Background on Ethnobridging
The possibility that ethnic differences exist in different populations with regards to metabolism and distribution of drugs has been documented for years. These differences may be manifest in difference in safety, efficacy and/or dosages, or in terms of adverse profiles in these ethnically diverse populations. Based on the premise that one should not have to repeat an entire clinical drug development program, the three regions represented by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), published a document entitled “Ethnic Factors in the Acceptability of Foreign Clinical Data” (E-5) on 5 Feb 1998.
In this document the concept of “extrinsic” and “intrinsic” ethnic factors were discussed. Extrinsic factors are factors associated with the environment and culture in which a person resides. Examples of extrinsic factors include diet, use of tobacco and alcohol, exposure to environmental pollutants and sunshine, local normal bacterial and viral flora, etc. Intrinsic factors include genetic polymorphism, age, gender, weight, lean body mass, etc. All of these factors can have potentially profound effects on drug distribution, metabolism and elimination. This, in turn may affect the pharmacokinetics, pharmacodynamics, and therefore the safety and efficacy of drugs in different ethnic populations.
In light of these potential ethnic factors, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuteicals for Human Use (ICH)* prepared the E5 guidancewhich was endorsed by the three regulatory agencies on February 5, 1998. The guidance is intended to recommend a framework for evaluating the empact of ethnic factors on drug efficady and safety with the goal of minimizing duplication of clinical studies and accelerating drug approval process. The goal is to be able to use bridging studies to extrapolate foreign clinical data into a new region.
Ethnic differences have been noted in three major areas: 1) PK profiles (eg. WCCT Study) 2) pharmacodynamic endpoints, 3) different adverse event profiles (eg sildnafil : 100 mg in Japanese causes abnormal vision in 10.8% vs 3.4% in 50 mg with no added efficacy resulting in a lower maximum dose in Japan).
*ICH consists of the regulatory and industry representatives from three regions, the US, Europe, and Japan: European Commission, Eurpoean Federation of Pharmaceutical Industries Associations, Kapanese Ministry of Health and Welfare, Japanese Pharmaceutical Manufacturers Association, The Centers for Drug Evaluationand Rersearch and Biologics Evaluation and Research, FDA, and the pharmaceutical Research and Manufacturers Associations (IFPMA).
In traditional drug development, companies with a promising new chemical entity (NCE) would develop the drug in the US or EU markets first. Then if the drug became successful , the companies would then turn their attention to developing the NCE for the Japanese market. This approach led to a “Japan gap” with a 5 to 7 year time lag from approval of a compound in the US/EU versus approval in Japan. Because of the size of the Japanese market, billions of dollars of “lost sales” was left on the table by pharmaceutical companies.
After the issuance of the E5 guidelines, companies who have been developing compounds in the US and Europe have adopted bridging or ethnobridging strategies which typically involves comparing Caucasian and Japanese cohorts to show equivalence or lack of equivalence with respect to PK data. In one review (Uyama, Y et al. Clin Pharmacol Ther 2005: 78: 102-13), the PMDA (the Japanese regulatory agency) published data showing that a new drug approval (NDA) took 32 months when bridging strategy was used versus 56 mo for NDA approval when full repeat development program with no bridging was done.
With the pressures of making the drug development process more cost effective and time efficient, most multinational pharmaceutical sponsors are developing strategies where they are accelerating global development by planning to incorporate Asian data in their phase I program so that by the time a NCE reaches phase 3, the program is being run globally and including Asian sites. It is not uncommon for phase I study designs to integrate an Asian bridging arm into their single ascending dose (SAD) and multiple ascending dose (MAD) study designs rather than running an entirely separate bridging study.
*** For large, multinational pharmaceutical companies they are using these integrated SAD/MAD with ethnic subarms studies as a means to initiate small dose ranging Phase II studies in Asian countries which is then used to include those Asian countries in the global phase III program.
***For smaller biotechnology companies where the goal is to bring a compound thru phase 2a proof of concept (POC) and establish safety and PK data, incorporating ethnobridging in the phase I development program is a way to increase their product’s value when out-licensing occurs. Options include 1) outlicensing the NCE for the rights to Japan and China separate from the US and European development rights., 2) extracting a better market value and milestone payments for the NCE for a global pharmaceutical company which wants to develop the compound in Asia as well as in Europe and the US.
WCCT Experience in Bridging
WCCT is uniquely situated in Southern California which is home to diverse populations such as Asian Americans, hispanics, and African Americans.
WCCT has conducted over 50 Asian ethnobridging / Japanese bridging/ Chinese bridging trials in the last 5 years. In an interesting WCCT case study, a sponsor conducted a 120 volunteer study with 5 key endpoints: SAD, MAD, food effect, ethnobridging comparison, and monitoring of the primary pharmacodynamic endpoint (platelet aggregation). Such a study was a pivotal part of the development plan for allowing the program to include Japan and the rest of Asia in the global phase III program.
In one of the largest Asian ethnobridging studies ever, WCCT, as a single site, recruited 26 Japanese, 26 Caucasian, 26 Asian Indian, 26 Korean, 26 Chinese, 26 Filipino, and 26 Vietnamese volunteers for a rosuvastatin study. This study, along with other data generated, resulted in a label change for rosuvastatin stating that Asians, but not Asian Indians, needed to be given half the dose as compared to Caucasians.
For sponsors who are interested in increasing the value of their NCE asset, WCCT can contract and draft a complete phase I program development that incorporates bridging into their program. In terms of innovative study design, it is not uncommon to add small cohorts of Korean or Chinese subjects in addition to Japanese subjects to an ethnobridging trial depending on the company goals for the compound.
WCCT Global Ethnobridging Video Series