Clinical Trials in Latin America

Meeting the Challenges Can Reduce Time-to-Market

By: Diego Glancszpigel, APC

Aggressive financial targets and intense global competition are creating tremendous pressures on pharmaceutical companies to develop and introduce novel therapies as quickly as possible. But at the same time that speed to market is more important than ever, the growing number of potential new drugs entering clinical development increases competition for the finite number of subjects and investigators available in the most popular locations for clinical trials: the United States, Canada, and Western Europe.

The emerging shortage of clinical resources can significantly delay the start of trials for many sponsors—adding to the already steep cost of drug development and heightening the risk of competitive products reaching the market first.

To avoid such delays, many pharmaceutical companies are using or considering alternative sites in Latin America, Asia, and Central and Eastern Europe to conduct a portion of their clinical trials. One recent study predicted that by 2008, the number of global clinical trials that take place outside of the United States, Canada, and Western Europe will double. The number of sites outside the United States and Western Europe chosen by pharmaceutical companies will increase from the 1998 15% to 30% by 2008.1

Latin America offers a number of advantages as a location for clinical trials—a large population, highly qualified medical personnel, a tradition of Western medicine, and well-established regulations for clinical trials in most countries. The ready access to these resources can help pharmaceutical companies reduce trial delays and speed up development times. At the same time, those companies face significant cultural, medical, regulatory, and logistical challenges inherent to conducting trials in Latin America. Sponsors willing to take the time to understand and adapt to the differences, however, can rise to the challenges and successfully conduct a wide range of clinical trials in Latin America to support an efficient global drug development program.

Why Latin America?. Potential subjects.

For pharmaceutical companies seeking to speed the drug development process, a key benefit of conducting clinical trials in Latin America is access to a large subject population. More than 500 million people live in the region, with approximately 70% of that total concentrated in urban areas. The four largest cities in Latin America—Mexico City, Mexico; Sao Paulo and Rio de Janeiro, Brazil; and Buenos Aires, Argentina—are among the largest urban centers in the world, with populations between 10 and 20 million people. These population concentrations offer significant advantages for subject recruiting and trial logistics. Equally important, a large percentage of this population qualifies as naïve subjects—who are increasingly difficult to find and recruit elsewhere.

Qualified investigators. Another important characteristic of the region is the availability of well-qualified medical professionals and investigators with clinical trial experience. Latin America has a long tradition of Western medicine. Many of the region’s physicians were trained in the United States or Europe. As a result, knowledge of International Conference on Harmonization (ICH) guidelines is widespread, and awareness of Good Clinical Practice (GCP) standards is growing. Sponsors will also find investigators eager to participate in clinical trials. In addition, the structure and traditions of the medical profession in Latin America give physicians more time to devote to clinical trials than their counterparts in the United States or Europe.

Established regulations. Many countries in Latin America—Brazil, Mexico, and Argentina, for example—have well-established regulations governing the conduct of clinical trials and regulatory agencies that provide efficient review and approval processes. Most of the other countries in the region have some kind of legislation or Ministry of Health regulations covering the conduct of clinical trials. With the proper level of preparation and a knowledge of each country’s requirements, it is possible to undertake successful studies in such nontraditional locations as Chile, Costa Rica, Colombia, Peru, Panama, and Venezuela.

Common language. When sponsors wish to conduct multinational trials, Latin America offers the additional advantage of a common language, Spanish, across most of the region; an exception is Brazil, where Portuguese is spoken.

Growing markets. Sponsors can also leverage their clinical trials in Latin America to gain an advantage in one of the fastest growing pharmaceutical markets in the world. Latin America represented approximately 25% of global pharmaceutical sales in 2000, and that share is expected to exceed 30% by the end of 2002.2

The growing success of the pharmaceutical business in the region reflects the significant investments made in Latin America by most of the world’s major pharmaceutical companies, as well as the presence of numerous contract research organizations (CROs) and other companies that supply support services to the pharmaceutical industry. The availability of these resources in turn supports the growth of clinical trials in the region.

Latin America’s advantages as a location for clinical trials are confirmed by the hundreds of ICH-compliant trials already successfully conducted or under way in Latin America. But even with this growing popularity, tremendous untapped potential and capacity for trials exists throughout the region.

The regulatory environment

The region’s increasingly sophisticated regulatory environment demonstrates the evolution of pharmaceutical research in Latin America. In many countries specific legislation directly regulates the conduct of clinical trials.

In Brazil, for example, one major legislative provision details the processes and procedures that sponsors must follow to gain approval for clinical trials, including reviews of protocols, consent forms, and investigators by a local ethics committee, the Research & Ethics National Commission (ANMAT, Administración Nacional de Alimentos, Medicamentos, y Tecnología Médica), and the Health Care Surveillance Office (ANVISA, Agência Nacional de Vigilância Sanitária). The latter two are under the jurisdiction of the national Ministry of Health (MOH). The MOH must also authorize research sites. Another legislative provision specifies the responsibilities of the investigators.

In Argentina, a specific agency within the MOH regulates clinical trials—the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT). This agency has the power to authorize and monitor all clinical trials in Argentina. Its regulations contain detailed provisions outlining the obligations of sponsors and investigators and the participation of independent ethics committees or review boards. ANMAT also performs audits of clinical trials.

Mexico, Chile, and Uruguay also have formal MOH involvement in clinical trial approvals. Most of the other Latin American countries have some type of public health or regulatory oversight for clinical studies.

Approval times for ethics committees or review boards are typically 30 to 60 days. Approval times for the ministries of health or their agencies can range from 30 to 90 days. In some countries, the growing workload of the regulatory agencies is slowing the review process. Most Latin American regulatory bodies are, however, working to increase their clinical trial resources and shorten approval times to encourage clinical research in their countries.

The ICH Guideline for Good Clinical Practice is well understood in Latin America, and investigators in most countries follow that guideline. In some countries, however, the regulations governing ethics committees do not fully comply with the ICH guideline for the type and number of members, SOPs, or frequency of meetings. In those cases, sponsors should make use of an independent review board in Latin America that does meet ICH standards.

In recent years, adherence to GCP standards for clinical trials has been growing in Latin America, but the regulatory agencies in most countries are just beginning to gain experience with these standards. As a result, the regulatory environment in Latin America continues to evolve, and frequent changes to the regulations for clinical trials are not uncommon. Local knowledge of each country’s regulations and close communications with the respective regulatory agencies are essential to keep up with these changes.

In every country, all key regulatory documents must be translated into the local language. Strict regulations covering the import of drug supplies and the export of biological materials, such as subject samples, are another common factor throughout the region. A partner with expertise in local customs regulations to review import documents in advance of study supply shipments and the capabilities to facilitate the local distribution can save considerable time and help avoid customs delays.

Understanding cultural issues

The first step in understanding the cultural issues that affect the conduct of clinical trials in Latin America is to recognize that each country is unique. Although Latin American countries share many cultural traits, the region is not a homogenous whole. Just as the cultures of the United Kingdom, Germany, and France are very different despite their common European heritage, the cultures of Mexico, Brazil, and Argentina are distinct. Awareness of, and respect for, those differences is as important in Latin America as it is in Europe. To be successful, a sponsor must have a source of local knowledge that provides the insight to accommodate this diversity while also leveraging Latin America’s shared characteristics. And while most of the principal investigators will be able to speak English, the ability of a sponsor’s representatives to communicate in Spanish (or Portuguese) can go a long way toward fostering both communication and respect.

It is also important to understand some key differences in the way the medical community works in many Latin American countries. For example, physicians often perform their hospital rounds in the morning, and then work in private clinics in the afternoon. In some public hospitals, the majority of the staff works only in the morning. These differences must be acknowledged when scheduling subject visits, as well as when determining who will be available to help a principal investigator carry out a trial. The handling of case report forms (CRFs) may also be different. Because of their training, resident physicians often fill out the CRFs themselves.

Economic conditions must also be accounted for when planning clinical trials in the region. Given the fact that medical personnel in some Latin American countries receive very low pay, it is vital that all site staff members involved in a clinical trial be compensated for their efforts. Economic restrictions may also make it necessary for a sponsor to supply certain types of equipment needed to support or conduct a clinical trial.

Although economic factors must be a part of the planning process, it is important to understand that the investigators in Latin America do not participate in clinical trials primarily for economic gain. They participate for the same reasons that investigators participate anywhere in the world: They want to make a contribution to medical science that could help the people of their countries, and they want to gain the respect of their peers for their scientific contributions. Those contributions should be acknowledged by including key regional investigators in scientific publications and presentations at conferences and symposia.

Selecting the right partner

An essential component of a sponsor’s successful clinical trials in Latin America is having local partners with staff members who understand the diverse regulatory, medical, and cultural issues in the countries where the trials are to be undertaken. Whether the resource chosen is an affiliate of the sponsor, a CRO, or some other organization, selecting the right partner may be the single most important decision a sponsor makes to sustain an efficient clinical trial program in Latin America.

Although many criteria must be considered when selecting a partner, the potential partner’s previous clinical trials experience is paramount. The sponsor needs to thoroughly assess the partner’s performance in selecting study sites and investigators, enrolling subjects, and meeting study deadlines. The partner’s prior experience with trials in the particular therapeutic area to be studied is also a vital consideration. Other important questions also need to be addressed during the selection process.

What are the operating capacities and management resources of the partner in each country where the study is to be conducted?

How will the partner recruit subjects?

What procedures does the partner use for the training and oversight of monitors?

Will all of the sites and investigators comply with ICH and GCP standards?

What are the quality assurance processes and SOPs of the partner and the sites?

How will the data from multiple sites be handled to maintain transparency and quality?

What are their communication and data transmission capabilities?

How will the investigators, staff, and subjects be compensated?

By carefully verifying the available partners’ previous performance and capabilities, a sponsor should be able to select one with the right combination of experience, resources, and commitment to quality—plus the proven ability to successfully deal with the regulatory, cultural, and logistical challenges of Latin American clinical trials.

Other key success factors

Several other factors can have a significant impact on the potential success of a sponsor’s clinical trials in Latin America—planning and monitoring, for example.

Planning. A vital part of early planning should be formulating a strategy for the selection of trial sites that balances each country’s regulatory approval times, subject recruitment potential, and other factors affecting study timelines to create an efficient development program. The planning process should also include a thorough review of the regulations, drug importation procedures, and other country-specific issues, so that expectations are appropriately set before the trials begin. Equally important, a sponsor’s plan should provide sufficient flexibility to allow for the unexpected.

Monitoring is also a critical success factor. Consistent oversight at every stage and level of the development process must be a priority. Monitors should visit each site at least every six weeks. Sponsors should maintain close contact with their local partners. And sponsors should follow up with government agencies at regular intervals throughout the regulatory process. Such close monitoring benefits everyone by keeping small issues from growing into large problems and by avoiding the delays that can result from misunderstandings or insufficient communication.

Ultimately, the most important success factor may be respect—respect for the unique cultures of the countries in Latin America, respect for differences between Latin America and other regions, and respect for the abilities of people in the region who will be the sponsor’s partners in the development effort.

By leveraging the many benefits of conducting clinical trials in Latin America, and by understanding and respecting the region’s differences, global pharmaceutical companies can meet the challenge of conducting successful Latin American clinical trials—and those successful trials can bring greater efficiency to their drug development programs and reduce the time it takes to bring new therapies to market.

References 1. High Performance Drug Discovery: Speed to Value (Accenture, 1345 Avenue of the Americas, New York, NY 10105) 1.