An ethnic group is defined as a group of people who identify with each other based on intrinsic factors, such as genetic similarities due to common ancestry, and extrinsic factors, such as shared cultural experiences or environment. Therefore, one’s ethnicity is a fundamental aspect of life that defines a person, and that differentiates that person from others.
Ethnic differences have become important in the field of clinical drug development because they may impact the absorption, distribution, metabolism, or excretion (ADME) of drugs, and may be relevant to an understanding of a drug’s efficacy and safety.
Some regulatory agencies require that clinical trial data be obtained in specific populations in order to document drug effects in those populations. The Japanese Ministry of Health, Labour and Welfare is one such agency that seeks to ensure that drugs marketed in Japan have been tested in Japanese subjects. Pharmaceutical companies can conduct clinical trials in Japan in order to meet these requirements, but this can be rather costly. Alternatively, they may conduct “bridging studies” outside of Japan in order to document similar ADME and safety profiles in Japanese and non-Japanese subjects, allowing them to bridge Phase III data collected outside of Japan to the Japanese environment.
The concept of ethnic bridging studies took shape in the mid 1990’s when pharma companies began noticing a five- to seven- year delay in the approval of their drugs in the Japanese market, sometimes referred to as the “Japan gap.”
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Gary K. Zammit, Ph.D., President & CEO, Clinilabs |
- Make sure the clinical data package is complete
- Adequate characterization of PK/PD, efficacy & safety, dose, response, etc.
- Determine requirement of bridging study
The E5 document also explains under what conditions a bridging study is not needed. A Japanese bridging study is not needed if the drug is ethnically insensitive, meaning that there are no adverse effects when taken by a person of Japanese descent. When extrinsic factors, like environment and habits, are similar to the original study population, an ethnic bridging study can be overlooked. If it is decided that a study is needed, researchers will be looking for the following drug properties to determine the compound’s ethnic sensitivity.
- Linear or nonlinear PK
- Concentration – effect curve
- Therapeutic margin
- Bioavailability
- Pro – drug requiring rapid conversion
- Protein binding
- Need for co-medications
- Likelihood for inappropriate use
Traditionally, testing drugs for ethnic variances was a long, costly process. It involved the repetition of the study in a Japanese population, causing the “Japan gap.” This process would begin with the filing of an investigational new drug (IND) application in the United States, followed by a first-in-human trial. Single ascending dose (SAD) and multiple ascending dose (MAD) studies are then followed by later Phase I, II and III studies, ultimately leading to an NDA. If metabolic information was needed for Japanese subjects, this process would be repeated in Japan. Not only would this increase costs, but would take an extensive amount of time to complete. Japanese bridging studies allow for the simultaneous testing of the drug on multiple populations, and enables sponsors to use Phase III data collected outside of Japan in their regulatory filing. ICH –E5 recommends introducing the bridging study after the initiation of MAD, eliminating the repetitive data. Therefore, the reductions in development time and cost, as well as the opportunity to bring a new drug to market faster in Japan, have led to the acceptance of the Japanese bridging study as a common strategy for drug makers seeking to market their products in Japan.
The typical Japanese bridging study involves the assessments of cohorts of healthy Japanese subjects in comparison to cohorts of healthy non-Japanese subjects. Typically, in order to be considered for a trial, Japanese subjects must have two parents and four grandparents who also are Japanese. Non-Japanese subjects typically are Caucasian, African-American, or Hispanic. Criteria may be applied to “match” the non-Japanese subjects in a study to the Japanese participants. One such criterion often is body mass index (BMI). Other inclusion/exclusion or matching criteria may be applied, but these are among the most common.
One of the most critical factors related to the successful completion of Japanese bridging studies outside of Japan is the enrollment of appropriate subjects. It therefore is important for sponsors to identify experienced and capable research units that have access to the local Japanese community. Another critical factor relating to successful completion involves the staffing of the research unit and the cultural environment in which studies will take place. It is important that Japanese study participants have the opportunity to interact with unit staff who are fluent in Japanese, and that they feel comfortable and “at home” with the facilities where studies are taking place. In addition to these factors, there are many others that are critically important to the conduct of bridging studies.
While Japanese bridging studies are perhaps the most common type of ethnobridging study, recent years have seen an increase in requests for the inclusion of other special populations. For example, race has been shown to be associated with variability in the dosing requirements for warfarin, with African Americans needing higher doses than Caucasians, and Asians needing lower doses. Broad definitions of Asian subjects also have begun to include those who are not Japanese. For example, an Asian bridging study may require the involvement of Japanese, Chinese, Taiwanese, or other Asian populations. One report has indicated that there is greater exposure to rosuvastatin in Asian subjects (Chinese, Filipinos, Asian Indians, Koreans, Vietnamese, and Japanese) residing in the United States than in Caucasians.
For more information about Asian bridging studies, please go to www.clinilabs.com.
Gary K. Zammit, PhD
President & CEO, Clinilabs
