Presentation on theme: "Regulatory Perspectives on the Thorough QT/QTc Study"— Presentation transcript:
1Regulatory Perspectives on the Thorough QT/QTc Study 2005 FDA/Industry WorkshopWashington DCSeptember 16, 2005Juan (Joanne) Zhang, Ph.D.CDER/FDA*Acknowledgement: Drs. Stella Machado & George Rochester
2DisclaimerThis presentation represents the opinions of the author, and not necessarily those of the U.S. Food and Drug Administration.
3Outline I. Thorough QT/QTc Study - Introduction Design Considerations Statistical Test for a Negative ‘Thorough QT/QTc Study’- Statistical Hypothesis & Test- Intersection-Union TestsFalse Positive and False Negative ProbabilitiesAssay SensitivitySummary
5IntroductionQT interval represents the time between start of ventricular depolarization and end of ventricular repolarization (QT).QTc is the QT-interval corrected for heart rates
6Introduction (2)QT/QTc prolongation may cause ventricular arrhythmias including ventricular fibrillation and Torsade de Pointes, which can be fatal even though the degree of this association is not knownCurrent ICH E 14 Guidance requests all sponsors submitting new drug applications to conduct a thorough QT/QTc studyGenerally conducted in early clinical development after some knowledge of the pharmacokinetics of the drug
7Introduction (3) ICH E14 Guidance (Step 4, Adopted May 2005) “The ‘thorough QT/QTc study’ is intended to determine whether the drug has a threshold pharmacologic effect on cardiac repolarization, as detected by QT/QTc prolongation.”“The study is typically carried out in healthy volunteers (as opposed to individuals at increased risk of arrhythmias) and is used to determine whether or not the effect of a drug on the QT/QTc interval in target patient populations should be studied intensively during later stages of drug development.”
8Negative ‘Thorough QT/QTc Study’ ICH E14 Guidance (Step 4, Adopted May 2005)“…a negative ‘thorough QT/QTc study’ is one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms.”
9Non-negative ‘Thorough QT/QTc Study’ If a ‘thorough QT/QTc study’ is not negative, i.e., if at least one upper bound of the one-sided 95% confidence interval of the time-matched difference exceeds the threshold of 10 ms, the study is termed “Non-negative”.
10Implications of Results from the ‘Thorough QT/QTc Study’ ICH E 14:IF the ‘thorough QT/QTc study’ is negative – “the collection of baseline and periodic on-therapy ECGs in accordance with the current investigational practices in each therapeutic field is almost always sufficient evaluation during subsequent stages of drug development.”IF ‘thorough QT/QTc study’ is non-negative – “additional evaluation in subsequent clinical studies should be performed.” Hence, expanded ECG safety evaluation during later stages of drug development are needed.
12Design Considerations To better control variability and potential biasRandomized, double blinded, placebo and active controlled, single or multiple doses of the drug, crossover or parallel studyHealthy volunteers, it is better to have similar number of males and females in the study (randomization stratified by gender)Crossover design recommended if possibleFor a crossover study, baseline at each period is recommended
13Design Considerations (2) QT data are highly variable, so control of all sources of variability is criticalReplicated QT measurements at each time-point are recommended. Typically ≥3 replicates. The mean of these replicates is used.The baseline QT measurements should be taken as close to the treatment date as possible; typically eitherAt matching time-points on the day prior to drug treatment; orAt time 0 before dosing, the same day of treatmentQT interval data are adjusted for heart rate (HR) to obtain QTc values which are correlated with HR as little as possible.Fridericia’s corrected valuesIndividual corrected valuesBazett’s corrected values
14Crossover DesignA crossover QT/QTc study is recommended as opposed to a parallel study if possible sinceIt requires smaller number of subjectsThe precision of estimated treatment differences is greater since subjects act as their own controlMethods and practice applicable in any cross-over trial should be applied in a crossover QT/QTc trial.Some issues encountered in a crossover-trial need to be considered here; including period effect and carry-over or residual effect.
15Crossover Design (2) Suppose a 4 TRT arm study DH: drug, high dose DL: drug, low doseP: placeboPC: positive controlSome designs we have seen:(Example 1)Problems? – Can’t distinguish the period effect from the treatment effect.Period 1Period 2Period 3Period 4PCPDLDH
16Crossover Design (3) Example 2 Group Period 1 Period 2 Period 3 Problems? – Period effect is confounded with the treatments. Thisconcern only pertains to PC though.GroupPeriod 1Period 2Period 3Period 4ADLDHPPCBCDEF
17Crossover Design (Continued) One recommended design for a 4 treatment study (a Williams Square)Group Period 1Period 2Period 3Period 4ADLDHPPCBCD
18Parallel For drugs with long elimination half-lives Parallel group studies may have to be used under certain circumstances:For drugs with long elimination half-livesFor drugs whose carryover effects are prominent
19Sample Size Required for a Crossover Design and a Parallel Design Notations:N1 - # of subjects in a crossover studyN2 - # of subjects per arm in a parallel study - observed difference in treatment (adjusted for baseline) for an individualSD() = 1 for a crossover;2 for a parallelD – SD for the drugP – SD for placebo12 – Correlation coefficient between the drug and placebo for the same individual (>0)Relation between N1 and N2In order to make Var(mean of ) the same for both crossover and parallel studies, we haveN2 = (2/ 1)2N1Relation between 1 and 2: 22 = 12 + 212DPFor a 4 arm trial, sample needed for a parallel study can be at least 4 times more than a crossover study
20Statistical Test for a Negative ‘Thorough QT/QTc Study’
21Calculating Time-matched Mean Difference How to estimate the time-matched population mean effect?Qit: (Baseline adjusted) QT/QTc value for the ith subject at time t after receiving the drugPit: (Baseline adjusted) QT/QTc value for the ith subject at time t after receiving placeboTime-matched mean difference at time t (suppose equal sample size N in both the drug and placebo groups)Qit/N - Pit/N = (For a crossover)N is the number of subjects
22Statistical Hypotheses H0: t(D) - t(P) ≥ ms for at least one tH1: t(D) - t(P) < ms for all t is the non-inferiority margin (10 ms in the guidance)t(D) and t(P) are the population means for the drug and placebo at time t, t=1,2,…,K. K is the total number of time points where QT has been measured.Claim a negative QT/QTc study if H0 is rejectedUse = 0.05
23Statistical TestLet be the observed average time-matched drug placebo difference after baseline adjusted at time t. Let Tt be the test statistic at time t, thenTt = ( )/SD( )Reject H0 if Tt < -t, N-1 for all t, where t, N-1 is the upper tail level critical value for the t distribution with N-1 df, and N is thesample size.The above procedure is to test if all one sided 95% CI upperbounds are < ms at each time point.
24Intersection-Union Tests Suppose Rt is the rejection region of a level- test for H0t: t(D) - t(P) ≥ ms, t=1,2,…,K, then the Intersection-Union Test with rejection region R= is still a level- test for H0No need for multiplicity adjustment to test for a negative thorough QT/QTc study
26Definitions Type I error: False Negative Probability (FNP) FNP = P(Tt < - t, N-1 for all t | at least one true difference ≥ )By IUT, FNP can be controlled under (0.05) levelType II error: False Positive Probability (FPP)FPP = P(Tt ≥ - t, N-1 for at least one t | true difference < 5 ms at each time point)Why 5 ms chosen: “… drugs that prolong the mean QT/QTc interval by around 5 ms or less do not appear to cause TdP” – ICH E14
27Simulation Study Purpose: to evaluate the FNP and FPP Assumptions: = 8 ms, 10 msSD () = 8.5 ms based on a crossover study in house# of times evaluated K = 5 and 15Multi-normal assumption: NK(, ) = 0.1 and 0.9Sample size 6510000 simulations per scenario
28Results: False Negative Probability Table 1K=5K=15 (0,0,8,0,0)(0,0,8,8,0)(0-0,8,0-0)(0-0,8,8,0-0) 80.10.0440.0050.0510.0040.90.0410.0360.0470.028(0,0,10,0,0)(0,0,10,10,0)(0-0,10,0-0)(0-0,10,10,0-0) 100.0370.0020.0520.0460.031
29Results: Power (1-FPP) Curves (=(2,3,4,4,3)’, =0.1)
30Results: Power (1-FPP) Curves (=(2,3,4,4,3)’, =0.9)
31Conclusions This simulation example shows: FNP is well controlled under the levelFPP (or 1 - Power) is driven byThe true mean difference of the drug and placeboThe Non-inferiority marginVariability of the dataSample size
32Assumed True Mean Difference Is it true the greater the number of time points, the higher the type II error? (N=65)Table 2Scenario, KAssumed True Mean Differencer=0.1r=0.9a8, 5(3,4,4.9,4,1)0.1340.109b 8, 15(0,0,0,1,1,3,4,4.9,4,1,1,1,0,0,0)0.1320.103c (1,1,1,4.9,1)0.1010.106d(0,0,0,1,1,1,1,1,4.9,1,1,1,0,0,0)0.1120.097e10, 50.001f 10,15g h10, 15
33Findings Focus on top half of table 2. As long as the time points chosen can capture the relatively big QT/QTc effect, the number of time points does not change FPP (Scenarios (a) vs. (b), (c) vs. (d))FPP can increase with the number of time points (Scenario (c) vs. (b))FPP can decrease with the number of time points (Scenario (a) vs. (d)).Conclusion: It is not always true that the FPP is an increasing function of the time points when QT/QTc are evaluated
35Assay Sensitivity ICH E14: “The positive control should have an effect on the mean QT/QTc interval of about 5 ms”The positive control “should be well-characterized and consistently produce an effect on the QT/QTc interval that is around the threshold of regulatory concern (5 ms, section 2.2.).”
36Statistical Procedures to Assess Assay Sensitivity H0: t(PC) - t(P) < c ms for all tH1: t(PC) - t(P) ≥ c ms for at least one tHow to choose c? Under discussion.Challenge: Multiple endpoint issues (can’t apply IUT here)
37SummaryA ‘thorough QT/QTc study’ is negative when the study drug is non-inferior to placebo in terms of the effect of QT/QTc interval.If all the one-sided 95% upper limits of the time-matched mean difference between the drug and placebo after baseline adjustment are below (the non-inferiority margin, 10 ms) at each time point, then we can claim a negative ‘thorough QT/QTc study’.By the Intersection-Union test, there is no need for the multiplicity adjustment to claim the drug is non-inferior to placebo.If possible, a crossover design should be considered.Need more thoughts on assay sensitivity issues.