Overseas trials: The trend has limitations

Experts discuss pros and cons

Clinical trials in the United States have trouble recruiting subjects, completing on time, and maintaining high quality and efficiency, and these problems are why major pharmaceutical companies and other sponsors are offering more business to international research organizations, experts say.

At the same time, regulatory and media pressures are pushing for a greater emphasis on safety with new drugs, so in order for trials to make safety a primary concern, they need even more subjects, says Vijai Kumar, MD, global medical director for Neeman Medical International of Raleigh, NC.

This is where international sites, in countries such as India and China, come into the picture.

When India agreed to abide by international standards of patent protection in early 2005, the groundwork was laid for increasing India's share of U.S.-sponsored clinical trials, says Asker Ahmed, director of iProcess Inc. of Cincinnati, which has a large network of investigator sites across North America.

The benefits of conducting trials in India are that it can reduce the cost by 40 percent per patient, depending on trial and lab work, and the patient accrual rate is faster, Ahmed says.

"You're adding a population of 1 billion people, and the urban centers have around 400 million, so there's a better chance of meeting the accrual target," Ahmed says.

Although some experts predict that India will have nearly 20% of the patients in global clinical trials by 2010, Kumar says that is an unrealistic expectation.

India's share of trial subjects could grow to 200,000 within the next four years, but not the more than one million predicted by some in the industry, Kumar says.

"Probably India now has about 1,000 investigators, maybe 800 good clinical practice-compliant investigators, but this number has to go up to at least 4,000 for patient intake," Kumar says.

"So the emphasis in India will have to be on imparting quality training — not only to investigators — but also to build up a cadre of clinical research professionals," Kumar says. "If you focus just on the business end and compromise the science and ethics, the bubble will burst, so I think it's very prudent to start low and go slow — do it right the first time."

India's share of the clinical trial industry is very small so far, with only a $50 million investment, but this is expected to grow to $300 million by 2010, says Dan McDonald, vice president of Thomson CenterWatch in Boston.

"The intellectual capital in India is impressive," McDonald notes. "I was in central India in March, and there are 600,000 English-speaking physicians trained in Western medicine, which is very significant." Those physicians are a potential pool of investigators, he adds. In the U.S., by contrast, there are about 600,000 practicing physicians, says Norman M. Goldfarb, CRCP, managing director of First Clinical Research and editor of The Journal of Clinical Research Best Practices. Goldfarb also is the chairman of the Model Agreement Group Initiative and chairman of the Clinical Research Relief Organization.

The drawbacks are that India continues to have extreme levels of poverty and infrastructure problems, such as rolling black-outs on a daily basis in some places, McDonald says.

While sponsors go overseas to reduce costs, there is some offset of those savings in the additional costs for travel, shipping, and bureaucratic hassle, Norman says.

"Over time, those costs will go down as infrastructure improves with, for example, more labs in the countries and as the import/export process becomes more accommodating," Goldfarb notes.

The other issue involves regulatory approval, which in some countries can take up to six months, Goldfarb says. But this will be streamlined as the clinical trial industry grows internationally, he adds.

"The last issue, which is a concern, is the human research protection aspects of international clinical trial sites," Goldfarb says. "My understanding is there are some issues in some developing countries, and these are because of a lack of training and a relatively low percentage of FDA audits, and because of cultural aspects."

For example, in some nations, doctors are revered, and if a doctor asked a patient if he or she would like to participate in a clinical trial, then the patient interprets that almost as an order and he or she will do it, Goldfarb explains.

"Then there are the incentives," he adds. "If your family is living on a dollar a day and you live 30 miles outside a city, and bus fare is $1, it's tough to buy that ticket."

But if the research site offers a bus ticket as an incentive, then that's a big incentive for participating in the study, Goldfarb says.

This places clinical trial sites in a Catch-22: if they don't provide bus fare, then they won't recruit rural subjects, but if they do provide it, then it might be too big of an incentive for participation, Goldfarb explains.

Access to free drugs and treatment also are powerful incentives in developing countries, Goldfarb notes.

On a positive note, pharmaceutical companies will choose countries that have strong human subjects protections over countries that have loose ones because they don't want to be hit by a scandal if something goes wrong in a trial, Goldfarb says.

"The race is not to the bottom in terms of protection, but to the top, and the trials will go to those who have the strongest protections," he adds.

The international business community's perceptions of India also are obstacles to rapid expansion, Ahmed suggests.

"Some people are cautious, so it will take time," Ahmed says. "I feel the clinical trial industry in India is where the [information technology industry] was 10 years ago in India—not yet an accepted trend."

With education and time, people will begin to accept trial outsourcing to India, he adds.

"The other concerns are regulatory issues and the timeline," Ahmed says. "There's some added padding to the time because you're doing business in India."

While U.S. companies never will outsource all of the clinical trial business, the trend of trial sites moving to international locations will continue, and the work will be spread around the globe, the experts say.

U.S. companies also are turning to central and eastern Europe for clinical trials to save money and time, McDonald says. "There's a 20% reduction in costs and 400 million treatment-naïve patients among a non-transient group across eight eastern European countries," McDonald says. "It's not difficult to find patients, and there's a significant and highly-trained and motivated investigator base over there that has been trained in western clinical practice guidelines."

For these reasons, there have been a number of contract research organizations that have opened their doors in Eastern Europe, he adds.

India and Eastern/Central Europe have moved beyond the infancy and discovery stage, but there are other places that are attracting a small number of clinical trials, including Singapore, Africa, and China, McDonald says.

"People see in China an enormous patient population and a lot of the same benefits you see in India with several million doctors, giant city hospitals that see 10,000 patients daily, and 1 billion treatment-naïve people," McDonald explains. "China has a good accreditation bureau, and it's one of the few countries to have accreditation of research sites."

Most of the major pharmaceutical companies have established research and development enterprises in China within the past five years, and China is tightening its intellectual property laws, which was one of the major obstacles to companies moving there, McDonald says.

Also, China is planning to build a new biotechnology center and is actively courting businesses to buy development space, McDonald says.

The clinical trial industry also is looking at South America for new sites, Kumar says.

Costa Rica, Chile, Argentina, and Brazil hold promise for future clinical research sites, Kumar says.

"Regulatory changes have taken place, and more and more investigators are being identified and trained," Kumar says.

The timeline for trials still is a little slow, but the infrastructure rapidly is being built up, he adds.

As clinical trial sites move out of the United States, there is a need for careful follow-up and analysis of trials in emerging markets to see how many patients are enrolled and what the timeline is for completion of clinical trials, as well as the impact on production, Kumar says.

Also, international sites need to follow the example of India and build capacity and tighten the regulatory process in accordance with ICH guidelines, Kumar adds.