New lease on life? The ethics of offshoring clinical trials

When several patients with Aids died after an experimental drug trial at Ditan Hospital in Beijing in 2003, human rights activists and local media turned on the pharmaceutical group involved.

Viral Genetics, a Californian biotechnology company, was criticised for failing to explain adequately to participants that they were taking part in a trial rather than receiving a proven medicine. Others question whether it was right that, while some patients were given its test VGV-1 compound, the rest received a placebo instead of antiretroviral therapy, long accepted in the west as the most effective treatment. The company declined to comment.

The trial complied with current international standards and a Chinese investigation concluded that there was “no serious violation of ethical principles”. Even so, such practices highlight both the rapid growth in clinical trials in the developing world and the tensions caused by this latest form of globalisation.

The changing pattern of clinical trials is helping drug companies that are under pressure to deliver innovative medicines more quickly and sell them into new markets. But it also raises concerns over quality, research ethics and the very lives of the patients participating, and is coming under increased political and regulatory scrutiny.

The European medicines agency and the European parliament both stepped up their scrutiny late last year, with discussions on the topic. Irene Schipper from Somo, a Dutch research group that presented to the European parliament, argues that existing guidance from the International Commission on Harmonisation – which governs best clinical practice among regulators in the US, Europe and Japan – “leaves all the options open and gives research efficiency priority over ethical considerations”.

During the 20th century, clinical trials – for many years a legal necessity to demonstrate that experimental medicines are safe and effective before their approval – were predominantly conducted on patients in North America and western Europe, close to companies’ scientists, regulators and principal markets. Since 2000, however, the expansion of western pharmaceutical companies around the world and the emergence of local rivals in developing countries have meant that the number of trials taking place in the emerging economies of China, India, eastern Europe and Latin America is catching up.

Jennie Sykes, medical director for GlaxoSmithKline’s international region, says that in 2005 the company set out “our intention to nearly double the number of patients in trials” outside North America and western Europe. Just over two years later, that objective has already been met, with 48 per cent of recruitment of new patients now in central and eastern Europe, Asia, Latin America and Africa.

The pattern is mirrored elsewhere. Clinicaltrials.org, a US website on which all government-funded and many company trials are listed, shows nearly 50,000 under way, of which 10 per cent involve countries outside North America, western Europe and Japan.

The proportion of principal investigators – the lead researchers on a trial – registered with the US Food & Drug Administration (FDA) but based outside the US and western Europe rose from 5 per cent in 1997 to 29 per cent last year. The fastest growth in the past five years has come from India, China, Russia and Argentina. “We’re doubling in size every year and expect to keep doing so in each of the next few years,” says Mark Engel, chairman of Excel PharmaStudies, a clinical research organisation that runs trials in China for a number of western drug companies.

One factor driving such “offshoring” has been growing demand for patients to assess the effects of medicines. Stung by safety concerns including those around Vioxx, the Merck painkiller that was withdrawn from sale in 2004, regulators led by the FDA are seeking ever more information as a pre-condition for approving new drugs. That means more clinical trials enrolling additional patients for longer periods: sometimes several thousand participants over many months.

But recruitment in western markets is increasingly difficult and costly. Patients are generally willing to participate in Phase 2 and Phase 3 trials, designed to measure efficacy, assess the appropriate dose and identify any side effects. But for rarer diseases, including for many cancers, the number of patients who are not already enrolled in trials for rival new drugs is limited – and the cost of finding them high.

By contrast, a number of the emerging markets offer good and improving medical infrastructure, at least for a significant proportion of their population, supported by well-trained doctors and assistants available at a fraction of western salaries – including many who speak English and were partly educated in the west. That can reduce the direct costs of trials by half or more.

Just as important, such countries offer large pools of patients willing to be tested, including many who are “treatment naive”, because the relatively low standard of healthcare compared with western countries means they have not had access to the latest and most expensive medicines.

Equally, whereas in many developed countries each general practitioner or hospital doctor can only provide a handful of patients able and willing to take part in a trial, in populous countries such as China a single specialist may see dozens each day, allowing recruitment into trials far more quickly from just a few sites.

That can speed up testing by several months, offering the chance to win regulatory approval more rapidly – and the prospect of an extended period of sales before the patents on a new drug expire and generic manufacturers can offer cut-price equivalents. “Time is money,” says Ole Molskov from Novo Nordisk, the Danish company that was among the first to establish a research centre in Beijing. “They have big hospitals here treating thousands of patients, for whom there is much less competition with other trials.”

Many developing countries forbid “first in man” trials to prevent their citizens from being treated as human guinea pigs. But in countries such as India and China, regulators are increasingly prepared to allow local trials to take place after initial tests have been conducted elsewhere.

This can help build up their own scientific expertise and domestic pharmaceutical companies. It also ensures that a drug is clinically appropriate, given genetic differences around the world. For instance, Iressa, AstraZeneca’s lung cancer drug, failed to show benefit and did not win approval in the west, but works better in Asians and is sold in China and Japan.

In the past, developing world patients tested drugs to treat illnesses predominant in those regions, such as malaria. Today, there is a growing incidence of, and willingness to pay for, treatments for diseases occurring everywhere such as diabetes, heart disease and cancer. Ms Sykes at GSK says: “The main reason for us testing in these regions today is that our portfolio has global treatments.”

But globalisation also brings problems. Russia and China have both in recent times limited the export of blood and patient tissue samples, partly out of concern over illegal organ trafficking as their fledgling regulators find their bearings. That makes participation in international trials more complex and difficult.

While patient recruitment is rapid, initial regulatory and ethical approval to conduct trials in the developing world is often slower than in the west – one reason why new drugs have tended to be launched later in these markets.

Equally, there have been concerns over the risk of fraud and poor-quality data, which would make the clinical trials unreliable. The FDA recently established an office in China and is stepping up inspections abroad from extremely low levels. Other regulators are doing the same.

Ken Getz, senior research fellow at the Tufts Centre for the Study of Drug Development, says that so far “the evidence suggests that concerns about compliance and fraud are unfounded”. Issues identified in audits have been no more, and sometimes less, widespread or worrying than those in the developed world, he argues.

He believes that a more practical brake may come from the growing focus on biological medicines and the shift towards more stratified treatments targeted at smaller sub-groups of patients with a particular genetic make-up. “That might reverse the globalisation of trials,” he says.

More generally, western regulators are seeking to ensure that trial data is representative of their populations, discussing caps defining the maximum proportion of trial participants from other parts of the world. A fiercer debate has concerned the ethics of trials in the developing world. At stake is how far researchers are exploiting a lower “standard of care” and weaker local supervision than exists in the west.

One issue is the use of placebo-controlled trials – administering the drug under test to some participants while giving to the rest simply a sugar pill against which to measure efficacy – rather than comparing the new treatment with the best approved existing medicine available in the west.

Another is that patients may be unduly coerced to take part because a trial offers access to medical care they could not otherwise afford; and because they may lack adequate “informed consent” to understand they are taking risks by using an experimental medicine – or from receiving a placebo rather than the new drug.

A third concern is the lack of post-trial access to medicines. The country where a trial is conducted may not gain access until long after the drug is approved in the west. Often even the patients on whom a medicine is successfully tested are not guaranteed that they will continue to receive it once a trial comes to an end.

Ms Schipper argues that the World Medical Association’s 2004 declaration of Helsinki calls for stringent ethical practices in trials, but these remain voluntary. She also expresses frustration at the lack of public information on trials, with globalisation and outsourcing to clinical research organisations creating additional hurdles to external scrutiny.

But one senior European regulator says that because the trend is still recent, few “pivotal” late-stage trials submitted for approval by western pharmaceutical companies have yet taken place in the developing world. He suggests a greater concern today is scrutiny of trials conducted by local innovative and generic companies, subject to the sometimes less demanding supervision of national regulators.

Rory Collins, co-head of Oxford University’s clinical trial service unit, who helped co-ordinate a 50,000-patient trial of Plavix, a blood-thinning drug, in China three years ago, even warns that tighter regulation in the developed world is one of the main factors driving trials elsewhere. “The stated intention of patient safety is reasonable, but the way people are going about it has the opposite effect,” he says, criticising a culture of box-ticking audits that often throw up only minor errors.

As the number of patients from the developing world increases, researchers, regulators and ethicists alike need to be careful to get the right balance of benefit and justice.

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