Abstract
Abstract:
Although modern clinical trials are traditionally conducted in Western countries, currently there is a shift to involve developing countries, particularly China and India. For these trials, the large population size of India and China means that substantial numbers of individuals affected by rare diseases may be found, increasing the likelihood of successfully completing enrollment in a clinical trial. Furthermore, the increasing involvement of Asian countries in global clinical trials is likely to lead to greater appreciation of the value of evidence-based treatment decisions in the region. These sites are more cost-effective, although this advantage is being eroded over time. Asian participants in clinical trials are also typically more likely to complete study follow-up and procedures, and to adhere to their randomized treatment allocation than individuals from Western countries. Challenges include relevance of the proposed trial to the region, capacity limitations because of undeveloped training, and ensuring research implementation quality and different intellectual property practices. There are specific challenges to conducting clinical trials in India, such as the status of ethics committees, health insurance and coverage for participants, and variability in languages and record-keeping. Challenges in both countries are substantial but are able to be managed with appropriate planning.
It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us, we were all going direct to heaven, we were all going direct the other way—in short, the period was so far like the present period, that some of its noisiest authorities insisted on its being received, for good or for evil, in the superlative degree of comparison only. (Charles Dickens, A Tale of Two Cities)
Modern clinical trials are highly complex and tightly regulated affairs that are continuously evolving. While trials have traditionally been conducted completely or mainly in Western countries (e.g., North America and Western Europe), a range of circumstances are causing more trials to involve developing countries, with a particular focus on China and India.
Paralleling the quote from Dickens above, conducting clinical trials in China and India may be great or terrible, straightforward or incredibly difficult, and at times, all of these concurrently. While these countries offer great promise in overcoming some of the major challenges in contemporary clinical trials, a range of equally important challenges must be considered to ensure optimal trial conduct. A clear understanding of these issues can help to avoid problems and maximize the likelihood of successful trial completion. We review some of the major developments and issues for clinical trials in China and India.
Capacity
The Asian region is home to approximately half of the world population, and two-thirds of the people in Asia live in either China or India. As a result, trials requiring large numbers of participants, who may be difficult to recruit in a timely fashion from traditional countries, are increasingly looking to Asia in general, and China and India specifically, to contribute a substantial proportion of the total study population. While most individuals in these countries have not necessarily had access to high-quality, Western-style health care in the past, both countries are in the midst of an unprecedented socioeconomic transition. Vast numbers of citizens have joined a burgeoning middle class, enjoying the type of lifestyle traditionally taken for granted in the West and including good access to high-quality health care. Although many poor areas persist, particularly in rural regions distant from the main cities, the total size of the population means that changes affecting even a few percent of the population represent tens of millions of people. As a result, hundreds of millions of individuals in both China and India now have access to and expect high-quality health care that matches or even exceeds that available in many countries more traditionally involved in clinical trials. It appears likely that these changes will continue, and perhaps even gain pace, in the coming years. The likelihood of identifying large numbers of participants who are receiving high-quality health care and could potentially participate in local or international clinical trials is, therefore, very high in China and India.
Some types of trauma are more common in Asia. Over 300,000 people are injured each year, and accidents and injury cause approximately 10% of all deaths in India1. In addition, the distribution of many diseases may also be different than in other regions. These factors help with the recruitment of people with rare conditions for clinical trials. The large population size of India and China means that substantial numbers of individuals affected by rare diseases may increase the likelihood of successfully completing enrollment.
More importantly, the increasing involvement of Asian countries in global clinical trials is likely to lead to greater appreciation of the value of evidence-based treatment decisions in the region. Most trials conducted in China and India are currently initiated elsewhere, and they involve participation from centers in these countries in an effort to address health issues that are relevant internationally2. A relatively small proportion of trials are currently initiated in China or India, so comparatively little evidence is being generated to address specific local needs. With the additional development of clinical trials experience and capacity, as well as growth in local funding availability, it is hoped that this discrepancy will be corrected in the future. This should be facilitated further by the growing interest in Asia exhibited by large pharmaceutical companies that remain the biggest funders of major clinical trials globally2. Investment in Asian research facilities to initiate and support clinical trial activity has grown substantially over recent years, and this trend appears to be accelerating. Therefore, the contribution of Asian countries to global clinical trials should continue to grow.
Cost
While the Asian region is undergoing broad and deep socioeconomic changes, salaries remain much lower than in Western countries. The availability of large numbers of tertiary qualified workers and the relatively low cost base in the region means that trials can be conducted at a cost that is half or less of the cost in Europe and North America. As a result, the costs of running trials at individual sites, of monitoring and supporting these sites, and of the logistics involved in clinical trials may be greatly reduced compared with other countries3. This is true for both China and India, as well as many other countries in the region, and has been a strong driver for the increased number of clinical trials being undertaken in Asia. This is of particular interest for many of the large, long-term international trials in which total costs may run into the several hundreds of millions of dollars.
The cost advantage of Asian countries is being eroded by a range of factors. Rapid economic growth and inflation are driving up consumer prices and workers’ wages. The large and growing number of trials being conducted in this region has led to strong competition for the still modest number of experienced research sites and clinical trials staff. This is particularly an issue in China, where the regulatory body (the Sino Food and Drug Administration [SFDA]) approves sites for participation in international clinical trials. At any particular time, there are typically 200 to 300 sites that are approved in China across a range of specialties, while some disease conditions might have dozens of trials that are seeking sites for participation. This is putting pressure on available sites, and costs are rising as a result. Competition for qualified and experienced study sites is also an issue in India and other parts of Asia, and it is likely that the cost advantage will be further eroded going forward.
Adherence
Participants in clinical trials in Asia are typically more likely to complete study follow-up and procedures, and to adhere to their randomized treatment allocation than individuals from Western countries. Clinical trials involving long periods of treatment and follow-up (e.g., those that run several years examining effects on outcomes that occur infrequently) may benefit greatly from this trait. As seen in the recent ADVANCE trial, participants from Asia commonly persist with randomized therapy in over 90% of cases, compared with 60% to 70% in Western countries4. Since the effects of most agents occur only while the participant is exposed to them, differences in this magnitude may have substantial implications for the detectable effect size and, therefore, the power of a trial. While few trials have reported the effects on participants in Asia separately, a greater effect has been identified in those that have. In both the PROGRESS5 and RENAAL6 trials, the benefits of lowering blood pressure on stroke and kidney disease, respectively, were greater in the participants from Asian countries than in those from other regions (Fig. 1).
At the same time, it should be noted that many sites in these countries have less research experience than their Western counterparts and thus may require more support and guidance. This is particularly important because sites in Asia typically recruit more participants per site to clinical trials, further compounding the need for greater assistance from the coordinating group.
Logistics
While coordinating the management of samples, therapies, and data has previously been a major challenge for the successful completion of trials in India and China, modern trial methodologies (e.g., electronic data capture) and the professionalization of trial support functions (e.g., drug management and laboratories), as well as general improvements in transport and communications, have helped to combat the challenge. The leading role of India in information technology and of China in electronics manufacturing has helped accelerate these developments.
Relevance
As a result of the advantages outlined above, many global trials are now looking to China and/or India to facilitate recruitment of the required number of participants at a lower cost. This is perfectly appropriate when the trial addresses a locally important condition and offers a treatment that will be available to the local populace if the trial results are positive. When these conditions are not met (e.g., when a pharmaceutical company does not plan to market an agent in one of these countries) or when there is uncertainty, it may not be appropriate to involve participants from these regions. This is a very sensitive issue in India where sensationalized media stories describing trial participants as guinea pigs and accusing local doctors of colluding with foreign pharmaceutical companies for their own benefit have been widely reported. As the economies of China and India evolve and both become major consumers of health care services at a global level as well as the focus of clinical trials, this issue is likely to become less of a problem. In the meantime, the local relevance of any proposed trial must be carefully considered.
Capacity
While the number of potential participants in China and India is extremely large, the capacity to enroll them into clinical trials as well as to manage and oversee their participation is growing more slowly. While there is a great interest in clinical trials in both countries, training opportunities are still developing. Additionally, the number of experienced research management staff is limited, leading to huge competition for their services among pharmaceutical companies, contract research organizations, and academic research organizations. As well as contributing to substantial pressure on salaries and therefore costs, staff turnover may be higher in these countries than in others, creating challenges with the continuity of the study. Individuals involved in the support and oversight of clinical trials in these countries may also be less experienced than those in countries with more mature research infrastructure, highlighting the importance of having good support systems, processes, quality oversight, and training. For example, most medical schools in India lack a formal course in training for clinical research, so investigators have relied on mentors to learn how to conduct clinical trials, and there is a shortage of trained personnel. India is estimated to have about 500 to 1000 investigators in the country, as compared with the United States, which has 50,000 investigators3. Training from accredited organizations would play a major role in increasing the number of trained personnel in India. Specific strategies to improve retention of experienced staff are important for organizations planning to invest in managing clinical trials in China and India.
Ensuring Research Implementation Quality
Although the situation is changing rapidly as more research moves to these countries, many sites in China and India are at a relatively early stage of development with regard to their clinical trial experience, so their understanding of key aspects of clinical trial processes may also be evolving. Many potential investigators lack knowledge of regulations, ethics, and good clinical practice, as well as skills for clinical trial management. The level of experience in global and local clinical research is not uniform. This is particularly the case outside the major cities in both countries, and highlights the importance of having strong trial management and support structures. Specific issues may also pose challenges (e.g., outpatients at many hospitals in China own and take home their medical records, making reconciliation of source data and confirmation of trial results challenging unless specific strategies to deal with this issue have been developed in advance). Similarly, because many trial participants in both countries may have little or no literacy skills, ensuring that they are adequately informed before being enrolled in clinical trials requires particular attention.
Additionally, the regulatory bodies are evolving in both countries with support from the U.S. Food and Drug Administration and other regulatory bodies around the world. This has an impact on timelines, particularly in China where it commonly takes twelve months or more to obtain regulatory approval for trials of new agents.
Both India and China have had a relatively relaxed approach to the protection of intellectual property in the past, leading to concerns that running trials in these countries may simply allow local manufacturers to reverse-engineer and copy products more easily. This situation is changing as both countries move to approaches that provide better patent protection, but many companies with headquarters in Western countries remain concerned about this problem, leading to reluctance to include these countries in trials.
India is one of the world's fastest-growing clinical research destinations. The number of registered international clinical trials that include India have increased by 30% each year for the past three consecutive years for many of the reasons outlined above2,3. Furthermore, India's hospital-based and urban-centric health care system allows for its clinical trial sites to be among the most productive in the world. India has vast numbers of hospitals and over 200 medical colleges, many with state-of-the-art facilities. The investigators are typically well trained and experienced, and excellent English-language skills are the rule. This is also true for other site-based staff such as coordinators and pharmacists3.
The regulatory situation in India continues to evolve, and the regulatory bodies have accepted the principles of the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines for clinical trials, as well as related guidelines for other aspects of research. While gaining approval for studies is still slower than in other countries, a range of initiatives has helped speed up regulatory processes. Differences in timelines persist depending on the nature of the study and which countries have been approved for studies at the time of regulatory submission in India. The status of ethics committees in India is more variable. A number of high-quality ethical review committees have been established, but many others are rudimentary and may not be of the standard expected in other countries.
A range of other challenges exists in India. These include uncertainty about health insurance status and coverage for participants in clinical trials (currently being addressed by the government), the large number of languages spoken in different parts of the country, variability in approaches to medical record-keeping, the protection of privacy and confidentiality, and other factors that require specific management strategies to ensure a successful outcome.
Fortunately, India's government appears to be taking the importance of clinical trials seriously and has several initiatives under way aiming to facilitate future clinical research in the country.
As the Chinese economy grows and its residents’ lifestyles change accordingly, the spectrum of disease is increasingly transforming toward that of developed countries. The government has realized this and is investing more resources in health care, creating a greater need for high-quality clinical studies to guide this investment. A number of positive signs are emerging. For example, the Ministry of Public Health has announced that a unified electronic medical record system will be fully implemented in the next decade, allowing health care providers to view the entire medical history of patients at different hospitals. This is likely to substantially improve the opportunities for clinical trials in China.
The challenges in China are substantial but are able to be managed with appropriate planning. Expertise in English-language skills remains variable but is improving rapidly. A cautious approach by Chinese regulatory authorities (the SFDA) means that the review/approval time frame for clinical trials of new medicines is lengthy, often more than twelve months. The currently limited number of SFDA-accredited sites is a bottleneck for recruitment to trials in China. Similarly, the approach to the management of medical records in this country can make collecting and reviewing adequate source documents difficult, requiring more resources than in other countries. Like India, ethics committees are often less experienced than their counterparts in Western Europe and North America. Finally, ensuring adequate investigator time at sites, especially in a health care system that places large demands on staff who are managed like governmental employees, can often be difficult.
With their vast populations and emerging status, both China and India have the opportunity to become global leaders in clinical trials over the coming years and decades, and to generate evidence that is relevant to their own populations, those of other countries in the region, and globally. It is likely that the number of local and global trials being run in these countries will continue to grow exponentially in the foreseeable future, limited mainly by the finite numbers of trained individuals. The challenges of running trials in these countries remain substantial, but they are gradually being overcome. As a result, the importance of the participation of China and India in clinical trials is likely to grow.
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