Navigating Rocky Terrain
by Elisa Ludwig
January 2007
Many clinical trial sponsors are heading to Latin America—but there are still plenty of obstacles to overcome.
In his medical center office overlooking the verdant campus of Universidad Austral in Pilar, Argentina, Dr. José Luis Fernández is busy. The director of the clinical research unit has investigators to meet, documentation to review, pharmaceutical companies to call and patients to visit. Currently, his department in the six–year–old academic hospital oversees 27 clinical studies. His group recently started work in five centers throughout Buenos Aires in the coordination of a U.S. National Institutes of Health (NIH) study on the secondary prevention of subcortical stroke. “It’s our first NIH study and it’s very exciting,” Fernández says. “This is a new experience for us.”
A Fertile Field
When Fernández, a hepatologist, began practicing clinical research in 1987, there were few internationally sponsored clinical trials in Argentina. Now, with large, multicenter studies requiring thousands of patients, Argentina and Latin America in general have become global destinations for clinical research.
Indeed, the number of new trials conducted in the top three Latin American countries for clinical research—Argentina, Mexico and Brazil—increased by 1000 percent between 1995 and 2000, according to Clinical Trials In Latin America, a 2001 study by Fast Track Systems Inc., a Conshohocken, Pa., USA–based provider of clinical trial software and services. The numbers reflect Latin America’s popularity as a staging ground for international research. A heterogeneous population of more than 430 million people in urban areas makes the arduous process of recruiting patients for a multicenter trial relatively easy. Many potential patients in Argentina, Mexico and Brazil have never participated in clinical trials, and many are not being treated for their underlying diseases. In addition, all three nations are plagued with heart disease, cancer and diabetes—the global ailments at the top of many American and European pharmaceutical companies’ research agendas.
Latin America also offers industry sponsors reliable and efficient patient enrollment, as well as high levels of retention and compliance. Patients often have a strong motivation to enroll in trials, which provide medical attention and treatment they may not receive elsewhere. At the same time, the health care infrastructure in the region is highly developed when compared with other developing areas of the world, providing the requisite resources for conducting trials.
At present, Phase III trials sponsored by American and European pharmaceutical companies are the bread and butter of Fernández’s department. Argentina is the third–largest pharmaceutical market in Latin America, and most major multinational pharmaceutical companies have a presence there. Even after a financial crisis in 2001, the country maintains a large health care sector, and clinical research continues to thrive, despite some initial setbacks. The devaluation of the peso has made Argentina an even more attractive place for conducting clinical trials, Fernández says, particularly since costs in Eastern Europe continue to rise.
Delays Ahead
From a regulatory standpoint, Argentina, Brazil and Mexico are associated with high levels of Good Clinical Practice compliance and adherence to international harmonization standards. The regulatory environment in all three countries has evolved in accordance with such guidelines, and regulations governing clinical trial conduct—as well as the agencies to enforce them—are in place to help facilitate the drug approval process.
In Argentina, new drugs are approved by Administración Nacional de Medicamentos Alimentos y Tecnología Médica (ANMAT), a federal agency established in 1992 that regulates trials in Phases I, II and III. The agency also oversees post–approval studies for new indication, new dosing, bioequivalence, bioavailability and other kinetics studies. Before ANMAT reviews protocols for trials testing new drugs, sponsors first must obtain approval from an Institutional Review Board (IRB) and an Independent Ethics Committee—a process that takes three to five months on average. Although speed–to–trial is faster than in other developing nations hosting trials, such as India and China, the process of getting a drug to market still can be a source of frustration for sponsors.
ANMAT is a strong regulatory agency, says Patricia Eriksson, regional CRA manager for Latin America Clinical Operations at Sanofi Pasteur in Buenos Aires, Argentina. However, one large difficulty is that the lack of personnel in some areas does not allow this agency to become more efficient. “For instance, having more protocol evaluators and inspectors would be a plus,” she says. “The regulations need to be updated, which would reduce the process timelines.” Eriksson recommends that sponsors have experienced local people follow up with ANMAT submissions. But even with knowledgeable personnel on location to guide an application, sponsors face ethical and cultural barriers that can lead to costly delays.
A major ethical issue in Argentina is the use of placebo–controlled trials. Local IRBs tend to support the World Medical Association position that placebo–controlled trials generally should be used only where existing therapies do not exist. “It’s been a big problem here,” Fernández says. “Our IRB and ANMAT have rejected protocols solely because of the use of placebos.”
When a trial protocol is approved, ANMAT grants permission for the import and export of study drugs, materials, documents and biological samples. This is another barrier for industry sponsors, since there are high import duties on pharmaceutical products—including free samples—in Argentina. Products for clinical trials require supporting documentation and can be delayed by bureaucratic proceedings.
Common Problems
Many of these regulatory and procedural difficulties also exist in Brazil and Mexico. In Brazil, the number of studies more than doubled between 1999 and 2004, when 214 studies were approved, says Dr. Sérgio Nishioka, manager of the Office of New Drugs, Research and Clinical Trials at Agência Nacional de Vigilãncia Sanitária (ANVISA). Despite such growth in clinical research, however, ANVISA only just began in 2004 to formally recognize the contract research organizations that conduct a large share of these studies. The majority of trials held in Brazil are Phase III, which has left ANVISA less equipped to manage early studies, Nishioka says. To date, ANVISA still has no meaningful regulation, tradition or process for assessing preclinical data, he adds.
A Brazilian protocol review typically gets held up in ethics evaluation by the local Comitê de Ética em Pesquisa (CEP) or IRB. A regulatory update in 2005, however, has made it easier to approve multicenter trials by requiring only one CEP to submit a trial protocol to Comissão Nacional de Ética em Pesquisa (CONEP), the national ethics review board. CONEP meets every two weeks to review drug studies by foreign sponsors, but it receives a larger number of submissions than it can handle, and the approval process is slow. As in Argentina, Brazil is a difficult place to conduct placebo–controlled studies for ethical reasons. Unless no other proven therapy exists, in many cases sponsors must design trials around this stipulation, while adhering to sound statistical methods to assess the safety and efficacy profile of the investigational drug.
Just as CONEP focuses on ethical considerations, ANVISA considers methodological issues and the relevance of data for future submissions. This “two–barrel” system of ethical and regulatory oversight is inefficient, Nishioka says. In the future, there is a strong possibility that CONEP will restrict its role to supervising the local CEPs, which might shorten time to approval, he says. ANVISA also is revising and strengthening its regulations with regard to adverse event reporting, and, according to Nishioka, the agency may start conducting GCP inspections as well.
In Mexico, where the Comisión Federal para la Protección contra Riesgos Sanitarios was established in 2001, the review process is quicker—although the regulatory process still is evolving.
More than 70 percent of clinical trials in Mexico are conducted in public health institutions. IRBs move quickly, typically reviewing protocols in less than the stated 30 days. Some even grant approval the day of the meeting. The maximum time for Ministry of Health approval is 20 to 25 working days. If a response hasn’t arrived in that timeframe, it is understood that the protocol is approved unless the agency has specifically asked for more information, says Itzigueri Robles, director of clinical operations for MDS Pharma Services Mexico, Mexico City, Mexico.
Intellectual Property Protection
Even as the region evolves into a clinical research hub, it continues to present significant post–approval challenges to the industry. Both the Brazilian and Mexican governments favor generic drugs, and price controls and price monitoring are major issues of concern to the patented drug manufacturers. Furthermore, in Brazil, a lack of cooperation between the patent agency, Instituto Nacional da Propriedade Industrial, and ANVISA compromises enforcement of patent protection.
In Argentina, non–patent drugs are a major problem. The country is obligated under the World Trade Organization’s Agreement on Trade–Related Aspects of Intellectual Property Rights (TRIPS) to establish a functional system of protecting intellectual property. However, implementation of this agreement has been slow, and the patent law is rarely enforced. Official generic drugs, therefore, do not exist. Instead, local companies produce pirated copies that are approved for physiochemical similarities and sometimes bioequivalence, but not for safety or efficacy. Although doctors sometimes ask for these studies before prescribing the therapies to their patients, Fernández says, many are faced with patients who are not responding to treatments, and pirated copies usually are suspected to be the culprit. The Argentine government’s promotion of cheaper drugs has left industry sponsors afraid to bring proprietary products into the country for research in the initial phases, Fernández says.
As a physician, Fernández is concerned primarily with the health of his patients, and the issue of copies may put his patients at risk. “With this kind of policy you may win with price but lose with quality,” he says. Fernández does note, however, that not all copies are of poor quality. “The absence of [meaningful] patent law is mentioned by industry representatives as a real problem for research in the initial phases.”
Local Access
Yet neither the copies nor the patented drugs that are tested and approved here reach the sickest population. “Health care in Argentina has important social inequalities, and poor people are still not regularly getting medical attention,” Fernández says. Data from the Health Ministry shows that only 56 percent of employed and 42 percent of unemployed people received prescribed medication in 1997. What’s more, with the largest share of trials being initiated by international companies, the preponderance of drugs studied in Argentina are more likely to be marketed and sold in the United States and Europe.
In recent years, Austral has begun a few locally initiated preclinical trials, and Fernández would like to see more of them. “The Phase III studies we do are useful. It’s important for us to participate in this process, and of course they certainly provide resources for us. But Argentina does not participate in the intellectual part of the research, in the design of the study or the analysis of results. We are treating patients and sending data to the United States or Europe.”
A lack of epidemiological research on the prevalence of diseases in Argentina makes it difficult even to generate studies geared toward local health needs. “Our resources are limited,” Fernández says. “I think university centers have an important role in reaching this objective.”
Even so, Fernández recognizes the continuing value of industry involvement, he says. Much of his personal research is focused on developing new therapies for Hepatitis C, a disease that affects about 170 million people worldwide. “Some of the studies in this field I saw that were initially experimental are currently the standards for treatment,” he says. “When we began treating patients, only 15 percent responded to treatment. Now 50 to 60 percent are seeing the benefits, so we are always improving the practice by participating in this process.”
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