This article focusses on how to leverage the regional strengths of key Asia-Pacific countries such as China and Japan in clinical trials, while at the same time proactively ensuring consistency and quality.
The historical approach to clinical drug development, and one that served drug companies well for the past thirty years, was to initiate testing in humans at clinical research units, typically located in the UK and the US and to proceed further to Phase II testing and beyond to patients with clinical evidence of the disease with investigators mostly located in the US, Canada and Western European countries.
An increasingly intense competitive environment and the shrinking pools of treatment populations in the traditional North American and Western European markets, however, have led sponsors and CROs to ‘discover’ emerging markets to source high quality research and secure timely enrollment of patients. This article focusses on two of the most dynamic emerging markets, both Asian: China and Japan.
The advantages of being in China for an international CRO
The importance of China to get miracles to market is absolutely indisputable. China represents the fourth biggest economy on the planet and its own drug market is growing at a pace that is enviable to any western market, at 28 per cent CAGR. Presence of regional affiliates of global CROs in important locations such as Beijing and Shanghai makes it possible for global pharmaceutical companies to offer easy access to leverage the tremendous potential of this key Asian market. They can also help pharmaceutical companies to extend their reach into a large and important source of patients, investigators and sites. With good local understanding, experienced monitoring, project management and other staff, including regulatory experts, it can provide seamless support to sponsors with regards to high quality clinical development services or assistance with regional registration.
Naturally, not only international CROs but also international pharmaceutical companies have discovered’ China as their destination. This, in fact, is a benefit to the CROs. The increasing footprint of a growing number of global pharmaceutical companies in China is vital and has an unequivocal benefit in that it helps escalate the understanding and adoption of fundamental international clinical trial requirements such as ICH and GCP amongst an ever increasing number of investigators and sites. Equally, the commitment by sponsors to engage China first-hand opens up even more opportunities for CROs to work with global sponsors and their local affiliate offices to provide global, regional and local clinical development services.
The Chinese regulatory environment
The Chinese regulatory environment is highly dynamic and is maintaining open lines of communication which is absolutely crucial to ensure success. Acknowledging the paramount importance of local regulatory understanding, it is important to build a strong, local team of Chinese regulatory experts who understand the current requirements and work with the clients to understand their needs. Similarly, sponsors and CROs alike need to invest considerable time and effort to understand the evolving Chinese regulatory requirements.
Challenges in clinical development
The demand for access to patients and high-quality clinical development delivered on time and to budget, is rapidly increasing. This growth in demand is pushing the limits of local supply, meaning it can be a challenge to staff up as quickly as required. However, it is recommended to always put quality first. It is not good enough to just have the footprint and the access. The CROs and sponsors need clear assurance that they are working with qualified investigators who are capable of conducting global trials. They also need to be assured that sites and trial results stand up to any regulatory scrutiny. Insisting on quality like this of course raises the bar even further. However, it is noted that by systematically demonstrating dedication to proactive, transparent site interaction and by helping investigators develop, it is possible to attract a steady supply of highly motivated investigators and sites.
Short- and long-term goals
Many international companies have long recognised China’s potential as a source of patients for clinical trials and as a growing market for new medicines. Investment in internal infrastructure in China is set to continue, to meet the increasing needs of current and future clients. Specifically, the investment includes significantly increasing monitoring capabilities, growing in-country project management and expanding regulatory capabilities. Basically, both short and long-term strategies are centered on the key capabilities to help clients effectively leverage China for high-quality clinical development.
A Closed Country No more
Two overriding trends drive the majority of events influencing the clinical research potential in Japan. First, Japan has taken a number of steps to make it easier to include the country in global trials. Second, Japan is encouraging its own drug companies to reach out to neighbouring Asian countries such as South Korea and China, to help make the clinical trial process more effective and efficient.
These developments bode well both for Japan and the region at large. This being said, certain regulations and restrictions in Japan (e.g. limiting the length of time a CRA is permitted to spend at an investigative site) appear more burdensome than those in other countries. This means trial conduct can be very costly in Japan, even in comparison to traditional markets such as the US and Western Europe, as well as the emerging markets across the globe. Even today, efficient trial management faces an additional set of hurdles in Japan—hurdles not found in other countries looking to claim a stake in global clinical trials.
More international clinical trials
In the not too distant past, Japan would have rarely come up for inclusion into clinical trials, considering past hurdles to trial conduct. This picture is changing fast, however Japan still requires very careful consideration, for instance, with regards to cost impact and start-up and enrollment timelines. To overcome frustrations and disappointments in future, a very clear analysis of benefits versus challenges needs to be done before including Japan into trials.
Covance has run clinical trials where Japan was included on the same timeline as all other countries in the trial, and indeed Japan did not ‘finish last’—the sites in Japan performed along standard expectations. This type of solid, predictable performance will help draw more trials to Japan which, in turn, helps Japanese investigators and research staff build more experience—it’s a positive spiral.
The obstacles to simultaneous drug development
The obstacles to simultaneous drug development in Japan are well known. Interestingly, the Japanese Ministry of Health, Labour and Welfare has signalled that the so-called bridging studies are at best a tactical solution to a strategic problem and at worst have helped delay the necessary globalisation of Japanese trials. Instead, the long-term focus is on reaching out to countries such as China and South Korea for sharing clinical data as the populations of these countries are considered sufficiently close to the native Japanese population. Also of note is that Japan plans to network their major clinical trial sites into ‘hubs’ and nodes—this is a five-year plan which started in 2007, to promote better coordination, efficiencies and sharing of experience. These initiatives amongst others will help Japanese investigators and research staff build more experience and help close gaps versus the global market.
Local Japanese CROs increasingly contribute to global trials and this exposure has helped the CRO industry in Japan mature. To grow internationally, the Japanese CROs will likely need to engage in strategic transactions with other CROs or grow organically by establishing a presence in key markets. As the Japanese CRO industry enters this phase, a new set of challenges will present itself—similar ones that CROs face elsewhere, and it will be interesting to see the developments as the Japanese CRO industry matures further.
It’s crucial to keep in mind that Japan is an established, experienced market when it comes to clinical trials, ICH and GCP. In Japan, the clinical trial industry does not start from a small or less developed base—rather, the task at hand is to finally start leveraging the established strengths resident in what is in fact the world’s second largest pharmaceutical market. These strengths have not historically been easily accessible, just as circumstances have not permitted for the industry to effectively and efficiently leverage them.
The composition of markets that contribute to international clinical trials clearly has changed and will continue to change. One requirement of clinical trials will, however, be emphasised consistently: the focus on quality in clinical trials. Here, quality is defined in terms of trial design, the validity of the results, the protection of subject rights and well-being, and of course regulatory compliance. Most of outsourcing’s focus is on time, cost and scope, but a major challenge is in the quality of the process and the major deliverables. Though it must be conceded that many current practices were reactively triggered in response to quality problems, the future will require that quality management be more proactively and comprehensively integrated into study planning and execution regardless of where the trial takes place.
When performing trials in markets such as China and Japan, the number of potential pitfalls, site idiosyncrasies and country-specific regulatory, ethical and administrative requirements increases exponentially. Any challenges which plagued trial performance in ‘traditional’ western markets previously tend to multiply, and no single adjustment can be counted on to remedy those challenges.
Instead, an integrative, quantitative, proactive trial management is required and it needs to be geared towards handling not only current day site performance variability, but also the variability in the underlying patient population which can dramatically impact trial outcomes, especially in the complex long-term studies that are increasingly common. A key component in successfully leveraging the potential of emerging markets is a proactive and predictive operational approach. The approach should focus more on risk prevention rather than remediation of investigator errors, and also deliver improved productivity, lower operational risk, and improved scientific robustness—not to mention increased investigator satisfaction.