TCS Daily

TCS Exclusive: 'No Black and White Answers'?

By James K. Glassman - January 10, 2005 12:00 AM

The top official of the Global Fund to Fight AIDS, Tuberculosis and Malaria drew a sharp distinction last week between his organization's policy on AIDS drugs and the policy of the United States, his largest source of funds.

In an interview with TechCentralStation Wednesday, Richard Feachem, executive director of the Global Fund, said that recent de-listings of questionable Indian-made medicines that had earlier been "pre-qualified" by the World Health Organization were "obviously a setback to the global effort" to fight AIDS.

But he said he stood by his policy of allowing distribution of AIDS drugs given a green light by the WHO -- even if they are not approved by the U.S. Food and Drug Administration or an equivalent regulatory agency in a developed country.

The WHO list is maintained by a tiny staff with no facilities for testing, and the WHO does not warrant safety or effectiveness. Drugs that do not meet even these standards are now floating all over Africa, with no means of recall.

In the interview, Feachem did not answer a vexing and pressing question -- what to do about a large shipment of AIDS drugs funded by his organization that recently reached Ethiopia -- even though, according to press reports, the medicines had been de-listed by WHO.

By contrast, the U.S., through its own agency, the President's Emergency Program for AIDS Relief (PEPFAR) -- the largest such effort in the world, with $15 billion scheduled to be spent over five years -- has made it clear that it will not spend money on AIDS drugs in Africa or the rest of the developing world unless the drugs are as safe as those given Americans.

The U.S. policy is that people sick with AIDS in Kampala and Kinshasa deserve medicines just as good as those given patients in Chicago and Copenhagen -- especially since such drugs are available and affordable.

AIDS has become largely a disease of poor nations. Currently, according to a new U.N. report, 25 million people in Africa -- roughly two-thirds of patients globally -- are infected with HIV. Last year, 2.3 million Africans died of AIDS, compared with 22,500 in all of Western and Central Europe and North America.

The American policy on drug approval was initially criticized by non-governmental organizations as a means of generating revenue for U.S. research pharmaceutical companies, but a study by the Hudson Institute, using data from Doctors Without Borders, found that patented drugs actually cost less, on average, than generic or copy drugs in poor countries.

Still, last spring, Tommy Thompson, secretary of Health and Human Services, announced a fast-track process for anti-retroviral (ARV) drugs, which stop the progress from HIV to full-blown AIDS. The process was aimed, especially, at speeding approval for generic drugs that were originally developed and manufactured by U.S. and European firms and copied by manufacturers in developing countries, mainly India.

So far, however, none of the copy drugs has been approved, and the FDA will not say if any have been submitted. But, since June, 18 Indian-made ARVs that were once listed by WHO as pre-qualified for use in relief programs were removed by the United Nations agency or voluntarily by the manufacturers -- Ranbaxy, Cipla and Hetero.

The laboratories that conducted studies on "bioequivalence" -- to find whether the copied drugs had the same chemical composition and potency as the original patented drugs -- "did not," according to the WHO's website, "comply with international standards of good clinical and laboratory practices."

While the firms presented the problem as a paperwork foul-up, only two of the 18 drugs have so far been reinstated by the WHO. Those went back on the list Nov. 30, but the Medicines Control Council of South Africa still ranks them as undesirable.

Africans have complained in recent months about being used as "guinea pigs" for inferior products.

The de-listings appear to vindicate the U.S. policy of insisting on high scientific standards -- in large measure because taking AIDS drugs of inadequate potency can lead to resistance and the obligation to foot a far higher bill for second-line AIDS medicines, or, worse, the spread of mutant strains for which there are no therapies.

Last summer, the respected American Foundation for AIDS Research sternly warned that a flood of untested generics, made by more than two dozen companies in developing nations, "could lead to widespread misuse and eventually to drug resistance, eradicating years of progress."

But, in the interview with TCS, Feachem said that his faith in the WHO was not shaken and that the Global Fund would keep using WHO's list as a "Good Housekeeping Seal of Approval."

"We rely on the WHO pre-qualification process," he said. "Of course, there are concerns, but most technical observers... believe the WHO process is rigorous." He added that "clinical evidence is solid and growing."

This interviewer pointed out that the main clinical evidence on behalf of the copy drugs was a brief study, by Christian Laurent and colleagues, using a small number of patients in Cameroon. The study, as the researchers acknowledged, was "not a controlled trial."

Feachem, a British subject who formerly taught at the University of California and headed the Institute for Global Health in San Francisco, acknowledged that more research would be welcome but that "we face this crisis" right now. "None of this is easy, straightforward and without risk."

The contrast between Feachem's views and U.S. policy is stark. American officials believe that the risk of using drugs that have only been pre-qualified by the WHO is too great, especially when a swift pathway to approval at the FDA is available.

Feachem, who was interviewed in the cafeteria of the Longworth House Office Building between visits with members of Congress, tried to put a friendlier face on his relations with American officials. "We're converging rapidly," he said. In Tanzania, for example, he said that the Global Fund was buying first-line ARVs that will be administered in fixed-dose combinations (FDCs), that is, as single tablets of three medicines. PEPFAR, the U.S. relief agency, will provide second- and third-line drugs.

But no three-drug FDC -- patented, generic, or copy -- has been approved by the FDA, and scientists have warned that the technology of making such combinations is not so simple as it seems.

The most important evidence of convergence would be U.S. approval of some of the Indian copy drugs -- even as individual FDCs -- but that hasn't happened yet.

The WHO has come under criticism both for the pre-qualification process and for its overstated claims of being able to treat three million patients for AIDS by 2005 ("three by five"). But a phalanx of international officials has lined up behind the beleaguered WHO. For example, Stephen Lewis, former Canadian ambassador to the United Nations and now U.N. special enjoy to Africa for HIV/AIDS, said in an interview with that de-listings and withdrawals from the WHO list have "not threatened" WHO policies "one whit."

And, despite the de-listings, the WHO continues to laud the Indian copy-drug companies. For example, Jim Yong Kim, who heads the AIDS effort at the WHO, recently claimed in a letter to the Indian government that "India is the leader in the global supply of affordable antiretroviral drugs and other essential medicines."

But Kim is certainly aware that the Indian companies have not invented a single ARV on their own. They copy the work of others -- even before patent lives have expired. It is highly unlikely that the next round of AIDS drugs will come from India.

The Global Fund, however, is independent of the U.N. and WHO. It can set its own policies. The key question now, with "convergence" still a ways off, is whether Feachem will take his cues from the WHO or from Washington, his largest funder. The interview indicates that, for now, he continues to side with the WHO.

"The system is working," Feachem said, referring to the WHO. At any rate, he said, there is no alternative. "We face this crisis, and we find that we have drugs that can make a difference."

The Global Fund in 2005 expects to raise $1.3 billion -- including $435 million from the U.S. "to extend its initial grants to their full five-year term. The U.S. share for 2006 will be $1.1 billion with another $1 billion annually thereafter.

The Global Fund does not procure drugs itself but provides grants to national and non-governmental agencies. The Fund does, however, set down principles to be followed by purchasers of drugs, including that the medicines meet standards of "assured quality." Currently, one way to meet that standard is for a drug to be on the WHO list.

But the Global Fund faces a dicey situation in Ethiopia, where, according to a recent report in Addis Fortune, 50,000 cartons of drugs, manufactured in India and stuffed into a half-dozen aircraft, entered the country in mid-December, "dodging inspections by the Federal Drug Administration and Controlling Agency and the Ethiopian Customs Authority," according to the publication's sources.

The drugs, said the publication, were "part of procurements funded by the Global Fund's $50 million financial assistance" to Ethiopia. But, reported Addis Fortune, "the manufacturers were not able to submit the good manufacturing practice (GMP) certificate the World Health Organization demands." The reason, said the publication, was that the Indian manufacturers could not produce a GMP since their ARVs had been removed from the WHO list.

When this interviewer asked Feachem about the Ethiopia situation, he said his office would provide an answer later, but so far it has not.

Feachem, a skilled and personable health expert, is having a difficult time reconciling support from the United States with following WHO policies that trouble many American officials. "There are no black and white answers to these questions," he said.



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