Global clinical trials: Calling the hype to task
The results of two recent studies suggest that the dispersion of clinical trials is not nearly as global as commonly believed.
The promise of conducting clinical trials in emerging regions, gaining access to well-trained investigators and a large volume of treatment-naïve patients, and the realization of economic and efficiency advantages has been hyped. Clinical trials regulated by the FDA remain predominantly in mature global markets.
The Tufts Center for the Study of Drug Development (Tufts CSDD) recently evaluated FDA data on Form 1572 filings. It found that the number and distribution of clinical investigators has declined in some of the most ballyhooed countries, such as China and India.
Between 2009 and 2013, the number of unique investigators declined in India (with just 362 unique investigators working there in 2013), China (177 unique investigators that same year) and Brazil (343). The number of clinical investigators in Japan (658 unique investigators in 2013), Hungary (488), Bulgaria (333), Ukraine (514) and Great Britain (964) increased.
“Japan is now big commercially as well as on the development side,” said Alistair MacDonald, president and chief operating officer of INC Research, who focuses closely on the company’s expanding global operations. “There’s a big population there, and though the process has in the past been tough there, the research sector there is changing, becoming more Westernized and easier to work with.”
Industry insiders say the Hungary, Ukraine and Bulgaria upticks are seen as part of the Eastern Europe surge of recent years, as more countries successfully court the research sector.
Great Britain, however, is a comeback country.
“Great Britain is an old, traditional market that fell out of favor, but the government there has made a major push in recent years to recapture the research market, and it has worked,” said John Lewis, senior vice president of policy and public affairs at the Association of Clinical Research Organizations (ACRO).
“Great Britain now offers healthy tax credits, for example, to companies based outside the country that conduct research there,” noted Lewis. That strategy has been embraced warmly by CROs because it helps them with one of their highest costs: wages. Lewis said the policy contrasts with that of the U.S., which offers tax credits to the company that owns the technology or the intellectual property—usually the sponsor— rather than the company on the ground doing the research, which is usually the CRO.
Great Britain is looking at ways to leverage its national health system in order to increase awareness about clinical research and to get patients into trials. It’s also been amassing a large site network in an effort to attract more CROs and sponsors, according to Christine Pierre, founder and president of the Society for Clinical Research Sites (SCRS), and founder and CEO of the Maryland-based site group RxTrials.
“Some of the countries who want to take back their share of clinical trials work are being very collaborative and creative, and Great Britain is definitely one of those,” she said.
“Great Britain has moved the needle some 4 or 5% on patient involvement, and everybody speaks English there. It’s an easy country to go to,” said Kent Thoelke, executive vice president of scientific affairs, medical affairs and safety/commercialization services for the CRO PRA.
Tough going in China and India
Thoelke believes that a difficult operating environment in India and China and the lack of infrastructure there have contributed to declining activity and disappointment.
“There’s a common theme in these regions: All of the drop-off we’ve seen in these countries comes from serious regulatory issues,” said Thoelke, who also serves as chief executive officer of WuXiPRA, a joint venture between PRA and the Chinese CRO WuXi.
Thoelke explained that in China, for instance, timelines have been long, and the country recently announced that it would prioritize trials for innovative medicines coming from its own domestic companies, rather than courting research from outside China. Thus, timelines for trials originating at non-Chinese companies have gotten even longer. On top of that trend, there are multiple pathways for approval there, making trial startup very complicated, he said.
“Protection of intellectual property in China has also been an issue,” said ACRO’s Lewis.
In India, the clinical trials market nosedived when regulatory authorities there mandated that drug companies and CROs should shoulder uncapped liability toward patients who had adverse events.
“There was no understanding of what the process was for determining fault, and from a business standpoint, you really can’t operate in that environment,” said Lewis.
More recently, there have been issues with the quality of data coming out of local CROs there, and also with protection of intellectual property. In 2012, Lewis said, India instituted compulsory licensing, giving its government the right to grant a license for any drug it likes—foreign or domestic—to local producers.
“They can just say, ‘We like this drug of yours that you’ve been testing here. We’re going to start producing it locally. Sorry!’ If you’re a drug company and see you see that happening in a country, you run,” Lewis said.
Brazil has extremely long timelines. According to Thoelke, it doesn’t help that the health system there and the body that regulates clinical research are not very cooperative with one another.
Despite the highly anticipated growth in clinical trial activity in less mature and emerging countries, the lion’s share of clinical trials still takes place in the U.S.
The Tufts CSDD analysis found that there were 39,791 unique investigators actively involved in phase I-III clinical trials for which 1572 forms were filed in 2013. Just more than half (55%) of the total number of unique investigators are based in the U.S. That proportion of U.S. investigators to the total number has remained flat since 2009. The Tufts CSDD analysis also shows that the proportion of unique 1572 investigators based in Western Europe also has remained relatively unchanged.
Harold Glass, a longtime industry observer, said he believes the data in the Bioresearch Monitoring Information System (BMIS) 1572 database—which Tufts used in scrutinizing where the investigators are globally—doesn’t offer a comprehensive enough picture because sponsors aren’t required to file 1572s. And not all of the 1572s filed are made public.
Sponsors and CROs are, however, required to report each trial they conduct to ClinicalTrial.gov. And that practice, said Glass, is a far better way to look at trends in global trials.
Glass, a research professor of health policy and public health and an adjunct professor of pharmaceutical and healthcare business at the University of the Sciences in Philadelphia, recently analyzed data from ClinicalTrials.gov and corroborated the Tufts CSDD findings. Glass and his colleagues only looked at phase III trials between 2008 and 2012, and found little change in the proportion of clinical investigators in the U.S. and in Western Europe.
“There is no evidence of a shift of studies or sites away from Western Europe and North America to areas like Latin America, Africa, South Asia and Eastern Europe. Global is just a big myth,” said Glass, adding that there is far more hype about it than reality.
“CROs and sponsors are putting great efforts into developing markets, making efforts to link into research communities [and] getting to know who the opinion leaders are,” he said. “But they’re not setting up substantial drug development operations. Au contraire.
“And in five years? They won’t be there either. It’s too much of a hassle,” added Glass.
Prudence, not hype
“To some extent I would agree with [Glass’] assessment,” said pharmaceutical industry veteran Hani Zaki, founder and managing director of the consulting group Clinical Development Outsourcing Strategies. “Our initial projections about global markets and what we could deploy in various regions may have been too aggressive. We may have oversold these projections.
“One of the things we do in this industry is follow the leader, rather than looking to tailor movement and operations for your company and your particular therapeutic areas. That can get you into trouble.
“After rushing into global markets sometimes willy-nilly over the last decade or so, sponsors and CROs have learned more about which trials are appropriate in certain markets vs. others, and they’ve learned about regulations they can and can’t work with,” added Zaki. “Sponsors and CROs have also learned that, due to all the red tape, clinical trials in ‘emerging countries’ can actually be more expensive than trials conducted in mature markets. There’s been a bit of a contraction out of the wild frontiers that formerly had seemed so attractive.
“Today we’re much wiser, much more aware of what’s actually possible. Planning today is much better and people are more realistic with their global forecasting.”
CenterWatch interviews with sponsor companies indicate that many firms are more prudently conducting their clinical trials in global markets.
“We will not conduct a clinical trial where we do not have an intention to commercialize,” said Victoria DiBiaso, associate vice president and head of the office of patient participation and preferred partnerships at Sanofi. “We really try to show regulators we have representative populations for them to base their decisions, and ICH guidelines are very strong on that.”
DiBiaso said Sanofi’s trials are heavily weighted toward North America and Western Europe, and that’s how it’s always been. She said she sees others in the field making similar decisions based on data rather than trends or whims.
“We as an industry have matured,” she said. “We want the data on a region to support why we’re there. If it doesn’t, many of us just won’t go.”
Cardiologist Michael Koren, founder and chief executive officer of the Jacksonville Center for Clinical Research, and founder and director of Encore, a network of multi-specialty sites in Florida, has small site operations in Panama. But he said many clients are just interested in having their clinical trials stay in the U.S.
“There’s no doubt that there’s an interest in doing as much work as possible in the U.S.,” he said. “I like to think the quality in the U.S. is higher than anyplace else, and the regulatory scrutiny here is certainly higher.”
Mark Lacy, founder and CEO of the Austin, Texas-based investigator site group Benchmark Research, agreed.
“Drug companies have figured out that they can’t get the kind of data they need from sites in other countries,” said Lacy. “They’ve also realized that the cost of taking a clinical trial overseas is not actually lower than doing the clinical trial in the U.S.
“Sponsors and CROs now recognize that the big cost advantages they thought were there are—in actuality—not there. Trained personnel are also not there. And the startup times in emerging countries often just put them way behind.”
Suz Redfearn is an award-winning journalist and former senior staff writer for ClinPage.com. Her articles have appeared in numerous publications, including the Atlantic.com, The Washington Post, Slate, Salon, Politico, Men’s Health, MedPage Today and Physicians Practice. Suz holds a degree in print journalism from Loyola University in New Orleans and has been a medical writer since 1990, focusing on clinical research since 2007. Email firstname.lastname@example.org.
This article was reprinted from Volume 22, Issue 09, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>