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Over half of all supporting trials for FDA-approved drugs remained unpublished 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.

BACKGROUND: Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS. OBJECTIVES: To evaluate the efficacy and safety of rituximab for MS treatment. DATA COLLECTION: Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies. MAIN RESULTS: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. AUTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.

Background: Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS. Objectives: To evaluate the efficacy and safety of rituximab for MS treatment. Data collec

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.

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.

The measurement of antiretroviral concentrations in hair is emerging as an important technology to objectively quantify adherence to combination antiretroviral therapy. Hair levels of antiretrovirals are the strongest independent predictor of virologic success in large prospective cohorts of HIV-infected patients and surpass self-report in predicting outcomes. Hair is easy to collect and store, but validated methods to analyze antiretroviral levels in hair using liquid chromatography tandem mass spectrometry (LC-MS/MS) are expensive. We report here on the development of a thin-layer chromatography (TLC) assay for the semiquantitative analysis of nevirapine in hair. TLC assay results from 11 samples were consistent with results using LC-MS/MS [Spearman correlation coefficient 0.99 (95% CI 0.95-0.996)]. This simple, low-cost method of analyzing nevirapine concentrations in hair may provide a novel monitoring tool for antiretroviral adherence in resource-limited settings and merits further study in clinical settings.

Objective

To evaluate how the accuracy of present-on-admission (POA) reporting affects hospital 30-day acute myocardial infarction (AMI) mortality assessments.

Data sources

A total of 2005 California patient discharge data (PDD) and vital statistics death files.

Study design

We compared hospital performance rankings using an established model assessing hospital performance for AMI with (1) a model incorporating POA indicators of whether a secondary condition was a comorbidity or a complication of care, and (2) a simulation analysis that factored POA indicator accuracy into the hospital performance assessment. For each simulation, we changed POA indicators for six major acute risk factors of AMI mortality. The probability of POA being changed depended on patient and hospital characteristics.

Principal findings

Comparing the performance rankings of 268 hospitals using the established model with that using the POA indicator, 67 hospitals' (25 percent) rank differed by ≥10 percent. POA reporting inaccuracy due to overreporting and underreporting had little additional impact; POA overreporting contributed to 4 percent of hospitals' difference in rank compared to the POA model and POA underreporting contributed to <1 percent difference.

Conclusion

Incorporating POA indicators into risk-adjusted models of AMI care has a substantial impact on hospital rankings of performance that is not primarily attributable to inaccuracy in POA hospital reporting.

The objective was to evaluate the presence of a positive family history (FH) of vascular risk factors between patients with migraine with aura (MA) and migraine without aura (MO), and in chronic migraine (CM) compared to other headache types. As migraine patients are typically too young to have developed vascular events, studying older relatives of migraine patients may be a practical means of evaluating associations between vascular risk factors and migraine. A cross-sectional study of a clinic-based sample of adults with migraine headache was carried out at the University of Utah. Predictor variables comprised first or second degree relatives with stroke, hypertension, diabetes or hypercholesterolaemia. Outcome measures comprised diagnosis of MA, MO or CM according to the revised International Headache Society criteria. There was no significant difference in FH of vascular risk factors in MA compared to MO (adjusted OR 1.04, 95% CI 0.61-1.78). CM was associated with a decreased risk of FH of stroke (OR=0.11, 95% CI 0.02-0.87, p=0.036). There was no significant difference in FH of vascular risk factors in MA patients compared to MO. CM patients were more likely to have a negative FH of stroke compared to other headache types, suggesting that CM is likely a neuronal disease rather than a vascular one.

Background & aims

Early recognition of prediabetes can lead to timely clinical interventions to prevent type 2 diabetes. Both Latino ethnicity and chronic hepatitis C (HCV) have been identified as diabetic risk factors. We aimed to investigate predictors of impaired fasting glucose (IFG), a common prediabetic state, among Latinos with and without HCV.

Methods

One hundred Latino adults with no history of diabetes or cirrhosis underwent clinical, laboratory, and metabolic evaluation, including oral glucose tolerance testing (OGTT) and insulin suppression testing to quantify directly measured insulin resistance (IR). Isolated IFG was defined as fasting glucose ≥100 mg/dl and <140 mg/dl at 2 h during normal glucose tolerance during OGTT.

Results

Overall subject characteristics included median age 44 years, 64% male, 40% HCV-positive and 32% with isolated IFG. Factors associated with isolated IFG included subject age (OR 2.42 per decade, 95%CI 1.40-3.90, P = 0.001), HCV infection (OR 4.0, 95%CI 1.71-9.72, P = 0.002) and alanine aminotransferase (ALT) (OR 2.35 per doubling, 95%CI 1.46-3.77, P < 0.0001). Multipredictor logistic regression analysis identified ALT (OR 2.05 per doubling, P = 0.005, 95% CI 1.24-3.40) and age (OR 2.20 per 10 years, P = 0.005, 95%CI 1.27-3.80) as factors independently associated with IFG. While HCV was associated with 4-fold higher odds of IFG, this entire effect was mediated by ALT.

Conclusions

We found strong evidence that liver inflammation is a risk factor for prediabetes among Latinos with and without HCV. Among HCV-infected individuals, early antiviral therapy could mitigate the effect of inflammation and represent an important intervention to prevent diabetes in this at-risk population.