The increasing globalisation of clinical research raises serious questions about the ethical and scientific integrity of this trend and who really benefits from it, an article in The New England Journal of Medicine warns.

Writing in the 19 February issue of the NEJM, researchers from Duke University School of Medicine and the University of North Carolina School of Medicine in the US note that, since 2002, the number of active trial investigators regulated by the US Food and Drug Administration (FDA) and based outside the US has grown by 15% per year, while the number of US-based investigators has declined by 5.5%.

To explore this trend further, the researchers examined patient recruitment in Phase III clinical trials sponsored by the 20 leading US-based pharmaceutical companies as of November 2007, using the ClinicalTrials.gov study registry. They found that 157 of 509 trials (30.8%) were being conducted solely outside the US and that a majority of study sites (13,521 of 24,206, or 55.9%) were outside the US. Many of these trials were being run in developing countries, the researchers add.

They also reviewed 300 articles reporting the results of clinical trials in the NEJM, The Lancet and The Journal of the American Medical Association between 1995 and 2005. These showed that the number of countries serving as trial sites outside the US more than doubled from 33 to 70 over the 10-year period while the share of overall trials conducted in the US and Europe declined, from 53.8% to 42.6% and from 40.0% to 36.5% respectively.

The researchers offer a number of explanations for the shift away from established markets for clinical research, such as cost savings (one pharmaceutical executive reported that a first-rate academic medical centre in India charges US$1,500 to US$2,000 per case report, less than one tenth the cost at a second-tier centre in the US), shorter timelines, a larger pool of potential research participants and lower barriers to drug approval in those markets.

Too much bureaucracy

One important stimulus, they suggest, is “the increasingly bureaucratic and expensive regulatory environment in many wealthy countries”. In the US, for example, the costs of running clinical trials “have generally outstripped federal funding for clinical research and strained industry’s site-level research budgets”.

While the regulations governing clinical trials are well intended, “they are generally uncoordinated and frequently have not been subjected to empirical study to determine which elements improve the conduct of trials and which elements add cost without benefiting participants or the research mission”, the authors claim.

Although the article sees some “clear benefits” in conducting trials in developing countries, such as answering questions about the safety of drugs and devices that are of global interest, it also raises several concerns on thus front.

These include the ability of regulatory authorities to monitor the quality of research conducted outside their jurisdiction, the ethical implications of wide disparities in healthcare systems as well as the educational and economic status of potential trial subjects, relative lack of understanding both of the investigational nature of study drugs and the use of placebo groups, the transparency of clinical research in developing countries, and the experience level of investigators.

Standards of healthcare in the developing world may “allow ethically problematic study designs or trials that would not be allowed in wealthier countries”, the researchers comment. They cite one study in which only 56% of 670 researchers surveyed in developing countries reported that their research had been cleared by a local institutional review board or health ministry.

Local not global

Given the increasing prevalence of conditions such as cardiovascular disease, it is important to test the relevant drugs and devices on a global scale, the authors acknowledge. At the same time, clinical research should be responsive to the health needs and priorities of the communities in which it occurs.

Yet among the ongoing Phase III trials reviewed for the NEJM article that were sponsored by US-based companies in developing countries, none were for diseases like tuberculosis that disproportionately affect the populations of these countries, the researchers point out. By contrast, a variety of trials were being run in developing countries for conditions such as allergic rhinitis or overactive bladder.

The authors also question how much, given differences in the social ecology and genetic make-up of the study populations, the results of these trials can be extrapolated to those countries where the treatments are most likely to be used.

Patients in developing countries are often under-treated or treatment-naïve, which may present a different outcome from testing a compound in patients who are also receiving multiple effective therapies, they observe. Varying genetic profiles may also influence pharmacological response – for example, in trials for cardiac, circulatory or neurological disorders addressed with nitroglycerin or nitric oxide-dependent therapies.

The researchers propose multiple approaches to dealing with the concerns raised by the globalisation of clinical research, such as matching trial populations to target markets; publishing all clinical trial data regardless of location; creating a formal mechanism for shared regulatory oversight of clinical trials on a global basis; creating formal training programmes on clinical research and ethics for investigators in developing countries; and creating mechanisms for tracking investigators who are formally trained in, or prohibited from conducting, clinical trials.

They also recommend a “careful effort” to streamline regulations governing clinical trials in developed countries, while ensuring adherence to ethical standards. “Greater use of centralised institutional review boards, standard terms for research contracts, and the development of streamlined best practices to reduce unnecessary work for investigators and medical institutions are needed,” they comment.

Yes, it’s ethical

Ken Johnson, senior vice president of Pharmaceutical Research and Manufacturers of America (PhRMA), said US companies “develop drugs for a worldwide market” and “make every effort to combat diseases that are common in the developed, as well as the developing world”. Moreover, running clinical trials in countries such as India, China or Japan is often a requirement if products are to be launched in those markets, he added.

“Is it ethical to conduct such studies outside of the US?”, Johnson asked. “In a word: yes.” Wherever trials were conducted, PhRMA companies still have to adhere to Good Clinical Practice (GCP) guidelines, he noted. And companies seeking product approval in the US must comply with FDA requirements on GCP as well as meeting whatever requirements apply “in these important emerging markets”.

The US-based Association of Clinical Research Organization (ACRO) welcomed some of the NEJMJ article’s recommendations, such as making sure industry sponsors, contract research organisations and the academic community take full responsibility for the ethical conduct and quality oversight of trials in developing markets.

“ACRO members have been leaders in driving global standards for patient protection and safety and ACRO looks forward to engaging sponsors and academic institutions in a discussion to establish parameters in this regard,” it stated.

It is unfortunate, though, that the authors “ignored one of the primary drivers behind the globalisation of clinical research: the limited participation rate in clinical trials in the United States and Western Europe”, ACRO commented.

According to the Center for Information & Study on Clinical Research Participation, 80% of clinical trials in the United States are delayed for at least one month due to unfulfilled enrolment. The US National Cancer Institute estimates that fewer than 5% of cancer patients participate in clinical trials. Yet if the participation rate doubled to just 10%, studies could be completed in one year rather than the three to five years typical now.

“ACRO and its members work extensively to increase clinical trial participation in the US and Western Europe, yet multinational studies are not only necessary but also desirable in order to meet the demands of today's global pharmaceutical industry,” the association said.