European regulators Struggle with Globalisation of Clinical Trials

Traditionally, clinical trials were predominantly conducted in North America, Western Europe and Japan, but over the past decade there has been a dramatic shift towards using other regions. The extent of this international trend was illustrated in a global analysis of the period between 2002 and 2006, which examined the regional share of total sites and the growth rates for different regions (1). According to this analysis, the share of global sites accounted for by Western Europe increased by a modest 3%, whereas for Eastern Europe the share rose by 24%. Meanwhile, both Asia and Latin America's shares increased by around 20%. The trends come as little surprise, since it is now almost standard practice to incorporate so-called emerging market regions and rapidly developing countries in clinical development programmes (2).

Nathan Jessop

Faster patient recruitment and lower trial operational costs are factors that have attracted companies to newer regions. In addition, many of these areas represent pharmaceutical markets in their own right and products may be looked upon more favourably if they have been tested in local populations. Many governments in emerging markets have recognised this interest from global companies and have taken measures to attract investment by decreasing bureaucracy and improving their regulatory systems. In China, for example, centralising the regulatory agency helped to decrease the number of conflicting standards between the central and local governments, and has led to improvements in approval times (3).

Growing criticism

While the pharmaceutical industry has expanded its clinical trials internationally, this shift has been viewed with concern in some quarters. Some observers believe that there has been too much emphasis on economic benefits and that the ethical angles of globalisation have not been fully explored (2). In particular, there have been several media reports criticising the use of developing world regions for clinical trials. In a television programme called "Dying for Drugs," which aired in the UK, Pfizer was heavily criticised for the manner in which it conducted a trial in Nigeria (4–7).

The anti-industry slant of the programme prompted a furious response from the Association of the British Pharmaceutical Industry (ABPI) and Pfizer said that the coverage of the company's activities was "misleading" (8). Nevertheless, unfavourable media coverage continues to emerge. In 2011, the UK's Independent newspaper ran a series of articles highlighting a series of clinical trial violations in India (9-11). The newspaper highlighted how drug trials were carried out on survivors of the 1984 Bhopal gas disaster without their knowledge and how certain Indian hospitals were generating considerable revenue from UK, US and French pharmaceutical companies for clinical trials (10). The resulting outcry led to pressure on India's regulatory agency to tighten regulations and protect subjects from exploitation. However, the media coverage then expanded to highlight examples in different countries, including those in Europe (10).

The Dutch nongovernmental organisation, Wemos, which advocates for the right to health of people in developing countries, together with international partner organisations and journalists, began to document cases of unethical trials and lobby European politicians and policymakers to address the highlighted problems (12). Wemos' campaign has involved collecting and publishing testimonies from trial subjects, their relatives and others investigating the issue, but the organisation has not singled out individual companies (12).

These campaigns have had an effect, with groups of influential European MEPs raising the issue in the European parliament and calling for an appropriate response from the European regulators (9–11). Dr Peter Liese, a German Christian Democratic MEP was of the opinion that the European ban of an unethically tested drug would serve as an appropriate deterrent to wrongdoers in the pharmaceutical industry (10). He believed that appropriate laws to prevent breaches in conduct existed, but were not being implemented. Meanwhile, Margrete Auken, a Danish Green Party MEP, was quoted in the media as equating unethical clinical trials with organ trafficking and called for companies to be "named and shamed" (10).

The EMA under pressure

The EMA has received criticism from several MEPs for its perceived lack of action (9–11). In 2011, the EMA responded directly to the media, arguing that the globalisation of clinical trials was presenting it with a huge regulatory challenge that it was ill equipped to deal with. The EMA expressed the need for more resources and improved cooperation from the pharmaceutical industry to respond to the matters raised in the European Parliament, pointing out that all clinical trials, regardless of their nature, are required to meet internationally agreed ethical and data quality standards or their equivalent.

However, critics of the EMA are not satisfied. Wemos has argued that the regulatory agency is not being proactive and should be closely questioning companies about their conduct before granting regulatory approval for products (10, 11). In March 2012, MEPs on the Environment, Public Health and Food Safety Committee renewed demands for answers from the EMA regarding allegations of informed consent, inadequate investigation of deaths, conflicts of interest and other breaches for several trials conducted in India (11). The EMA acknowledged that there were still problems and promised to increase transparency to show how it was trying to enforce standards, but Dr Fergus Sweeney, the EMA's head of inspections, appeared to reject the demands of certain MEPs to refuse market authorisation for any ethical breaches (11).

Perhaps as a response to this criticism, the EMA has been keen to highlight the recent work it has been doing to ensure a robust global framework for the conduct and oversight of clinical trials. In April this year, the EMA's Working Group on Clinical Trials conducted outside of the EU and European Economic Area published a final reflection paper on the issue (13). The paper entered into force on 1 May 2012, with the aim of making sure that all standards are formally enforced, regardless of where in the world clinical trials are conducted.

One of the key steps that the EMA believes will enable it to enforce standards is better international cooperation. The agency recommended that a common international approach to the oversight of clinical trials be adopted, particularly with respect to countries where ethical and regulatory systems are not fully developed. A clear difficulty identified in the paper is for countries where EU regulators have limited existing formal contacts or experience in the local conduct of clinical trials (10).

As a starting point to prioritise its international focus, the EMA has collected data on the numerical distribution of patients participating in pivotal trials included in regulatory applications submitted to the Agency (10). In Africa, it identified South Africa as the major contributing country, whereas in Asia it was India, the Philippines, Thailand and China. In Latin America, a number of countries were highlighted including Brazil, Argentina, Mexico, Costa Rica and Peru. However, the EMA's data can only account for centrally authorised products, and so it is continuing to collect information at a Member State level and from international sources, such as the World Health Organisation (WHO) to create up a better picture of the situation.

From the available and emerging information, the EMA has proposed that high level "mapping" of information should be established in cooperation with individual European regulatory authorities and other international organisations (10). The exercise will effectively grade countries on the basis of the strengths and weaknesses of their regulatory systems, and whether the EMA can offer any assistance in the field of clinical trial regulation.

There will also be discussion on opportunities for collaboration based on the needs identified in the countries included in the priority list. The EMA already runs international collaborative projects in other areas, such as GMP inspections (14). The success of these programme can serve as a suitable framework to build collaboration for the purposes of enforcing clinical trial regulations.

The EMA has also noted that there are existing collaborative programmes in other regulatory areas, which may feature aspects of clinical trial regulation. Therefore, the agency is keen to look for synergies with other initiatives and to avoid the duplication of effort. However, the EMA has acknowledged that the results of some of the initiatives that have been conducted to date have not always been well documented, so there may be gaps in knowledge to overcome if its proposed international work is to complement existing programmes (13). There are also some basic, practical issues that the EMA must deal with such as developing a contact list of representatives of the foreign organisations it wants to deal with and determining appropriate communication measures.

For the EMA to become a stronger force for the enforcement of clinical trial regulations, it will also need greater resources and training. The final reflection paper mentions that training will involve courses, workshops and support for the preparation of guidelines and SOPs (10). However, it is not clear where the EMA will be getting additional resources from to cope with the growth of its activities or how they will be financed.

Summary

The globalisation of clinical trials is now an accepted trend, although not all observers are content about the way it has developed and continues to progress. Documented cases of unethical conduct during clinical trials have led to both public and media outcry, and have prompted calls in the European Parliament for the stronger enforcement of international standards. The EMA has comeunder heavy criticism over its role in overseeing trials conducted on foreign territories, although it argues that it is responding to the need for better regulation and intends to become transparent regarding its future activities in this field.

References

1. F. Thiers et al, Nature Reviews Drug Discovery,7, 13–14 (2008).

2. S. Glickman et al. N. Engl. J. Med., 360, 816–823 (2009).

3. China Clinical Trials Outsourcing Congress, "Welcome to the 4th Annual China Clinical Trials Outsourcing Congress" (Event website, 2012). www.clinical-trials-events.com, accessed 30 April 2012.

4. J. Aronson, British Medical Journal, 326(7396), 990 (2003).

5. BBC News Anger at deadly Nigerian drug trials. www.news.bbc.co.uk/2/hi/africa/6768799.stm <http://news.bbc.co.uk/2/hi/africa/6768799.stm, accessed 8th May 2012

6. BBC News. Pfizer denies dirty tricks claims in Nigeria. http://www.bbc.co.uk/news/world-africa-11971805 <http://www.bbc.co.uk/news/world-africa-11971805 accessed 8th May 2012.

7. The Guardian, 2012. Pfizer pays out to Nigerian families of meningitis drug trial victims. http://www.guardian.co.uk/world/2011/aug/11/pfizer-nigeria-meningitis-drug-compensation <http://www.guardian.co.uk/world/2011/aug/11/pfizer-nigeria-meningitis-drug-compensation, accessed 8th May 2012.

8. I. Hall, "Pharma firms hit back at C4's drugs documentary" (PR Week, 2003). www.prweek.com, accessed 30 April 2012.

9. N. Lakhani "From tragedy to travesty: Drugs tested on survivors of Bhopal" (The Independent, 2011). www.independent.co.uk, accessed 30 April 2012.

10. A. Buncome, "Delhi to examine weak regulation' of clinical trials" (The Independent, 2011). www.independent.co.uk, accessed 30 April 2012.

11. N. Lakhani, "Europe targets drug firms over unethical practices" (The Independent, 2011). www.independent.co.uk. accessed 30 April 2012.

12 Wemos, "The Globalization of Clinical Trials: Testimonies from Human Subjects" (Wemos website, 2010). www.wemos.nl, accessed 30 April 2012.

13 EMA, "Towards a robust global framework for conduct and oversight of clinical trials" (EMA website, 2012). www.ema.europa.eu, accessed 30 April 2012.

14. EMA, "International collaboration on good manufacturing practice inspections expanded" (EMA website, 2012). www.ema.europa.eu, accessed 30 April 2012.