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Orchestra rehearsal

Brazil's participation in clinical trials creates complex system in the research environment

MARCOS GARUTIClinical research in Brazil has experienced substantial growth in the last few years. In 1996, when clinical trial regulations were finally properly established in the country, only 30 requests for authorization for drug trials had been submitted to the Ministry of Health. However, Anvisa, Brazil’s National Sanitary Surveillance Agency, the government bureau in charge of authorizing and controlling studies on medication and healthcare products, approved 248 trials last year. This advance had an impact on the country’s research environment. In a substantial number of Brazilian hospitals, clinical research departments with specialist staff were set up as a result. Thus, these hospitals became qualified to both treat patients and to submit them to trials of new medication or new applications of established drugs, for scientific validation of their clinical and pharmacological effects. On the pharmaceutical industry side, the dissemination of trials spurred the development of the complex system that the legislation dictates. “A combination of factors, such as the patents law, which prohibited domestic industry from copying drugs, the creation of clear clinical trial standards, and the professionalization of research centers established a virtuous circle that has been qualifying Brazil to take part in such studies more and more”, says Dagoberto Brandão, director of PHC Pharma Brasil, a clinical trials consulting firm.

Estimates indicate that in the last 10 years, more than 100 thousand Brazilians took part in clinical studies. Some 550 medical institutions and research centers in the country qualify for conducting drug trials, such as the Octávio Frias de Oliveira Cancer Institute at the Medical School of the University of São Paulo (FMUSP), which is currently involved in 35 trials, mostly of molecules for potential drugs, and which is to implant another 60 trials shortly. “We have created a clinical research structure with 30 people, including financial staff, who look after trial budgets and negotiations with companies; legal staff, in charge of contract issues; regulations staff, who keep track of the ethic committees’ approvals; and nurses and oncologists, who work on the patient care end of things”, states Professor Paulo Hoff from FMUSP, the institute’s clinical director.

Besides hospitals and the pharmaceutical industry, a complex set of players must enter the scene for trials to materialize. Take the case of Recepta Biopharma, a Brazilian firm that engages in research and development of monoclonal antibodies for cancer treatment and which began its activities with a portfolio of antibodies researched and validated by the Ludwig Institute of Cancer Research. Its maiden trial, to assess the safety and efficacy of a monoclonal antibody among ovarian tumor patients, was the first phase II clinical trial ever in Brazil to be registered with both Anvisa and the United States’ Food and Drug Administration (essential for international validation of the trial). To organize it, Recepta had to coordinate an orchestra of institutions. World Courier, a logistics firm, was hired to distribute the monoclonal antibodies in four states, at – 2oo Celsius and with a guarantee of back-up power. “I discovered that such a service existed, but was only provided for multinational clinical trials”, says José Fernando Perez, Recepta’s C.E.O., who was FAPESP’s scientific director from 1993 to 2005. SafeLab, also in the logistics area, was put in charge of collecting and transporting the biological material. A Portuguese firm, EuroTrials, was hired to organize and supervise the procedures of the trial, while a clinical tests laboratory was hired to do all the tests. Abroad, it was also necessary to hire an auditing firm to ensure that the production of the monoclonal antibodies by a US biotechnology firm and their packaging in ampoules at the University of Iowa complied with the legal norms. Nine hospitals in four Brazilian states are taking part in this trial.

“To conduct its R&D activities, Recepta uses an open innovation method, with its own team of 32 scientists and technicians, which it maintains under a partnering arrangement with centers of excellence”, states Perez. “A simple outsourcing of research, without the firm’s active involvement in its conception and conduction, would cause a project to compete with the other tasks of the research centers’ scientists, rendering execution by the deadlines that a company requires unfeasible”, he says. Recepta’s expertise resulted in its being invited by CNPq, Brazil’s National Scientific and Technological Development Council, to collaborate with the four research groups that are to take part, as of 2010, in the development of the protocol for and execution of a phase II clinical trial, as part of the Brazilian Cancer Research Network, using monoclonal antibodies to prevent and control breast cancer metastasis.

MARCOS GARUTIYet another indication of the Brazil’s progress in the field of clinical trials can be measured by the fact that 17 firms that organize and supervise such studies’ formalities, working as a link between the pharmaceutical industry and the hospital research centers, have established themselves in Brazil. They are the so-called CROs, i.e., the clinical research organizations, or ORPCs in Portuguese. These enterprises take care of the general procedures involved in the trials. They are the interlocutors of the recruited research institutions, besides ensuring compliance with the protocols, auditing results, taking care of the transportation of biological samples and tests, and observing whether legal and ethical requirements have been met, among other activities. “There are also CROs that, like ours, have a scientific consulting vocation”, says physician Maria Cecilia Lorenzi, the clinical operations manager of EuroTrials, a firm headquartered in Portugal that has been active in Brazil’s CRO market since the beginning of this decade. “We help to design the study and to prepare the protocol and other documents involved in the clinical research stage, besides analyzing data and training the research centers”, she states. Brazil has been attracting branches of multinational CROs, such as PPD and PRA, both headquartered in the United States. “It is common for pharmaceutical multinationals to hire international CROs to organize trials in several parts of the world”, says Cecilia.

As most phase II and III clinical trials are conducted by multinationals, Perez, from Recepta, says he has heard in meetings with CROs sentences such as “Professor, it’s a thrill to talk about clinical trials in Portuguese”. In such cases, the protocol comes from the headquarters, being only translated and adjusted to Brazil’s regulatory requirements. “Designing and preparing a protocol for a clinical trial is a skill yet to become disseminated in our country”, Perez says. A protocol, according to him, is a complex document that demands a scientific basis to justify the use of the drug, to define patient eligibility criteria, and to detail the medical procedures that are to be conducted.

There are also Brazilian CROs that work in a market niche that does not compete with the international enterprises. Such CROs work mainly for Brazilian pharmaceutical firms that, thanks to the progress of generic drugs, have capitalized themselves and started investing more in R&D. Successful examples of drugs developed by domestic firms, such Laboratório Cristália’s Helleva and Aché’s Acheflan point to the growing, although still incipient, efforts in this direction. According to Dagoberto Brandão from PHC Pharma Brasil, a Brazilian CRO, in the past, the country only took part in phase IV trials, which monitor the effects of drugs that have already been launched. “In the 1990’s, we started doing phase III research, which assesses the efficacy of the drug among a large group of patients, and now there are even examples of products developed from scratch, in which the risk of research failure is greater”, he states. Brandão is one of the holders of the Acheflan patent, the trade name of the first anti-inflammatory drug made from the extract of a native Brazilian plant. His firm took part in all the phases of the product’s development, which cost R$15 million in research. “We also took part in the phase III trials of Helleva”, referring to the erectile dysfunction drug created in Brazil.

The advent of CROs is a global phenomenon that is tied to the outsourcing of tasks that are not the pharmaceutical industry’s core business. According to Acro, the Association of Clinical Research Organizations of the United States, 30% of phases I to IV clinical trials are now conducted by CROs. This is the most outsourced stage of the drug R&D process. According to Acro, the chief advantage of having CROs rather than the pharmaceutical firms conduct the clinical trials is cutting trial time by some 30%.

Brazil’s inclusion in the clinical trials itinerary is considered advantageous for a number of reasons. “Patients gain access to treatment possibilities that would only become available far later otherwise”, says Paulo Hoff. Other advantages include the physicians becoming familiar with proven methodological standards and the opportunity for institutions to get funding from the pharmaceutical companies. “Perhaps one of the chief advantages is the qualification that we are acquiring. If before we were mere trial participants, today we are involved with the protocols right from their earliest phases and have become important supporting actors”, states Hoff.

MARCOS GARUTIDespite all this progress, there is something of a consensus that the sector’s regulation, created to keep the country from hosting trials that rich countries do not wish to host or that fail to meet ethical standards, could involve less red tape. All the institutions that propose to coordinate or take part in clinical studies involving humans must consult their ethics committees, which analyze the protocol and assess whether it meets the standards. In specific cases, such as studies with foreign participation, indigenous populations and human reproduction, after it is analyzed by the institution’s committee, the study must also be assessed by Conep, Brazil’s National Research Ethics Commission, which provides the final opinion.

The need for protocol approval from two government bodies, Conep and Anvisa, is considered a source of slowness. “Conep assess the ethical aspects, whereas Anvisa provides sanitary approval and evaluates the safety aspects and research methodology”, says Patrícia Ferrari Andreotti, Anvisa’s research, clinical trials and new drugs coordinator.

According to Paulo Hoff, this duplication reduces the competitiveness of Brazil’s participation in clinical trials. “Countries that comply strictly with ethical standards, such as Canada and the United States, approve the research far faster”, he says. According to him, the ideal thing would be for Conep to rubber-stamp the ethics committees’ decisions, especially when these committees belong to public teaching hospitals and institutions whose reputation is renowned. “It doesn’t make sense for Conep to take two months to reevaluate what the ethics committees of Inca (the National Cancer Research Institute) or our institute have already evaluated”, he says. “This sluggish approval of studies, which can take as much as one year is Brazil, is only matched by China. Approval is faster even in our Latin American neighbors”. Hoff highlights that this does not mean disregarding ethical principles. “In Anvisa’s case, it could authorize the studies faster and take longer when it comes to assessing the drug’s marketability. It’s not because the molecule was developed abroad that it merits more extensive analysis. Scientific criteria should always prevail”, he states. Patrícia Ferrari, from Anvisa, says that it is managing to cut down the time. “For multi-center international studies, in which the center is in a hurry because it must keep up with the timetable of the other countries, we now have a special administrative procedure that is faster”, she stated.

Even with difficulty, says Maria Cecília Lorenzi, from EuroTrials, Brazil’s competitive advantages are strong. “Brazil has a major advantage when it comes to recruiting patients in the therapeutic areas of oncology, the central nervous system, cardiovascular diseases and diabetes. Because of the great potential of including patients and the environment of excellence for the conducting of clinical research, we expect the country to become the host of a substantial portion of the clinical trials held outside the United States”, she states.