We Can Only Presume: Relationship between Protection of Commercial Interests and General Presumptions of Confidentiality Shrouded in Mist as Court of Justice Upholds European Medicines Agency Disclosure of Clinical Study Reports

2021 ◽  
pp. 1-8
Author(s):  
Eógan HICKEY
Keyword(s):  
Clinical Study ◽  
European Medicines Agency ◽  
Court Of Justice ◽  
Clinical Study Reports

scholarly journals Reporting of harms in oncological clinical study reports submitted to the European Medicines Agency compared to trial registries and publications—a methodological review

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Asger S. Paludan-Müller ◽  
Perrine Créquit ◽  
Isabelle Boutron
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Study ◽  
Primary Source ◽  
European Medicines Agency ◽  
Clinical Trial Registries ◽  
Number Of Patients ◽  
Journal Publications ◽  
Clinical Study Reports ◽  
Completeness Of Reporting

Abstract Background An accurate and comprehensive assessment of harms is a fundamental part of an accurate weighing of benefits and harms of an intervention when making treatment decisions; however, harms are known to be underreported in journal publications. Therefore, we sought to compare the completeness of reporting of harm data, discrepancies in harm data reported, and the delay to access results of oncological clinical trials between three sources: clinical study reports (CSRs), clinical trial registries and journal publications. Methods We used the EMA clinical data website to identify all trials submitted to the EMA between 2015 and 2018. We retrieved all CSRs and included all phase II, II/III or III randomised controlled trials (RCTs) assessing targeted therapy and immunotherapy for cancer. We then identified related records in clinical trial registries and journals. We extracted harms data for eight pre-specified variables and determined the completeness of reporting of harm data in each of the three sources. Results We identified 42 RCTs evaluating 13 different drugs. Results were available on the EMA website in CSRs for 37 (88%) RCTs, ClinicalTrials.gov for 36 (86%), the European Clinical Trials Register (EUCTR) for 20 (48%) and in journal publications for 32 (76%). Harms reporting was more complete in CSRs than other sources. We identified marked discrepancies in harms data between sources, e.g. the number of patients discontinuing due to adverse events differed in CSRs and clinical trial registers for 88% of trials with data in both sources. For CSRs and publications, the corresponding number was 90%. The median (interquartile range) delay between the primary trial completion date and access to results was 4.34 (3.09–7.22) years for CSRs, 2.94 (1.16–4.52) years for ClinicalTrials.gov, 5.39 (4.18–7.33) years for EUCTR and 2.15 (0.64–5.04) years for publications. Conclusions Harms of recently approved oncological drugs were reported more frequently and in more detail in CSRs than in trial registries and journal publications. Systematic reviews seeking to address harms of oncological treatments should ideally use CSRs as the primary source of data; however, due to problems with access, this is currently not feasible.

The European Medicines Agency and Publication of Clinical Study Reports

JAMA ◽  
2017 ◽  
Vol 317 (9) ◽  
pp. 905 ◽  
Author(s):  
Anna L. Davis ◽  
James Dabney Miller
Keyword(s):  
Clinical Study ◽  
European Medicines Agency ◽  
Clinical Study Reports

scholarly journals European Medicines Agency Policy 0070: an exploratory review of data utility in clinical study reports for academic research

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jean-Marc Ferran ◽  
Sarah J. Nevitt
Keyword(s):  
Clinical Study ◽  
Adverse Events ◽  
Phase 1 ◽  
Academic Research ◽  
Careful Consideration ◽  
European Medicines Agency ◽  
Published Data ◽  
Structured Interviews ◽  
Data Utility ◽  
Clinical Study Reports

Abstract Background Clinical study reports (CSRs) have been increasingly utilised within academic research in recent years. European Medicines Agency (EMA) Policy 0070 ‘Phase 1,’ which came into effect in January 2015, requires the publication of regulatory documents such as CSRs from central applications in an anonymised format. EMA Policy 0070 requires sponsors to demonstrate careful consideration of data utility within anonymised CSRs published within the scope of the policy, yet the concept of data utility is not clearly defined in the associated anonymisation guidance. Objective To review the use of data from CSRs in published academic research and to hypothesise the potential data utility of CSRs anonymised under the objectives of EMA Policy 0070 for future academic research. Methods Review of the objectives, research methodologies and findings of academic research reports using unpublished data from CSRs (prior to EMA Policy 0070). Semi-structured interviews with authors of academic research reports, including questions related to data utility of anonymised CSRs published under EMA Policy 0070. Results Thirteen academic research reports were identified and reviewed. The research purposes ranged from assessment of reporting bias, comparison of methods and results with published data sources, detailed evaluation of harms and adverse events, re-analysis and novel analyses including systematic reviews and meta-analysis. All of the examples identified required access to the methods and results sections of CSRs (including aggregated summary tables) and research purposes relating to evaluation of adverse events also required access to participant narratives. Retaining anonymised participant narratives relating to interventions, findings and events, while maintaining an acceptably low risk of participant re-identification, may provide an important gain in data utility and further understanding of drug safety profiles. Conclusions This work provides an initial insight into the previous use of CSR data and current practices for including regulatory data in academic research. This work also provides early guidance to qualitatively assess and document data utility within anonymised CSRs published under EMA Policy 0070.

scholarly journals Efficacy and safety of sacubitril/valsartan in the treatment of heart failure: protocol for a systematic review incorporating unpublished clinical study reports

2021 ◽  
Vol 3 ◽  
pp. 5
Author(s):  
David Byrne ◽  
Tom Fahey ◽  
Frank Moriarty
Keyword(s):  
Heart Failure ◽  
Clinical Study ◽  
Grey Literature ◽  
Phase Iii ◽  
Cochrane Library ◽  
European Medicines Agency ◽  
Efficacy And Safety ◽  
Neprilysin Inhibitor ◽  
Safety Outcomes ◽  
Clinical Study Reports

Background: Sacubitril/valsartan is a first-in-class angiotensin-receptor neprilysin inhibitor used to treat heart failure. The evidence for this novel medication is largely based on one pivotal phase III trial which was stopped early due to significant clinical benefits being shown. However potential limitations in trial design have been highlighted in recent literature, necessitating a thorough review of all evidence for sacubitril/valsartan. Methods: This review will be conducted using the PRISMA reporting guidelines. Relevant randomised controlled trials (RCTs) for sacubitril/valsartan will be systematically searched for in Medline (PubMed), Embase, Cochrane library, Google Scholar, Web of Science, Toxline and Scopus. Clinical trials registries will be searched, as will eight grey literature databases. In addition, unpublished clinical study reports (CSRs) of relevant trials will be requested from the European Medicines Agency (EMA) and the Clinical Study Data Request database. Studies will be included if they involve randomising adult patients with heart failure to either sacubitril/valsartan or usual care, with either an active comparator or placebo as a control. Heart failure of any subtype or NYHA class will be included. All relevant clinical and safety outcomes will be reviewed, particularly hospitalisation due to heart failure and cardiovascular mortality. Two reviewers will assess eligibility of selected studies for inclusion. Data extraction will be performed separately for trial publications, clinical trial registries and for CSRs using a piloted form. Methodological quality of included trials from published sources will be assessed separately using the Cochrane Risk of Bias tool (RoB 2). Narrative synthesis of included studies will be conducted and, if appropriate, meta-analysis for clinical efficacy and safety outcomes. Discussion: This review will collate all available RCT data on sacubitril/valsartan including published and unpublished sources in order to obtain a more complete picture of the evidence base for sacubitril/valsartan. Registration: This protocol is registered on PROSPERO (reference CRD42020162031).

scholarly journals Transparency of Regulatory Data across the European Medicines Agency, Health Canada, and US Food and Drug Administration

2021 ◽  
Vol 49 (3) ◽  
pp. 456-485
Author(s):  
Alexander C. Egilman ◽  
Amy Kapczynski ◽  
Margaret E. McCarthy ◽  
Anita T. Luxkaranayagam ◽  
Christopher J. Morten ◽  
...  
Keyword(s):  
Clinical Study ◽  
Drug Administration ◽  
Clinical Data ◽  
Food And Drug Administration ◽  
European Medicines Agency ◽  
Regulatory Data ◽  
Laws And Policies ◽  
Health Canada ◽  
Information Requests ◽  
Clinical Study Reports

AbstractBased on an analysis of relevant laws and policies, regulator data portals, and information requests, we find that clinical data, including clinical study reports, submitted to the European Medicines Agency and Health Canada to support approval of medicines are routinely made publicly available.

scholarly journals Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis

BMJ Open ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. e024886 ◽  
Author(s):  
Klaus Munkholm ◽  
Asger Sand Paludan-Müller ◽  
Kim Boesen
Keyword(s):  
Systematic Review ◽  
Clinical Study ◽  
Effect Size ◽  
Meta Analysis ◽  
Evidence Base ◽  
Risk Of Bias ◽  
Depression Symptom ◽  
Meta Analyses ◽  
The Impact ◽  
Clinical Study Reports

ObjectivesTo investigate whether the conclusion of a recent systematic review and network meta-analysis (Ciprianiet al) that antidepressants are more efficacious than placebo for adult depression was supported by the evidence.DesignReanalysis of a systematic review, with meta-analyses.Data sources522 trials (116 477 participants) as reported in the systematic review by Ciprianiet aland clinical study reports for 19 of these trials.AnalysisWe used the Cochrane Handbook’s risk of bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the risk of bias and the certainty of evidence, respectively. The impact of several study characteristics and publication status was estimated using pairwise subgroup meta-analyses.ResultsSeveral methodological limitations in the evidence base of antidepressants were either unrecognised or underestimated in the systematic review by Ciprianiet al. The effect size for antidepressants versus placebo on investigator-rated depression symptom scales was higher in trials with a ‘placebo run-in’ study design compared with trials without a placebo run-in design (p=0.05). The effect size of antidepressants was higher in published trials compared with unpublished trials (p<0.0001). The outcome data reported by Ciprianiet aldiffered from the clinical study reports in 12 (63%) of 19 trials. The certainty of the evidence for the placebo-controlled comparisons should be very low according to GRADE due to a high risk of bias, indirectness of the evidence and publication bias. The mean difference between antidepressants and placebo on the 17-item Hamilton depression rating scale (range 0–52 points) was 1.97 points (95% CI 1.74 to 2.21).ConclusionsThe evidence does not support definitive conclusions regarding the benefits of antidepressants for depression in adults. It is unclear whether antidepressants are more efficacious than placebo.

scholarly journals Benefits and harms of the human papillomavirus (HPV) vaccines: comparison of trial data from clinical study reports with corresponding trial register entries and journal publications

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Lars Jørgensen ◽  
Peter C. Gøtzsche ◽  
Tom Jefferson
Keyword(s):  
Systematic Review ◽  
Clinical Study ◽  
Hpv Vaccine ◽  
Meta Analysis ◽  
Trial Data ◽  
Link Type ◽  
Trial Register ◽  
Journal Publications ◽  
Meta Analyses ◽  
Clinical Study Reports

Abstract Background No study has looked at differences of pooled estimates—such as meta-analyses—of corresponding study documents of the same intervention. In this study, we compared meta-analyses of human papillomavirus (HPV) vaccine trial data from clinical study reports with trial data from corresponding trial register entries and journal publications. Methods We obtained clinical study reports from the European Medicines Agency and GlaxoSmithKline, corresponding trial register entries from ClinicalTrials.gov and corresponding journal publications via the Cochrane Collaboration’s Central Register of Controlled Trials, Google Scholar and PubMed. Two researchers extracted data. We compared reporting of trial design aspects and 20 prespecified benefit and harm outcomes extracted from each study document type. Risk ratios were calculated with the random effects inverse variance method. Results We included study documents from 22 randomized clinical trials and 2 follow-up studies with 95,670 healthy participants and non-HPV vaccine comparators (placebo, HPV vaccine adjuvants and hepatitis vaccines). We obtained 24 clinical study reports, 24 corresponding trial register entries and 23 corresponding journal publications; the median number of pages was 1351 (range 357 to 11,456), 32 (range 11 to 167) and 11 (range 7 to 83), respectively. All 24 (100%) clinical study reports, no (0%) trial register entries and 9 (39%) journal publications reported on all six major design-related biases defined by the Cochrane Handbook version 2011. The clinical study reports reported more inclusion criteria (mean 7.0 vs. 5.8 [trial register entries] and 4.0 [journal publications]) and exclusion criteria (mean 17.8 vs. 11.7 and 5.0) but fewer primary outcomes (mean 1.6 vs. 3.5 and 1.2) and secondary outcomes (mean 8.8 vs. 13.0 and 3.2) than the trial register entries. Results were posted for 19 trial register entries (79%). Compared to the clinical study reports, the trial register entries and journal publications contained 3% and 44% of the seven assessed benefit data points (6879 vs. 230 and 3015) and 38% and 31% of the 13 assessed harm data points (167,550 vs. 64,143 and 51,899). No meta-analysis estimate differed significantly when we compared pooled risk ratio estimates of corresponding study document data as ratios of relative risk. Conclusion There were no significant differences in the meta-analysis estimates of the assessed outcomes from corresponding study documents. The clinical study reports were the superior study documents in terms of the quantity and the quality of the data they contained and should be used as primary data sources in systematic reviews. Systematic review registration The protocol for our comparison is registered on PROSPERO as an addendum to our systematic review of the benefits and harms of the HPV vaccines: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20180320.pdf: CRD42017056093. Our systematic review protocol was registered on PROSPERO on January 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf. Two protocol amendments were registered on PROSPERO on November 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf. Our index of the HPV vaccine studies was published in Systematic Reviews on January 2018: 10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published on September 2018: 10.1136/bmj.k3694.

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