Scarce quality assurance documentation in major clinical trial registries for approved medicines used in post-marketing clinical trials

BackgroundThe proven worrisome quality of medicines marketed in developing countries also affects clinical trials (CTs) as they may be used as Investigational Medicinal Products (IMPs). By regulation, CT sponsors should assure IMP’s quality and describe their quality measures in CT protocols that should be registered in a CT Registry (CTR). To check compliance with this regulation, we reviewed major CTRs to assess the availabilities of data fields on IMP quality for post-marketing CTs.MethodsTwo reviewers independently assessed English versions of CTRs of International Committee of Medical Journal Editors (ICJME) and WHO platforms in July 2017. Each CTR was checked for availability of data fields on: brand name; manufacturer’s name; regulatory approval status; approving regulator; manufacturer’s compliance with Good Manufacturing Practices (cGMP); and quality testing (IMP appearance, impurities, microbial contamination, dosing). In case of discrepancy, consensus was sought.ResultsOf 19 CTRs identified, 8 and 6 belonged to WHO and ICMJE, respectively, and 5 were equally part of both platforms. All CTRs had an ‘intervention’ data field to capture data on IMPs and IMP comparators. Unlike all others, the Canadian CTR used ‘drug name’ rather than ‘intervention’. Only the EU CTR had data fields for ‘manufacturer’s name’, ‘product approval status’, and ‘approving authority’. None of the CTRs had data fields on ‘cGMP’ or ‘quality testing’.ConclusionNone of the CTRs of ICMJE and ICTRP has adequate data fields to establish that the source of post-marketing IMPs is of assured quality. This is astonishing given the extensive requirements in WHO and ICMJE guidelines. The gap of quality assurance fields should be bridged by adding them to CTRs. Specifically, IMP quality testing should be conducted before, during, and after clinical trial completion. Until adoption of these measures, EU-CTR should be favoured for registration of CTs conducted in developing countries.

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Tuberculosis and viral hepatitis in patients treated with certolizumab pegol in Asia-Pacific countries and worldwide: real-world and clinical trial data

Clinical Rheumatology ◽

10.1007/s10067-020-05248-4 ◽

2020 ◽

Author(s):

Chak Sing Lau ◽

Yi-Hsing Chen ◽

Keith Lim ◽

Marc de Longueville ◽

Catherine Arendt ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Viral Hepatitis ◽

Central Europe ◽

Real World ◽

Certolizumab Pegol ◽

Safety Data ◽

Asia Pacific ◽

Hbv Reactivation ◽

Post Marketing

Abstract Introduction/objectives To evaluate the incidence rate (IR) of tuberculosis (TB) and viral hepatitis B and C (HBV/HCV) during certolizumab pegol (CZP) treatment, worldwide and in Asia-Pacific countries, across clinical trials and post-marketing reports (non-interventional studies and real-world practice). Method CZP safety data were pooled across 49 clinical trials from 1998 to June 2017. Post-marketing reports were from initial commercialization until March 2015 (TB)/February 2017 (HBV/HCV). All suspected TB and HBV/HCV cases underwent centralized retrospective review by external experts. Incidence rates (IRs) were calculated per 100 patient-years (PY) of CZP exposure. Results Among 11,317 clinical trial patients (21,695 PY), 62 TB cases were confirmed (IR 0.29/100 PY) including 2 in Japan (0.10/100 PY) and 3 in other Asia-Pacific countries (0.58/100 PY). From > 238,000 PY estimated post-marketing CZP exposure, there were 31 confirmed TB cases (0.01/100 PY): 5 in Japan (0.05/100 PY), 1 in other Asia-Pacific countries (0.03/100 PY). Reported regional TB IRs were highest in eastern Europe (0.17/100 PY), central Europe (0.09/100 PY), and Mexico (0.16/100 PY). Across clinical trials, there was 1 confirmed HBV reactivation and no HCV cases. From > 420,000 PY estimated post-marketing CZP exposure, 5 HBV/HCV cases were confirmed (0.001/100 PY): 2 HCV reactivations; 1 new HCV; plus 2 HBV reactivations in Japan (0.008/100 PY). Conclusions CZP TB risk is aligned with nationwide TB rates, being slightly higher in Asia-Pacific countries excluding Japan. Overall, TB and HBV/HCV risk with CZP treatment is currently relatively low, as risk can be minimized with patient/physician education, screening, and vigilant treatment, according to international guidelines. Key Points:• TB rates were highest in eastern/central Europe, Mexico, and Asia-Pacific regions.• With the implementation of stricter TB screening and risk evaluations in 2007, especially in high TB incidence countries, there was a notable reduction TB occurrence.• Safety profile of biologics in real-world settings complements controlled studies.• TB and hepatitis (HBV/HCV) risk with certolizumab pegol (CZP) treatment is low.

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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 ◽

10.1186/s12916-021-01955-0 ◽

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.

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Results availability and timeliness of registered COVID-19 clinical trials: interim cross-sectional results from the DIRECCT study

BMJ Open ◽

10.1136/bmjopen-2021-053096 ◽

2021 ◽

Vol 11 (11) ◽

pp. e053096

Author(s):

Maia Salholz-Hillel ◽

Peter Grabitz ◽

Molly Pugh-Jones ◽

Daniel Strech ◽

Nicholas J DeVito

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Journal Article ◽

Cross Sectional Study ◽

Sensitivity Analyses ◽

Cross Sectional ◽

Registration Data ◽

Clinical Trial Registries ◽

Treatment And Prevention

ObjectiveTo examine how and when the results of COVID-19 clinical trials are disseminated.DesignCross-sectional study.SettingThe COVID-19 clinical trial landscape.Participants285 registered interventional clinical trials for the treatment and prevention of COVID-19 completed by 30 June 2020.Main outcome measuresOverall reporting and reporting by dissemination route (ie, by journal article, preprint or results on a registry); time to reporting by dissemination route.ResultsFollowing automated and manual searches of the COVID-19 literature, we located 41 trials (14%) with results spread across 47 individual results publications published by 15 August 2020. The most common dissemination route was preprints (n=25) followed by journal articles (n=18), and results on a registry (n=2). Of these, four trials were available as both a preprint and journal publication. The cumulative incidence of any reporting surpassed 20% at 119 days from completion. Sensitivity analyses using alternate dates and definitions of results did not appreciably change the reporting percentage. Expanding minimum follow-up time to 3 months increased the overall reporting percentage to 19%.ConclusionCOVID-19 trials completed during the first 6 months of the pandemic did not consistently yield rapid results in the literature or on clinical trial registries. Our findings suggest that the COVID-19 response may be seeing quicker results disclosure compared with non-emergency conditions. Issues with the reliability and timeliness of trial registration data may impact our estimates. Ensuring registry data are accurate should be a priority for the research community during a pandemic. Data collection is underway for the next phase of the DIssemination of REgistered COVID-19 Clinical Trials study expanding both our trial population and follow-up time.

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Clinical Trials in Precision Oncology

Clinical Chemistry ◽

10.1373/clinchem.2015.247437 ◽

2016 ◽

Vol 62 (3) ◽

pp. 442-448 ◽

Cited By ~ 5

Author(s):

Susan M Mockus ◽

Sara E Patterson ◽

Cara Statz ◽

Carol J Bult ◽

Gregory J Tsongalis

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Egfr Mutation ◽

Bioinformatics Analysis ◽

Precision Oncology ◽

Reporting Standards ◽

Clinical Trial Registries ◽

Genomics Research ◽

Trial Outcomes ◽

Programmatic Access

Abstract BACKGROUND Availability of genomic information used in the management of cancer treatment has outpaced both regulatory and reimbursement efforts. Many types of clinical trials are underway to validate the utility of emerging genome-based biomarkers for diagnostic, prognostic, and predictive applications. Clinical trials are a key source of evidence required for US Food and Drug Administration approval of therapies and companion diagnostics and for establishing the acceptance criteria for reimbursement. CONTENT Determining the eligibility of patients for molecular-based clinical trials and the interpretation of data emerging from clinical trials is significantly hampered by 2 primary factors: the lack of specific reporting standards for biomarkers in clinical trials and the lack of adherence to official gene and variant naming standards. Clinical trial registries need specifics on the mutation required for enrollment as opposed to allowing a generic mutation entry such as, “EGFR mutation.” The use of clinical trials data in bioinformatics analysis and reporting is also gated by the lack of robust, state of the art programmatic access support. An initiative is needed to develop community standards for clinical trial descriptions and outcome reporting that are modeled after similar efforts in the genomics research community. SUMMARY Systematic implementation of reporting standards is needed to insure consistency and specificity of biomarker data, which will in turn enable better comparison and assessment of clinical trial outcomes across multiple studies. Reporting standards will facilitate improved identification of relevant clinical trials, aggregation and comparison of information across independent trials, and programmatic access to clinical trials databases.

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Therapeutic improvements expected in the near future for schizophrenia and schizoaffective disorder: an appraisal of phase III clinical trials of schizophrenia-targeted therapies as found in US and EU clinical trial registries

Expert Opinion on Pharmacotherapy ◽

10.1517/14656566.2016.1149164 ◽

2016 ◽

Vol 17 (7) ◽

pp. 921-936 ◽

Cited By ~ 16

Author(s):

Ricardo P. Garay ◽

Leslie Citrome ◽

Ludovic Samalin ◽

Chen-Chung Liu ◽

Morten S. Thomsen ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Schizoaffective Disorder ◽

Targeted Therapies ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

Clinical Trial Registries ◽

Near Future

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Part 2: Implementing Clinical Trials: A Review of the Attributes of Exemplary Clinical Trial Sites

Journal of Oncology Practice ◽

10.1200/jop.2010.000185 ◽

2011 ◽

Vol 7 (1) ◽

pp. 61-64 ◽

Cited By ~ 7

Author(s):

Robin Zon ◽

Gary Cohen ◽

Dee Anna Smith ◽

Allison R. Baer

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Quality Assurance ◽

Trial Process ◽

Awareness Programs

Part two of this series focuses on the remaining three exemplary attributes: quality assurance, multidisciplinary involvement in the clinical trial process, and clinical trials awareness programs.

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Guidance on the use of MRI for treatment planning in radiotherapy clinical trials

British Journal of Radiology ◽

10.1259/bjr.20190161 ◽

2020 ◽

Vol 93 (1105) ◽

pp. 20190161

Author(s):

Robert I Johnstone ◽

Teresa Guerrero-Urbano ◽

Andriana Michaelidou ◽

Tony Greener ◽

Elizabeth Miles ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Quality Assurance ◽

Treatment Planning ◽

Sufficient Information ◽

Planning Systems ◽

Imaging Guidance ◽

Safety Issues ◽

Treatment Planning Systems ◽

Trial Protocols

The aim of this article is to propose meaningful guidance covering the technical and safety issues involved when designing or conducting radiotherapy clinical trials that use MRI for treatment planning. The complexity of imaging requirements will depend on the trial aims, design and MRI methods used. The use of MRI within the RT pathway is becoming more prevalent and clinically appropriate as access to MRI increases, treatment planning systems become more versatile and potential indications for MRI-planning in RT are documented. Novel MRI-planning opportunities are often initiated and validated within clinical trials. The guidance in this document is intended to assist researchers designing RT clinical trials involving MRI, so that they may provide sufficient information about the appropriate methods to be used for image acquisition, post-processing and quality assurance such that participating sites complete MRI to consistent standards. It has been produced in collaboration with the National Radiotherapy Trials Quality Assurance Group (RTTQA). As the use of MRI in RT is developed, it is highly recommended for researchers writing clinical trial protocols to include imaging guidance as part of their clinical trial documentation covering the trial-specific requirements for MRI procedures. Many of the considerations and recommendations in this guidance may well apply to MR-guided treatment machines, where clinical trials will be crucial. Similarly, many of these recommendations will apply to the general use of MRI in RT, outside of clinical trials. This document contains a large number of recommendations, not all of which will be relevant to any particular trial. Designers of RT clinical trials must therefore take this into account. They must also use their own judgement as to the appropriate compromise between accessibility of the trial and its technical rigour.

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The risk of malignancy is not increased in patients with multiple sclerosis treated with subcutaneous interferon beta-1a: analysis of data from clinical trial and post-marketing surveillance settings

Multiple Sclerosis Journal ◽

10.1177/1352458511403642 ◽

2011 ◽

Vol 17 (4) ◽

pp. 431-440 ◽

Cited By ~ 17

Author(s):

Magnhild Sandberg-Wollheim ◽

Gabrielle Kornmann ◽

Dorina Bischof ◽

Margaretha Stam Moraga ◽

Brian Hennessy ◽

...

Keyword(s):

Multiple Sclerosis ◽

Clinical Trial ◽

Clinical Trials ◽

Safety Data ◽

Data Set ◽

Safety Database ◽

Post Marketing Surveillance ◽

Risk Of Malignancy ◽

Post Marketing ◽

Medical Dictionary

Background: Risks that are potentially associated with long-term therapies should be assessed. Objective: The present analyses were performed to determine the risk of malignancy in patients with multiple sclerosis (MS) receiving subcutaneous (sc) interferon (IFN) beta-1a, using pooled safety data from key clinical trials and data from the Merck Serono Global Drug Safety database. Methods: The standard Medical Dictionary for Regulatory Activities query “malignancies” was used to retrieve relevant cases from each data set. The incidence of malignancies per 1000 patient-years was calculated using the pooled safety data from clinical trials. The reporting rates of malignancy types were calculated for the post-marketing setting based on sales volume. Malignancies were grouped by organ localization and classified as medically confirmed or not medically confirmed according to the source of each report. The number of reported cases of each type was compared with the expected number in the general population. Results: Analysis of pooled safety data from 12 key clinical trials did not show an increased incidence of malignancy per 1000 patient-years with sc IFN beta-1a (4.0; 95% confidence interval (CI): 2.9–5.5) compared with placebo (6.4; 95% CI: 3.3–11.2). Analysis of the database shows that among the medically confirmed cases, reported to expected ratios ranged from 1 : 6 to 1 : 18 for solid tumours and from 1 : 2 to 1 : 9 for lymphohaematopoietic tumours. Conclusion: Safety data from both clinical trial and post-marketing settings suggest that treatment with sc IFN beta-1a does not increase the risk of malignancy in patients with MS.

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