Wemos betwijfelt bewering ACRO

Clinical trials carried out in emerging countries such as India and China are now subject to the same standards as those conducted in developed countries, an industry-sponsored report reveals (1,2).

While there have been "legitimate concerns" in the past about clinical trials conducted in emerging countries, things have improved "enormously" over the last ten to 15 years, says the report commissioned by the Association of Clinical Research Organizations, which represents the global CRO industry.

The report, entitled The Case for Globalization: Ethical and Business Considerations in Clinical Research, was initiated because of the dramatic increase in clinical trials conducted in emerging markets over the past decade and concern expressed by some regarding their quality (3,4). In addition, there has been a decline in clinical trial participation rates in the US.

The report highlights the key role played by the "globalisation" of clinical research in expediting the drug development process; in 2008, ACRO-member companies conducted more than 9,000 clinical trials in 115 countries. It also recommends several steps to ensure that a robust global research infrastructure continues to facilitate accelerated drug development.

The report estimates, for example, that it would take around 5.8 years to fully enrol all currently open Phase III trials if only US locations were to be used. This time period, it says, can be reduced to 1.9 years by using both US and global trial sites.

ACRO seeks to dispel the common perception that emerging countries are becoming a preferred destination for pharma companies and CROs to conduct clinical research because the regulations in these jurisdictions are lax.

Regulatory and cultural norms regarding clinical research in developing nations, it claims, are often more, rather than less, strict than in developed countries.

Examples of this include the difficulty of conducting early phase studies in India (5) and placebo-based studies in Latin America. Patients in these countries may also seek greater input from friends and family before deciding to enrol in a trial, the report says, adding that 76% of all first-in-man trials (Phase I) still take place in just three countries: the US, Canada and the Netherlands.

The outsourcing of clinical trials also benefits developing countries in terms of new employment opportunities and improved health systems. In Poland, for example, 30% of hospital therapy is funded by clinical trial sponsors.

Improving environments

The ACRO report notes that while the globalisation of clinical trials has brought advantages, there have been some "rare", but well-publicised, lapses in standards. Most notable among them is the 1996 Nigerian clinical trial of Pfizer's meningitis drug Trovan (trovafloxacin mesylate), which resulted in the death or disability of a number of children (6).

The report says that Nigeria has made strides to tighten its standards. After the Trovan trial, capacity building initiatives have been launched aimed at training bioethicists and researchers and two national research ethics training programmes have been undertaken in the past five years.

Further, the Association for Good Clinical Practice in Nigeria, which has been working to expand the clinical trial infrastructure, has trained more than 350 health professionals since its founding in 2005 and it is also working to improve the informed consent process.

The ACRO report makes several recommendations to make sure the quality and ethical standards match the international spread of the trials. It suggests, among other things, that the US Food and Drug Administration be provided with sufficient resources to conduct inspections on a global basis.

Also, it recommends that all clinical trial participants be protected with the same level of safety and ethical considerations, including adherence to the good clinical practice principles promulgated by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

"The public will never have confidence in trials conducted in emerging regions like Asia and Latin America, unless we level the playing field with the US, Canada, Western Europe and Japan," says ACRO executive director Doug Peddicord. "If the entire world plays by the same rules and gets the same resources, patients worldwide will benefit from lifesaving drugs more quickly and cost-effectively."

The report notes that governments worldwide, as they have come to recognise the benefits of globalised clinical research, are initiating measures to improve the regulatory framework in their respective jurisdictions.

In Russia, for example, the first western pharma-sponsored trials took place in 1993; since then the country has adopted international GCP guidelines and participated in over 1,000 international multicentre trials.

China has established clinical research centres with experienced researchers and advanced equipment within major hospitals. To staff these centres, the Chinese government has been engaged in an active effort to attract knowledgeable expatriates.

India in 2006 implemented a two-track approval system for clinical trials. Under this, expedited (three-month) approval is provided for Category A studies, ie studies with protocols that have been approved by regulators in the US, Canada, the UK, Germany, Japan and other countries with advanced review capabilities. All other trials fall into Category B and undergo the normal (six-month) approval process.

South Africa first implemented GCP guidelines in 2000 and updated them in 2006. The guidelines, the report says, are in line with the policies of the ICH and the World Health Organization, but have been adapted somewhat for the South African context. One of the measures designed to increase accountability is that a study must include a principal investigator who is a resident in the country.

The report concludes that much of the improvements in infrastructures of developing countries have been funded by the billions of dollars invested by pharmaceutical companies and CROs, who have a major stake in ensuring high standards in global trials as these are ultimately aimed at gaining regulatory approval for new products.

Commercial sponsors of clinical trials, the report claims, would not engage in unethical or poor quality research because they have so much at stake. Doing so would run the risk of them not gaining regulatory approval for their new product and they would have no way to recoup their R&D investments.

Disagreement with findings

The report's claim that clinical trials conducted in developing countries meet the same quality and safety standards as in developed nations is being disputed by the Wemos Foundation, a Netherlands-based advocacy group (7).

Wemos points out that while drug regulators in most developed countries require sponsors to prove compliance with GCP guidelines, last year the US FDA changed its regulations by discarding the Declaration of Helsinki as the ethical standard for clinical trials conducted overseas (8).

The Declaration of Helsinki is regarded as the world's most widely recognised source of ethical guidance for medical research involving humans. Its abandonment, says Wemos project co-ordinator (medicines) Annelies den Boer, "means leaving disadvantaged people in developing countries virtually unprotected against exploitation".

The picture in the European Union, she says, is similar. While the EU directives refer to the Declaration of Helsinki, "in practice, drug regulators use the ICH Good Clinical Practice guidelines, which are less strict on ethics".

Wemos is also challenging the claim that "lapses in standards [in trials conducted in developing countries] are rare". The problem, it says, is that many of these clinical trials are not registered in a publicly accessible database, making it impossible to establish the exact scope of ethical violations.

Pharmaceutical companies and CROs, says Ms den Boer, have an interest in carrying out a clinical trial as fast as possible. This interest is often at odds with the interest of trial subjects, which calls for careful ethical review.

Last year, Wemos along with a research group, the Centre for Research on Multinational Corporations (SOMO), issued a set of reports alleging that medicines tested unethically in low- and middle-income countries are being marketed in the EU (9).

Pfizer settles Trovan case

Meanwhile, Pfizer announced on 30 July that it had reached a $75 million out-of-court agreement with the Kano state government in Nigeria to settle claims arising from the Trovan trial (10).

In return for Kano state dismissing both the civil and criminal Trovan-related cases filed against Pfizer and various individuals, the company has agreed to: establish a $35 million healthcare/meningitis fund from which trial participants will be able to receive support; underwrite several healthcare initiatives totalling $30 million chosen by the Kano state government; and reimburse $10 million in legal costs associated with the litigation.

Pfizer - which has all along maintained that all allegations that the company conducted an unethical trial are untrue - has issued a statement that the settlement does not mean it has accepted any wrongdoing or liability in connection with the Trovan study.

Under the terms of the settlement, the healthcare/meningitis fund will be available to all individuals who participated in the trial; qualification criteria will be set up to establish this. The fund will be administered by an independent six-member board of trustees, with three members each chosen by Pfizer and the Kano state.

"With the procedures in place for the Healthcare/Meningitis Fund, the people of Nigeria will have confidence that the parties have taken strong steps to ensure that the funds reach only those for whom they are intended," Pfizer said.

WHO introduces unique numbering system

Separately, the WHO has established a system of assigning a number to each clinical trial to make it easier to uniquely identify trials through its International Clinical Trials Registry Platform (11,12).

The Universal Trial Number will also make it possible to track trials that are taking place in several countries and at different institutions. The aim of the UTN is to facilitate the unambiguous identification of clinical trials - it is not a registration number.

Until now, information on the same study could be submitted to multiple databases by different people in slightly different ways. This, the WHO says, makes it difficult to see if they are multiple trials or one trial with multiple records.

The UTN will work by linking multiple records on the same trial together on the ICTRP portal. While the UTN is not currently mandatory, the WHO says that some registries may choose to make providing the UTN mandatory in order to register a trial on their registry.

The WHO is recommending that the UTN be obtained early in the trial process. The UTN, it says, should become permanently attached to the trial; be used whenever information about the trial is communicated; become part of the trial's identity; be documented in the trial protocol; and be submitted every time the trial is registered.

The WHO recognises that some UTNs will be attached to trials that do not progress; that is, trials that never become fully developed protocols and that never recruit participants. Some UTNs will, therefore, never appear attached to a registered trial.

References
1. ACRO press release, 21 July 2009, www.acrohealth.org/press-release-detail.php?serial=58
2. ACRO, The Case for Globalization: Ethical and Business Considerations in Clinical Research, 21 July 2009, www.acrohealth.org/globalization/Globalization.pdf
3. The Regulatory Affairs Journal - Pharma, 2009, 20(5), 298-299
4. The Regulatory Affairs Journal - Pharma, 2008, 19(4), 249-251
5. The Regulatory Affairs Journal - Pharma, 2008, 19(12), 840-841
6. The Regulatory Affairs Journal - Pharma, 2008, 19(2), 127-128
7. Personal communication, Wemos, 30 July 2009
8. The Regulatory Affairs Journal - Pharma, 2008, 19(6), 421-422
9. See Reference 4
10. Pfizer press release, 30 July 2009, www.pfizer.com/news/press_releases/pfizer_press_releases.jsp?rssUrl=http://mediaroom.pfizer.com/portal/site/pfizer/index.jsp?ndmViewId=news_view&ndmConfigId=1016273&newsId=20090730005769&newsLang=en
11. WHO, International Clinical Trials Registry Platform, Unique numbering system for clinical trials, 26 June, www.who.int/ictrp/news/utn/en/index.html
12. WHO, The Universal Trial Number, site accessed on 31 July 2009, www.who.int/ictrp/unambiguous_identification/utn/en/index.html

Copyright Informa UK Limited 2009

Laatst gewijzigd: 8 februari 2010