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2021-4764

Research Proposal

Project Title: 
Reporting of harms in SGLT2 clinical study reports compared to trial registries and publications: a methodological review
Scientific Abstract: 

Background: The prevalence of symptomatic type 2 diabetes in the Irish population is approximately 5.2%, a figure which has more than doubled over the course of almost 20 years. The Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a novel group of medications which are recommended as a second-line option after metformin in type 2 diabetes, and more recently have been cited as having benefits in those with heart failure. Some safety concerns have been raised in relation to these medications, so it is important that all evidence for these safety signals are reported in a timely and consistent manner.
Objective: Focusing on the SGLT2 inhibitors, the objectives of this project are to document procedures for identifying, accessing, extracting data from, and analysing CSRs for research purposes. To evaluate the differences between published sources and clinical study reports in terms of reporting of safety outcomes. To assess the completeness of reporting of harms, discrepancies in reported safety data and timeliness of access to such data across three main sources of trial data, namely publications, clinical trial registries and clinical study reports.
Study Design: A methodological review of reporting of harms for SGLT2 medications across three main sources of trial data
Participants: Clinical trials involving SGLT2 inhibitors
Outcomes: Total adverse events, serious adverse events (SAEs), SAEs leading to death and leading to discontinuation. Renal impairment, DKA, UTI, amputation, fracture, hypovolaemia/osmotic diuresis and any other clinically relevant outcome. Timeliness of reporting of safety outcomes across sources.
Statistical Analysis: Completeness / consistency of reporting
Descriptive statistics will be reported for the relevant trials. Completeness of reporting of the pre-specified outcomes will be reported for each of the three sources, including proportions of trials with discrepancies between sources. Where relevant, narrative descriptions of the discrepancies in reporting between each source will included.
Timeliness
Delays in the availability of safety results for all three sources will be reported as median time (in days) from study completion to the availability of results, and the relevant interquartile range. Kaplan-Maier analysis will be performed to assess the delay from trial completion to the availability of results for each source.

Brief Project Background and Statement of Project Significance: 

The Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a novel group of medications used in diabetes, of which four are currently licenced for use in the EU; Dapagliflozin, Canagliflozin, Empagliflozin and Ertugliflozin. SGLT2 inhibitors have been recommended for use as a second-line option, after metformin, in patients with type 2 diabetes, including by the National Institute for Health and Clinical Excellence (NICE). Recently SGLT2 inhibitors have been discussed as potential options in the management of heart failure, even in the absence of diabetes.
Specific safety concerns have been raised in relation to these medications, with acute kidney injury (AKI), euglycaemic DKA, urinary tract infections (UTI), fractures and lower limb amputations being highlighted, with calls for further research to refine the evidence for these outcomes. The EMA has updated the summary of product characteristics (SmPC) for all SGLT2 inhibitors in relation to Diabetic Ketoacidosis (DKA) risk perioperatively. Safety updates have been circulated by the Medicines and Healthcare products Regulatory Authority (MHRA) in relation to the potential risk of Fournier’s gangrene and by the FDA in relation to the risk of severe UTI.
In addition, several studies have highlighted the delays and associated risks in the reporting of safety concerns by regulators for medications. To the author’s knowledge, to date no study has used clinical study reports in assessing the consistency and timeliness of reporting of safety outcomes for SGLT2 inhibitors.

Specific Aims of the Project: 

The aim of this project is to assess the completeness of reporting of harms, discrepancies in reported safety data and timeliness of access to such data across three main sources of trial data, namely publications, clinical trial registries and clinical study reports.
Focusing on the SGLT2 inhibitors, the objectives of this project are to document procedures for identifying, accessing, extracting data from, and analysing CSRs for research purposes. To evaluate the differences between published sources and clinical study reports in terms of reporting of safety outcomes. To assess the completeness of reporting of harms, discrepancies in reported safety data and timeliness of access to such data across three main sources of trial data, namely publications, clinical trial registries and clinical study reports.
The specific hypothesis to be evaluated is that clinical study reports provide an earlier opportunity to access safety data for clinical trials and that this earlier access will allow for safety issues to be highlighted and quantified earlier and more comprehensively compared to traditional sources.

What is the purpose of the analysis being proposed? Please select all that apply.: 
New research question to examine treatment safety
Confirm or validate previously conducted research on treatment safety
Research on clinical trial methods
Software Used: 
STATA
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: 

All relevant available documents of randomised control trials involving Canagliflozin / SGLT2s will be analysed. Clinical Study Reports of the main trials involved in the regulatory approval of SGLT2 inhibitors have been requested directly from the EMA, from Yale Open Data Access (YODA) and have been obtained directly from the EMA’s public Clinical Data platform. Matched publications for each trial have been obtained using PubMed, and matched clinical trial registry entries on ClinicalTrials.gov have also been identified.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: 

Main safety outcomes of interest include those highlighted already as potential safety issues with these medications. They include total adverse events, serious adverse events (SAEs), SAEs leading to death and leading to discontinuation. Renal impairment, DKA, UTI, amputation, fracture, hypovolaemia/osmotic diuresis, timeliness of reporting of safety outcomes across sources and any other clinically relevant safety outcome.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: 

The above outcomes will be analysed with particular focus on completeness of reporting and discrepancies in their reporting.

Statistical Analysis Plan: 

Descriptive statistics will be reported for the outcomes analysed in the relevant trials. Completeness of reporting of the pre-specified outcomes will be reported for each of the three sources, including proportions of trials with discrepancies between sources. Where relevant, narrative descriptions of the discrepancies in reporting between each source will included.
Delays in the availability of safety results for all three sources will be reported as median time (in days) from study completion to the availability of results, and the relevant interquartile range. Kaplan-Maier analysis will be performed to assess the delay from trial completion to the availability of results for each source. Data extraction will be analysed separately for clinical study reports and published trial reports.

Narrative Summary: 

Focusing on the SGLT2 inhibitor medications, the aim of this project is to assess the consistency in reporting of harms in clinical trials and timeliness of access to safety data between clinical study reports and the usual sources, namely publications, clinical trial registries.
Requests for trial data related to the SGLT2 inhibitors have been requested directly from the EMA, from Yale Open Data Access (YODA) and have been obtained directly from the EMA’s public Clinical Data platform. Matched publications for each trial have been obtained using PubMed, and matched clinical trial registry entries on ClinicalTrials.gov have also been identified.

Project Timeline: 

It is anticipated that analysis will be completed within a year of this date (September 2022) and the results of the study submitted for publication within a further year after this. Results can be reported back to the YODA Project at this time.

Dissemination Plan: 

Following completion of this doctoral project it is planned that the results of each relevant part will be published in high impact peer reviewed journals to ensure that the results of the study are appropriately disseminated. It is envisaged that results will include the completeness and timeliness of reporting of safety outcomes. Specific target journals of interest include the British Medical Journal, BMJ Evidence Based Medicine, BMJ Open, BMC Series and Plos Medicine as a number of similar relevant papers in relation to clinical study reports have been published through these media previously.

Bibliography: 

1. Doshi P, Jefferson T. Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports. BMJ open. 2013;3(2).
2. Doshi P, Jefferson T, Del Mar C. The imperative to share clinical study reports: recommendations from the Tamiflu experience. PLoS Med. 2012;9(4):e1001201.
3. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. The New England journal of medicine. 2008;358(3):252-60.
4. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. Bmj. 2014;348:g2545.
5. Heneghan CJ, Onakpoya I, Thompson M, Spencer EA, Jones M, Jefferson T. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. Bmj. 2014;348:g2547.
6. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. Risk of bias in industry-funded oseltamivir trials: comparison of core reports versus full clinical study reports. BMJ open. 2014;4(9):e005253.
7. Wieseler B, Kerekes MF, Vervoelgyi V, McGauran N, Kaiser T. Impact of document type on reporting quality of clinical drug trials: a comparison of registry reports, clinical study reports, and journal publications. Bmj. 2012;344:d8141.
8. Doshi P, Jefferson T. Open data 5 years on: a case series of 12 freedom of information requests for regulatory data to the European Medicines Agency. Trials. 2016;17:78.
9. Davis AL, Miller JD. The European Medicines Agency and Publication of Clinical Study Reports: A Challenge for the US FDA. Jama. 2017;317(9):905-6.
10. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine. 2015;373(22):2117-28.
11. la Cour JL, Brok J, Gotzsche PC. Inconsistent reporting of surrogate outcomes in randomised clinical trials: cohort study. Bmj. 2010;341:c3653.
12. Donnan JR, Grandy CA, Chibrikov E, Marra CA, Aubrey-Bassler K, Johnston K, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ open. 2019;9(1):e022577.
13. Torjesen I. Three new treatments for diabetes recommended by NICE. BMJ. 2016;353:i2980.
14. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. The New England journal of medicine. 2019;381(21):1995-2008.
15. Donnan JR, Grandy CA, Chibrikov E, Marra CA, Aubrey-Bassler K, Johnston K, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open. 2019;9(1):e022577.
16. European Medicines Agency. PRAC recommendations on signals adopted at the 2-5 September PRAC meeting 2019 [Date accessed: 19th December 2019]. Available from: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmac....
17. European Medicines Agency. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes. 2016. Available from: https://www.ema.europa.eu/en/news/ema-confirms-recommendations-minimise-....
18. DTB Team. MHRA drug safety update: risk of Fournier's gangrene with SGLT2 inhibitors for diabetes. Drug and therapeutics bulletin. 2019;57(8):117.
19. Paludan-Müller AS, Créquit P, Boutron I. 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;19(1):88.
20. Bhasale A, Mintzes B, Sarpatwari A. Communicating emerging risks of SGLT2 inhibitors-timeliness and transparency of medicine regulators. BMJ (Clinical research ed). 2020;369:m1107.
21. European Medicines Agency. EMA: Clinical Data Website. 2021 [Available from: https://clinicaldata.ema.europa.eu/web/cdp].

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