E-DRUG: The Botswana Conference on FDCs: A Voice out of Africa
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The Botswana Conference on FDCs: A Voice out of Africa
I attended the conference in Botswana on fixed dose combination (FDC) drug products for HIV/AIDS, tuberculosis and malaria, the three major, but treatable killer infections in Third World countries. Judging by media accounts in the U. S. and on the Internet, there must have been another conference on this topic occurring at the same time. Therefore, I would like to inform you about the one I attended as a clinician from South Africa.
Held on March 29-30, the purpose of this open scientific conference was to finalize a document on principles to facilitate the development and evaluation of FDC drugs. It was co-sponsored by the World Health Organization (WHO), UNAIDS, the Southern Africa Development Community (SADC), and the U. S. Department of Health and Human Services (HHS). The document used for discussion had been prepared at a preliminary conference in Cape Town in February by an international panel of experts from drug regulatory agencies of several developed and SADC countries and of WHO.
Prior the opening session, the activist community orchestrated an incessant drum-roll of negative articles to the U. S. media, which I picked up from the Internet. Letters were directed to the White House and the U. S. Department of State, with copies to media outlets, claiming that the conference itself was �yet another barrier� to HIV/AIDS treatment. Further, that it was a pretext to subordinate WHO�s Pre-qualification system in favor of a system supported by the pharmaceutical industries of the United States as the largest financial supporters of the President�s election campaign.
On day one, the Cipla/USA representative commented that the US media and Congress characterized the meeting differently from what the co-chairs had just stated in their preliminary remarks at the opening of the conference. The co-chair from South Africa responded: �this is not a meeting for the US election�.
This media barrage was, however, to no avail. Science prevailed! Having failed, the activists nonetheless were able to utilize the last 15 minutes of the conference to read off prepared statements, which were reprinted by a compliant media within eight hours.
As context is important, some historical background is required. In April 2002, WHO for the first time permitted the listing of HIV/AIDS therapies on its Essential Drugs List. Up until then, WHO had only advised on HIV prevention activities. Shortly after this, Indian generic drug companies, including Cipla, began to promote the use of FDC antiretroviral (ARV) drug products. FDCs have several major practical and therapeutic advantages, compared to individual drugs used separately in, what is commonly known as a �cocktail�. For instance, adherence to a drug regimen is more easily enhanced, and drug management and supply can be simplified; tuberculosis (TB) is a good example of this. However, the manufacturing of drugs as FDCs has potential problems which may result in reduced activity and enhanced toxicity, as is well known from some anti-TB FDCs.
It is not unusual that applications for licensing of generic drugs have only minimum, often inadequate supporting data to convince stringent drug regulators that they meet standards of quality, safety and efficacy when compared to originator products. These deficiencies than, of course, delay the licensing and use of such products.
In October 2003 the Clinton Foundation announced completion of successful negotiations with Indian generic manufacturers of ARV FDCs, and stated that these would be available at $140 per person per year. In December 2003 WHO pre-qualified the first FDCs for use in HIV/AIDS treatment. But in pre-qualifying these drugs, WHO issued a Disclaimer, saying that it did not warrant them in regard to �safety and/or efficacy in the treatment of HIV/AIDS�. In addition, WHO would not release the site inspection reports or dossiers of the drugs they pre-qualified, for external evaluation.
In the President�s Emergency Plan for AIDS Relief (PEPFAR), an impressive $15 billion is being made available over the next five years in 14 developing countries.
All drugs used internally in the U. S., as well as all drugs that are imported into the country, must be approved by its Food and Drug Administration. This principle holds for most countries. The U. S. government could find no reason to have double standards: one for the U.S citizens and a lesser standard for the people in Third World countries.
In Third World countries, NGOs have been using originator and generic ARVs for some time, and more recently FDCs. However, as these products are not used under controlled (and labor intensive) circumstances and conditions , the data collected during field use, even if there is evidence of clinical benefit, is often inadequate to support their licensing. Generic drug manufacturers in Third World countries rarely conduct independently validated clinical trials to assess the efficacy and safety of their products and do not have the mechanisms in place to do post-marketing studies to determine adverse effects.
In recognition that the world faces a global health emergency, the U. S. government decided to promote the Botswana conference as a means to allow its grantees to procure and use generic drug products, including FDCs, if these satisfied the necessary standards of quality, safety and efficacy. It was advertised on the Internet as an open meeting. The draft document was posted on the Web before the conference, accompanied by an invitation to submit comments.
The conference resulted in a draft document on principles to be taken into account with regard to FDCs. It is intended for use by the pharmaceutical industry, drug regulatory agencies of developing countries, government agencies, and NGOs evaluating the use of these products in their programs. Consensus on this draft document was reached by combining the inputs of senior officials from several leading regulatory agencies in both developed and developing countries and from WHO.
Despite what has been claimed in US media outlets and on the Internet, there are no new requirements for licensing of drugs in this document. These allegations must, therefore, probably have been put forward to mislead U. S. authorities and the U. S. public, perhaps also in order to delay the implementation of PEPFAR.
In the not so distant past, drugs of unknown, and even of known inferior standards of
quality, safety and efficacy, as well as drugs near or past their licensed expiry dates, have been bought by, or donated to developing countries by well-meaning NGOs. But people in these same countries have become increasingly aware that drugs used in their countries frequently have not been vetted by drug regulatory agencies of repute. On past experience, they are justifiably concerned that these drugs may not always be effective and may sometimes even be toxic.
Therefore, there is an increasing awareness of the need for drugs to have proven quality, safety and efficacy. Individually, though, these countries frequently do not have the scientific capacity to provide the necessary directives and requirements for acceptability of new drug applications submitted for licensing, or even to assess new drug applications. Moreover, manufacturers of generic drugs often have similarly limited scientific capacity to produce the essential documentation on quality, safety and efficacy, as required in applications submitted for the proposed licensing of such drugs.
By providing a set of principles, the Botswana document on FDCs will facilitate these processes. In addition, new FDCs and pediatric FDCs are urgently needed and manufacturers of generic and of new originator FDCs need to be informed on how to approach the development of such new products.
Representatives of several drug regulatory agencies in African countries welcomed this document, saying they were aware that inferior drugs had been, and still are, being used in many African countries. They felt that the document provided them with information on what to look for when assessing applications for the licensing of new and generic FDCs. They were most appreciative of the investment in this conference by the sponsors. Furthermore, they were extremely grateful that this conference was held in an African country. The discussion on the finalization of the document provided them with a much appreciated learning experience. One delegate from Botswana�s ministry of health commented: �the African regulators are not being unreasonable by asking generic companies to show them the data�.
Yet, on the morning following the close of the conference, the U. S. media branded it as a failure to reach consensus. Advocates of generic FDCs still seem to believe that drugs of uncertain quality, uncertain efficacy, and of unknown safety, are good enough for the Third World. And that the principle of drugs needing to be of universally accepted standards anywhere in the world is not all that important to generic manufacturers.
It would indeed be very, very sad, and a shame to those who believe so strongly in freedom of speech, if the untruths about this document on principles for FDCs were to delay the implementation of PEPFAR, thereby probably condemning millions to unnecessarily die in developing countries.
Bernard W. van de Wal
MB; ChB, M. Med (Internal Medicine)
Physician
South Africa
bwvdewal@sun.ac.za
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