TCS Daily

Is Less Always More?

By Roger Bate - March 5, 2004 12:00 AM

Pretoria, South Africa -- Against the background of the utter failure of the World Health Organisation's Roll Back Malaria program, the current aim to treat 3 million AIDS patients by 2005 seems delusional. And in the vain attempt to treat the millions, the WHO is prepared to cut too many corners. Next week in Pretoria the US government has arranged a meeting of drug experts from industry, the academy and government to discuss the WHO push for untested fixed-dose combination (FDC) drugs. FDCs are a great idea, and are already being used in a limited setting, but not testing them sufficiently, as WHO is doing, will encourage drug resistance and patient death.

FDCs have been successfully deployed in the fight to combat malaria (Novartis' Coartem is a mix of artemether and lumefantrine delivered in one pill), and many other diseases. However, the limited numbers of drugs approved have all been extensively tested and comply with the best standards for single-therapy drugs.

One of the biggest mistakes made by WHO in RBM was to persist in supplying single therapy drugs to which the malaria parasite had developed resistance. This is not only wasteful (since the drugs didn't cure the patient) but dangerous as resistance was increased making failing drugs totally useless. The international community, ignored by WHO, encouraged the deployment of double combination therapies for malaria. Because the WHO dropped the ball on malaria, many influential commentators and public figures, from the Wall Street Journal to Senators Judd Gregg and Russell Feingold, are worried that WHO can also fail over AIDS. And more is at stake with AIDS -- more lives and a lot more money.

WHO is yet to correct its policy error, despite doing such a disservice to the millions of malaria victims, but for the HIV '3 by 5', it appears to have learned from its malaria failure. Since HIV mutates quickly, single dose drug regimes are vulnerable to resistance. Current thinking is that single pill, triple therapy for HIV/AIDS, which relies on three drugs given simultaneously, should lower the likelihood that resistance will develop.

Interest in this approach has followed from all quarters: the research-based drugs industry, companies that copy drugs, government officials and numerous non-governmental organisations. And all groups are represented at the Pretoria meeting. The big problem is that single pill HIV/AIDS triple therapy has had minimal testing.

Most regulatory agencies, including the Food and Drug Administration in US, insist on testing new formulations almost as rigorously as if they were a new drug, even though the individual drugs have all been registered. This is because there could be different and unknown pharmacokinetic and pharmacodynamic effects from the packaging of the chemicals. The WHO seems prepared to bypass this testing and quickly treat millions of HIV/AIDS victims with these new formulations.

But this approach conflicts with the widespread, if largely implicit, assumption that there should only be one international standard for drugs testing. This assumption is backed up even by those groups who are desperate to see drugs deployed in Africa. The Red Cross and Doctors Without Borders said: "There should be no double standard in quality: if the quality of an item is unacceptable in the donor country, it is also unacceptable as a donation."

At present, only GlaxoSmithKline (GSK) and Abbott Laboratories have obtained US and EC approvals for combination AIDS drug products. And the only triple therapy drug in one pill is GSK's product Trizivir, which is a complete treatment in that it contains Abacavir, Lamivudine and Zidovudine in one tablet.

GSK has one other product that contains two ARVs, but this needs to be combined with another drug. Similarly, Abbott has a product, Kaletra, which combines two protease inhibitors, ritonavir and lopinavir, which also needs to be combined with a third product.

In other words, no other fixed-dose combination product has passed FDA-standard approval. Nevertheless, WHO has pre-approved several products for use in Africa. Several Indian manufacturers are creating and marketing FDCs without submitting them for approval in either the US, the EC, Japan or any other country with a similarly stringent regulatory process. One of these has already been registered in Guinea, Central African Republic, Malawi and the Democratic Republic of the Congo. Let's be clear, these FDCs, which as individual drugs are safe and efficacious, would not be approved for use in any developed country, yet WHO has allowed them to be used in Africa.

We simply do not know the effects on patients of these untested FDCs. If the effects are slight, such as slightly decreased efficacy, it may take a very long time before that is known, as only a few more patients die in the short run, and resistance to all three drugs (combined in the FDC) builds up -- devastating for those patients harmed and worrying for society.

FDCs should be encouraged, but they must be tested. Their benefit is potentially lower costs and also they can lower drug resistance. Drug resistance is a major problem and FDCs increase the likelihood that patients will continue to take the drugs as prescribed, and hence will lower resistance over time.

But as Jerry Norris, of the Hudson Institute, and an expert on drug resistance, explains: "Its like the tortoise and the hare." The tortoise is equivalent to careful evaluation of FDCs, the hare is the immediate deployment of untested FDCs. It appears that the WHO in its laudable desire to treat millions of Africans is running like the hare. But we all know who won the race in the end.

Dr. Roger Bate is a fellow of the American Enterprise Institute, and a Director of health advocacy group Africa Fighting Malaria.


TCS Daily Archives