TCS Daily

Slow and Steady Wins the Race

By Roger Bate - July 14, 2004 12:00 AM

Drug therapy and US policy jumped to the top of the agenda of this week's UN conference on HIV/AIDS in Bangkok, Thailand. A key talking point has been whether countries should be switching from existing therapies of brand-name drugs to formulations made from knockoff drugs that are simpler for patients to take.

Complex mixing of different drugs into a single pill holds the potential to make life easier for patients and is, in principle, a great idea. But it's a political hot potato because one of the few single pills on the market, and the one most promoted in Africa, is made by an Indian generics firm called Cipla and is made from copies of drugs developed by western companies. Furthermore, there are concerns that the drug has not been sufficiently tested, causing false hope and potentially leading to drug resistance. Cipla has taken producers in the right direction but its lack of quality control is worrying, especially to the patients taking it.

Cipla saw the single pill drug combination niche in the HIV drug market and went for it. It was a bold move, and its triple drug therapy, Triomune, is being widely used by thousands of patients in Africa. In the July 6th issue of the Lancet medical journal, several medical experts analyzed its efficacy in a small trial in Cameroon. Even though it was not a clinical trial and there was no control group, the Lancet authors were encouraged by what they found and are endorsing its use.

Cipla stole the march on the western companies who are now more belatedly developing combination therapies, usually called FDCs (fixed-dose combinations). Part of the reason for the inertia is that it is costly to test the drug combinations properly for bioequivalence.

"Combining different drugs leads to unexpected and often unknowable effects," says Dr John Martin, CEO of Gilead, a pharmaceutical company with two FDA approved HIV medicines. It's essential that the tests are done to ensure that the single dose pill acts in the same way for the patient as the pills do taken individually. Without such action there is a very real likelihood that inappropriate (usually sub-optimal) absorption of the drugs by the patient will lead to drug failure. This could be potentially fatal for the patient and very damaging to society by encouraging drug resistance.

Another reason for inertia is that the drugs one needs to combine to develop a single pill to combat HIV are patented by different companies. Cipla's Triomune uses drugs developed and patented by Boehringer Ingelheim, GlaxoSmithKline and Bristol Myers Squibb. But since Cipla can ignore patents in India (and most African markets), it just uses whatever drugs it wants without paying a royalty or negotiating with the patent-holder.

The research-based industry has been criticized by some doctors and health experts in Africa for not moving fast enough, in their view, to actively develop and market FDCs. African doctors require as much simplicity in treatment as possible, given the lack of both infrastructure and medical support staff. A more complex treatment regime often means the difference between life and death, since compliance is lower with complex treatments.

Gilead's John Martin is a fan of FDCs, and his company's two approved HIV drugs, Emtriva and Viread, are being combined as an FDC. It is expected to be approved before Sept. 12th, the date the FDA has set as its own deadline for a decision. Dr. Martin explained to us that his drug combinations have gone through extensive bioequivalence tests monitored by the FDA, which is why the FDC is not on the market yet.

Furthermore, when producing FDCs it's vital (and it's always important in single-drug formulations) that good manufacturing practice is followed. FDA officials descend randomly on Gilead's factories and all production facilities in the US to check that standards are maintained.

It is extremely unlikely that the Indian equivalent of the FDA randomly drops in on Cipla's facilities to check on performance. Very little is known about the reliability of supply of Cipla's HIV products. As such, the Triomune study discussed in the Lancet could be replicable to tens of thousands of patients; or it might have been just a lucky, well-produced batch that led to encouraging results. We don't know.

But even if the Indian officials did test facilities in the same manner as the FDA, the bioequivalence testing undertaken for Triomune would not conform to FDA standards. The World Health Organization pre-qualified some drugs for use, including lamivudine and lamivudine + zidovudine produced by Cipla. Since 2001, these drugs have been components of combination therapies, but WHO had to withdraw that prequalification (after thousands of patients have been taking the drug) in May this year because the drugs are not bioequivalent. Apart from anything else, this episode should be setting off alarm bells when it comes to the value of WHO's approval process.

The serious concerns regarding the quality of Triomune aside, FDCs will be part of the future of HIV/AIDS treatment. Indeed, following the slower, but safer, US procedures, Gilead, Merck and BMS are working together to produce a complete triple-drug FDC. It incorporates Gilead's two drugs and Efavirenz (patented by BMS and Merck). Testing is ongoing and the combined treatment, when approved, should only require patients to take one pill once a day, compared with Triomune's one pill twice a day, which should further help with treatment compliance.

While the Cipla hare was first to market extensively, the research-based, FDA-backed, tortoise will probably win eventually since Cipla is playing fast and loose with quality. Presidential nominee Kerry is currently backing Cipla, but he may have to change his mind after the election if he wins. Whoever wins out, the progress towards developing sound and effective FDCs should leave patients in poor countries better off.

Dr. Roger Bate is a visiting fellow of the American Enterprise Institute and Richard Tren is Director of Africa Fighting Malaria.


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