Jen-pei Liu

Better Prediction of Prognosis for Patients with Nasopharyngeal Carcinoma Using Primary Tumor Volume

Heterogeneity of primary tumor volume within tumors of the same classification indicates a need to elucidate the effects of primary tumor volume on treatment outcomes in patients with nasopharyngeal carcinoma (NPC).

Sample size determination for the two one-sided tests procedure in bioequivalence.

Approximate formulae of sample sizes for Schuirmanns two one-sided tests procedure are derived for bioequivalence studies with the 2×2 crossover design. These formulae are simple enough to be carried out with a pocket calculator.

Sample Size Determination for a Specific Region in a Multiregional Trial

Recently, geotherapeutics have attracted much attention from sponsors as well as regulatory authorities. A bridging study defined by the International Conference on Harmonisation (ICH) E5 is usually conducted in the new region after the test product has been approved for commercial marketing in the original region due to its proven efficacy and safety. However, extensive duplication of clinical evaluation in the new region not only requires valuable development resources but also delays availability of the test product to the needed patients in the new regions. To shorten the drug lag or the time lag for approval, simultaneous drug development, submission, and approval in the world may be desirable. On September 28, 2007, the Ministry of Health, Labour and Welfare (MHLW) in Japan published the “Basic Principles on Global Clinical Trials” guidance related to the planning and implementation of global clinical studies. The 11th question and answer for the ICH E5 guideline also discuss the concept of a multiregional trial. Both guidelines have established a framework on how to demonstrate the efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region by conducting a multiregional trial. In this paper, we focus on a specific region and establish statistical criteria for consistency between the region of interest and overall results. More specifically, four criteria are considered. Two criteria are to assess whether the treatment effect in the region of interest is as large as that of the other regions or of the regions overall, while the other two criteria are to assess the consistency of the treatment effect of the specific region with other regions or the regions overall. Sample size required for the region of interest can also be evaluated based on these four criteria.

On the assessment of variability in bioavailability/bioequivalence studies

A procedure is proposed for the assessment of bioequivalence of variabilities between two formulations in bioavailability/bioequivalence studies. This procedure is essentially a two one-sided Pitman-Morgan’s tests procedure which is based on the correlation between crossover differences and subject totals. The nonparametric version of the proposed test is also discussed. A dataset of AUC from a 2×2 crossover bioequivalence trial is presented to illustrate the proposed procedures.

Radiographic Assessment of Skeletal Maturation Stages for Orthodontic Patients: Hand-wrist Bones or Cervical Vertebrae?

BACKGROUND/PURPOSE The skeletal maturation status of a growing patient can influence the selection of orthodontic treatment procedures. Either lateral cephalometric or hand-wrist radiography can be used to assess skeletal development. In this study, we examined the correlation between the maturation stages of cervical vertebrae and hand-wrist bones in Taiwanese individuals. METHODS The study group consisted of 330 male and 379 female subjects ranging in age from 8 to 18 years. A total of 709 hand-wrist and 709 lateral cephalometric radiographs were analyzed. Hand-wrist maturation stages were assessed using National Taiwan University Hospital Skeletal Maturation Index (NTUH-SMI). Cervical vertebral maturation stages were determined by the latest Cervical Vertebral Maturation Stage (CVMS) Index. Spearmans rank correlation was used to correlate the respective maturation stages assessed from the hand-wrist bones and the cervical vertebrae. RESULTS The values of Spearmans rank correlation were 0.910 for males and 0.937 for females, respectively. These data confirmed a strong and significant correlation between CVMS and NTUH-SMI systems (p less than 0.001). After comparison of the mean ages of subjects in different stages of CVMS and NTU-SMI systems, we found that CVMS I corresponded to NTUH-SMI stages 1 and 2, CVMS II to NTUH-SMI stage 3, CVMS III to NTUHSMI stage 4, CVMS IV to NTUH-SMI stage 5, CVMS V to NTUH-SMI stages 6, 7 and 8, and CVMS VI to NTUH-SMI stage 9. CONCLUSION Our results indicate that cervical vertebral maturation stages can be used to replace hand-wrist bone maturation stages for evaluation of skeletal maturity in Taiwanese individuals.

Statistical evaluation of similarity factor f2 as a criterion for assessment of similarity between dissolution profiles

This paper addresses statistical issues of similarity factor f2 as a criterion for assessment of similarity between two in vitro dissolution profiles as proposed in “Guidance on Immediate Release Solid Oral Dosage Forms; Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence Documentation” (SUPAC), issued by the United States Food and Drug Administration on November 30, 1995. These issues include the invariant property of f2 with respect to the location change and the consequence of failure to take into account shape of the curve and unequal spacing between sampling time points. The similarity factor f2 is a sample statistic which cannot be used to formulate a statistical hypothesis for assessment of dissolution similarity. It is, therefore, impossible to evaluate false positive and false negative rates of decisions for approval of drug products based on f2. Implementation of f2 to assess dissolution similarity is, in fact, a one-sided problem rather than an interval criterion suggested by the SUPAC. Complexity of the form in the distribution off even under a very strict assumption prevents one from finding its expected variance and hence, confidence interval for the mean. The large-sample distribution of f2 by the usual delta method fails to provide an adequate approximation to the empirical distribution obtained by simulation. In addition, simulation results also indicate that the similarity factor is too liberal in concluding similarity between dissolution profiles.

BAYESIAN APPROACH TO EVALUATION OF BRIDGING STUDIES

We address the issue of analysis of clinical data generated by the bridging study conducted in the new region to evaluate the similarity for extrapolation of the foreign clinical data. A bridging study is usually conducted in the new region only after the test product is approved for commercial marketing in the original region due to its proven efficacy and safety. Sufficient information on efficacy, safety, dosage, and dose regimen has already generated in the original region. The empirical Bayesian approach is proposed to synthesize the data generated by the bridging study and foreign clinical data generated in the original region for assessment of similarity between the new and the original regions. A method for sample size determination for the bridging study is also suggested. It can be shown that the total sample size is inversely proportional to the strength of the evidence for the efficacy presented in the original region and the proportion of the patients assigned to receive the test product in the bridging study. *The views expressed in this article are personal opinions of the authors and may not necessarily represent the position of the National Cheng-Kung University, the National Health Research Institutes, and the National Cheng-Chi University, Taiwan.

Bridging studies in clinical development.

Global development of pharmaceutical products has become the key to the success of any pharmaceutical sponsors. It is therefore crucial to address the efficacy and safety variations of a new test pharmaceutical product among different geographic regions due to ethnic factors. Recently, geotherapeutics has attracted much attention from sponsors as well as regulatory authorities from different geographic regions. To address this issue, the International Conference on Harmonization (ICH) has published a guideline entitled “Ethnic Factors in the Acceptability of Foreign Clinical Data,” which is known as ICH E5 guideline. The ICH E5 guideline provides a general framework for evaluation of the impact of ethnic factors on the efficacy, safety, dosage, and dose regimen. We provide an overview of ICH E5 guideline including ethnic sensitivity, necessity of bridging studies, types of bridging studies, and assessment of similarity between regions based on bridging evidence. In addition, challenges on the establishment of regulatory requirements, the assessment of bridging evidence, and design and analysis of bridging studies are addressed.

Design and Analysis of Animal Studies in Pharmaceutical Development

Experimental design principles for animal studies in pharmaceutical development interval estimation with small samples for Median Lethal Dose (LD50) or Median Effective Dose (ED50) principles in statistical testing in randomized toxicological studies subacute toxicity studies - proof of safety versus proof of hazard design of long-term carcinogenicity studies analysis of long-term carcinogenicity studies design of reproductive studies analysis of reproductive and development studies the in vitro Ames tests the in vitro Chinese hamster ovary cell mutagenesis studies.

Predicting healthcare utilization using a pharmacy-based metric with the WHO's Anatomic Therapeutic Chemical algorithm.

Background:Automated pharmacy claim data have been used for risk adjustment on health care utilization. However, most published pharmacy-based morbidity measures incorporate a coding algorithm that requires the medication data to be coded using the US National Drug Codes or the American Hospital Formulary Service drug codes, making studies conducted outside the US operationally cumbersome. Objective:This study aimed to verify that the pharmacy-based metric with the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) algorithm can be used to explain the variations in health care utilization. Research Design:The Longitudinal Health Insurance Database of Taiwan’s National Health Insurance enrollees was used in this study. We chose 2006 as the baseline year to predict the total cost, medication cost, and the number of outpatient visits in 2007. The pharmacy-based metric with 32 classes of chronic conditions was modified from a revised version of the Chronic Disease Score. Results:The ordinary least squares (OLS) model and log-transformed OLS model adjusted for the pharmacy-based metric had a better R2 in concurrently predicting total cost compared with the model adjusted for Deyo’s Charlson Comorbidity Index and Elixhauser’s Index. The pharmacy-based metric models also provided a superior performance in predicting medication cost and number of outpatient visits. For prospectively predicting health care utilization, the pharmacy-based metric models also performed better than the models adjusted by the diagnosis-based indices. Conclusions:The pharmacy-based metric with the WHO ATC algorithm and the matching ATC codes were tested and found to be valid for explaining the variation in health care utilization.