Kirby Lee

Coverage by the News Media of the Benefits and Risks of Medications

BACKGROUND The news media are an important source of information about new medical treatments, but there is concern that some coverage may be inaccurate and overly enthusiastic. METHODS We studied coverage by U.S. news media of the benefits and risks of three medications that are used to prevent major diseases. The medications were pravastatin, a cholesterol-lowering drug for the prevention of cardiovascular disease; alendronate, a bisphosphonate for the treatment and prevention of osteoporosis; and aspirin, which is used for the prevention of cardiovascular disease. We analyzed a systematic probability sample of 180 newspaper articles (60 for each drug) and 27 television reports that appeared between 1994 and 1998. RESULTS Of the 207 stories, 83 (40 percent) did not report benefits quantitatively. Of the 124 that did, 103 (83 percent) reported relative benefits only, 3 (2 percent) absolute benefits only, and 18 (15 percent) both absolute and relative benefits. Of the 207 stories, 98 (47 percent) mentioned potential harm to patients, and only 63 (30 percent) mentioned costs. Of the 170 stories citing an expert or a scientific study, 85 (50 percent) cited at least one expert or study with a financial tie to a manufacturer of the drug that had been disclosed in the scientific literature. These ties were disclosed in only 33 (39 percent) of the 85 stories. CONCLUSIONS News-media stories about medications may include inadequate or incomplete information about the benefits, risks, and costs of the drugs as well as the financial ties between study groups or experts and pharmaceutical manufacturers.

Factors Associated with Findings of Published Trials of Drug-Drug Comparisons: Why Some Statins Appear More Efficacious than Others

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 sponsors product compared to the comparator drug. This bias in drug–drug comparison trials should be considered when making decisions regarding drug choice.

Publication of Clinical Trials Supporting Successful New Drug Applications: A Literature Analysis

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.

Measuring the effectiveness of scientific gatekeeping

Significance Peer review is an institution of enormous importance for the careers of scientists and the content of published science. The decisions of gatekeepers—editors and peer reviewers—legitimize scientific findings, distribute professional rewards, and influence future research. However, appropriate data to gauge the quality of gatekeeper decision-making in science has rarely been made publicly available. Our research tracks the popularity of rejected and accepted manuscripts at three elite medical journals. We found that editors and reviewers generally made good decisions regarding which manuscripts to promote and reject. However, many highly cited articles were surprisingly rejected. Our research suggests that evaluative strategies that increase the mean quality of published science may also increase the risk of rejecting unconventional or outstanding work. Peer review is the main institution responsible for the evaluation and gestation of scientific research. Although peer review is widely seen as vital to scientific evaluation, anecdotal evidence abounds of gatekeeping mistakes in leading journals, such as rejecting seminal contributions or accepting mediocre submissions. Systematic evidence regarding the effectiveness—or lack thereof—of scientific gatekeeping is scant, largely because access to rejected manuscripts from journals is rarely available. Using a dataset of 1,008 manuscripts submitted to three elite medical journals, we show differences in citation outcomes for articles that received different appraisals from editors and peer reviewers. Among rejected articles, desk-rejected manuscripts, deemed as unworthy of peer review by editors, received fewer citations than those sent for peer review. Among both rejected and accepted articles, manuscripts with lower scores from peer reviewers received relatively fewer citations when they were eventually published. However, hindsight reveals numerous questionable gatekeeping decisions. Of the 808 eventually published articles in our dataset, our three focal journals rejected many highly cited manuscripts, including the 14 most popular; roughly the top 2 percent. Of those 14 articles, 12 were desk-rejected. This finding raises concerns regarding whether peer review is ill-suited to recognize and gestate the most impactful ideas and research. Despite this finding, results show that in our case studies, on the whole, there was value added in peer review. Editors and peer reviewers generally—but not always—made good decisions regarding the identification and promotion of quality in scientific manuscripts.

Acute and Chronic Fluoxetine Treatment Decreases the Sensitivity of Rats to Rewarding Brain Stimulation

The effects of fluoxetine on rewarding brain stimulation were determined in eight Wistar rats using a rate-independent discrete-trial threshold measure. Rats were implanted with bipolar, stainless steel electrodes either into the ventral tegmental area (VTA) or medial forebrain bundle (MFB). Acute administration of fluoxetine significantly raised the reward threshold (decreased sensitivity) at doses of 2.5, 5.0, 10.0, and 20.0 mg/kg, i.p., without altering latency of response. There were no significant differences between VTA and MFB groups. To determine the effects of chronic treatment, daily injections of 5.0 mg/kg fluoxetine were administered to rats for 21 days. Chronic treatment of fluoxetine continued to significantly elevate reward thresholds with no evidence of tolerance. The results of these experiments suggest that fluoxetine does not possess abuse potential and that serotonin produces an inhibitory effect on the mesolimbic dopaminergic reward system. Furthermore, these results suggest that the antidepressant effects of fluoxetine are not the direct result of excitation of brain reward systems, at least in the same manner as abused substances, for example, cocaine.

Association of trial registration with the results and conclusions of published trials of new oncology drugs

BackgroundRegistration of clinical trials has been introduced largely to reduce bias toward statistically significant results in the trial literature. Doubts remain about whether advance registration alone is an adequate measure to reduce selective publication, selective outcome reporting, and biased design. One of the first areas of medicine in which registration was widely adopted was oncology, although the bulk of registered oncology trials remain unpublished. The net influence of registration on the literature remains untested. This study compares the prevalence of favorable results and conclusions among published reports of registered and unregistered randomized controlled trials of new oncology drugs.MethodsWe conducted a cross-sectional study of published original research articles reporting clinical trials evaluating the efficacy of drugs newly approved for antimalignancy indications by the United States Food and Drug Administration (FDA) from 2000 through 2005. Drugs receiving first-time approval for indications in oncology were identified using the FDA web site and Thomson Centerwatch. Relevant trial reports were identified using PubMed and the Cochrane Library. Evidence of advance trial registration was obtained by a search of clinicaltrials.gov, WHO, ISRCTN, NCI-PDQ trial databases and corporate trial registries, as well as articles themselves. Data on blinding, results for primary outcomes, and author conclusions were extracted independently by two coders. Univariate and multivariate logistic regression identified associations between favorable results and conclusions and independent variables including advance registration, study design characteristics, and industry sponsorship.ResultsOf 137 original research reports from 115 distinct randomized trials assessing 25 newly approved drugs for treating cancer, the 54 publications describing data from trials registered prior to publication were as likely to report statistically significant efficacy results and reach conclusions favoring the test drug (for results, OR = 1.77; 95% CI = 0.87 to 3.61) as reports of trials not registered in advance. In multivariate analysis, reports of prior registered trials were again as likely to favor the test drug (OR = 1.29; 95% CI = 0.54 to 3.08); large sample sizes and surrogate outcome measures were statistically significant predictors of favorable efficacy results at p < 0.05. Subgroup analysis of the main reports from each trial (n = 115) similarly indicated that registered trials were as likely to report results favoring the test drug as trials not registered in advance (OR = 1.11; 95% CI = 0.44 to 2.80), and also that large trials and trials with nonstringent blinding were significantly more likely to report results favoring the test drug.ConclusionsTrial registration alone, without a requirement for full reporting of research results, does not appear to reduce a bias toward results and conclusions favoring new drugs in the clinical trials literature. Our findings support the inclusion of full results reporting in trial registers, as well as protocols to allow assessment of whether results have been completely reported.

Additive effects of intra-accumbens infusion of the cAMP–specific phosphodiesterase inhibitor, rolipram and cocaine on brain stimulation reward

Evidence from cocaine self-administration studies suggests that increasing the activity of cyclic AMP (cAMP) pathways within the nucleus accumbens may produce a reduction in cocaines reinforcing effects. Rolipram may increase intra-cellular levels of cAMP by selectively inhibiting Type IV phosphodiesterases, enzymes that catalyze cAMP breakdown. The present study was undertaken to test the hypothesis that infusion of rolipram into the nucleus accumbens would decrease cocaine-induced enhancement of the sensitivity of brain stimulation reward (BSR) pathways. BSR thresholds were determined in rats after the systemic administration of cocaine (4 mg/kg IP) and the infusion of rolipram (0.2 microg/side) into the nucleus accumbens both alone and in combination. Thresholds also were determined after the systemic administration of rolipram alone and, as a positive control, for amphetamine (10 microg/side) infused into the nucleus accumbens. BSR thresholds were significantly lowered below baseline levels following d-amphetamine administration suggesting that cannulae were in place to allow perfusion of reward pathways. Compared to values for saline alone, thresholds were lower after the injection of cocaine (4 mg/kg IP) or the infusion of rolipram (0.2 microg/side) into the nucleus accumbens. Treatment with the combination of cocaine and intra-nucleus accumbens rolipram produced a greater lowering of the BSR threshold than did administration of either rolipram or cocaine alone. Systemic administration of rolipram (0.5 mg/kg IP) either blocked the effects of BSR or raised BSR thresholds and produced stimulation-induced head jerking in most of the test animals. These results suggest that infusion into the nucleus accumbens of rolipram, an agent that putatively elevates cAMP levels in this structure, can enhance the sensitivity of reward pathways to BSR and can augment cocaines actions on these pathways.

Predictors of Completeness of Patients’ Self-reported Personal Medication Lists and Discrepancies With Clinic Medication Lists

Background: Transfer of medication information during transitions in care is crucial to preventing medication errors. Few studies evaluate patients’ self-reported personal medication lists. Objectives: To assess completeness of personal medication lists and identify factors associated with incomplete personal lists and discrepancies between personal and clinic medication lists. Methods: We analyzed patients’ personal medication lists at an academic hospital preoperative clinic from January 2010 to October 2010. Completeness of personal medication lists was measured as reporting the name, dose, and frequency for all prescription and nonprescription medications or dietary supplements. Discrepancies between personal and clinic medication lists were measured as omitted medications or differing directions. Results: Among 94 patients meeting inclusion criteria, 82 (87%) personal medication lists were evaluated. Most personal lists were incomplete (56%; 46/82), missing information for at least one medication reported; 94% (77/82) of personal lists had at least one discrepancy with clinic medication lists (median 4 discrepancies per patient list). On multivariate analyses, taking 10 or more medications (adjusted odds ratio [OR] = 3.52; 95% CI = 1.37 to 9.08) and being divorced, widowed, or single (adjusted OR = 3.10; 95% CI = 1.05 to 9.12) were independent predictors of incomplete personal medication lists. Taking 10 or more medications (adjusted OR = 3.44; 95% CI = 1.35 to 8.78) was also associated with higher rates of medication discrepancies. Conclusions: Patients’ self-reported personal medication lists are often incomplete and have discrepancies with clinic medication lists. Interventions are needed to improve medication information transfer between patients, providers and healthcare systems.

“Whose job is it, really?” physicians', nurses', and pharmacists' perspectives on completing inpatient medication reconciliation

Medication reconciliation, when performed well, effectively identifies discrepancies and reduces medication errors in the hospital setting.1–3 This process involves four major steps: 1) obtain and document a comprehensive medication history on admission, 2) compare the medication history to medication orders in the hospital and identify and resolve discrepancies, 3) provide the patient with a written list of discharge medications, and 4) educate the patient about their discharge medication regimen.4–6

Development of an adaptive, personalized, and scalable dementia care program: Early findings from the Care Ecosystem

Katherine Possin and colleagues report on the implementation, development, and early findings of the Care Ecosystem, an adaptive, personalized, and scalable dementia care program.