Public Policy: Clinical Trials Without Ethical Review

A recent series of unethical, and in some cases illegal, clinical trials in India is fuelling concern over the incidence of clinical trials conducted without ethical approval in other countries where legislation may be either inadequate or not implemented.

In a series of articles last year, Chandra Gulhati, Editor of the Monthly Index of Medical Specialities (an independent pharmaceuticals journal in India), shed light on the conduct of illegal trials and subsequent promotion of the anti-cancer drug, letrozole, as a fertility drug in India.

More than 400 women, who had been trying in vain to conceive, were enrolled without their knowledge or consent to take part in clinical trials across India to see if the drug induced ovulation. The drug, which was produced by Mumbai-based generics manufacturer, Sun Pharmaceuticals, was a copy of Novartis's patented drug, Femara®. The women were under the impression they were receiving an expensive fertility treatment.

Belonging to a class of drugs known as aromatase inhibitors, letrozole has been approved globally for the treatment of breast cancer in post-menopausal women, but it is not approved for any other use in any country, including India.

Since then, India has seen a huge public outcry over the regulatory authorities' failure to crack down on a recent series of illegal, and legal but unethical, clinical trials.

A New Delhi-based nongovernmental organization is filing a complaint about the letrozole case to India's Supreme Court. And the Indian government has pledged to push through tougher, more effective legislation to tackle the problem later this year.

Gulhati contends that although the company as well as the physicians who carried out the trials broke the law, no one has been subjected to criminal investigation by the Indian authorities.

The letrozole trials are a shocking example of a widespread global phenomenon. A recent survey of more than 200 health researchers concluded that a quarter of clinical trials conducted in developing countries do not undergo ethical review. The survey, which was commissioned by the former US National Bioethics Advisory Commission, was published in February 2004.

John Williams, Director of the Ethics Section of the World Medical Association (WMA), said drug approval agencies in developed countries, such as the US Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA), require ethics committee approval of trials for the sale and distribution of any drug.

"These are strong incentives to seek such approval," Williams said, adding that editors of major journals also require such approval for studies submitted for publication.

"There are efforts under way to strengthen ethical review throughout the world through SIDCER and its regional committees," Williams said, referring to the Strategic Initiative for Developing Capacity in Ethical Review, an international project to develop the ethical review of biomedical research globally.

Most but not all developing countries have ethical review committees in the form of research institutes or other scientific panels. But training must be provided to ensure that these panels are independent and able to review clinical trials without prejudice.

The letrozole case illustrates this problem well. Gulhati said pharmaceutical companies in India often have a "cozy relationship" with regulators and bribe researchers -- hired to conduct purportedly independent clinical trials -- with expensive gifts, paid speaking engagements, over-paid consultancy work, and free overseas holidays. He said there was no independent safety monitoring of clinical trials and that participants sometimes do not even know they are participating in tests.

"Neither the regulatory authorities nor the ethics committees seek conflict of interest information from investigators," Gulhati said, adding, "Most of the clinical trials here are conducted without any arrangement for compensation in case of study-related injury, disability, or even death."

These initiatives come at a time when pharmaceutical and biotechnology companies try to save time and money by conducting clinical trials in developing countries, where there are plenty of willing subjects and often more relaxed regulatory mechanisms.

Harvard Medical School's Eugene Braunwald, who chairs a clinical trials group, told the New York Times recently that half as many US patients are enrolling in clinical trials compared to five years ago.

The trend of outsourcing clinical trials to developing countries has sparked concerns about unscrupulous biotechnology and pharmaceutical firms exploiting the healthy, who hope to earn some cash, and the sick, who hope to get free treatment.

A key question for regulators is whether US drug manufacturers should apply FDA standards when they conduct trials abroad. This will be less of an issue once developing countries tighten laws and make their ethical review panels truly independent.

Editor's Note: This article is reprinted here with permission from the World Health Bulletin_._

Back to the July 2004 issue of IAPAC Monthly.