April 21, 2004
by Jeremiah Norris
According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), there are approximately 41 million people around the world infected with HIV, of which some 6 million are in need of immediate treatment through antiretroviral drugs (ARVs). However, only 400,000 are currently receiving them. To understand some of the obstacles to effective treatment - and how activists are threatening to make the current unfortunate situation could considerably worsen - we need to understand some basics of HIV/AIDS treatment.
The UN/Accelerated Access Initiative, a program that is conducted in collaboration with six pharmaceutical firms, provides low cost patented ARVs to 150,000+ AIDS patients, mainly in Africa. A commonly used ARV product in these programs is a two drug combination called Combivir under its trade name, administered twice each day, with a single dose product called Stocrin, administered once daily. This makes for a total pill count of three per day per patient. Both Combivir and Stocrin have been approved by the FDA and other regulatory authorities in developed countries. They are used also by such firms as Heineken Breweries and Ford/Africa in their treatment of AIDS infected employees and their dependents.
In December 2003, the World Health Organization (WHO) pre-qualified ARV manufacturers and drugs in a triple fixed dose combination product called Triomune when produced by the Indian firm Cipla, or Triviro when produced by Ranbaxy, another firm in India. A fixed dose combination (FDC) combines three ARV drugs into one single tablet. Either of these, when administered as an FDC, would require a total pill count of two per day per patient. However, neither product has been approved by regulatory authorities in the U. S., Europe, Canada, Japan or Australia.
Combivir is composed of lamivudine/zidovudine, while Stocrin is efavirenz. The pharmaceutical products in the trade name products Triomune and Triviro are the same: lamivudine/stavudine/nevirapine. However, in February 2004, the U. S. FDA put nevirapine on its medical product safety list, as it causes "severe, life threatening and, in some cases, fatal" problems stemming from liver toxicity.
The drugs made by Indian firms are copies of patented products. WHO, as well as organizations such as Medecins Sans Frontieres (MSF), and other non-governmental organizations, have been pressuring the Bush Administration to use some of its $15 billion in AIDS funding to purchase these Indian FDCs. They claim that since FDCs are less expensive, and easier for patients to take (since it requires taking fewer pills). As such they believe more AIDS victims can be treated for less costs. In other words, by eliminating one pill per patient per day with the Indian products, the trade-off in known FDA-type standards would be worth it.
FDCs have several attractive features. For one, instead of a patient having to take three tablets a day, only two would be required. Therefore, patient adherence to a drug regimen promised to be somewhat higher. For another, it would simplify shipment, storage, and distribution, permitting more ARV products to arrive in a country at a faster rate to treat more people. However, their clinical benefits have not been established through independently validated trials or post-marketing surveys. As such, what should American and global policy be toward FDCs?
The Bush Administration program is operated through the U. S. State Department, under the overall direction of Ambassador Randall Tobias. While he has spoken publicly of the U. S. government's willingness to purchase copy drugs at less cost, he has also been quite firm in stating that such drugs must first be of proven quality, safety and efficacy. When WHO pre-qualified FDCs, it also issued a Disclaimer, saying that they were not warranted in regard of their safety and/or efficacy in the treatment of HIV/AIDS.
This Disclaimer placed Ambassador Tobias in a bind. If the FDCs are not approved for use in developed countries, and WHO felt compelled to issue this Disclaimer, then by using U. S. government funds for their purchase, he would be endorsing a double treatment standard: an unproven FDC (triple combination) for poor Africans, and a proven FDC (double combination) for more well-to-do citizens in Western countries.
The global health community has long pushed to avoid double standards in treatment. Indeed, WHO has had long standing guidelines on humanitarian relief operations, developed in cooperation with the Red Cross, the United Nations, and MSF. One of its core principles is: "there should be no double standard in quality".
Policy by Press Release
In order to resolve this issue and address the concerns of groups like MSF, the Department of Health and Human Services (HHS), and three other co-sponsors decided to host a conference in Botswana to discuss and draft Scientific and Technical Principles for Fixed-Dose Combination Antiretroviral Products. The other co-sponsors were: WHO; the Southern African Development Community (SADC); and UNAIDS. The principles to be discussed and developed would focus on quality, safety and efficacy of drug products for AIDS treatment among the world's poorest. The objective was to determine if it would be possible to develop a set of standards for FDCs that were not as stringent as those used by other regulatory authorities, yet would still ensure that these products had proven quality, safety and efficacy attributes.
Beginning on March 22, MSF and others began issuing press releases and letters to Members of Congress and to the President. They directed their angst solely at HHS rather than all of the co-sponsors. This media blitz called for a cancellation of the conference, stating that is was a pretext for replacing the Pre-qualification system of WHO with that of the FDA. The fact that FDCs have not been approved within the E.U. or other developed countries was of no immediate concern in this blitz: the target was the U. S.
I attended the Botswana conference. If there was any failure coming from it, this can be attributed to those who worked so hard to discredit a single co-sponsor before the meeting was even underway. Having failed in that endeavor, they then accelerated their disdain for its joint and collaborative proceedings through compliant media outlets. They read prepared statements in the last 15 minutes of the conference, and within several hours, the media was quoting from them, proclaiming that the conference had failed to reach a consensus.
None of these press releases mentioned that the two co-chairs of the conference, WHO and SADC, had agreed to integrate all of the inputs from various parties into a comprehensive document for final review. This, then, would constitute the Scientific and Technical Principles for Fixed-Dose Combination Antiretroviral Products.
And, of all the press releases out of Botswana, none gave voice to African participants. Let's hear a few: "We are holding all drugs to the same high standard" (delegate from Botswana's ministry of health); "Yes, people are dying in Africa, but should we throw out standards and buy anything" (delegate from the Food and Drug Board, Ghana); "Poor quality means poor access. We have to balance quality with need" (delegate from the Medicines Control Council, South Africa); "The African regulators are not being unreasonable by asking generic companies to show them the data" (delegate from Botswana).
Then, on April 12, the Financial Times carried an article by Thompson Ayodele, Director, Institute of Public Policy, Lagos, Nigeria. He wrote: "HIV medicines, whether original or generic, should meet the most stringent, rigorous clinical and testing reviews. If the proposed drugs are rejected by pharmacies in Brussels, Geneva, London, Tokyo, or Washington, accepting the use of the same drugs in Africa with little resources and lack of equipment to do a proper clinical and scientific evaluation may further compound the woes of HIV/Aids victims".
These African voices are representative of the conference I attended. Perhaps the advocates for FDCs from India attended an entirely different meeting in Botswana. If public health by press release rather than through the uncompromising dictates of science and medicine, can address global AIDS effectively, then the advocates for this drug of indeterminate quality, safety and efficacy might be on to something. They should submit these FDCs for independent clinical validation from a recognized, stringent regulatory authority. If approved, patients will win. All else is immaterial, and the elimination of one pill per patient per day might well be worth it.
Jeremiah Norris is a Senior Fellow and Director of Hudson Institute's Center for Science in Public Policy. He specializes in public-private partnerships in development assistance, trade and development, and global AIDS, tuberculosis, and malaria policies.
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