Asia currently represents some of the fastest growing markets for pharmaceuticals. Accessible patient populations, coupled with a strong and growing infrastructure for quality conduct of clinical research, make Asia very attractive for inclusion in global development programs. However, an absence of meaningful harmonisation in the regulatory environment, especially with regard to the requirements, processes and timelines for approval of clinical trials, continues to present a challenge. In this article, the reasons for and potential strategies to overcome these challenges are discussed.
The last decade has seen a significant increase in the number of global clinical trials being conducted in Asia. In China and India, the number of new global studies approved rose from less than 20 in each country in 2004 to more than 200 in India and to more than 300 in China in 2008 . This growth is due to a number of factors which have aligned to make Asia an attractive region for global clinical development.
Perhaps the most significant factor is population size. The populations of the countries in Asia represent a huge patient pool, much of which is located in urban areas and close to sites and investigators involved in global studies. The combined population of China and India alone is equivalent to over one-third of the total global population. Asian patient populations are generally quite motivated to participate in clinical studies, and levels of patient compliance are usually high. Healthcare delivery systems in Asia, and particularly in China, are characterised by very large hospitals, where a single site or investigator may have access to a large patient population, making patient recruitment more efficient once the right sites have been selected. Many patients are treatment-naïve, enhancing the likelihood of meeting inclusion criteria.
In terms of therapeutic indications, while Asia will continue to be an important region for the development of products for infectious diseases and endemic tropical conditions, its contribution to more ‘Western’ conditions has steadily increased. The proportion of study sites in Asia in 2008 for oncology (19.6 per cent), cardiology (14.9 per cent) and psychiatry (12.7 per cent) were higher than the overall global proportions, demonstrating that Asia has now firmly cemented its place in the global clinical development landscape for such indications.
With respect to investigators, many Asia-based physicians have been trained in Europe or the United States. English is widely used at the professional level, and investigator participation is usually driven by interest in research in the disease area, with investigator fees often being ploughed back into local research activities. Additionally, many investigators in Asia are also considered global opinion leaders in their fields, making their regular involvement in clinical development essential.
Asia also offers some cost efficiencies; a higher patient recruitment rate per site can translate into lower study management overhead. Shorter recruitment time frames can keep operating costs under control.
Finally, with economies booming in many countries in Asia, getting drugs to Asian markets is another key factor in the appeal of Asia for clinical development.
Along with this rapid growth in clinical studies in the past decade came a need for local regulatory authorities to quickly bring their processes and guidelines up to date and in alignment with the changing clinical trial environment, to ensure medical needs are met, healthy growth of the local pharmaceutical industry and, above all, patient safety. While some countries, such as Japan and Australia, already had mature regulations in place, the majority of countries in the region have had to play catch up.
The evolving regulatory environment in Asia plays an important role in the decision to include countries from the region in clinical development programs. Although there is no formal regulatory harmonisation between the requirements of the different countries in terms of process, requirements and timelines for clinical trial approvals, there is a certain element of convergence as the various regulatory authorities have, over the last decade, absorbed information and intelligence and ideas from other regulatory authorities in the region and the more well-established agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This has led to a certain degree of convergence as regulatory authorities try to find a common approach to regulatory pathways and principles while implementing local regulatory changes in a way that is compatible with local resources and environments.
The most challenging aspect of Asia’s regulatory environment is the development and execution of strategies that will most effectively address new drug registration regulations that require inclusion of a local or regional population in a clinical study if the desired outcome is local market approval. This is a key requirement in China, Korea, India, Japan and Taiwan. A development plan that can cover the unique needs of these countries in a timely and efficient manner is an important consideration in planning Phase III studies in Asia. Strategies are often a balance between the global priorities for a new product against specific clinical, regulatory and commercial needs in Asia. The earliest possible discussion of and agreement on an Asia Pacific strategy is therefore key as it allows for optimal inclusion within a global development programme.
Agreement on an over-arching strategy requires the in-depth commitment and contribution of experts in clinical development, regulatory affairs and commercialisation. However, it is often the case that resources, both financial and operational, prove to be constraining factors. A compromise usually has to be worked out to ensure that such plans dovetail with the global development and regulatory strategies.
Operationally, a number of areas can be identified for focus in order to overcome challenges and ensure optimisation of regulatory performance.
Early planning and decision-making is critical in order to determine the most effective overall strategy, including country selection. This will ensure that the appropriate personnel are assigned to build an Asia regulatory strategy that takes into account key macro-factors, including:
Sufficient patients allocated to meet regulatory requirements and expectations
Appropriate recruitment windows for the different countries, taking into account regulatory lead times
Epidemiology and prevalence and perceived seriousness of disease in Asia, which can impact the clinical trial submission and approval strategy
Local comparator drug regulations (e.g., in China, comparator drugs must be approved and available)
Perceived ethnosensitivity – clinical relevance of observed differences in Asian populations compared to those of other populations globally
Protocol design, including dose selection (compared to “global” dose), relevance of comparators and endpoints
Future acceptance of data for USA, EU and other regulatory submissions.
Once countries, target numbers of patients, and an overall project plan have been determined, the regulatory-specific planning and actions need to be developed and executed. Regulatory professionals have to be able to build a plan that manages a number of countries with different requirements, timelines and processes, yet they should deliver appropriate regulatory approvals to meet the scheduled study start up times. In addition, as most of the countries in Asia are actively working on strengthening and improving their guidelines and infrastructure, sometimes with limited resources, there are regular changes to requirements, processes and timelines, not all of which are proactively communicated.
It is important for the regulatory manager of any project to ensure the project team is aware of the likelihood of changes that may take place in the middle of the project.
Absolutely critical to success in the regulatory management of a clinical study in Asia is quality, up-to-date regulatory knowledge and experience with the local regulatory environment and requirements. In this respect, there is no substitute for having personnel on the ground dedicated to the planning, preparation, submission and approval of clinical trial applications.
In addition, these team members may also be responsible for the required ethics committee approvals. If not, they should at least be very closely aligned with those responsible for these tasks as there are usually strong process, documentation and timeline links between ethics committee and regulatory authority approvals. Much efficiency can be realised through close coordination of these two key activities.
Local regulatory personnel should also be familiar with the key personnel at local regulatory authorities to ensure they can easily check on the latest processes and perspectives within the agencies, as well as to be able to effectively manage any queries or delays. In some countries, for specific studies, the opportunity may be taken to have formal or informal pre-submission meetings with the regulatory authority. The local regulatory personnel should be very familiar with standard practice in this area and be able to effectively organise and coordinate such meetings if needed.
Not every pharmaceutical company will have experienced local staff in all Asian countries, and it may be necessary to use regulatory resources of contract research organisations (CROs) or other third-party providers. Such parties can have experience with a large number and broad range of regulatory applications and can add significant value to the planning and application process.
The benefits of quality execution of regulatory strategy by experienced, local regulatory personnel can only be fully realised if they are effectively integrated into an overall regulatory structure, allowing the local execution to dovetail with the global regulatory strategy. The most effective way to ensure this strategy is by appointing a global regulatory lead for each project who ensures the following:
Effective planning – a comprehensive global regulatory plan, with specific timelines for each key activity by country
A comprehensive inventory of all required documentation for regulatory submissions. Ideally this should have already have been assimilated during the planning phase so that the generation (and required translations) of these documents do not cause unnecessary delays
A seamless relationship and communication link between all regulatory players. This is best achieved through regular progress reports as well as scheduled meetings to ensure close tracking against a project plan
Effective liaison between the regulatory group and other key stakeholders of a drug development program to ensure full alignment and understanding of strategy and outcomes
Flexibility in adjusting a development plan and related actions as a project progresses. Changes are almost inevitable in every project, so the ability of the regulatory lead and local regulatory resources to create and deliver alternative plans according to changing priorities is an important asset to any project. This may also involve the innovative and proactive management of resources and budget in line with project constraints
A special focus on China and its regulatory processes, timelines and requirements, including patient numbers for subsequent drug registrations which have their own unique challenges. Capable and experienced regulatory resources on-the-ground in China is absolutely essential, especially as more change is expected in this area in the next few years.
Finally as with all regulatory activities, there is usually no such thing as a quick fix or loophole to deliver any regulatory outcome in a way that is not in line with the regulations and practices of local authorities. There is no substitute for strong local knowledge, good teamwork, careful planning and effective delivery.
Any interaction with regulatory authorities should be carried out with integrity, openness and transparency. Such values will add considerably to the long term development of relationships between pharmaceutical companies, their representatives and regulatory authorities and will help render any regulatory barrier into a much more manageable challenge.