Pharmaceutical studies must take into account cultural differences, as well as regulations that require the use of clinical data from native populations. Stanford Jhee reports
Financial and competitive pressures mean that multinational pharmaceutical companies are constantly looking for ways to make the drug development process more effective and efficient.
The same pressures are inducing them to expand their efforts into wider international markets. According to IMS , Asia has the world’s highest rate of pharmaceutical sales growth, rising at an average annual rate of 15% between 2007 and 2012. Naturally, this is contributing to a shift in industry focus from Europe to Asia.
Japan is currently the world’s second largest pharmaceutical market, and is growing at a faster rate than the EU. Despite this, if projections by IMS hold true, China will overtake Japan by 2017 (currently it’s third after the US and Japan).
Similarly, it’s been suggested that clinical research in China for global drug development is increasing at an annual pace of 25%, in South Korea that figure’s even higher at 30%. Such rapid growth presents new opportunities and challenges for pharmaceutical organisations.
Sponsors of pharmaceutical studies must take into account cultural differences, as well as regulations that require the use of clinical data from native populations. The time required to navigate regulatory environments can cause delays costing billions of pounds in potential lost sales.
Some of the aforementioned opportunities have come about as a result of changes in the Chinese, Taiwanese, Japanese and South Korean regulatory environments, which now allow for biopharmaceutical companies to incorporate Asian countries into the early stages of drug development programmes and speed up product introduction into these growing markets. Via ‘ethnobridging’, companies developing drugs in Europe can collect and analyse data from native Asians living in other countries to employ cost-effective, multi-ethnic approaches to clinical trial programmes.
While regulatory changes have made ethnobridging more practical, the concept isn’t a new one. In 1998, the International Conference on Harmonisation (ICH) published guidance (E5) entitled ‘Ethnic Factors in the Acceptability of Foreign Clinical Data’. The guidelines recommended regulatory and development strategies on the use of clinical data collected in one region to support drug and biologic registrations in another, a condition being that ethnic factors were addressed using bridging studies.
The E5 guidelines facilitated drug and biologic registration among ICH regions by recommending a framework for evaluating the result of ethnic factors on a drug’s effectiveness and safety. Recommended regulatory and development strategies would allow for sufficient evaluation of the impact of ethnic factors, reduce clinical study duplication and accelerate the drug approval process.
At the time, the difficulties involved in sending clinical data to Japan were noted. While pharmaceutical organisations could make use of data generated in the West, they would still need to supply bridging or comparative studies between Japanese and Caucasian trial patients. The premise of this was sound; however, collecting data on Caucasian participants in Japan proved near-impossible due to the ethnic makeup of Japan and the pharmaceutical industry’s limited success with initial bridging pharmacokinetic (PK) studies. As a result of this, the Japanese Ministry of Health and Welfare was engaged to discuss how companies could go about conducting studies outside of Japan with Japanese natives.
By 2005, interest in performing global trials that involved Asian countries at an early stage had increased considerably. At this time, European, Japanese and US pharmaceutical companies began designing trials, starting in Phase I, which included Asian countries.
In 2007, Japan, Korea and China began to cooperate on clinical development issues. Regulatory authorities in Japan led this effort and started accepting Phase II/III and efficacy data from other Asian countries in lieu of Japan-only data as long as pharmacokinetics were the same between Japanese and Chinese and/or Koreans.
Regulatory authorities in China began to request ethnic Chinese data for global trial participation. While the Chinese Food and Drug Administration (CFDA) has always required Chinese PK data for product registration in the country, it has not always required Chinese Phase 1 data for global trials participation. This has begun to change as regulatory bodies in China follow the Japanese example and ask for Chinese PK data to enjoin global trials.
Speeding drug development
Studies involving ethnobridging must meet strict ‘bridging’ criteria if they are to be accepted by Japan’s and China’s regulatory authorities, as must the volunteers that take part in them. Rules state that all volunteers should be natives of the country and cannot have lived outside of their homeland for more than five-to-10 years at the time of the participation. Factors including lifestyles and a participant’s diet should also be considered.
Additionally, other health-related factors cannot have changed significantly since relocating. Such stringent requirements mean that volunteers are usually found in areas with large Asian communities, like London, where they are more likely to have upheld their native lifestyles.
Through the early evaluation of efficacy, safety, dosage and dosing regimen ethnobridging can significantly reduce the cost of drug development and accelerate the speed at which the Phase I process can be completed; expenditure can be reduced by as much as 30 to 40%. In Japan specifically, a bridging study is used to cut time from the four or five additional years it takes to complete local studies (compared with those in the West) – a challenge known as ‘drug-lag’. One given example of this comes from the PMDA (the Japanese regulatory agency) which showed a new drug approval taking just 32 months when employing a Japanese bridging strategy, compared to 56 when not.
Key considerations
There are several key challenges to consider when deciding whether to develop products for Asian markets outside of those territories. Not only will pharmaceutical companies have to negotiate complex regulatory issues, they must also bear in mind the tight timeframe of trials and the possibility that ethnic variability will impact the safety and efficacy of medicines.
Before starting an ethnobridging study there are a number of questions to ask: is initial development in the EU? Will Phase II or Phase III global trials include China, Japan or South Korea? Or, will the next trial conducted by the pharmaceutical company or clinical research organisation involve China, Japan or South Korea? The answers to these questions will determine the strategic design of the Phase I programme. Perhaps only Japan will be considered for Phase II, and the Phase I programme will be limited to adding Japanese subjects.
A strategic approach would include a Japanese, Korean and Chinese subject in Phase I, establishing a more solid and diverse foundation that allows for true global development. A scientific understanding of potential ethnic differences, especially pharmacokinetics, and satisfying the Phase I regulatory requirement with authorities will help set a sound stage for further global development.
The governments of China, Japan and South Korea, and of course, their pharmaceutical industries, have a vested interest in accelerating and growing the marketing of novel therapeutics. While regulatory requirements are evolving it will be those companies that recognise how to make use of ex-Asian populations in their global development strategy that gain the best advantage.
One important success factor is involving Asian subjects as early in the development process as possible. By introducing them in Phase I, it becomes possible to detect ethnic differences early on compared to Western subjects. For example, differences in PK related to absorption, tolerability or drug metabolism. The advantage is realised when companies are able to plan early for later phase studies; the later the inclusion of Asian subjects, the more money that could be lost as a result of unforeseen, late-stage modifications. Knowing this vital information can add value to the compound being considered and might even draw co-development and licensing opportunities.
Others factors that influence success include:
* Establishing a broad ethnic base of data and creating studies that can bridge data between countries and regions;
* Performing PK, PD and other Phase I testing with multiple populations as early as possible to reduce ethnicity-based safety risks;
* Working with Asian regulators to ensure study designs, protocols, analytical methods and bridging strategies meet their individual requirements;
* Ensuring all participating nations and institutions conduct trials under Good Clinical Practices regulations as defined by ICH.
The Future
The Asian pharmaceutical industry is growing and changing rapidly. As the regulatory environment also evolves, the broader industry will find itself challenged to find and employ the right resources and best practices. While coping with this, sponsors must also consider the differences that continue to characterise the different drug approval process in each region.
Taking the right approach, it is possible for global pharmaceutical companies to gather a percentage of clinical data from ethnic-Asians living outside of their native homelands, and, in doing so, speed up drug development. Pharmaceutical businesses that make the most of ethnobridging practices will not only save time and money, but will also maximise the value of their products thereby gaining competitive advantage.
Stanford Jhee, Pharm D, is a Vice President of Scientific Affairs, Early Phase, at PAREXEL International.
