Global development has become an important issue for pharmaceutical sponsors.
After the new chemical entity has been tested to show efficacy and safety in clinical trials in one region, it is important to apply for the registration of the new drug in other regions. To extrapolate the original clinical data to new populations, the differences on race, diet, environment, culture, and medical practice among regions might cause impact upon a medicine’s effect. Consequently how to address the ethnic variations of efficacy and safety for the product development is the key issue for global drug development. It will strongly depend upon the size of the market, development cost and the factors influencing the clinical outcomes for evaluation of efficacy and safety. If the size of the market for some new geographic region is sufficiently large, then it is understandable that the sponsor may be willing to repeat the whole clinical development program after the test product has completed its development plan and maybe obtain the market approval in the original region.
Ideally, one, of course, can directly conduct studies in the new region with similar sample size to the phase III trials conducted in the original region for confirmation of the efficacy observed in the original region. Nonetheless, extensive duplication of clinical evaluation in the new region not only demands valuable development resources but also delay availability of the test product to the needed patients in the new regions. To address this issue, the International Conference on Harmonisation (ICH) has published a guideline entitled “Ethnic Factors in the Acceptability of Foreign Clinical Data” known as ICH E5 (1998).
A general framework is provided by the ICH E5 document for evaluation of the impact of ethnic factors on the efficacy, safety, dosage, and dose regimen. The ethnic
factors are classified into the following two categories by the ICH E5 guideline.
Intrinsic ethnic factors are factors that define and identify the population in the new region and maybe influence the ability to extrapolate clinical data between regions.
They are more genetic and physiologic in nature, e.g., genetic polymorphism, age, gender, etc. On the other hand, extrinsic ethnic factors are factors associated with the environment and culture. Extrinsic ethnic factors are more social and cultural in nature, e.g., medical practice, diet, practices in clinical trials and conduct. In addition, the ICH E5 guideline provides regulatory strategies of minimizing duplication of clinical data and requirement of bridging evidence for extrapolation of foreign clinical data to a new region.
Several statistical procedures have been proposed to assess the similarity based on the additional information from the bridging study and the foreign clinical data in the CCDP. Shih (2001) used the method of Bayesian most plausible prediction for drug approval for countries in the Asian-Pacific region. Since substantial information from multicenter studies has already shown efficacy in the original regions (say for example, the United States or the European Union) when a drug manufacturer seeks marketing approval in another new region (say for example, an Asian country), the result from the new region is consistent with the previous results if it falls within the previous experience. Chow, Shao, and Hu (2002) proposed to use reproducibility probability and generalizability to assess the necessity of bridging studies in the new region. Liu, Hsueh, and Chen (2002) used a hierarchical model approach to incorporating the foreign bridging information into the data generated by the bridging study in the new region. Lan, Soo, Siu, and Wang (2005) introduced the weighted Z-tests in which the weights may depend on the prior observed data. for the design of bridging studies.
On the other hand, the increasing evidence that genetic determinants may mediate variability among persons in the response to a drug implies. In other words, after the intake of identical doses of a given agent, some patients may clinically significant side effects, whereas others may have no therapeutic response. One example can be seen in Caraco (2004). Caraco points out that some of this diversity in rates of response can be ascribed to differences in the rate of drug metabolism, particularly by the cytochrome P-450 superfamily of enzymes. While ten isoforms of cytochrome P-450 are responsible for the oxidative metabolism of most drugs, the effect of genetic polymorphisms on catalytic activity is most prominent for three isoforms—CYP2C9, CYP2C19, and CYP2D6. Among these three, CYP2D6 has been most extensively studied and is involved in the metabolism of about 100 drugs including beta-blockers and antiarrhythmic, antidepressant, neuroleptic, and opioid agents. Several studies revealed that some patients are classified as having “poor metabolism” of certain drugs due to lack of CYP2D6 activity. On the other hands, patients having some enzyme activity are classified into three subgroups: those with
“normal” activity (or extensive metabolism), those with reduced activity (intermediate metabolism), and those with markedly enhanced activity (ultrarapid metabolism).
Most importantly, the distribution of CYP2D6 phenotypes varies with race. For instance, the frequency of the phenotype associated with poor metabolism is 5 to 10 percent in white populations but only 1 percent in Chinese and Japanese populations.
In this paper, we will develop statistical methodologies to incorporate the variation among genetic polymorphisms for drugs into the evaluation of bridging studies. More specifically, criteria will be established in order to assure that the results from the new region are consistent with the results from the original region. This
paper is organized as follows. In Section 2, we establish criteria to examine whether the results from the new region are consistent with the results from the original region.
In Section 3, we incorporate the variation among genetic polymorphisms into the evaluation of bridging studies. Some numerical results are given in Section 4.
Discussions are given in Section 5.