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Summary box Access to data for drugs and vaccines has historically been fairly limited to journal article publications and hard-to-access and difficult to read regulatory reports.1 But the past decade has witnessed strides in clinical trial data transparency. A wide range of institutions, from pharmaceutical companies, government agencies, trade organisations, journals and not-for-profit organisations, have all acknowledged the importance of data sharing, including the release of deidentified individual participant data. Many policies, regulations and platforms now exist to facilitate data access, including landmark transparency policies from the European Medicines Agency (EMA)2 3 and Health Canada.4 Both regulators now post on their websites, sections of the licensure dossier received by the industry (https://clinicaldata.ema.europa.eu/ and https://clinical-information.canada.ca/). There are also industry and academic platforms to facilitate third-party access to trial data and documents, including ClinicalStudyDataRequest.com, Yale University Open Data Access (YODA) Project and Vivli.5 In 2013, the US and European industry trade organisations endorsed a joint statement on clinical trial data sharing, making a series of commitments that ‘recognise the importance of sharing clinical trial data in the …

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.

Approval by the US Food and Drug Administration (FDA) of a drug for a given indication is thought to reassure clinicians, other health care providers, and patients that substantial evidence of effectiveness exists for specific indicated populations (patients and diseases). This study examines whether FDA approval of certain antibiotics should be so reassuring for all patient populations identified in the FDA-approved labels. Specifically, this study compared patient populations covered by FDA-approved labels for 21 novel antibiotics approved between 1999 and 2018 to the patient exclusion and inclusion criteria of pivotal trials that supported those approvals. We found that every FDA-approved label for these antibiotics included at least one identifiable patient population that was explicitly excluded from enrolling in the supporting pivotal trials. Two antibiotics, bedaquiline and ceftazidime-avibactam, were approved for use in populations that were fully excluded from enrolling in registration trials.

Objective to review the evidence from studies relating SARS-CoV-2 culture with the results of reverse transcriptase polymerase chain reaction (RT-PCR) and other variables which may influence the interpretation of the test, such as time from symptom onset Methods We searched LitCovid, medRxiv, Google Scholar and the WHO Covid-19 database for Covid-19 to 10 September 2020. We included studies attempting to culture or observe SARS-CoV-2 in specimens with RT-PCR positivity. Studies were dual extracted and the data summarised narratively by specimen type. Where necessary we contacted corresponding authors of included papers for additional information. We assessed quality using a modified QUADAS 2 risk of bias tool. Results We included 29 studies reporting attempts at culturing, or observing tissue infection by, SARS-CoV-2 in sputum, nasopharyngeal or oropharyngeal, urine, stool, blood and environmental specimens. The quality of the studies was moderate with lack of standardised reporting. The data suggest a relationship between the time from onset of symptom to the timing of the specimen test, cycle threshold (Ct) and symptom severity. Twelve studies reported that Ct values were significantly lower and log copies higher in specimens producing live virus culture. Two studies reported the odds of live virus culture reduced by approximately 33% for every one unit increase in Ct. Six of eight studies reported detectable RNA for longer than 14 days but infectious potential declined after day 8 even among cases with ongoing high viral loads. Four studies reported viral culture from stool specimens. Conclusion Complete live viruses are necessary for transmission, not the fragments identified by PCR. Prospective routine testing of reference and culture specimens and their relationship to symptoms, signs and patient co-factors should be used to define the reliability of PCR for assessing infectious potential. Those with high cycle threshold are unlikely to have infectious potential.

Background Participants 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. Methods We 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. Results Four (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. Conclusions Our results suggest that consent forms rarely disclose investigators’ intentions regarding the sharing of de-identified data or publication of trial results.

Objectives The objective of this study was to determine whether disagreements among multiple data sources affect systematic reviews of randomized clinical trials (RCTs). Study Design and Setting Eligible RCTs examined gabapentin for neuropathic pain and quetiapine for bipolar depression, reported in public (e.g., journal articles) and nonpublic sources (clinical study reports [CSRs] and individual participant data [IPD]). Results We found 21 gabapentin RCTs (74 reports, 6 IPD) and 7 quetiapine RCTs (50 reports, 1 IPD); most were reported in journal articles (18/21 [86%] and 6/7 [86%], respectively). When available, CSRs contained the most trial design and risk of bias information. CSRs and IPD contained the most results. For the outcome domains “pain intensity” (gabapentin) and “depression” (quetiapine), we found single trials with 68 and 98 different meta-analyzable results, respectively; by purposefully selecting one meta-analyzable result for each RCT, we could change the overall result for pain intensity from effective (standardized mean difference [SMD] = −0.45; 95% confidence interval [CI]: −0.63 to −0.27) to ineffective (SMD = −0.06; 95% CI: −0.24 to 0.12). We could change the effect for depression from a medium effect (SMD = −0.55; 95% CI: −0.85 to −0.25) to a small effect (SMD = −0.26; 95% CI: −0.41 to −0.1). Conclusions Disagreements across data sources affect the effect size, statistical significance, and interpretation of trials and meta-analyses.

This cohort study of FDA- and drug sponsor–written communications evaluates the communication of nonefficacy benefits of new drugs approved on the basis of noninferiority trials alone.

Purpose Regulators approve written medical information for healthcare professionals and consumers, but the consistency of these sources has not been studied. We investigated the consistency of information regarding four cardiovascular risks of attention-deficit/hyperactivity disorder (ADHD) medications approved in four countries. Methods Professional and consumer product labeling for five ADHD medications approved in Australia, Canada, the UK, and the USA were obtained in March/April 2016. Language describing the relationship between medication and elevated blood pressure and/or heart rate, myocardial infarction, stroke, and sudden death was extracted verbatim and classified into one of four categories based on the described relationship between medication and adverse event: “confirmed,” “unconfirmed,” “mixed,” and “not mentioned.” We judged the consistency of messages delivered to healthcare professionals and consumers as either “consistent” or “inconsistent.” Results We obtained 20 healthcare professional labels and 20 corresponding consumer labels for the five ADHD medications registered in all four countries. Not all professional and consumer labeling contained language regarding all four adverse events. Of the 80 theoretically evaluable drug-risk pairs, 38 (48%) were not evaluable because of absence of mention of the adverse event in the consumer label. For the remaining 42, the potential causal relationship was expressed consistently in professional and consumer labeling in 25 (60%) cases. The cardiovascular risk profile was not described consistently across all four countries for any of the five drugs. Conclusions Product labeling provides healthcare professionals and consumers with inconsistent messages regarding the potential causal relationship between stimulant use and specific cardiovascular risks in children and adolescents. Copyright © 2017 John Wiley & Sons, Ltd.

Ethical, evidence-informed decision making is undermined by the grave concerns that have emerged over the trustworthiness of clinical trials published in biomedical journals. The inescapable conclusion from this growing body of research is that what we see, even in the most highly regarded peer-reviewed journals, cannot be trusted at face value. Concerns of inaccurate, biased, and insufficient reporting of trials are impossible to resolve without access to underlying trial data. Access to such data, including things like clinical study reports—huge, unabridged, detailed reports of clinical trials—would minimise the risk of distortions and selective publication. But the FDA, the world’s greatest custodian of those data, just sits on them. We see no reason why FDA should not publicly release clinical study reports with minimal redactions. The European regulator is already doing this, but FDA’s holdings are far greater. Data transparency is not simply an “opportunity” FDA might consider, but rather an ethical imperative. The Blueprint is good but does not go far enough. We do not need gates, barriers and committees between us and access to aggregate reports on drugs and other interventions which we are prescribing or using daily. Let’s leave the nannies at home.

The world has bet the farm on vaccines as the solution to the pandemic, but the trials are not focused on answering the questions many might assume they are. Peter Doshi reports

It seemed a truth universally acknowledged that the human population had no pre-existing immunity to SARS-CoV-2, but is that actually the case? Peter Doshi explores the emerging research on immunological responses

With knowledge of covid-19 less than a year old, treatment remains fraught with uncertainty. Preprint data and adaptive clinical trials are imperfect but can guide active decision making in life-or-death situations, says Raymond M Johnson. But Peter Doshi and David Healy argue that doctors and professional societies should state that, without complete data transparency, they will not endorse covid-19 products as being based on science

Objectives We examined systematic adverse events (AEs) in Part 1 (of 2) of a study describing the assessment and reporting of AEs in clinical trials. Study Design and Setting We examined 52 public and nonpublic data sources about trials of quetiapine for bipolar depression using data from the Multiple Data Sources study. We extracted and compared information about systematic AEs (i.e., AEs assessed for all participants) in six prespecified domains: cardiovascular, cholesterol, endocrine, extrapyramidal symptoms, mania, and weight. Results Eligible trials did not assess and report the same systematic AEs, and most results were not available in public sources. Overall, public sources reported 159 results, of which 92 of 159 (58%) included sufficient statistical information to calculate the treatment effect and its precision. Nonpublic sources reported 636 results; 630 of 636 (99%) reported sufficient statistical information. Conclusion Systematic AEs were defined and analyzed in many ways, which led to many numerical results. Most systematic AEs were not mentioned in public sources. To minimize bias, methods for defining and analyzing potential AEs should be prespecified in trial registers and protocols. All trial results should be publicly available so that stakeholders can compare benefits and AEs. Trials could report core sets of AEs to facilitate decision-making.

After three years of trying to access trial data for HPV vaccines, Lars Jorgensen and colleagues find current transparency policies unfit for their purpose

Reporting bias is a major threat to the validity and credibility of systematic reviews. This article outlines the rationale for accessing clinical study reports and other regulatory documents (regulatory data) as a means of addressing reporting bias and identifies factors that may help decide whether (or not) to include regulatory data in systematic reviews. The article also describes the origins and current state of regulatory data access and summarises a survey of current systematic reviewers’ practices in considering regulatory data for inclusion in systematic reviews. How to access and extract regulatory data is not addressed. Organisations and other stakeholders such as Cochrane should encourage the use of data from clinical study reports as an important source of data in reviews of pharmaceutical interventions particularly when the intervention in question is of high importance and the risk of reporting bias is great.

Background Clinical study reports (CSRs) are produced for marketing authorisation applications. They often contain considerably more information about, and data from, clinical trials than corresponding journal publications. Use of data from CSRs might help circumvent reporting bias, but many researchers appear to be unaware of their existence or potential value. Our survey aimed to gain insight into the level of familiarity, understanding and use of CSRs, and to raise awareness of their potential within the systematic review community. We also aimed to explore the potential barriers faced when obtaining and using CSRs in systematic reviews. Methods Online survey of systematic reviewers who (i) had requested or used CSRs, (ii) had considered but not used CSRs and (iii) had not considered using CSRs was conducted. Cochrane reviewers were contacted twice via the Cochrane monthly digest. Non-Cochrane reviewers were reached via journal and other website postings. Results One hundred sixty respondents answered an open invitation and completed the questionnaire; 20/160 (13%) had previously requested or used CSRs and other regulatory documents, 7/160 (4%) had considered but not used CSRs and 133/160 (83%) had never considered this data source. Survey respondents mainly sought data from the European Medicines Agency (EMA) and/or the Food and Drug Administration (FDA). Motivation for using CSRs stemmed mainly from concerns about reporting bias 11/20 (55%), specifically outcome reporting bias 11/20 (55%) and publication bias 5/20 (25%). The barriers to using CSRs noted by all types of respondents included current limited access to these documents (43 respondents), the time and resources needed to obtain and include these data in evidence syntheses (n = 25) and lack of guidance about how to use these sources in systematic reviews (n = 26). Conclusions Most respondents (irrespective of whether they had previously used them) agreed that access to CSRs is important, and suggest that further guidance on how to use and include these data would help to promote their use in future systematic reviews. Most respondents who received CSRs considered them to be valuable in their systematic review and/or meta-analysis. Electronic supplementary material The online version of this article (10.1186/s13643-018-0766-x) contains supplementary material, which is available to authorized users.

BackgroundNeuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.ObjectivesTo (1) describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu®, Roche) treatment on mortality in patients with 2009A/H1N1 influenza.MethodsWe searched trial registries, electronic databases and corresponded with regulators and sponsors to identify randomised trials of NIs. We requested full CSRs and accessed regulators’ comments. We included only those trials for which we had CSRs. To examine the effects of oseltamivir on 2009A/H1N1 influenza mortality, we requested individual patient data (IPD) from corresponding authors of all included observational studies.ResultsEffect of oseltamivir and zanamivir (Relenza®, GlaxoSmithKline) in the prevention and treatment of influenza: Oseltamivir reduced the time to first alleviation of symptoms in adults by 16.8 hours [95% confidence interval (CI) 8.4 to 25.1 hours]. Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days). Oseltamivir reduced unverified pneumonia in adult treatment [risk difference (RD) 1.00%, 95% CI 0.22% to 1.49%]; similar findings were observed with zanamivir prophylaxis in adults (RD 0.32%, 95% CI 0.09% to 0.41%). Oseltamivir treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90% to 7.39%) and vomiting (RD 4.56%, 95% CI 2.39% to 7.58%). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75% to 10.29%). Both oseltamivir and zanamivir prophylaxis reduced the risk of symptomatic influenza in individuals (oseltamivir RD 3.05%, 95% CI 1.83% to 3.88%; zanamivir RD 1.98%, 95% CI 0.98% to 2.54%) and in households (oseltamivir RD 13.6%, 95% CI 9.52% to 15.47%; zanamivir RD 14.84%, 95% CI 12.18% to 16.55%). Oseltamivir increased psychiatric adverse events in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07% to 2.76%) and the risk of headaches while on treatment (RD 3.15%, 95% CI 0.88% to 5.78%).Effect of oseltamivir on mortality in patients with 2009A/H1N1 influenza: Analysis of summary data of 30 studies as well as IPD of four studies showed evidence of time-dependent bias. After adjusting for time-dependent bias and potential confounding variables, competing risks analysis of the IPD showed insufficient evidence that oseltamivir reduced the risk of mortality (hazard ratio 1.03, 95% CI 0.64 to 1.65).ConclusionsOseltamivir and zanamivir cause small reductions in the time to first alleviation of influenza symptoms in adults. The use of oseltamivir increases the risk of nausea, vomiting, psychiatric events in adults and vomiting in children. Oseltamivir has no protective effect on mortality among patients with 2009A/H1N1 influenza. Prophylaxis with either NI may reduce symptomatic influenza in individuals and in households. The balance between benefits and harms should be considered when making decisions about use of NIs for either prophylaxis or treatment of influenza.Study registrationThis study is registered as PROSPERO CRD42012002245.FundingThe National Institute for Health Research Health Technology Assessment programme.

Vaccines are considered one of public health’s greatest success stories. But is all promotion of vaccines necessarily a good thing, or does it depend on the details? Peter Doshi investigates the semi-transparent world of vaccine advocacy organizations

Importance Potential research participants may assume that randomized trials comparing new interventions with older interventions always hypothesize greater efficacy for the new intervention, as in superiority trials. However, antibiotic trials frequently use “noninferiority” hypotheses allowing a degree of inferior efficacy deemed “clinically acceptable” compared with an older effective drug, in exchange for nonefficacy benefits (eg, decreased adverse effects). Considering these different benefit-harm trade-offs, proper informed consent necessitates supplying different information on the purposes of superiority and noninferiority trials. Objective To determine the degree to which the study purpose is explained to potential participants in randomized clinical trials of antibiotics and the degree to which study protocols justify their selection of noninferiority hypotheses and amount of “clinically acceptable” inferiority. Design and Setting Cross-sectional analysis of study protocols, statistical analysis plans (SAPs), and informed consent forms (ICFs) from clinical study reports submitted to the European Medicines Agency. The ICFs were read by both methodologists and patient investigators. Main Outcomes and Measures Protocols and SAPs were used as the reference standard to determine prespecified primary hypothesis and record rationale for selection of noninferiority hypotheses and noninferiority margins. This information was cross-referenced against ICFs to determine whether ICFs explained the study purpose. Results We obtained trial documents from 78 randomized trials with prespecified efficacy hypotheses (6 superiority, 72 noninferiority) for 17 antibiotics conducted between 1991 and 2011 that enrolled 39 407 patients. Fifty were included in the ICF analysis. All ICFs contained sections describing study purpose; however, none consistently conveyed study hypothesis to both methodologists and patient investigators. Methodologists found that 1 of 50 conveyed a study purpose. Patient investigators found that 11 of 50 conveyed a study purpose, 7 accurately and 4 inaccurately compared with the reference standard. Seventy-one of 72 noninferiority trial protocols or SAPs provided no rationale for selection of noninferiority hypothesis. None provided a clinical rationale for the chosen amount of decreased efficacy. Conclusions and Relevance Patients were not accurately informed of study purpose, which raises questions regarding the ethics of informed consent in antibiotic trials. Noninferiority and superiority trials entail different benefit-harm trade-offs that must be conveyed for ethical informed consent.

Donald Trump’s war with the media shows why medical journalists must acknowledge that not everyone thinks as they do, says Peter Doshi

One group’s efforts to monitor misreporting of outcomes has irritated several medical journals, which argue that the differences discovered are not clinically important. So how seriously should we be taking it? Peter Doshi reports Glimpses inside SmithKline Beecham’s secret clinical trials programme for the antidepressant paroxetine began in the early 2000s. Amid a growing storm over the safety of selective serotonin reuptake inhibitors for children, a leaked memo revealed by the BBC’s Panorama programme1 depicted a company trying to manage the unfavourable results of two important trials. “It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine,” the memo read. A reviewer for the US Food and Drug Administration considered both trials as “failed.”2 But then there was the public face of the data. One of the two trials–Study 329–was published in the peer reviewed literature.3 The manufacturer told its sales representatives that the “landmark study … demonstrates REMARKABLE efficacy and safety.”4 Study 329 has become a classic example of what is known as outcome reporting bias, in which trial authors selectively present trial results leading, almost inevitably, to a rosier picture than would have occurred had the trial been reported according to the original protocol. The data showed no difference between paroxetine and placebo for all eight of the originally specified outcomes of interest, and an increase in harms.5 6 7 Yet the 2001 trial publication3 reported on four outcomes not specified in the protocol (all of which had statistically significant differences) and concluded that paroxetine was “generally well tolerated and effective.” Put simply, the goalposts set when the trial commenced had moved by the time the trial was reported. Some may have suspected that Study 329 was an anomaly. …

BACKGROUND: The Cochrane risk of bias tool is a prominent instrument used to evaluate potential biases in clinical trials. In three updates of our Cochrane review on neuraminidase inhibitors, we assessed risk of bias on the same trials using different levels of detail: the trials in journal publications, in core reports, and in full clinical study reports. Here we analyse whether progressively greater amounts of information and detail in full clinical study reports (including trial protocols, statistical analysis plans, certificates of analyses, individual participant data listings and randomisation lists) affected our risk of bias assessments. METHODS AND FINDINGS: We used the Cochrane risk of bias tool to assess and compare risk of bias in 14 oseltamivir trials (reported in 10 clinical study reports) obtained from the European Medicines Agency (EMA) and the manufacturer, Roche. With more detailed information, reported in clinical study reports, no previous assessment of 'high' risk of bias was reclassified as 'low' or 'unclear' in the main analysis, and over half (55%, 34/62) of the previous assessments of 'low' risk of bias were reclassified as 'high'. Most assessments of 'unclear' risk of bias (67%, or 28/42) were reclassified as 'high' risk of bias when our judgements were based on full clinical study reports. The limits of our study were our relative inexperience in dealing with large information sets, sometimes subjective bias judgements and focus on industry trials. Comparison with journal publications was not possible because of the low number of trials published. CONCLUSIONS: We found that as information increased in the document, this increased our assessment of bias. This may mean that risk of bias has been insufficiently assessed in Cochrane reviews based on journal publications.

Background Clinical trial (and other) data from the European Medicines Agency (EMA) offers the best available opportunity to address the extensive reporting bias in pharmaceutical trial literature. Data are requested via freedom of information requests, but 5 years on, little is known about how the system is working. Methods Case series of 12 requests for regulatory data (clinical study reports and other regulatory data) relating to 29 different compounds. We logged start and end dates for correspondence with and data releases from the EMA, the need for additional correspondence and appeal of initial negative decisions, and inspected data releases for redaction. We measured: time from initial request to first substantive response from the EMA, to final decision from the EMA (in case of appeal), to initial receipt of documents, and to completion of request; number of data transmission batches generated; number of pages received for each request; average number of pages per batch over time (for releases in multiple batches); judgment as to whether the request was satisfied. Results We found great variability in time to receive an initial decision from the EMA (1 to 13 weeks). Additional correspondence with the EMA was necessary in 10 of 12 requests. Four of 12 were initially refused but 3 of 4 were allowed on appeal after 3 to 33 additional weeks. One request was denied despite appeal. Time to final decision was 1 to 43 weeks. We received data for 11 of 12 requests in 98 batches. While two requests remain outstanding as at June 2015 the remaining nine requests took a median 43 weeks to completion (range: 17 to 186 weeks). Despite redaction in 10 of 11 releases (mainly of researcher and participant identifying information), 8 requested were wholly satisfied. Conclusions The EMA is the only regulator in the world that is routinely releasing original clinical trial data, but release can take considerable time to occur and often only after a lengthy correspondence. Given its importance for research and significance for transparency we suggest ways in which the process could be made more efficient. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1194-7) contains supplementary material, which is available to authorized users.

In an opinion piece in the New York Times , the spouse of a lung cancer patient called a pharmaceutical company “shameful” for airing a television commercial that “prey[ed] upon the fears and waning hopes of terminal cancer patients.”[1][1] The commercial trumpeted “a chance to live longer

The European Medicines Agency has scaled back its landmark clinical trial data policies, the drug regulator has announced. Policy 0043, which granted public access to documents in the regulators’ archives, including clinical trial data, is now limited to EU citizens only, and work related to publishing new data packages under its clinical data publication policy (policy 0070) has been suspended. The agency said that the cutbacks were a response to an “excessive workload”1 and were part of its planning amid substantial staff loss as it prepared for Brexit.2 Transparency advocates have described it as a blow to critical transparency efforts with potential patient safety ramifications. “Deaths and other serious harms are much under-reported in published trials, and we therefore need unhindered and immediate access to clinical study reports and other relevant documentation that the EMA holds,” said Peter Gotzsche, director of the Nordic Cochrane Centre. Gotzsche is credited with “opening up” the EMA after his successful appeal to the European ombudsman over a denied request for data a decade ago.3 He said that the EMA’s announcements were “very …

The correct title of the article [1] should be “Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol”.

Objectives. I sought to describe trends in historical influenza mortality data in the United States since 1900 and compare pandemic with nonpandemic influenza seasons. Methods. I compiled a database of monthly influenza-classed death rates from official US mortality tables for the years 1900 to 2004 (1905–1909 excluded), from which I calculated adjusted influenza season (July 1–June 30) mortality rates. Results. An overall and substantial decline in influenza-classed mortality was observed during the 20th century, from an average seasonal rate of 10.2 deaths per 100 000 population in the 1940s to 0.56 per 100 000 by the 1990s. The 1918–1919 pandemic stands out as an exceptional outlier. The 1957–1958 and 1968–1969 influenza pandemic seasons, by contrast, displayed substantial overlap in both degree of mortality and timing compared with nonpandemic seasons. Conclusions. The considerable similarity in mortality seen in pandemic and non-pandemic influenza seasons challenges common beliefs about the severity of pandemic influenza. The historical decline in influenza-classed mortality rates suggests that public health and ecological factors may play a role in influenza mortality risk. Nevertheless, the actual number of influenza-attributable deaths remains in doubt.

Background Systematic reviews should provide trustworthy guidance to decision-makers, but their credibility is challenged by the selective reporting of trial results and outcomes. Some trials are not published, and even among clinical trials that are published partially (e.g., as conference abstracts), many are never published in full. Although there are many potential sources of published and unpublished data for systematic reviews, there are no established methods for choosing among multiple reports or data sources about the same trial.

The drug industry’s rhetoric over transparency of clinical trial data may not be reflected in practice

A massive proposed US law claims to accelerate the discovery, development, and delivery of new medicines, but critics warn about the implications for drug and device safety. Peter Doshi sets out some of the more controversial changes

OBJECTIVE: To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments ("regulatory information"). DESIGN: Systematic review of regulatory information. DATA SOURCES: Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza. MAIN OUTCOME MEASURES: Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population. RESULTS: From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P

The US Food and Drug Administration (FDA) has announced it will disclose clinical study reports (CSRs) in a pilot programme to begin this month.12 Participation in the pilot will be voluntary for sponsors, include up to nine recently approved drug applications, and is limited to CSRs for the key “pivotal” trials that underpin drug approval. Declaring that “transparency can be a powerful tool for innovation,”3 FDA commissioner Scott Gottlieb also argued the public CSRs would help streamline the FDA’s evaluation of drug applications and “create a more efficient review process.”4 The announcement, made on 16 January at a transparency forum led by Johns Hopkins School of Public Health, thrusts the regulator into an activity senior officials have in recent years resisted, arguing that data sharing was an activity best left to the companies that own the data, not middlemen like the FDA. Historically, the agency’s position has been that laws such as the Trade Secrets Act prohibit it from releasing trial data,5 and there have been only a handful of cases where the FDA has released CSRs, sometimes in response to …

The connectivity problem I described for the website of the US government Vaccine Adverse Event …

Academics who refused calls to share the data underlying their landmark trial that triggered the downfall of starches for fluid resuscitation have announced an “independent reanalysis,” which confirms their original findings.1 However, they have not made their data available to the wider scientific community—a key element of transparent research practice and what other academics have been calling for.23 The 7000 patient trial, CHEST (Crystalloid versus Hydroxyethyl Starch Trial),4 is one of the most important pieces of evidence concerning the effects of hydroxyethyl starch solutions for increasing intravascular volume in patients in intensive care. Published in the New England Journal of Medicine in 2012, CHEST reported that the hydroxyethyl starch investigated, Voluven, was no different than saline in terms of mortality but led to greater use of renal replacement therapy. The trial helped persuade drug regulators in Europe and the US to issue safety warnings in 2013. In February the US health watchdog Public Citizen sent a petition to the Food and Drug Administration calling for hydroxyethyl starch intravenous solutions to be removed from the market,5 a move supported by CHEST’s lead author, John Myburgh.6 But the global healthcare company Fresenius Kabi, which makes Voluven and was a major funder (€3.5m (£3.15m; $4m)) of the trial, has long contended that the study was improperly reported.2 Before the trial the company took the unusual step of signing away all rights to the data, a decision it later came to regret. In 2014 it sought the assistance of The BMJ to intervene with the CHEST investigators. It then asked the Yale Open Data Access Project (YODA) to serve as an independent intermediary between the CHEST investigators and a reanalysis team to be determined, but the academic investigators rejected YODA’s offer.2 The latest “independent analysis” is …

Peter Doshi asks why no one seems to have noticed that the website isn’t working properly and what it says about the state of pharmacovigilance

Why they must help us improve the evidence base In 1990, a research scientist at the US Food and Drug Administration wrote in a letter to the New England Journal of Medicine ( NEJM ), “I review many clinical-trial protocols. The results of some of these trials subsequently appear in the medical literature. On occasion, the published description of the study may differ from the prospective protocol in important aspects of study design or statistical analysis—eg, study size, clinical end-points, and statistical tests used. The potential for misuse … is tremendous.”1 These comments were eerily prophetic: subsequent years brought the scandals of rofecoxib,23 celecoxib,4 paroxetine,56 and oseltamivir.7 The comments also suggest that each of these scandals could have largely been averted if journals had taken better account of what regulators—particularly the FDA—had to say about the relevant trials. We agree. Long before NEJM issued an expression of concern about data on harms missing from its report of the VIGOR trial of rofecoxib, those same data were available on the FDA’s website.2 JAMA reported CLASS as a six month trial …

A little noticed FDA report reveals internal opposition to Trump plans to speed drugs to market. Peter Doshi looks at its arguments

Objectives To investigate the practice of post-marketing studies in Germany during a three year period and to evaluate whether these trials meet the aims specified in the German Medicinal Products Act. Design Survey of notifications submitted to German regulatory agencies before post-marketing studies were carried out, 2008-10. Setting Notifications obtained through freedom of information requests to the three authorities responsible for registering post-marketing studies in Germany. Main outcome measures Descriptive statistics of post-marketing studies, including the products under study, intended number of patients, intended number of participating physicians, proposed remunerations, study plan and protocol, and availability of associated scientific publications and reports on adverse drug reactions. Results Information was obtained from 558 studies, with a median of 600 (mean 2331, range 2-75 000) patients and 63 (270, 0-7000) participating physicians per study. The median remuneration to physicians per patient was €200 (€441, €0-€7280) (£170, £0-£6200; $215, $0-$7820), with a total remuneration cost of more than €217m for 558 studies registered over the three year period. The median remuneration per participating physician per study was €2000 (mean €19 424), ranging from €0 to €2 080 000. There was a broad range of drugs and non-drug products, of which only a third represented recently approved drugs. In many notifications, data, information, and results were, by contract, strictly confidential and the sole property of the respective sponsor. No single adverse drug reaction report could be identified from any of the 558 post-marketing studies. Less than 1% of studies could be verified as published in scientific journals. Conclusions Post-marketing studies are not improving drug safety surveillance. Sample sizes are generally too small to allow the detection of rare adverse drug reactions, and many participating physicians are strictly obliged to maintain confidentiality towards the sponsor. High remuneration and strict confidentiality clauses in these studies could influence the physicians’ reporting behaviours of adverse drug reactions. BMJ2017;356:j337