Timothy H. Montague

Non-traditional study designs to demonstrate average bioequivalence for highly variable drug products

Abstract Objective: To demonstrate average bioequivalence, the ninety-percent confidence intervals (CI) on the ratio of geometric means for area under the concentration–time curve (AUC) and maximum observed plasma concentration (Cmax) must lie within 0.80–1.25. Demonstration of average bioequivalence (ABE) for highly variable drug products requires large numbers of subjects in a standard, adequately powered, two-period crossover. Methods: Application of non-traditional study designs can help to meet this hurdle. Study design and analysis for replicate and group sequential–replicate study designs are presented and illustrated using examples. It is demonstrated how to use such approaches to meet the difficult regulatory hurdle of average bioequivalence for a highly variable drug product. Results: To illustrate, data are provided from three separate ABE studies for a highly variable drug product at three dosage strengths. In all three studies, a replicate study design was used to compensate for high intrasubject variation. Additionally, for the last study, a group sequential study design was imposed to provide early evidence of conclusive results. Conclusion: Replicate designs and group-sequential designs in bioequivalence should be used to demonstrate average bioequivalence for highly variable drug products or when uncertain of true intrasubject variability in order to ensure conclusive study results.

Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs'.

In 2008, this group published a paper on approaches for two-stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second-stage sample size based on the variance estimated from the first-stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright

Optimal adaptive sequential designs for crossover bioequivalence studies

In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70-143% within each of two ranges of intra-subject coefficient of variation (10-30% and 30-55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at ≥ 80%, their average sample sizes were similar to or less than those of conventional single stage designs.

Re-introduction of a novel approach to the use of stable isotopes in pharmacokinetic studies.

The purpose of this investigation is to evaluate the scientific benefits of a novel approach in using stable isotopes to reduce the number of subjects needed to perform relative bioavailability and bioequivalence pharmacokinetic studies for formulations that are qualitatively and quantitatively the same and quality by design (QbD) pharmacokinetic studies. The stable isotope approach was investigated using simulations to determine the impact this approach would have on the estimation of variability and, subsequently, the sample size for a bioequivalence study. A biostudy was conducted in dogs in a two period crossover to explore the viability of the stable isotope approach. For a drug product with within-subject variability (CVw) of 50% and assuming a correlation of 0.95 between the enriched and non-enriched pharmacokinetics (PK), simulations showed that the variability can be reduced by 70% and the required sample size can be reduced by 90% while maintaining 90% power to demonstrate bioequivalence. The dog study showed a strong correlation (R2, > 0.99) between the enriched and non-enriched area under the curve and maximum observed concentration, and a significant reduction in the variability (reduction in % coefficient of variation from 79.9% to 6.3%). Utilization of a stable isotope approach can markedly improve the efficiency and accuracy of bioavailability and bioequivalence studies particularly for highly variable drugs in formulations that are qualitatively and quantitatively the same and for studies designed for QbD investigations.

Statistical Analysis Plans for ECG Data

The safety and regulatory needs to detect small drug-induced changes in the QT interval have created many challenges for the design and analysis of “thorough” QT studies. The measurement techniques available, the correlation between the RR interval and the QT interval, and the high variability in the QT interval have made the detection of changes in the QT interval difficult, and the verification of a lack of an effect on the QT interval even more difficult. The purpose of this chapter is to provide statistical and empirical rationales for key elements of study design, and statistical analysis that will control for sources of QT variability and will enhance study sensitivity. We will identify study design and statistical techniques to reduce QT variability, discuss the assumptions inherent in many of the choices available in study design, and recommend study designs based on these principles.

A definitive study of the effects of PDE-5 inhibitors on cardiac repolarization in middle-age males

Patients with erectile dysfunction may use PDE5 inhibitors such as vardenafil (V) and sildenafil (S), which alter the hERG channel of transfected cells only at suprapharmacologic nonclinical concentrations. This study evaluated effects of therapeutic and supratherapeutic doses of V and S on QT/QTc duration. A placebo‐ and active‐control (moxifloxacin, M, at therapeutic dose), period balanced, double blinded, 6 way crossover study evaluated single oral doses of V 10 mg, V 80 mg, S 50 mg, S 400 mg, M 400 mg and placebo in 58 healthy men (mean age 53) with doses separated by 3 days. Six replicate 12‐lead digital ECGs were recorded at 3 time points prior to and 5 time points post dose to cover the full exposure of drugs and metabolites. An independent lab blindly analyzed the ECGs. PK blood samples were drawn at the same 5 time points post dose. For placebo, mean change in QTcF (Fridericia) duration from baseline at 1 hour post dose (approximate Tmax of V and S) was 0 msec (+/‐ 0.7 SD). QT and QTc variability was small across regimens, indicating statistically powerful results due to large sample size and number (17,000) of ECGs. M demonstrated an expected 8 msec mean change and was the only drug to prolong absolute QT. Placebo‐corrected values of mean change from baseline at 1 hour post‐dose for each regimen are shown below. QT corrected using linear and nonlinear methods and each individuals QT/HR data (QTci) yielded similar trends of drug effect on QTc. PK/PD modeling demonstrated a very shallow QTc‐concentration relationship for V and S. Therapeutic and supratherapeutic doses of V and S produced no increase of absolute QT and similar small increases in QTc interval. We conclude that these findings, and the absence of postmarketing reports of torsades de pointes with S, indicate that small increases in QTc for V and S are clinically insignificant. This study design may serve as a guide for future definitive QT assessment. (See Table )

Better decision making in drug development through adoption of formal prior elicitation

With the continued increase in the use of Bayesian methods in drug development, there is a need for statisticians to have tools to develop robust and defensible informative prior distributions. Whilst relevant empirical data should, where possible, provide the basis for such priors, it is often the case that limitations in data and/or our understanding may preclude direct construction of a data-based prior. Formal expert elicitation methods are a key technique that can be used to determine priors in these situations. Within GlaxoSmithKline, we have adopted a structured approach to prior elicitation on the basis of the SHELF elicitation framework and routinely use this in conjunction with calculation of probability of success (assurance) of the next study(s) to inform internal decision making at key project milestones. The aim of this paper is to share our experiences of embedding the use of prior elicitation within a large pharmaceutical company, highlighting both the benefits and challenges of prior elicitation through a series of case studies. We have found that putting team beliefs into the shape of a quantitative probability distribution provides a firm anchor for all internal decision making, enabling teams to provide investment boards with formally appropriate estimates of the probability of trial success as well as robust plans for interim decision rules where appropriate. As an added benefit, the elicitation process provides transparency about the beliefs and risks of the potential medicine, ultimately enabling better portfolio and company-wide decision making.

Assessing a composite end point for new tocolytics in clinical trials: Data from 4 US integrated delivery networks

A composite end point (CE) measuring neonatal benefit was created for use in tocolytic randomized controlled trials with rates assessed using data from one referral hospital. The goal of this study was to assess wider generalizability of the CE, using data from multiple integrated delivery networks, creating a cohort of linked mother‐neonate pairs to understand neonatal outcomes in a broad population.

PK/PD modeling of QTC duration for vardenafil & sildenafil in healthy volunteers

A placebo‐ and positive‐controlled (Moxifloxacin, M 400 mg), double‐blind, 6‐way crossover study evaluated the effects of single oral therapeutic and supratherapeutic doses of vardenafil (V 10, 80 mg), and sildenafil (S 50, 400 mg) on QT/QTcF duration.