As interest in Asia Pacific increases, CRO offshoring is beginning to make an impact in the region. Alan Davies and Janet Jones of Kendle International explore the various options.
Falling research and development productivity allied with the failure to bring new drugs to the market has resulted in declining financial performance for many pharmaceutical companies over the past five years. One driver to increase R&D productivity is to make better decisions on which potential drugs are commercially viable and which drugs could be out- licensed or withdrawn from development. A key component of this decision is the need to get patients into clinical trials quickly, efficiently and cost-effectively. Cutting one year from Phase II clinical trials would save an average of $71.4m from the total cost of a new drug, according to R&D Directions, April 2004. The same report also noted that the average clinical trial in the USA is delayed by 366 days. The relatively poor performance of US and Western European clinical trial sites in recruitment and retention of patients into trials has stimulated a vigorous examination of less traditional clinical trial countries in Central and Eastern Europe, Latin America, South Africa, India and Asia.
A second driver of outsourcing is consolidation of the CRO industry. The top ten public CROs have around 47.9 per cent of the global market, according to R&D Directions, September 2004. The desire of the pharmaceutical industry to work with fewer providers plays to the benefit of global, full-service providers. Moreover, patient recruitment is becoming a key issue, with demand soon scheduled to outstrip the capacity of the current trial infrastructure (both patients and physicians) in traditional countries used for clinical research. The USA and Western Europe currently consume around 90 per cent of current expenditure in clinical trials.
Those outsourcing into Asia Pacific typically have a series of questions, which fall into the following categories:
Asia Pacific has a huge potential patient base, far exceeding that of North America and Europe. The multiple countries within the region create a varied and complex region, with multiple cultures, languages and ethnicity. Adding another region to the USA and Western Europe adds a further layer of complexity to study delivery. One approach that will boost confidence is not to think of Asia Pacific as one region, but to target specific countries within the region that have sympathetic medical infrastructure. Clearly, Indian medical practice is very different from Indonesian practice in terms of traditions, organisation and facilities, just as the governance and organisation of healthcare in Taiwan differs from that of Bangladesh. By defining specific countries that meet the specific demands of a protocol, we can get maximum benefit from the ethnic and cultural diversity within the region.
A second fundamental question addresses the patient population. Are the patient populations the same, and will the study generate clear results or throw up complexities that will require further work? How do underlying nutritional, medical and genetic factors influence the disease and the response to the study drug? Furthermore, how applicable are the study end points devised for US or European regulatory submissions? Will they be understood, administered and interpreted correctly and reliably in this different medical and operational environment? Careful consideration has to be given to patient demographics and ensuring that the disease profile and management in a country matches that required for the study. A recent evaluation to assess whether the disease profile and pathology would be the same in the US patient population indicated that the risk of difference was too great, which in turn could have jeopardised the study. In other instances, similar detailed assessments of conduct in particular Asia Pacific countries have had a very beneficial impact.
The third and main issue to consider when outsourcing to Asia Pacific deals with data collection and data quality; just how reliable, robust and valid are the study data going to be? These are tough questions, and can best be answered by looking at data from individual countries and projects.
One particular area of confusion is the genetic and ethnic differences between and within countries. Regulatory authorities such as the FDA will often require the collection of demographic data. The recommended racial and ethnic categories in their draft guidance include American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, and Hispanic or Latino. For studies conducted either inside or outside the USA, more detailed racial and ethnic identities may be used, provided that they can be traced back to the major classifications.
Data quality is of fundamental importance. Audit, quality control and quality assurance have developed to ensure all interested parties that the patients exist, received proper informed consent and the study received correct ethical scrutiny. Researchers want to demonstrate that the patient received the right treatment and medication at the right time and the right data were collected in the correct manner. There is no substitute for detailed feasibility and site visits by well-trained clinical research staff to ensure that the sites are committed to data quality and accept the importance of vigilant monitoring as part of the clinical trial process. The critical point is to identify principal investigators who are enthusiastic about data quality and understand why it is so important.
Recruitment of subjects is what is generating all the excitement. There are huge numbers of patients available for studies. India is an excellent example. The total population of one billion people comprises some 200 million who live comfortable lives, are clustered in the large cities and have high expectations of receiving Western medical care. These patients are medically literate and well educated; they know what is available and how to get it.
The distributed nature of healthcare in some modern countries, such as the USA, can confound long-term follow up of patients. Patients require incentives to stay with their physicians, and long-term follow up is often incomplete. Incentives need very careful consideration and must not be coercive. Countries with more centralised healthcare systems fare better. Our experience of large, metropolitan hospitals in Asia Pacific as well as Central and Western Europe is that these patients are more inclined to continue their medical care with the same physician, thus facilitating long-term follow up. The strength of the doctor-patient relationship in these countries will also support strong retention by the site. In India, a critically important factor is the respect for physicians, which makes retention of subjects a much easier proposition. Plus, there are 600,000 physicians and 700,000 speciality hospital beds in India. We also see this factor operating in other Asia Pacific countries.
There are three basic outsourcing models from which companies can choose:
Sites tend to be less experienced at drug development and research than many comparable US and Western European sites, resulting in the majority of studies being conducted at relatively few sites. The result is that while the cost per site may be higher, the cost per patient recruited should be less. This is because of the requirement to put more professional hours into the sites, to ensure recruitment and data quality are an acceptable standard. Because the sites are fewer and larger, the sites recruit larger numbers of patients per site and when they commence recruitment, they typically recruit quickly and effectively. Because 40 per cent of the drug development cost is incurred in clinical trials, there are considerable cost advantages to placing studies in Asia Pacific. However, while it is likely that the cost advantage will decrease with time, this will be more than outweighed by the large sites, experienced trained physicians and excellent doctor-patient relationships.
It is an error to think of using Asia Pacific sites for study rescue, although this is a typical sponsor request. Administrative and regulatory start up is not quicker than many countries and can be slower. For example, it takes around five months to get going in India versus two months in Bulgaria.
Sponsors frequently express doubts about medical practice in Asia Pacific countries. Our experience is that physicians are well trained and patients want treatment. In India, for example, there are over three million patients with cancer and over ten million with psychiatric disorders, according to a CenterWatch article in August 2003.
Many of the best sites have physicians who have practised in Europe or the USA and have returned to their native country to run a practice. These sites tend to be large and well run, along US lines. There are differences between Asia Pacific countries, of course. Singapore and Hong Kong are very focused on US medical practice, while India offers a balance between US and European medical practice. The physicians and many of the site staff are English speaking, resulting in easier training and easier transfer of drug development skills from Western Europe and the USA.
We typically enrol two or three native sites into most studies to encourage the spread of medical practice and knowledge of drug development and best clinical research practice. This has successfully grown the number of sites we can use to maximise recruitment.
GCP and ICH guidelines are well understood, and are the benchmark against which all studies are audited. We have not had any significant problems in establishing GCP and ICH in studies in Asia Pacific countries. Many of the countries have focused on compliance with these standards, and have incorporated them into their procedures for Ethics Committee and regulatory approval.
It is an exciting time in clinical research in the Asia Pacific region. The development and understanding of the importance of clinical research to the local economy, the driving upwards of research practices through training and the large, well-equipped medical centres allow Asia Pacific countries to compete against the best in the world in drug development and research.
