TCS Daily

Haste Makes Waste of Resources and Lives

By Roger Bate - May 5, 2005 12:00 AM

HIV is a hugely successful organism; it replicates rapidly and easily develops resistance to incomplete or inappropriate therapy. A resistant strain is vastly more difficult and expensive to treat. For this reason the World Health Organization (WHO) recommends that, among other things, patients must be carefully assessed before treatment, as to the stage of disease they have reached (1 to 4) and whether they have already had some treatment and whether that treatment failed. When possible, no drug should be taken singly -- two and preferably three drugs taken in combination is best. In developing countries, where even clerical staff are hard to find and doctors trained in diagnosis and treatment of HIV/AIDS are desperately rare, fulfilling these exacting requirements is a challenge in itself.

One method to improve treatment adherence is a fixed-dose combination of AIDS medicines in one pill. The problem is that only one such treatment, Trizivir by GlaxoSmithKline, has US and European Community approval and it is not suitable for widespread use. In its urgency to treat three million HIV patients by the end of this year (through its "3-by-5" program), WHO pre-qualified (gave its blessing to) a list of fixed-dose combination drugs (FDCs) produced by copy-cat firms in developing countries. That is, WHO waived some of the FDA-standard requirements for new drugs in order to speed up supply to its treatment programs.

Meanwhile it's recently been announced that three of the world's leading research pharmaceutical companies, Gilead, Merck and Bristol-Myers Squibb, have just failed to achieve "bio-equivalence" in their first attempt at a triple-therapy, fixed-dose combination of their own HIV drugs. That is, if taken together, the drugs would not perform identically to when taken singly. This is not surprising as it is well known that absorption and excretion rates can change when drugs are combined. However, generic FDCs that have not been tested for bioequivalence are being sanctioned in developing countries by the WHO.

Cipla Ltd of India is a prominent generic drug producer of these FDCs. In response to pressure from NGOs and activist groups, in May 2004 the FDA issued guidelines that would fast-track applications for anti-retroviral (ARV) products from companies such as Cipla by speeding up paperwork and even waiving application fees. However, by November 2004, it became clear that Cipla and two other Indian generics companies, Ranbaxy Laboratories and Hetero Genix Pharma, could not provide evidence of bioequivalency for both individual and combination therapies, with the result that 18 antiretroviral medicines were withdrawn from the WHO 3-by-5 program.

WHO's effort to massively scale-up HIV/AIDS treatment was always ambitious, but it is becoming painfully obvious just how ill-conceived WHO's 3-by-5 campaign really is. Enrolling patients on treatment regimes and then suddenly withdrawing them is worse than if they had no treatment at all. In this case, doctors who prescribed generic FDCs in good faith now have no idea of the effect of their treatment. What they do next for their patients is anybody's guess. The WHO has offered no advice.

According to Merle Sande and Allan Ronald of the American Medical Association, "to scale up antiretroviral therapy for HIV without ensuring infrastructure, including trained practitioners, a safe and reliable drug delivery system, and simple but effective models for continuity of care, would be a disaster, leading to ineffective treatment and rapid development of resistance."[1]

The United States has been reluctant to purchase and distribute generic FDCs and this caution has been vindicated. Last Friday's announcement that the FDC by some of the world's leading drug firms had failed bioequivalence testing is a further blow to the advocates of hastily scaled-up treatment. It demonstrates the complexity of safe and reliable treatment and the careful persistence that's required.

Roger Bate is a Resident Fellow of the American Enterprise Institute.

[1] Merle A. Sande and Allan Ronald, "Editorial: Treatment of HIV/AIDS: Do the Dilemmas Only Increase?" Journal of the American Medical Association, July 14, 2004, 292 (2), p.267.


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