PHA-Exch> The Promise and Pitfalls of Clinical Trials Overseas

[Claudio Schuftan]

From: Vern Weitzel <vern.weitzel at gmail.com>
crossposted from: "[health-vn discussion group]" health-vn at cairo.anu.edu.au

http://www.sciencemag.org/cgi/content/full/322/5899/214?ijkey=UKfYGybirpqQM&keytype=ref&siteid=sci

Science 10 October 2008:
Vol. 322. no. 5899, pp. 214 - 216
DOI: 10.1126/science.322.5899.214
NEWS

The Promise and Pitfalls of Clinical Trials Overseas
Dennis Normile*

Big pharma has big incentives, including cost savings and more powerful
studies, to launch trials in developing countries. But can companies avoid
the ethical potholes?

 Queuing up. Clinical trials are coming to India--and elsewhere in Asia and
Eastern Europe--drawn by low costs and diverse populations.
CREDIT: PALLAVA BAGLA

The results of the clinical trial were puzzling. Some lung cancer patients
who received the experimental drug gefitinib several years ago showed almost
no benefit; in other patients, tumors shrank so much that one researcher
called it a "Lazarus type of response." After intense study, an answer to
the riddle emerged: Tumors that respond to gefitinib have a mutation in a
key protein affecting cell growth--a mutation common in Asians but rare in
other races.
As a result, gefitinib, which is marketed as Iressa by AstraZeneca, is
available only under special circumstances in North America, while in Asia
it has become an established therapy for non-small cell lung cancer that
fails to respond to other treatments. If AstraZeneca had done the initial
trials in a global setting, "they might have made the Asian connection
sooner and saved a lot of money and time," says Benny Zee, a biostatistician
and director of the Comprehensive Cancer Trials Unit at the Chinese
University of Hong Kong.

Differing ethnic responses to drugs is one of a host of reasons
pharmaceutical companies are globalizing clinical trials--and rushing to
developing countries. There are cost savings. There are new markets. And
trials help a multinational pharmaceutical company establish a presence in a
country and learn local needs.

Large pools of recruitable subjects and enormous market potential have drawn
drug companies to India and China. A July study by the Associated Chambers
of Commerce and Industry of India (ASSOCHAM) foresees India's clinical
trials business growing from less than $150 million currently to $546
million by 2010. Among developing countries, India and China are possibly
the best positioned to leverage multinational clinical trials to develop
their own pharmaceutical industries, thanks to their rapid economic
development and growing scientific capabilities.

But bioethicists worry that in the stampede to Asia, patients' rights
sometimes get trampled. "All those reasons [for doing clinical trials in
India] don't really add up to good ethical oversight," says Prathap Tharyan,
a psychiatry professor at Christian Medical College in Vellore, India.
Tharyan says India should view the boom in trials as an opportunity to raise
ethical standards.

In the latest flap sparking calls for closer scrutiny of trials, the All
India Institute of Medical Sciences in New Delhi acknowledged in response to
a query from a nongovernmental organization in August that 49 infants died
while enrolled in clinical trials at the institute over the past 2.5 years.
"The deaths were among patients who were extremely sick; there is no case of
a death because of an intervention," says institute spokesperson Y. K.
Gupta. All trials, he says, were vetted by an ethics committee and conducted
in accordance with good clinical practice. In early September, the institute
reported the results of an in-house investigation to the health ministry,
but the matter may not end there.

Cheaper, faster
Reliable statistics on who is doing which trials, and where, are hard to
come by. Few countries require the registration of clinical trials in public
databases, and individual trials are becoming more and more global. For
drugs for the U.S. market, the lead researcher at each site must file a
statement with the U.S. Food and Drug Administration as part of an
Investigational New Drug application. According to an analysis of filings by
CenterWatch, a Boston-based company that gathers data on clinical trials,
the number of investigators in developing countries working on drugs for the
U.S. market has risen dramatically: in India, from 46 in 2001 to 493 in
2007, and in China, from 16 to 97 over the same period. (The CenterWatch
analysis captures a fraction of ongoing trials.) Also telling, the ASSOCHAM
study found that India had been the site of a single clinical trial
outsourced by U.S.-based multinationals from 1996 to 2000--but 192 trials
between 2001 and 2005.

One factor behind this trend is economics. The Confederation of Indian
Industry boasts that trials in India can be 50% to 60% cheaper than in the
United States. But cost advantages are narrowing, says Kenneth Kaitin,
director of the Center for the Study of Drug Development at Tufts University
in Boston. "These countries realize there is no reason for them to reduce
costs to the degree they have in the past," he says. Still, costs are low by
Western standards (see p. 210).

Taking trials overseas can pay off in another way. The cost of running a
trial "is a factor to some degree, but not to the degree that people think,"
says Jorge Puente, vice-president for medical and regulatory affairs in
Japan and Asia for Pfizer Inc. in New York City. He explains that once a
drug is patented--typically before trials begin--the clock starts ticking on
the period of exclusivity. Trial sites in North America and Europe already
have hundreds of ongoing studies, so competition for patients delays
recruitment and a trial's completion. Target patient numbers can be gathered
more quickly if trials include sites in developing countries. "If you speed
up development by 1 year, you get an extra year of [patent] exclusivity;
that's the most important driver," Puente says.

It's in the genes
Liver cancer and gastric cancer kill more people in China every
year--600,000--than the number who die from all forms of cancer in the
United States, Puente says. Developing drugs against these and other
diseases that afflict China disproportionately is the main reason
pharmaceutical companies have opened R&D centers in China (Science, 27 July
2007, p. 436). The same goes for India, where the focus is on developing
drugs for malaria and other infectious diseases seldom seen in North America
and Europe. "We have to be part of those communities to understand the
health priorities and be part of the solutions," says Puente. He says that
more than 60% of Pfizer's revenue now comes from outside the United States,
and projections indicate an additional billion people in Asia will be
potential consumers of innovative medication.

The buildup of research infrastructure in China and India is leading to "a
more strategic approach" to trials, Kaitin says. In the past, overseas
trials were primarily part of large phase III studies. "Now companies may do
a phase II study to reach proof of concept more quickly so they can
determine whether to move forward, and more Western companies are looking to
conduct preclinical and research discovery phases of drug development in
these countries," he says.

As the gefitinib experience shows, ethnic groups often respond to drugs in
markedly different ways. Genomic data will allow the medical community to
better understand and exploit differences, Zee says. "Before talking about
personalized treatment, we can talk about the genetic makeup of different
ethnic groups," he adds.


SOURCE: CENTERWATCH ANALYSIS, 2008
Indian scientists are touting the country's diversity as an advantage. The
Indian Genome Variation Consortium is studying genetic differences among
India's ethnic groups and comparing them to variations in other populations.
Preliminary results covering 55 populations and several hundred genetic
markers were reported in the April 2008 issue of the Indian Academy of
Sciences' Journal of Genetics. Lead investigator Samir Brahmachari, a genome
analyst and director general of the Council of Scientific and Industrial
Research in New Delhi, says India offers a one-stop destination for clinical
trials, because so many human variations exist in the 1-billion-plus,
drug-naïve population.
Courting trials
A final factor that's fueling the boom in clinical trials in developing
countries is their active solicitation--a sharp turnabout from a mere decade
ago. "In the early to mid-'90s, there really was no infrastructure for
clinical research in Asia," says Puente, who worked for Pfizer in China and
Japan at that time. He says few researchers were interested. These days,
China and India are promoting themselves as the places to be for clinical
trials. The ASSOCHAM report boasts that India churns out 17,000 new doctors
each year, all of whom speak English. Kaitin says conducting trials brings
money and staff training to hospitals, medical schools, and local research
organizations.

Both countries also have domestic companies eager to move from making
copycat generics to developing their own drugs. At the East Asian
Pharmaceutical Regulatory Symposium in Tokyo last April, Zhang Wei,
director-general of the Department of Drug Registration at China's State
Food and Drug Administration (SFDA), reported that from 2001 to 2005,
China's domestic drug companies had received approval for 45 new drug
products and had 41 under review and 109 in various stages of clinical
trials. (The U.S. Food and Drug Administration approved more than 50 new
drugs in 2007 alone.) China's government has launched several schemes in
recent years to promote drug development, including a National Key New Drug
Creation Program approved by the cabinet last December that promises to make
up to $1.5 billion available to academics and biotech start-ups over the
next 15 years. China and India are working to streamline approvals
processes, crack down on corruption, and improve intellectual-property
protection. "These countries are really doing whatever they can to become
major players in this expanding global market," says Kaitin.

Still, China and India are held back by an underdeveloped infrastructure.
Zee, who studied and worked for more than 15 years in the United States and
Canada and whose research focuses on cancer radiation therapy trials, says
having lead scientists trained in North America and Europe is not enough.
"You need technicians; you need good laboratory and other [supporting
services] to do a trial properly," he says. China's SFDA allows new drug and
device trials at only 200 or so approved centers--a "terribly small" number
given China's size, Puente says. "The limiting factor for us," he says, is
the lack of SFDA-certified centers.

The biggest infrastructure gaps in both countries are in trial know-how and
ethical oversight. Wu Taixing, an epidemiologist at Sichuan University's
West China Hospital in Chengdu, says only a few hundred of the top hospitals
have ethics committees. Wu and colleagues found that just 207 of 2235
"randomized" trials reported in Chinese journals were randomized properly.
"Most authors of these reports lack an adequate understanding of rigorous
clinical trial design," Wu's group concludes. In India, too, "a large
majority of potential investigators lack knowledge of regulations, ethics
and good clinical practice, and skills for clinical trial management," says
Arun Bhatt, president of ClinInvent Research India, a contract research
organization in Mumbai.

Many trial sponsors use ethically dubious recruiting practices, such as
offering payments that dwarf participants' normal earnings and providing
medications they could not otherwise afford, alleges C. M. Gulhati, editor
of the Monthly Index of Medical Specialties, a reference work on drugs
published in New Delhi. Widespread illiteracy makes it easy to sidestep
informed-consent procedures, Gulhati adds: "Investigators frequently enroll
patients in trials as if their participation were a necessary next step in
their care."

Critics have pounced on such lapses. "There are good reasons to believe that
the rights of test subjects in developing countries are less secure than
those of their counterparts in the West," according to a January report, A
Bitter Pill, from the Wemos Foundation, an organization in Amsterdam that
advocates for developing-world health care.

Among several examples the Wemos report mentions is a case in which a
drug-eluting stent developed by Occam International in Eindhoven,
Netherlands, was implanted in about 70 Indian patients as part of a 2005
trial. According to a 2006 report by the Netherlands Health Care
Inspectorate, the procedure was done without proper informed consent and
without ethics committee approval. The Inspectorate slammed Occam for its
"amateurish" reliance on a local partner without verifying that the trial
would be conducted in accordance with European ethical standards. In a
statement responding to questions from Science, Biosensors International in
Singapore, Occam's parent company, said Occam has denied the accuracy of the
allegations and noted that investigations in both India and the Netherlands
produced "no finding of legal wrongdoing."

 Homegrown. Some products such as antiviral vaccines may be designed,
tested, and marketed in the developing world.
CREDIT: KHAM/REUTERS/LANDOV

Wemos called for authorities in developed countries to adopt stricter
controls to prevent drugs tested unethically from reaching the market. It
also urged developing countries to beef up health care systems and ethical
review capabilities and asked drug companies to be more transparent in
reporting on clinical trials.
Many researchers emphasize that the issue transcends big pharma.
"Pharmaceutical [companies] aren't the only ones that do clinical trials;
we're looking at academic researchers, device companies, and public health
researchers as well," says Davina Ghersi, coordinator of the World Health
Organization's International Clinical Trials Registry Platform (ICTRP),
established in August 2005 as a one-stop portal for trial registries around
the world.

To subject trials to greater scrutiny, groups in China and India launched
registries last year that ask for information such as who is paying for a
trial, the health issue being studied, the intervention, and the outcomes.
These are the first registries in developing countries; both are cooperating
with ICTRP. "Trial registration suggests an opportunity to help facilitate
the ethical design, scientific design, and good conduct and reporting of
trials," Tharyan says.

In addition to the minimum data required by ICTRP, Clinical Trials
Registry-India asks registrants to provide details such as the method of
randomization and blinding. The Indian registry also asks for information on
the ethics committee that approved the trial. It hopes to evaluate committee
qualifications and performance and eventually to accredit them. The Chinese
Evidence-Based Medicine Center, one of the sponsors of the Chinese Clinical
Trial Register, plans to help institutions set up and train institutional
review boards.

Neither China nor India requires trials to be registered. To encourage
registration, journal editors in both countries are following the lead of
the International Committee of Medical Journal Editors, which announced 4
years ago that member journals will consider a trial for publication only if
it is in a publicly accessible registry before enrollment of the first
patient. Last February, editors from 12 of India's top medical journals
announced a similar requirement to take effect in January 2010. In China, a
consortium of 56 journals has announced that as of January 2009, reports of
registered trials will get priority for publication over unregistered
trials. Eventually, they will publish results from only registered trials.

Wu and Tharyan acknowledge that registries and journal policies won't
resolve all ethics issues, but they are a start toward helping ethical
oversight keep up with the developing world's growing participation in
clinical trials.

With reporting by Pallava Bagla in New Delhi and Chen Xi in Beijing.

The editors suggest the following Related Resources on Science sites:
In Science Magazine
INTRODUCTION TO SPECIAL ISSUE
Lemons, Oranges, and Complexity
Eliot Marshall (10 October 2008)
Science 322 (5899), 209. [DOI: 10.1126/science.322.5899.209]
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