TCS Daily

The World's Largest Un-Scientific Clinical Trial

By Jeremiah Norris - June 21, 2004 12:00 AM

Recent developments suggest the world's preeminent global health organization is conducting the world's largest un-scientific clinical trial. The drugs and treatment guidelines it is recommending for poor nations raise troublesome questions.

On May 27, the World Health Organization (WHO) issued the 15th Edition of its Prequalification Project for AIDS drugs. Through this mechanism, WHO provides a list of manufacturers whose HIV-related medicines have been found acceptable, in principle, for procurement by United Nations agencies. In this last edition, WHO for the first time de-listed two previously prequalified antiretroviral (ARV) products. They were the single dose lamivudine, and the double dose lamivudine+zidovudine, manufactured by an Indian company. The reasons: "the outcome of an inspection in which compliance with Good Clinical Practices and Good Laboratory Practices was assessed, and data verification of the bioequivalence study at the Contract Research Organization used by the sponsor".

Generally, this means that the results drawn from site inspection reports were not consistent with what is considered Good Manufacturing Practices, and that the products were not interchangeable with the patented drugs. Only stringent adherence to bioequivalence standards can assure that a pharmaceutical product when administered to the same individual in the same dosage regimen, results in equivalent concentrations of drug in blood and tissues.

Lamivudine and zidovudine are pharmaceutical components of the Indian triple and double fixed dose combination drug products. These drugs combine two or three different drugs into one tablet. Their de-listing challenges assumptions made by WHO when on December 1, 2003 its "3 by 5 plan" was formally announced (the provision of AIDS treatment to 3 million patients by 2005). Why? Because within the four main recommended therapies, these two products are key components.

In all 15 Editions of WHO's Prequalification, this Disclaimer has been issued: "Inclusion in the list does not constitute an endorsement, or warranty of the fitness, of any product for a particular purpose, including in regard of its safety and/or efficacy in the treatment of HIV/AIDS".

When the two Indian manufacturing sites in question were initially inspected by WHO in November 2001, the outcomes were stamped "Compliance [with] GMP". Then, on June 17, WHO released a press statement, saying that "the raw data from patients failed to prove that the drugs in question were bioequivalent" to the patented drugs. Further on, this comment: "in some countries, contrary to WHO recommendations, bioequivalence is not necessarily a requirement for generic products".

Products destined for export from India need not demonstrate bioequivalency. WHO understands this, yet, the June press release goes on say that its "prequalification process includes rigorous assessment of data for bioequivalence in generic products". Since the only production sites prequalified to supply UN agencies with 'generic' ARVs are in India, Members States must have concluded rightly that they were procuring drugs tested against this standard.

Along with the promotion of copy drugs from India, WHO published a Treatment Guideline for ARV administration. WHO is recommending "that drug resistance testing will not become a routine part of clinical care in resource-limited settings and so it is not considered". This Guideline is presented as "the cornerstone of the WHO 3 by 5 plan".

Why are poor Africans being subjected to the world's largest un-scientific clinical trial?

Why is WHO allowing its supporters to promote these drugs as 'generics' when it fact they are copy drugs? Why is the country that produces these drugs not using them for its own AIDS-infected population?

In the first instance, the decision to do so has been made by neocolonialists at WHO's headquarters in Geneva: they know what is best for Africans. In the second instance, WHO itself never referred to the prequalified drugs as 'generics', yet it has taken no steps to inform Member States in Africa that the drugs of choice for treating 3 million by 2005 are actually copies. Under Indian law, patents can be broken and their products reversed engineered to produce drugs that are known as copycats, or more inelegantly, as 'knock-offs'. In the third instance, the Indian government provides incentives to its local pharmaceutical companies if they export. Schedule Y of its Drugs and Cosmetics Rules can permit exported product to forego toxicity, bioequivalence/bioavailability studies.

The Drugs Controller General (India), a rough equivalent to the U. S. FDA, issued a production license for the triple dose combination in July 2001. Of the several conditions listed for its use, one stated that the manufacturer shall make "no reference in the advertisement or medical literature that the Government has approved the drug". If the manufacturer isn't permitted to make such a statement, then why should this drug be administered to poor Africans under WHO's sponsorship!

The de-listing raises these questions: will WHO now insist that the Indian company recall the products, and conduct post-marketing surveys among those who have used it to determine if there have been adverse effects; and, if such effects are noted, what legal recourse do patients have for medical malpractice?

Until these questions are answered, poor Africans should not continue to be enrolled irresponsibility into the world's largest un-scientific trial. Can lesser treatment standards make a different to patients' outcome? Robert Gallo and Luc Montagnier, co-discovers of HIV, say: "if compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in multidrug-resistant HIV mutants whose further spread will only exacerbate the epidemic".

WHO needs to reassure its Members that it has compelling, scientific reasons for continuing its 3 by 5 plan with drugs and treatment guidelines of lesser standards than the higher standards now being used by other Member States, such as South Africa, Botswana, and Brazil. If a double standard between States that have the same disease is justified, then WHO would do well to commission risk-benefit studies and determine the real value of the latter against those who are so burdened with the former.

Since India is the only country prequalified to supply copy drugs to UN agencies, the re-evaluation of all bioequivalency data by WHO would restore confidence in the Prequalification Project. WHO can use this de-listing as an opportunity to be a proactive moral force in the service of science and medicine-rather than an advocate, to the benefit of poor patients. These ARV drugs may be all that their proponents claim; but the events of the past few weeks call for a large measure of re-assurance if the current question marks around the world's largest clinical trial are to be quickly removed.


TCS Daily Archives