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Generic Medicine for AIDS Raises New Set of Concerns

Recent offers by companies in India and elsewhere to make low-cost generic drugs for AIDS, and the decision on Thursday by brand-name drug makers to stop fighting South Africa's efforts to import cheaper products, have raised hopes that the medicines will finally reach at least some of the 25 million people infected with the virus in sub-Saharan Africa. But AIDS experts are divided over whether drug manufacture in developing countries is really the best way to ease the crisis.

Some worry about whether the generic makers are up to the task and can consistently provide reliable versions of the needed antiviral drugs. Products that are less than full strength could promote the growth of drug-resistant viruses. Some scientists also question whether developing countries, or international health groups acting on their behalf, will be able to monitor the safety and potency of the drugs and enforce manufacturing standards. 

Contaminated drugs for illnesses other than AIDS, some made locally and some from unknown origins, have killed hundreds of people in developing countries in the past decade or so.

But other AIDS experts say the situation is so desperate that what matters is moving ahead to make the drugs available, without getting caught up in red tape. 

"I feel a little uneasy in talking about quality," said Dr. Stefano Vella, the president of the International AIDS Society. "There is such a desperate need for drugs. Clearly the quality is important, but it's one of the points, not the major one. This is like saying: `We need bread. Is it fresh enough?' We need the drugs. From wherever they come they're welcome. 

"My position, and also that of Unaids," he said, referring to a United Nations agency fighting the disease, "is, whoever gives the drugs, thanks a lot. It's O.K. I'm not saying quality is a side issue, but I would address it later on."
But Dr. Mark A. Wainberg, the past president of the International AIDS Society and a professor of medicine at McGill University, took a different view. He said it would be "far superior" if the drugs were provided to Africa by the big companies that originally made them rather than by generic makers, particularly generic companies without proven track records.

"It's not only in the best interests of big pharma to want to play this role, it's in the world's best interest as well," Dr. Wainberg said. "It is ethically imperative to not treat people in developing countries with substandard versions of our drugs."

Generic makers in developing countries may be able to produce good drugs, he said, noting that they are apparently already doing so in Brazil. And Cipla, the large Indian company that is already making some generic AIDS drugs, is highly regarded.

But other contenders are not so well-known. Drug-making requires stringent procedures to ensure quality, and at big, established companies, Dr. Wainberg said, "the quality assurance is already there, and that's vitally important."

A recent editorial in The Bulletin of the World Health Organization warned that developing countries face a growing and underestimated threat from "the rise in substandard medicines with concomitant problems of toxicity, instability and ineffectiveness." The medicines come from both local production and poorly regulated imports. 

Questions of effectiveness are urgent when it comes to AIDS drugs, for individual patients and for public health, because a formulation that is not full strength may fail in the patient and may also foster the growth of drug-resistant viruses that are difficult to treat and that can be passed to other people.

Dr. Paul Volberding, a professor of medicine at the University of California at San Francisco, said, "If the costs were comparable or at least beginning to be, I think most of us would prefer to have the same drugs we use here in our patients. That's the ideal world.

"I think the Food and Drug Administration has a worldwide reputation for the seriousness with which it approaches drug purity and manufacturing standards," he added. "Why would we not want those standards applied in the developing world?"

Since last autumn, when the World Health Organization, Unaids and other health groups called on drug companies to provide low-cost AIDS drugs to developing countries, 34 companies have expressed an interest in doing so, including 29 makers of generic drugs, some in developing countries. 

Because of confidentiality agreements, the companies have not been publicly identified, except for Cipla and another Indian firm, Hetero, which both announced their interest. 

Dr. Yusef K. Hamied, chief executive of Cipla, which is based in Bombay, said his company was already making six drugs for AIDS, but would not try to manufacture the class of drugs known as protease inhibitors, which are included in some types of combination therapy. 

"Cipla has been inspected and approved by the F.D.A. and Australian and Brazilian authorities," Dr. Hamied said in a telephone interview from his home in London. "We are an approved manufacturer."

Dr. Hamied said that at least five other companies in India were also making AIDS drugs, including three that sell their products to Brazil. 

"I believe the quality is fine," he said. "Nothing is wrong. We have checked the quality, because they are competitors."

He said that some of the other Indian companies, unlike Cipla, had not been approved as manufacturers by the F.D.A. or similar agencies in other countries. "But in due course they will be," he said. 

Ben Plumley, a Unaids official, said his group was working with Unicef, the World Health Organization and the United Nations to evaluate the companies' ability to make the drugs. He said he hoped the evaluations would be finished by the middle of 2001.

"It's all about quality control and sustainability of supplies," he said. "Our role is to provide information on all suppliers to the governments, and then it's up to the governments, depending on their own priorities, patents and legal situations, to decide on how they proceed."

Developing countries, lacking safety nets like the Food and Drug Administration, are vulnerable in the world drug market. They may be unequipped to test drugs, and imports may pose a particular threat because in some exporting countries drugs made for foreign sales are not tested as rigorously as those meant for use at home, said Jean-Yves Videau, a pharmacist and the general manager of a nonprofit group concerned with drug safety, the Centrale Humanitaire Medico-Pharmaceutique, in Clermont-Ferrand, France. 

The risks are real. During the 1980's and 1990's, tainted medicines killed more than 500 people in Argentina, Bangladesh, Nigeria, Haiti and India. In the most recently reported episode, in 1998 in Gurgaon, India, at least 33 children died of kidney failure caused by a locally made cough syrup that was contaminated with a toxic solvent, diethylene glycol. 

Doctors who described the outbreak in a recent issue of the W.H.O. Bulletin said investigators could not find out how the solvent got into the cough medicine. They wrote, "there are major problems in enforcing pharmaceutical legislation in developing countries."

Poisoning outbreaks in the other countries also involved diethylene glycol, and have repeatedly occurred even though its toxicity has been widely known since the 1930's, when a product containing it, elixir of sulfanilamide, killed 105 people in the United States.

Mr. Videau said his group had encountered makeshift "grass pharmacies" in the streets in African cities and towns, selling medicines that were said to be antibiotics, but that really contained no antibiotic at all. 

"These products, we don't know from where they are coming," he said.
Even legitimate products can pose problems if different manufacturing methods alter basic properties like how fast a drug dissolves. When that occurs, Mr. Videau said, "the system of dosage has to be changed." The dosing of AIDS drugs is complex to begin with, and could become even more difficult if patients wind up taking products with different sets of directions.

For example, Mr. Videau said his group has tested seven generic forms of Lasix, which is not an AIDS drug, but is a widely prescribed diuretic or "water pill" used to treat high blood pressure and heart failure. The generics were made in western Europe, eastern Europe and Africa. Some dissolved at nearly the same rate as the brand-name drug, but, Mr. Videau said, "One was very different, and it was purely due to differences in the solubility of the raw material."

Dr. Volberding said that if different manufacturing techniques changed the way an AIDS drug was absorbed in the body, its potency could be diminished, which would harm both the patient and the community, by encouraging the growth of drug-resistant viruses.

"The vehicle matters, too — the starches, sugars, capsules, all the things that carry the active drug to the site where it's actually absorbed, and just to that site and not past that site," he said. "That has a lot to do with manufacturing standards."

Mr. Videau said that whoever tests the drugs needs complete information on manufacturing methods and raw materials. In addition to changing the solubility and absorption of drugs, different processes can lead to novel impurities turning up in the drugs, and unless the people doing the analyses know how the drugs were made, they will not know what contaminants to look for, and some may go undetected. 

Experts say that generic manufacturers are unlikely to try to make one important class of AIDS drugs, the protease inhibitors, which include the drugs ritonavir, indinavir, nelfinavir, amprenivir, saquinavir and kaletra. Protease inhibitors are expensive, time-consuming and difficult to make. 

Even a major drug company, Abbott, ran into problems making ritonavir several years ago. The drug was taken off the market for a while, and then returned in a foul- tasting liquid form that was the only way it could be made for a year and a half, until the manufacturing problems were resolved. 

Not all patients need protease inhibitors, but many do benefit from them, and countries that want them may still be forced to depend on name brands.