Global acceptability of clinical data - fact or fiction?
By Carly Anderson and Faiz Kermani
CMR International
A challenge in running clinical trials is obtaining adequate representation from all the groups in society that may receive a potential new medicine. As a result, regulators may be placed in a difficult position regarding the approval of new drugs where the majority of the dossier comprises of foreign clinical data.
The pharmaceutical industry is also in a difficult position as trials grow in size and become more expensive to run. With companies devoting up to 40% of their R&D expenditure to clinical evaluation, companies cannot afford to run trials that will account for every foreign patient group that might receive a potential drug.
This has led to worries that patients in some countries will not gain access to certain drugs because regulatory authorities will be reluctant to approve them. Japan is often cited as an example in such cases. For example, of the 149 drugs approved in the USA between 1992 and 1996, 51 percent were not available to patients in Japan by 2000 (1).
Ethnic differences and their clinical impact
Although one of the aims of national regulatory authorities is to increase the availability of new drugs to patients in their country, they must constantly be aware of any potential risks to their populations. It has been suggested that ethnic factors may be extremely important if the margin of safety for a compound is small (2).
On the other hand it is unclear how ethnic factors in general correlate with the biological actions of drugs being tested. For example, a retrospective study conducted by the Japanese Ministry of Health and Welfare (MHW; now referred to as the Ministry of Health, Labour and Welfare [MHLW]) and the Japanese Pharmaceutical Manufacturing Association (JPMA) on 80 new chemical entities approved both in Japan and the West found that in Phase I data intra-ethnic differences were greater than inter-ethnic differences (2). Some have argued that the evaluation methods for clinical trials of medicinal products in Japan, the EU and the USA may be one of the reasons for the interethnic differences that are often reported (3).
The ICH E5 guideline
In an effort to try and address these issues the International Conference on Harmonization for Registration of Pharmaceuticals for Human Use (ICH) developed the guideline on "Ethnic Factors in the Acceptability of Foreign Clinical Data", known as the E5 guideline (4). The ICH E5 guideline was introduced in February 1998 and subsequently implemented by the regulatory authorities of the USA, EU and Japan.
The main aims of this guideline are to prevent unnecessary and redundant repetition of experiments and trials in order to bring drugs to market in different regions, whilst adequately evaluating the impact of ethnic factors on the efficacy and safety of drugs.
The ICH E5 guideline describes regulatory strategies that facilitate the acceptance of foreign clinical data in ICH regions. It also outlines the use of bridging studies, if necessary, to allow extrapolation of data and developmental strategies with regard to ethnic factor influence on the safety, efficacy and dosage of new drugs. An important point is that clinical trials must be conducted according to the same rigorous standards in all three ICH regions, thus facilitating the implementation of the ICH E5 principles (2, 4).
One benefit of the ICH E5 guideline has been to tighten the definitions of what constitutes an ethnic factor. Ethnic differences have now been formally divided into extrinsic factors and intrinsic influences (Table 1).
The ICH E5 guideline and Japan
There have been some major benefits for industry in the adoption of this guideline, particularly with respect to Japan. A survey of companies was conducted by CMR International in 1997, involving companies from the three ICH regions. This indicated that the ICH E5 guideline was expected to have positive effects in terms of reducing the number of patients required for trials conducted in Japan. Compared with the West, it is generally harder to recruit patients for trials in Japan. Therefore companies find it difficult to run large scale Japanese trials. Another benefit identified by the study was that the ICH E5 guideline would ultimately lead to a reduction in costs and development times for new drugs.
Until the introduction of the ICH E5 guideline, repeat clinical trials were a fact of life in drug development if a company wished to market a drug in more than one ICH region (4). For example, less than a year after the guideline was finalised Pfizer was able to apply it to great effect to gain approval of Viagra ® in Japan by use of a bridging study (a key part of the ICH E5 guideline), as opposed to repeat clinical trial(s) as would have been required previously (4).
Other companies have also used the guideline to good effect. In April 2000, AstraZeneca submitted a new drug application in Japan for its triptan migraine treatment Zomig (zolmitriptan) (6). It was the second Japanese new drug application to be submitted by AstraZeneca based on the importation of Western data using the E5 guideline. AstraZeneca is the first company to seek approval in Japan for a second generation triptan compound for migraine (6).
What effect is the ICH E5 guideline having?
Despite the benefits that the ICH E5 guideline can bring, companies have expressed concern that there has been a conservative interpretation of this guideline in Japan. As Japan is the second largest national pharmaceutical market, companies are eager to maintain a strong presence there. In light of the radical changes in the regulatory and clinical environments that have taken place in Japan over recent years, the implementation of the ICH E5 guideline is very relevant.
In addition, some non-ICH countries in the Asia-Pacific area have adopted elements of the ICH E5 guideline. There is a need to understand how this guideline has been interpreted and implemented in these non-ICH countries.
CMR International is currently conducting a study looking at these issues. The study is designed to assess the extent of the implementation of the ICH E5 guideline within pharmaceutical companies and its impact on their global development strategies;
In addition, it aims to gather information on companies' recent experiences with submissions containing information prepared using the ICH E5 guideline and to identify problems encountered.
Two survey questionnaires have been developed and are in the process of being completed. One questionnaire focuses on the ICH E5 guideline with respect to the ICH region, whereas the other focuses on the utilisation and acceptance of foreign clinical data in non-ICH Asian countries.
The results of the survey will form the basis of a report that will be sent electronically to all participants of the study.
It is hoped that this report will help identify where the problems and issues lie in using the ICH E5 guideline. In addition, it will enable an understanding of what companies are currently doing in this area and how they are employing the guideline recommendations.
The study will also be useful in developing "best practice" for the use of the ICH E5 guideline, and will feature case studies of how bridging studies have been used. It will also highlight areas where the ICH E5 guideline is still to be implemented.
If you would like to learn more about this study please contact Carly Anderson (canderson@cmr.org).
About the authors
Faiz Kermani is Project Leader at CMR International. He was previously a research analyst for a Danish healthcare company, Informedica a/s, where he worked on European and North American healthcare issues, including pharmaceutical pricing, reimbursement and parallel importation. He has a PhD in immunopharmacology from St. Thomas' Hospital London.
Carly Anderson is a Research Associate at CMR International working on regulatory affairs. She graduated from King's College London with a molecular biology degree and a special interest in genetics.
About CMR International
CMR International is an independent research organisation founded in 1981. Our work has contributed to increased productivity and efficiency in over 50 of the world's leading pharmaceutical companies. We work closely with our clients to identify key trends and strategic drivers within pharmaceutical R & D. Please visit our web site http://www.cmr.org.
References
- Taurel S (2000). Healthcare policy in the twenty-first century: The outlook for innovation. CMR International annual lecture http://www.cmr.org/pdfs/annuallecture.pdf
- Dumitriu H (1998). Impact of the ICH guideline on ethnic differences. Drug Information Journal 32: 141-144.
- Balant LP et al. (1995). Interethnic factors important for drug development and registration. Clin Res Regulat Affairs. 12 (1): 23-46.
- The Value & Benefits of ICH to Industry (2000). http://www.ifpma.org/pdfifpma/ValueBenefits.pdf
- ICH Topic E5. Ethnic factors in the acceptability of foreign clinical data. CPMP/ICH/289/95 The European Agency for the Evaluation of Medicinal Products.
- AstraZeneca files NDA for Zomig – potentially first oral triptan in Japan
http://www.astrazeneca.com/NewsSection/NewsReleases/press_release_066.html