the papers; each time, the published conclusion favored the test drug.
What Do These Findings Mean?
These findings indicate that the results of many trials of new drugs are not published 5 years after FDA approval of the drug. Furthermore, unexplained discrepancies between the data and conclusions in NDAs and in medical journals are common and tend to paint a more favorable picture of the new drug in the scientific literature than in the NDAs. Overall, these findings suggest that the information on the efficacy of new drugs that is readily available to clinicians and patients through the published scientific literature is incomplete and potentially biased. The recent introduction in the US and elsewhere of mandatory registration of all clinical trials before they start and of mandatory publication in trial registers of the full results of all the predefined primary outcomes should reduce publication bias over the next few years and should allow clinicians and patients to make fully informed treatment decisions.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050217.
This study is further discussed in a PLoS Medicine Perspective by An-Wen Chan
PLoS Medicine recently published a related article by Ida Sim and colleagues: Lee K, Bacchetti P, Sim I (2008) Publication of clinical trials supporting successful new drug applications: A literature analysis. PLoS Med 5: e191. doi:10.1371/journal.pmed.0050191
The Food and Drug Administration provides information about drug approval in the US for consumers and for health-care professionals; detailed information about the process by which drugs are approved is on the Web site of the FDA Center for Drug Evaluation and Research (in English and Spanish)
NDAs for approved drugs can also be found on this Web site
The ClinicalTrials.gov Web site provides information about the US National Institutes of Health clinical trial registry, background information about clinical trials, and a fact sheet detailing the requirements of the FDA Amendments Act 2007 for trial registration
The World Health Organization's International Clinical Trials Registry Platform is working toward setting international norms and standards for the reporting of clinical trials (in several languages)
doi:10.1371/journal.pmed.0050217
PMCID: PMC2586350  PMID: 19067477
3.  Publication of Clinical Trials Supporting Successful New Drug Applications: A Literature Analysis 
PLoS Medicine  2008;5(9):e191.
Background
The United States (US) Food and Drug Administration (FDA) approves new drugs based on sponsor-submitted clinical trials. The publication status of these trials in the medical literature and factors associated with publication have not been evaluated. We sought to determine the proportion of trials submitted to the FDA in support of newly approved drugs that are published in biomedical journals that a typical clinician, consumer, or policy maker living in the US would reasonably search.
Methods and Findings
We conducted a cohort study of trials supporting new drugs approved between 1998 and 2000, as described in FDA medical and statistical review documents and the FDA approved drug label. We determined publication status and time from approval to full publication in the medical literature at 2 and 5 y by searching PubMed and other databases through 01 August 2006. We then evaluated trial characteristics associated with publication. We identified 909 trials supporting 90 approved drugs in the FDA reviews, of which 43% (394/909) were published. Among the subset of trials described in the FDA-approved drug label and classified as “pivotal trials” for our analysis, 76% (257/340) were published. In multivariable logistic regression for all trials 5 y postapproval, likelihood of publication correlated with statistically significant results (odds ratio [OR] 3.03, 95% confidence interval [CI] 1.78–5.17); larger sample sizes (OR 1.33 per 2-fold increase in sample size, 95% CI 1.17–1.52); and pivotal status (OR 5.31, 95% CI 3.30–8.55). In multivariable logistic regression for only the pivotal trials 5 y postapproval, likelihood of publication correlated with statistically significant results (OR 2.96, 95% CI 1.24–7.06) and larger sample sizes (OR 1.47 per 2-fold increase in sample size, 95% CI 1.15–1.88). Statistically significant results and larger sample sizes were also predictive of publication at 2 y postapproval and in multivariable Cox proportional models for all trials and the subset of pivotal trials.
Conclusions
Over half of all supporting trials for FDA-approved drugs remained unpublished ≥ 5 y after approval. Pivotal trials and trials with statistically significant results and larger sample sizes are more likely to be published. Selective reporting of trial results exists for commonly marketed drugs. Our data provide a baseline for evaluating publication bias as the new FDA Amendments Act comes into force mandating basic results reporting of clinical trials.
Ida Sim and colleagues investigate the publication status and publication bias of trials submitted to the US Food and Drug Administration (FDA) for a wide variety of approved drugs.
Editors' Summary
Background.
Before a new drug becomes available for the treatment of a specific human disease, its benefits and harms are carefully studied, first in the laboratory and in animals, and then in several types of clinical trials. In the most important of these trials—so-called “pivotal” clinical trials—the efficacy and safety of the new drug and of a standard treatment are compared by giving groups of patients the different treatments and measuring several predefined “outcomes.” These outcomes indicate whether the new drug is more effective than the standard treatment and whether it has any other effects on the patients' health and daily life. All this information is then submitted by the sponsor of the new drug (usually a pharmaceutical company) to the government body responsible for drug approval—in the US, this is the Food and Drug Administration (FDA).
Why Was This Study Done?
After a drug receives FDA approval, information about the clinical trials supporting the FDA's decision are included in the FDA “Summary Basis of Approval” and/or on the drug label. In addition, some clinical trials are described in medical journals. Ideally, all the clinical information that leads to a drug's approval should be publicly available to help clinicians make informed decisions about how to treat their patients. A full-length publication in a medical journal is the primary way that clinical trial results are communicated to the scientific community and the public. Unfortunately, drug sponsors sometimes publish the results only of trials where their drug performed well; as a consequence, trials where the drug did no better than the standard treatment or where it had unwanted side effects remain unpublished. Publication bias like this provides an inaccurate picture of a drug's efficacy and safety relative to other therapies and may lead to excessive prescribing of newer, more expensive (but not necessarily more effective) treatments. In this study, the researchers investigate whether selective trial reporting is common by evaluating the publication status of trials submitted to the FDA for a wide variety of approved drugs. They also ask which factors affect a trial's chances of publication.
What Did the Researchers Do and Find?
The researchers identified 90 drugs approved by the FDA between 1998 and 2000 by searching the FDA's Center for Drug Evaluation and Research Web site. From the Summary Basis of Approval for each drug, they identified 909 clinical trials undertaken to support these approvals. They then searched the published medical literature up to mid-2006 to determine if and when the results of each trial were published. Although 76% of the pivotal trials had appeared in medical journals, usually within 3 years of FDA approval, only 43% of all of the submitted trials had been published. Among all the trials, those with statistically significant results were nearly twice as likely to have been published as those without statistically significant results, and pivotal trials were three times more likely to have been published as nonpivotal trials, 5 years postapproval. In addition, a larger sample size increased the likelihood of publication. Having statistically significant results and larger sample sizes also increased the likelihood of publication of the pivotal trials.
What Do These Findings Mean?
Although the search methods used in this study may have missed some publications, these findings suggest that more than half the clinical trials undertaken to support drug approval remain unpublished 5 years or more after FDA approval. They also reveal selective reporting of results. For example, they show that a pivotal trial in which the new drug does no better than an old drug is less likely to be published than one where the new drug is more effective, a publication bias that could establish an inappropriately favorable record for the new drug in the medical literature. Importantly, these findings provide a baseline for monitoring the effects of the FDA Amendments Act 2007, which was introduced to improve the accuracy and completeness of drug trial reporting. Under this Act, all trials supporting FDA-approved drugs must be registered when they start, and the summary results of all the outcomes declared at trial registration as well as specific details about the trial protocol must be publicly posted within a year of drug approval on the US National Institutes of Health clinical trials site.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050191.
PLoS Medicine recently published an editorial discussing the FDA Amendment Act and what it means for medical journals: The PLoS Medicine Editors (2008) Next Stop, Don't Block the Doors: Opening Up Access to Clinical Trials Results. PLoS Med 5(7): e160
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health care professionals; detailed information about the process by which drugs are approved is on the Web site of the FDA Center for Drug Evaluation and Research (in English and Spanish)
ClinicalTrials.gov provides information about the US National Institutes of Health clinical trial registry, background information about clinical trials, and a fact sheet detailing the requirements of the FDA Amendments Act 2007 for trial registration
The World Health Organization's International Clinical Trials Registry Platform is working toward international norms and standards for reporting the findings of clinical trials
doi:10.1371/journal.pmed.0050191
PMCID: PMC2553819  PMID: 18816163
4.  Factors Associated with Findings of Published Trials of Drug–Drug Comparisons: Why Some Statins Appear More Efficacious than Others 
PLoS Medicine  2007;4(6):e184.
Background
Published pharmaceutical industry–sponsored trials are more likely than non-industry-sponsored trials to report results and conclusions that favor drug over placebo. Little is known about potential biases in drug–drug comparisons. This study examined associations between research funding source, study design characteristics aimed at reducing bias, and other factors that potentially influence results and conclusions in randomized controlled trials (RCTs) of statin–drug comparisons.
Methods and Findings
This is a cross-sectional study of 192 published RCTs comparing a statin drug to another statin drug or non-statin drug. Data on concealment of allocation, selection bias, blinding, sample size, disclosed funding source, financial ties of authors, results for primary outcomes, and author conclusions were extracted by two coders (weighted kappa 0.80 to 0.97). Univariate and multivariate logistic regression identified associations between independent variables and favorable results and conclusions. Of the RCTs, 50% (95/192) were funded by industry, and 37% (70/192) did not disclose any funding source. Looking at the totality of available evidence, we found that almost all studies (98%, 189/192) used only surrogate outcome measures. Moreover, study design weaknesses common to published statin–drug comparisons included inadequate blinding, lack of concealment of allocation, poor follow-up, and lack of intention-to-treat analyses. In multivariate analysis of the full sample, trials with adequate blinding were less likely to report results favoring the test drug, and sample size was associated with favorable conclusions when controlling for other factors. In multivariate analysis of industry-funded RCTs, funding from the test drug company was associated with results (odds ratio = 20.16 [95% confidence interval 4.37–92.98], p < 0.001) and conclusions (odds ratio = 34.55 [95% confidence interval 7.09–168.4], p < 0.001) that favor the test drug when controlling for other factors. Studies with adequate blinding were less likely to report statistically significant results favoring the test drug.
Conclusions
RCTs of head-to-head comparisons of statins with other drugs are more likely to report results and conclusions favoring the sponsor's product compared to the comparator drug. This bias in drug–drug comparison trials should be considered when making decisions regarding drug choice.
Lisa Bero and colleagues found published trials comparing one statin with another were more likely to report results and conclusions favoring the sponsor's product than the comparison drug.
Editors' Summary
Background.
Randomized controlled trials are generally considered to be the most reliable type of experimental study for evaluating the effectiveness of different treatments. Randomization involves the assignment of participants in the trial to different treatment groups by the play of chance. Properly done, this procedure means that the different groups are comparable at outset, reducing the chance that outside factors could be responsible for treatment effects seen in the trial. When done properly, randomization also ensures that the clinicians recruiting participants into the trial cannot know the treatment group to which a patient will end up being assigned. However, despite these advantages, a large number of factors can still result in bias creeping in. Bias comes about when the findings of research appear to differ in some systematic way from the true result. Other research studies have suggested that funding is a source of bias; studies sponsored by drug companies seem to more often favor the sponsor's drug than trials not sponsored by drug companies
Why Was This Study Done?
The researchers wanted to more precisely understand the impact of different possible sources of bias in the findings of randomized controlled trials. In particular, they wanted to study the outcomes of “head-to-head” drug comparison studies for one particular class of drugs, the statins. Drugs in this class are commonly prescribed to reduce the levels of cholesterol in blood amongst people who are at risk of heart and other types of disease. This drug class is a good example for studying the role of bias in drug–drug comparison trials, because these trials are extensively used in decision making by health-policy makers.
What Did the Researchers Do and Find?
This research study was based on searching PubMed, a biomedical literature database, with the aim of finding all randomized controlled trials of statins carried out between January 1999 and May 2005 (reference lists also were searched). Only trials which compared one statin to another statin or one statin to another type of drug were included. The researchers extracted the following information from each article: the study's source of funding, aspects of study design, the overall results, and the authors' conclusions. The results were categorized to show whether the findings were favorable to the test drug (the newer statin), inconclusive, or not favorable to the test drug. Aspects of each study's design were also categorized in relation to various features, such as how well the randomization was done (in particular, the degree to which the processes used would have prevented physicians from knowing which treatment a patient was likely to receive on enrollment); whether all participants enrolled in the trial were eventually analyzed; and whether investigators or participants knew what treatment an individual was receiving.
One hundred and ninety-two trials were included in this study, and of these, 95 declared drug company funding; 23 declared government or other nonprofit funding while 74 did not declare funding or were not funded. Trials that were properly blinded (where participants and investigators did not know what treatment an individual received) were less likely to have conclusions favoring the test drug. However, large trials were more likely to favor the test drug than smaller trials. When looking specifically at the trials funded by drug companies, the researchers found various factors that predicted whether a result or conclusion favored the test drug. These included the impact of the journal publishing the results; the size of the trial; and whether funding came from the maker of the test drug. However, properly blinded trials were less likely to produce results favoring the test drug. Even once all other factors were accounted for, the funding source for the study was still linked with results and conclusions that favored the maker of the test drug.
What Do These Findings Mean?
This study shows that the type of sponsorship available for randomized controlled trials of statins was strongly linked to the results and conclusions of those studies, even when other factors were taken into account. However, it is not clear from this study why sponsorship has such a strong link to the overall findings. There are many possible reasons why this might be. Some people have suggested that drug companies may deliberately choose lower dosages for the comparison drug when they carry out “head-to-head” trials; this tactic is likely to result in the company's product doing better in the trial. Others have suggested that trials which produce unfavorable results are not published, or that unfavorable outcomes are suppressed. Whatever the reasons for these findings, the implications are important, and suggest that the evidence base relating to statins may be substantially biased.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040184.
The James Lind Library has been created to help people understand fair tests of treatments in health care by illustrating how fair tests have developed over the centuries
The International Committee of Medical Journal Editors has provided guidance regarding sponsorship, authorship, and accountability
The CONSORT statement is a research tool that provides an evidence-based approach for reporting the results of randomized controlled trials
Good Publication Practice guidelines provide standards for responsible publication of research sponsored by pharmaceutical companies
Information from Wikipedia on Statins. Wikipedia is an internet encyclopedia anyone can edit
doi:10.1371/journal.pmed.0040184
PMCID: PMC1885451  PMID: 17550302

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