Statistician’s Perspective of Meta-Analysis to Establish Non-Inferiority Margin for Phase 3 Study Aparna Raychaudhuri, Ph.D., CSL Behring (Glaxosmithkline, at the time of this work) Fanny Mitrani-Gold MPH, GlaxoSmithKline

Outline of Presentation Introduction and FDA guidelines on non-inferiority clinical trial Setting up a non-inferiority clinical trial Experience of setting up a study in uncomplicated urinary tract infection Take home message for statisticians

Introduction Active-comparator, non-inferiority (NI) study designs are generally used in antibacterial drug development, due to ethical issues of using placebo treatment. The intent of a non-inferiority trial is to show that the new treatment is not worse than the existing treatment. Difficult to establish superiority against active control.

Introduction FDA Guidance Document, November 2016

FDA Guidance Document: Non-Inferiority Clinical Trials to Establish Effectiveness (2016) A general discussion on regulatory, study design, scientific and statistical issues associated with the NI studies to establish effectiveness of a new drug A focus on some of these issues in more detail, notably the statistical approaches used to determine the NI margin and to test for non-inferiority Commonly asked questions about NI studies Four examples of successful and unsuccessful efforts to define NI margins and test for non-inferiority.

Setting up a New Non-Inferiority Study To conduct a non-inferiority trial, an estimate of the treatment effect of the planned antimicrobial comparator must be obtained from historical trial data Here are the two definitions we need to keep in mind: M1 : The entire effect of the active control assumed to be present in the study M2 : The largest clinically acceptable difference (degree of inferiority) of the test drug compared to the active control

Setting up a New Non-Inferiority Study: How to estimate the treatment effect of the control Need to decide and justify the active control Please make sure that the regulators accept this active control Should be aligned with current standard of care for the indication Need to decide and justify the efficacy endpoint to measure “effect” of the control (primary efficacy endpoint) If there is no regulatory guidance on the primary efficacy endpoint to establish “effect” of the control then it is challenging to justify primary efficacy endpoint and treatment effect of the comparator

Setting up a Non-Inferiority Study in Uncomplicated Urinary Tract Infection (uUTI) uUTI is among the most commonly occurring bacterial infections Draft FDA guidance on uUTI published in May 2018 Clinical study planning commenced prior to this guidance being available and needed to justify appropriate non-inferiority margin estimation The comparator was identified (justification was prepared) Regulatory guidance was reviewed, conducted systematic literature reviews to identify historical studies that assessed the primary efficacy endpoint for this comparator

Setting up a study in uUTI: Endpoints Microbiological endpoint measures the eradication of the qualifying uropathogen (intent to treat population) Clinical endpoint measures the clinical signs and symptoms (intent to treat population) Please note that the subjects visit the doctor due to lower abdominal pain, discomfort, frequency of urination etc. Publications have described the signs and symptoms measured, but no standard validated scales consistently used in historical studies

Setting up a study in uUTI – Endpoints Continued Efficacy endpoints discussed in the FDA document in 2015: Microbiological eradication Clinical symptom resolution Combination of microbiological eradication and clinical symptom resolution Only two studies were identified Different active control group Small sample size Limited information on clinical symptom, schedule of assessment

Setting Up a Study in uUTI: Endpoints Continued Meta-analysis to estimate treatment effect based on the 2 studies for the combined endpoint (combination of microbiological eradication and clinical symptom resolution is shown below) M1 is 0.09 or 9% which implies M2 is 0.05 or 5% (commonly 50% of M1) Sample size for a non-inferiority based on 5% non-inferiority margin is unacceptable (more than 1500 subjects per treatment group)

Setting up a study in uUTI: FDA Guidance Document Draft guidance for industry for uncomplicated urinary tract infection became available in May 2018 The draft guidance document defined that the primary efficacy endpoint must be based on a combined microbiological and clinical response. “Non-inferiority margin of 10% is supported by historical evidence”. Appendix in the draft guidance presented meta-analysis along with the justification of literature search and the consideration of endpoints

Setting up a study in uUTI – Meta Analysis in FDA Guidance Please note that the therapeutic response rates in FDA Guidance is based on 2 studies and pooled efficacy for cefixime and pivmecillinam The comparator we considered is not included in this meta-analysis (1991) (2007)

Setting up a study in uUTI: FDA Guidance Document Please note that the new uUTI draft guidance no longer includes the Dubi et al. RCT (published in French) and includes a publication which has the data on the combined endpoint of microbiological eradication and clinical symptoms. Primary efficacy endpoint has been clearly defined M1 is 33.2%, which justifies M2 of 10% “Non-inferiority margin of 10% is supported by historical evidence”.

Take home message for statisticians If you are planning to set up a non-inferiority clinical trial for registration purpose then please make sure the regulatory guidance documents for industry are reviewed Please plan a meta-analyses to estimate treatment effect based on all available treatments in the class Treatment effect estimate is not necessarily based on the chosen comparator If there are no published trials with efficacy estimates for the active comparator chosen, then FDA may allow a NI margin based on treatment effect estimates from that class of drug. If no guidance document exists, then we must make sure with regulators about the primary efficacy endpoint and the estimated treatment effect based on meta-analysis to justify non- inferiority margin

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