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Field-testing for medicines

Authorization for clinical tests on Brazilians grows 10% a year

At this moment, in Brazil, a medicine called Evista, indicated for the treatment of osteoporosis, is being tested. Also being tested are hundreds of other drugs against Aids, latest generation anti-inflammatories, neurological, oncological and dermatological products and all kinds of remedies, innovative or not. There are as yet unlaunched medicaments that the pharmaceutical industry wants to see on the market in five years at the most. There are other drugs under study, for which a second therapeutic indication is being sought.

In the case of Evista, a product developed by the American company Eli Lilly, the objective is precisely this, the second indication. Lilly wants and expects to confirm that the medicine, besides its effects on osteoporosis, brings cardiovascular benefits for a great number of the women in the postmenopause. A group of 540 women spread over seven cities is taking part in the study. It is the Brazilian contribution for a task that began in 1997, involving 10,100 women from all over the world, and which should be concluded within two years. Half of the patients are taking Evista, and the other half a placebo.

Neither of the two groups quit their usual medicines for cardiovascular diseases, since it is not known if Evista really works in these cases. What is hoped for is to detect the product’s added value in the prevention of heart problems. Evista serves as an example for a kind of pharmaceutical study without frontiers, of a long duration, and not circumscribed to the industry’s technology centers, and which has become commonplace in Brazil over the last few years. It is the so-called clinical research – testing medicines on human beings, an activity full of ethical barriers and of great scientific and commercial value.

Since 1996, the year in which the law on patents was approved, the investments of the world pharmaceutical industry in testing medicines in Brazil have only increased. Until then, the laboratories were afraid of testing here, because of copies and of the lack of clear rules. Government and society, on the other hand, have equipped themselves to keep an eye on this research and to prevent Brazilians from being used as guinea pigs.

In recent times, many remedies invented by laboratories from the United States and Europe have been tested in Brazil. And not many occurrences of side effects have been seen, which indicates a good control level. In 2002 alone, 774 new projects were approved in the country. A single unexpected event, which took place in July, was the reason for halting a research. A person died, and the National Agency for Sanitary Surveillance (Anvisa in the Portuguese acronym) is currently investigating if the problem happened on account of the tests or due to complications associated with the patient’s chronic disease.

Generally speaking, though, the tests are going well. The figures confirm that the law boosted considerably the multiplication of clinical tests. Research in Brazil is carried out only on unpaid volunteers, unlike the United States, where the patients are paid. “In Brazil, because of poverty, remuneration could create a market in researches”, explains Paula de Sá, Anvisa’s coordinator for clinical research. The attraction for the patients is the chance of a cure being discovered, or at least some relief, for their ailments.

The annual growth rate in research between 1997 and 2001, according to Anvisa’s figures, has always been higher than 10% a year – from the 30 projects started in 1995, the number leapt to 845 projects approved by the National Council for Ethics in Research (Conep) last year. There has also been evolution in the ethical debate. Criticisms are increasing, for example, against testing a placebo. “Under our rule, the placebo needs to be justified, not only methodologically, but also ethically”, explains William Saad Hossne, a professor at Unesp’s School of Medicine in Botucatu, and Conep’s coordinator.

Interfarma, an association that gathers together the multinational research laboratories in Brazil, says that investments for long-lasting testing to be carried out in Brazil are going amount to R$ 112 million in 2002. In the next four years, the average annual budget should be in the region of R$ 175 million. Medical directors from international laboratories, like Aldair Pinto, from Pfizer, or André Feher, from Eli Lilly, praise the law on patents and the quality of work at the Brazilian universities. “In the medium term, investments may triple”, Pinto forecasts.

Pfizer will be laying out some US$ 4 million in 2002 to take forward its research in Brazil. There are 30 projects, including insulin that can be inhaled, a successor of Viagra, a product for sexual impotence, and a medicine against osteoporosis that is going to compete with Evista. Lilly is carrying out 38 clinical researches in the country and has a budget of US$ 3.6 million this year – in 1995, the budget was in the region of US$ 80,000. The major part of its tests are done with products in the areas of endocrinology, neurology and oncology. “Research carried out here is up to international standards”, explains Feher, who is also a vice-president of the Brazilian Society for Pharmaceutical Medicine. “The only problem is that the approval of the protocols takes three or four months more than in other parts of the world”.

The expansion of clinical research in Brazil has very objective reasons. There is the fact that the country has a population of over 170 million persons and that it is home to numerous groups of sick people, with a great ethnic variety. In addition, Brazilian research has good quality and low costs – the labor force is paid in reals and reaches results that are as good as those achieved in European or American centers. Add to this the existence of regulations to deal with the subject – Resolution 196, of 1996, of the National Health Council (CNS in the Portuguese acronym) -, and the creation of a structure for monitoring that has as its fundamental objective the identification, discussion and prevention of ethical shortcomings in clinical research.

Asymmetry in research
Brazil cannot yet compete with the select group of nations that discovers formulas and synthesizes active pharmaceutical active ingredients. But, here, the part of pharmaceutical knowledge that is related to the methodology for and the carrying out of medicine tests on human beings has the ability to prosper well. “What we have recommended now is that the researcher should not only take part in the carrying out of the research, but also in its conception”, says Saad Hossne.

Volnei Garrafa, a professor from the School of Sciences and the coordinator of the bioethics group at the University of Brasilia (UnB) calls attention to the asymmetry in the research process. “While one country goes in with technological resources, the other pitches in the people”, he says. The call here is for a greater intellectual involvement on the part of Brazilian researchers in drawing up the projects.

In the course of a clinical research, doctors and scientists, at the service of private or state sector laboratories, and always under the gaze of the Ethics Committee (CEP) check the clinical tolerance to the optimal dose and whether the medicines are acting on the patient’s body in a beneficial way, neutralizing or attenuating one or other pathology. The protocol for the study needs to be approved by Conep, in Brasilia, and by the institution’s CEP. A doctor is appointed as chief investigator and takes responsibility for the research. At the moment, there are some 400 CEPs in operation in the country, spread over almost 200 institutions.

The observation of sick people under the effects of the molecule under study or induced by placebos and the statistical work will define the results of the study. The general rule is that if a product prevents an illness or remedies it at percentage levels that are equal or higher than those of the predecessor recognized as effective and no side effects associated with its use are verified, then it deserves to reach the market. In many cases, the innovation is justified by the elimination of collateral effects found in the benchmark products.

Stages of research
Research into the effects of medicines on human beings has four stages. Stage 1 is not carried out in Brazil. Only healthy individuals take part in the study. The short term security of the product is tested, and an analysis is made of its pharmacokinetic profile – the way the drug is distributed through the body. Stage 2 is the pilot therapeutic study. A small group of patients is worked on, between 500 and 1,000 people, and the tests do not normally last more than one year. One of the objectives of the study is to establish the best dosage of the drug in a cost-benefit ratio. At this moment, there is an actual confirmation of the therapeutic potential of the drug, whether if fulfills the main function for which it was designed or not. Should it not fulfill it, the laboratory discontinues the research.

Research with Evista, for example, is at stage 3, when the expanded therapeutic study takes place. Sick volunteers are selected, and an analysis is made of the risk and effectiveness of the drug with large samples of patients. It is the most expensive stage, the one that involves the largest number of patients (thousands of people in several countries) and the longest (three or four years is a good average time span). When stage 3 is concluded, the product is registered with the health authorities and it is released to be marketed. The studies carried out after the medicine begins to be marketed are included in the so-called stage 4. Its protocols are similar to the ones for stage 3.

In Brazil, the great majority of studies belong to stage 3. In 2001, out of 846 protocols approved, 655 were for stage 3,103 for stage 2, 67 for stage 4, and only 1 for stage 1. On the schedule of 38 researches from the Lilly laboratory, 20 belong to stage 3, 15 to stage 4 and 3 to stage 2. It is precisely in stage 3 that the drug is better characterized and comparisons are made with other benchmark drugs or with placebos.

There is a noticeable tendency in Brazil towards questioning studies of testing against a placebo. “Reluctance to the use of the placebo has increased”, explains Feher. “Each case must be examined, and when it brings a serious risk, its use is unacceptable”, says Saad Hossne, from Conep. The restrictions increase, for example, in psychiatry and oncology. A seriously ill patient, a schizophrenic, for example, cannot be deprived of a medicine that has been proved to work and given an inactive pill just to check the quality of an innovation, say the critics of placebos. Cancer patients following treatments that are already known cannot be submitted to tests with placebos to the benefit of science, but counter to their own interests.

“Placebos must be eliminated”, says Garrafa, who has a seat on Conep. “In many cases, placebos are used just for convenience, or because they are cheaper”. Garrafa points to identifies excesses, for example, in research to test a new dosage for a medicine against onychomycosis, a fungal infection of the nails. With the approval of the CEP, the laboratory used a double placebo, according to Garrafa, in one of the test groups. Although the patients run no risk of dying, onychomycosis is a persistent mycosis, and several people have been deprived of a swift cure for the disease, since an effective medicine does exist. Scientific and commercial interests prevailed over the patients’ well-being.

The laboratories’ view is that testing against a placebo can be adopted in non-fatal diseases, in cases where suspending the use of a traditional product does not worsen the quality of life of the patient, or when a benchmark product does not exist. The majority of researches in Brazil, according to Saad Hossne, do not include testing against placebos. Discussions on their use, though, still have plenty to run. And Brazil, by all accounts, will be one of the fields where the ethical debate will be waged.