Issues in Selection of Deltas in Non-Inferiority Trials: Issues in Selection of Deltas in Non-Inferiority Trials John H. Powers, M.D. Lead Medical Officer Antimicrobial Drug Development and Resistance Initiatives Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration


Non-inferiority Margins (Deltas): Non-inferiority Margins (Deltas) What are deltas used for? After completion of trial = is the drug effective directly determining the how the efficacy of the test drug relates to the control drug indirectly determining the benefit of drug over placebo Prior to initiation of trial = can the trial be done practically setting sample size What is the appropriate sample size?


Clinical Trial Implications:Sample size per arm to achieve 80% power: Clinical Trial Implications: Sample size per arm to achieve 80% power D


Non-inferiority Trials: Non-inferiority Trials Risks involved in erroneously concluding non-inferiority are different for different diseases in severe diseases, treatment failure could translate into greater morbidity and mortality for patients in non-severe, self-resolving diseases, could lead to inappropriate prescribing with greater adverse effects (relative to placebo) and spread of antimicrobial resistance


Non-inferiority Margins (Deltas): Non-inferiority Margins (Deltas) Asking two separate but important questions in a drug development program: Is the drug an effective antimicrobial? Overall drug development program Is the drug effective in a specific infectious disease? Individual studies in a given disease indication drug characteristics site of infection host factors natural history of disease


How We Got Here: How We Got Here Points to Consider “step-function” not based on science relative to each disease February 2002 advisory committee agreement to look at the delta for each indication separately Internal attempt to look at placebo-controlled trials (PCTs) for each disease look at all available studies (not just those showing a benefit of antimicrobials over placebo) get estimate of range of benefit over placebo


What We See: What We See Types of diseases in relation to delta Magnitude of benefit of drug therapy over placebo is known and large acute bacterial meningitis, endocarditis Magnitude of benefit of drug therapy over placebo is unknown and may be small acute bacterial sinusitis, acute otitis media, acute exacerbations of chronic bronchitis Magnitude of benefit of drug therapy unknown but may be large enough to not be of concern when picking delta hospital-acquired pneumonia


Issues with Historical PCTs: Issues with Historical PCTs Differences in medical practice and adjunctive therapies Differences in range of organisms and resistance patterns of organisms Differences in enrollment criteria and endpoints compared to current trials Differences in cure rates across various patient populations (severe vs. less severe disease)


Non-inferiority Margins (Deltas): Non-inferiority Margins (Deltas) “Making delta” dependent on point estimate as well as sample size drugs for which point estimates of efficacy are close to control more likely to meet delta with same sample size


Possibilities: Possibilities Look at prior PCTs and determine range of deltas for indication has problems with data from PCTs as discussed ICH E-10 cautions about performing non-inferiority trials without data on delta 1 natural tendency to pick largest delta in the range of values but ICH E-10 cautions about being “suitably conservative” when selecting delta considerations within an indication characteristics of disease and severity of disease size and scope of development program characteristics of current study (e.g. micro data) number of trials per indication


Possibilities: Possibilities Alternative trial designs: (sample size may be smaller) superiority over control placebo-controlled trials with or without early escape therapy dose-ranging studies non-comparative data Superiority and placebo controlled trials also would allow examination of endpoints such as time to resolution of self-resolving diseases


Issues for Discussion: Issues for Discussion What approaches are available to select the appropriate non-inferiority margin in an active controlled trial when the benefit over drug therapy over placebo may be modest? Please discuss: problems with selecting delta based on previous placebo-controlled trials alternative trial designs such as superiority , dose ranging, placebo-controlled trials (+/- early escape)


Issues for Discussion: Issues for Discussion Please discuss the strengths and limitations of one study vs. multiple studies per indication. Are these considerations different when the study is part of an overall drug development plan studying multiple indications vs. a single indication? What are the strengths and limitations of non-comparative data as part of the development program for a drug?


Issues for Discussion: Issues for Discussion What are the issues involved in deciding on an acceptable treatment difference relative to a control drug? Please include in the discussion: The severity of the disease in question and the risk of treatment failure The practicalities of performing clinical trials in less common diseases Please discuss the utility of endpoints such as time to resolution of symptoms for spontaneously resolving diseases? Can these be measured in superiority trials or placebo-controlled (+/- early escape) trials?