Background: To improve reporting transparency and research integrity, some journals have begun publishing study protocols and statistical analysis plans alongside trial publications. We sought to assess the overall availability and characteristics of protocols and statistical analysis plans of randomized clinical trials published in the top five (by impact factor) general medicine journals. Methods: All randomized clinical trials published in Annals of Internal Medicine, BMJ, JAMA, Lancet, and NEJM in 2016 were identified. For each randomized clinical trial, we searched for protocols and statistical analysis plans on journal websites (including supplementary material) and in the article, for example, a referenced publication or link to trial or institutional website. Characteristics of randomized clinical trials were extracted from the publication and clinical trial registry. A detailed assessment of protocols and statistical analysis plans was conducted in a 20% random sample of randomized clinical trials. Results: Protocols were available for 299 (82%) trials, ranging from 50% in BMJ to >95% in NEJM and JAMA. Statistical analysis plans were available for 182 (50%) trials and varied from <10% for Annals of Internal Medicine, BMJ, and Lancet to 92% for NEJM. Of the 76 randomized clinical trials in the 20% random sample, 63 (83%) had a protocol but less than half (31; 44%) included an a priori (dated prior to patient enrollment) version of the protocol. Statistical analysis plans were available for 35 (46%) trials, and only 5 (7%) included an a priori version. Conclusion: Protocols and statistical analysis plans are publicly available for the majority of trials. However, the a priori versions of these documents are only available for a minority of trials. More attention must be paid to ensuring the public availability of a priori versions.

PurposeTrustworthy reporting of quadrivalent human papillomavirus (HPV) vaccine trials is the foundation for assessing the vaccine’s risks and benefits. However, several pivotal trial publications incompletely reported important methodological details and inaccurately described the formulation that the control arms received. Under the Restoring Invisible and Abandoned Trials initiative (RIAT), we aim to restore the public record regarding the content and rationale of the controls used in the trials.MethodsWe assembled a cohort (five randomised controlled trials) described as placebo-controlled using clinical study reports (CSRs) obtained from the European Medicines Agency. We extracted the content and rationale for the choice of control used in each trial across six data sources: trial publications, register records, CSR synopses, CSR main bodies, protocols and informed consent forms.ResultsAcross data sources, the control was inconsistently reported as ‘placebo’-containing aluminium adjuvant (sometimes with dose information). Amorphous aluminium hydroxyphosphate sulfate (AAHS) was not mentioned in any trial registry entry, but was mentioned in all publications and CSRs. In three of five trials, consent forms described the control as an ‘inactive’ substance. No rationale for the selection of the control was reported in any trial publication, register, consent form, CSR synopsis or protocol. Three trials reported the rationale for choice of control in CSRs: to preserve blinding and assess the safety of HPV virus-like particles as the ‘safety profile of (AAHS) is well characterised’.ConclusionsThe stated rationale of using AAHS control—to characterise the safety of the HPV virus-like particles—lacks clinical relevance. A non-placebo control may have obscured an accurate assessment of safety and the participant consent process of some trials raises ethical concerns.Trial registration numbersNCT00092482, NCT00092521, NCT00092534, NCT00090220, NCT00090285.

BackgroundParticipants are recruited into clinical trials under the assumption that the research will contribute to medical knowledge. Therefore, non-publication trials—and, more recently, lack of data sharing—are widely considered to violate the trust of trial participants. Existing practices regarding patient consent to publication and data sharing have not been evaluated. Analyzing informed consent forms (ICFs), we studied what trial participants were told regarding investigators’ intention to contribute to medical knowledge, publish trial results, and share de-identified trial data.MethodsWe obtained 98 ICFs of industry-funded pre-marketing trials for all (17) antibiotics approved by the European Medicines Agency and 46 ICFs of publicly funded trials from the National Heart, Lung and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) data repository. Three authors independently reviewed ICFs to identify and extract what was stated or implied regarding: (1) publication of results; (2) sharing de-identified data; (3) data ownership; (4) confidentiality of identifiable data; and (5) whether the trial will produce knowledge that offers public benefit. Consensus was obtained from the two reviewers with the greatest overall agreement on all five measures. Disagreements were resolved through discussion among all authors.ResultsFour (3%) trials indicated a commitment to publish trial results; 140 (97%) did not commit to publishing trial results; six (4%) indicated a commitment to share de-identified data with third party researchers. Commitments to share were more common in publicly funded trials than industry-funded trials (7% vs 3%). A total of 103 (72%) ICFs indicated the trials will or may produce knowledge that offers public benefits, while 131 (91%) ICFs left unstated who “owned” trial data; of those with statements, the sponsor always claimed ownership. Patient confidentiality was guaranteed in 137 (95%) trials.ConclusionsOur results suggest that consent forms rarely disclose investigators’ intentions regarding the sharing of de-identified data or publication of trial results.

than deaths involving opioids alone. Of the polysubstanceinvolved opioid overdose deaths, stimulants were most commonly involved.Our results are consistent with data from the general adult population, which shows stimulant-involved opioid overdose deaths increasing over the past decade. 3 Moreover, our study is consistent with data demonstrating that cocaine is now the substance most commonly coinvolved in opioid overdose deaths. 5 Limitations of this study include potential death misclassification, inaccurate identification of substances, and nonspecific reporting on death certificates causing undercounts of specific drug classes. The CDC WONDER data set is unable to stratify further deaths from psychostimulants other than cocaine, a category that includes methamphetamine and prescribed stimulants. Future studies should further delineate the age-related and geographic differences in polysubstance overdoses over time. 6 These results underscore the evolving heterogeneity of the overdose epidemic among youth. Treatment and harm reduction models for opioid use disorders among youth must recognize and address the co-occurrence of other substance use disorders.

About one-third of new therapeutics are tested in head-tohead, active-controlled trials prior to licensure. 1 Some of these trials test noninferiority hypotheses, which by design allow for some potential loss of efficacy in exchange for potential nonefficacy benefits. The literature specifies several hypothetical nonefficacy benefits that new interventions approved based on noninferiority trials may offer, including decreased adverse events, less invasiveness, more convenient formulation, and reduced cost. 2-5 However, empirical evidence of actual b e n e f i t s i s l a c k i ng. We sought to characterize the nonefficacy benefits of new molecular entities (NMEs) approved based on noninferiority trials.

Purpose To evaluate spillover effects of Medicaid antipsychotic prior authorization (PA) policies among commercially insured youth. Methods Commercially insured youth residing in nine US states that implemented PA exclusively for antipsychotics in 2011 or 2012 were identified using a 10% random sample of enrollees in the IQVIA PharMetrics Plus database spanning 2007 to 2015. Youth were included if they were ≤18 years, met the age criteria of the PA at the time of dispensing, and had at least 1 month of prescription drug coverage from 2007 to 2015. The primary outcome of interest was the monthly prevalence of antipsychotics. We implemented segmented regression of interrupted time series analysis to estimate changes in the monthly prevalence of targeted medications, overall and stratified by age. Trends were compared in the 4‐year period before and the 3‐year period after implementation of PA policies. Results Antipsychotics prescribing significantly decreased 6.74/10 000 (95% CI, −9.04 to −4.44) enrollees per month immediately after PA implementation. However, PA was not associated with significant long‐term trend changes (−0.06; 95% CI, −0.16 to 0.03). Antipsychotic prescribing in children <12 years‐old significantly decreased 0.14/10 000 (95% CI, −0.21 to −0.07) enrollees per month after PA implementation, while prescribing in adolescents 12 to 18 years‐old significantly increased 0.32/10 000 (95% CI, 0.16 to 0.47) enrollees per month. Conclusion While Medicaid PA polices for antipsychotic oversight did not affect overall prescribing, there were spillover effects in U.S. commercially insured children <12 years‐old. This suggests that state‐level Medicaid policies intended to improve the quality of care and safe use of antipsychotics can have broad reach.

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