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Applied Clinical Trials
The region and its regulatory agencies try to keep up with the rapidly growing clinical trials market.
Rapid increase in the number of new molecular entities and biologics introduced as human therapies after the 1970s generated great promise for patients around the world. During that period, drug development efforts were generally concentrated in three major biopharmaceutical markets: the United States, Europe, and Japan. Even so, efforts at global harmonization of technical requirements among the three major markets were not officially in place until 1990, when the International Conference on Harmonization (ICH) was established. 1
The ICH is a consortium comprising drug manufacturers and regulatory bodies in the three major drug development regions. The establishment of ICH has enabled significant contributions to the existing drug development processes, specifically from a regulatory perspective.
PHOTOGRAPHY: GETTY IMAGES ILLUSTRATION: PAUL A. BELCI
Over the past several years, biopharmaceutical companies have increased innovative research and development outside their traditional boundaries with dramatic expansion of clinical drug development into many countries around the world. The reason for this dramatic increase in globalization may be attributed to greater competition observed in the United States and European markets and also to the current challenges with high costs, slow patient recruitment, and greater demand on qualified clinical research professionals. Other reasons may include the rapid economic growth and improvement of regulatory processes in emerging regions, partly driven by wider adoption of ICH guidelines and principles. Sponsors can find many opportunities to develop their products in the nontraditional regions as part of their multinational strategy.
Like many parts of the developing world, Latin America continues to experience rapid population growth (see Table 1) and the rate is not expected to slow any time soon. A large population in this economically emerging region presents an opportunity and many advantages for drug development. Some advantages include rapid growth of the pharmaceutical market; population concentration in large urban centers such as Mexico City (Mexico), São Paulo and Rio de Janeiro (Brazil), and Buenos Aires (Argentina); population heterogeneity; two official languages spoken in the entire region; and English language proficiency of most investigators in the region.2
Table 1. United Nations world population growth rate (2008 Prospectus).
Latin America is composed of all countries in the American continent where the languages derived from Latin (such as Spanish and Portuguese) are primarily spoken. Spanning northern and southern hemispheres, the region has 21 countries with a total population of over 550 million people, made up of demographically heterogeneous groups.3 After Africa and Asia, Latin America has the highest projected population growth of 11.1% by 2015.
Most Latin American countries are not actively producing new medical therapies and therefore are not directly involved in the ICH decision making process. The ICH organization established a Global Cooperation Group (GCG) in 1999 and it has recently invited non-ICH regional harmonization groups such as the Pan American Network on Drug Regulatory Harmonization (PANDRH) to assign one permanent designee in the GCG. International harmonization in GCP is becoming a reality in the region's major markets.
This article reviews the current regulatory environment for the conduct of clinical research in Argentina, Brazil, and Mexico. The article also highlights recent key regulatory changes and describes strategies to ensure successful and efficient conduct of clinical trials in the region.
Based on data derived from seven of the largest markets in Latin America—Argentina, Brazil, Chile, Colombia, Mexico, Peru, and Venezuela (see Figure 1)—the pharmaceutical market was worth about US$ 50 billion in 2008 with a projection of US$ 80 billion in 2013.4 In light of the increasing global competitiveness, biopharmaceutical companies located in the major ICH regions have been conducting an increasing number of clinical trials in Latin America in the recent years as part of their global market expansion strategy (see Table 2 and Figure 2).
Figure 1. Seven of the largest markets in the Latin American pharmaceutical industry in 2006.
This strategy has the value to introduce the potential new medicine simultaneously in different markets following its development and, therefore, decrease the lag time between the first approval in the country of origin and the target market country. Participation in clinical trials also helps the region's regulatory agencies to familiarize themselves with the product earlier in the process, besides enhancing scientific exchange and contributing to economic growth.
Table 2. Registered clinical trials in the major Latin American markets (1998-2008)
Despite these advantages, sponsors must understand the impact of intrinsic ethnic factors, such as age, race, gender, organ dysfunction, genetic diseases, and pregnancy/lactation, and extrinsic ethnic factors like the environment, smoking, alcohol use, diet, drug-drug interactions from the Latin American perspective and in line with ICH E5 guideline: Ethnic Factors in the Acceptability of Foreign Data.5
Figure 2. A look at more than two decades of U.S.-sponsored INDs in Latin America that were submitted to the FDA.
The sponsor must also be aware of the current clinical research and regulatory infrastructures as well as inherent challenges such as approval inconsistencies and difficulties with import and export processes. Further, institutions and health care practitioners may not be willing to participate in clinical research activities.
Sponsors must also consider other socio-economic, political, legal, market environments, and innovation-specific factors that could impede the global competitiveness of the region.6 A survey conducted in the region lists major issues related to the delay in authorization of new medicines there. Limited internal resources and an inadequate pool of experienced reviewers were cited as major causes of concern by most regulatory authorities. Insufficient information technology resources are of lesser concern. Taken together, the impact is generally the slow regulatory process.7
Sponsors must also plan in advance and carefully assess how each regulatory authority works, with attention to timelines and the priorities of each country. Examples of priority therapeutic areas for clinical investigation are illustrated in Table 3. Such priority therapeutic areas for drug development are informed by the country's unmet public health needs and many are aligned with conditions under current investigation in developed countries.
Table 3. List of therapeutic areas receiving priority in clinical investigation in Latin America.
The regulatory environment in the Latin American biopharmaceutical sector has showed significant improvements in the past decade. More coordinated regulatory agencies and related infrastructures have been created.
Clinical trial regulations follow the spirit of the ICH guidelines. These improvements present an opportunity for sponsors intending to expand their business in the region as well as utilize trial data for approval in countries located in the core ICH regions. International collaboration activities such as ICH Good Clinical Practices (GCP) training programs have been sponsored by Pan American Health Organization (PAHO). Regional and international conferences for clinical research in Latin American have contributed to increase the knowledge and improve performance by establishing better partnerships between regulatory agencies and industry.
Brazil. In Brazil, the National Heath Surveillance Agency (ANVISA) is an autonomous agency linked to the Brazilian Ministry of Heath. ANVISA is responsible for all regulatory processes for medical products. Resolution 196 of 1996 establishes the GCP requirements for human clinical research.8 It took into consideration several international standards and guidelines for human subject protection.
Common pending issues delaying clinical research approval by the Brazilian National Commission on Research Ethics are illustrated in Figures 3 and 4. Sponsors or investigators should carefully plan their work to avoid delays caused by these issues.9
Figure 3. The primary issues that delay a protocol's approval in Brazil.
Resolution 39 of 2008 is the current regulation guiding the conduct of clinical research in Brazil. Documentation required for clinical research and import for biopharmaceutical products has been updated to capture more detailed information. Sponsors are responsible to monitor and report adverse effects using ANVISA's NOTIVISA database. A complete list of clinical research dossier forms are available in English on the ANVISA Web site: http://www.anvisa.gov.br/eng/index.htm.
Figure 4. Challenges Brazil faces in properly implementing the informed consent process.
Argentina. In Argentina, the National Administration of Food, Drugs and Medical Technology (ANMAT) is the national regulatory agency responsible for the regulation of medical products. ANMAT is linked to the Ministry of Health and has the legal mandate to authorize, audit, inspect, monitor, suspend or reprove preclinical studies and all aspects of clinical trials in Argentina.
Guidelines for GCP have been available in the country since 1997, when Disposition 5330/97 for drug products and Disposition 969/97 for medical devices were established.10 ANMAT recently published the guidance for pediatric clinical research elaborated by PAHO/PANDRH, which follows the current trends in clinical research in pediatric populations observed by FDA and EMEA.11
Mexico. In Mexico, The Federal Commission for the Protection against Sanitary Risk (COFEPRIS) under the Ministry of Health is responsible for regulation of medical products. Clinical research and its surveillance is controlled by the Secretary of Health. The majority of clinical research in Mexico is performed in government-funded hospitals and other institutions, but is sponsored by foreign companies. Title V, article 96 to 103 of the General Law of Health (published in 1987) describes the role of the Secretary of Health in the regulation of clinical investigation.12
Clinical research in human subjects must be approved by the Department of Health. The Regulation of the General Law of Health Pertaining to Clinical Research is the nation's complete guideline of ethics and codes of conduct for clinical research. The government recognizes the need for the creation of a centralized department that will become responsible for monitoring the nation's health care system in a more transparent, efficient, and coordinated manner.13
Despite many similarities among the countries in the region, each has its own set of regulations for the control of medical products. The regulatory framework in Latin American countries is constantly evolving. The dynamic changes in regulatory processes are observed by the number of new and updated national regulations created in the past few years. Table 4 lists the major regulations and requirements for clinical development in Argentina, Brazil, and Mexico.
Table 4. Regulations and requirements for clinical investigation in Argentina, Brazil, and Mexico.
The increasing number of clinical trials in Latin America reflects trends in global biopharmaceutical market expansion. To stay competitive, the industry is exporting their innovation outside of their traditional boundaries and has increased collaboration efforts. The perception that new drugs will cure diseases and ameliorate many others has encouraged people to participate in clinical trials with the hope these investments will bring therapies that can help alleviate unmet medical needs in their nations.
Figure 5. The different approval times from protocol submission to when clinical research starts for Argentina, Brazil, and Mexico.
Thanks to Amgen (Thousand Oaks, CA) for providing the resources for my participation in the Johns Hopkins Masters of Science in Biotechnology program; Ning Li, MD, PhD, and faculty members at Johns Hopkins University for their guidance and support during the International Regulatory Affairs course; and Jacquelyn Morton, Specialist Library at Amgen, for providing IDRAC database instructions.
Key Success Factors
1. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), http://www.ich.org/cache/compo/276-254-1.html (May 2009).
2. J. Fiuza, Pharm-Olam International: Strategies for Implementing Trials in Latin America, http://www.pharm-olam.com/pdfs/EPC-Winter-2006-LA.pdf (2006).
3. Latin America: Wikipedia, http://en.wikipedia.org/wiki/Latin_America.
4. The Outlook for Pharmaceuticals in Latin America to 2013, https://www.espicom.com/Prodcat.nsf/Search/00000395?OpenDocument.
5. ICH Harmonized Tripartite Guideline, Ethnic Factors in the Acceptability of Foreign Clinical Data E5(R1), http://www.ich.org/LOB/media/MEDIA481.pdf.
6. A. Madhu, Global Competitiveness in the Pharmaceutical Industry: The Effect of National Regulatory, Economic, and Market Factors (The Haworth Press, 1999).
7. CMR International R&D Briefing, Assessing the regulatory environment and its impact on patient's access to new medicines, Latin America (2005).
8. ANVISA VISA-LEGIS: Resolution 196 of October 10, 1996, http://e-legis.anvisa.gov.br/leisref/public/showAct.php?id=663&word=.
9. CEPs–CONEP system: Nine years, Brazil CONEP report, http://conselho.saude.gov.br/comissao/conep/relatorio.doc.
10. Argentina Ministry of Health (ANMAT), Good Clinical Practices Regulations, Drug Products: http://www.anmat.gov.ar/normativas_medicamentos_cuerpo.asp, Medical Devices: http://www.anmat.gov.ar/normativas_productosmedicos_cuerpo.asp.
11. Argentina Ministry of Health (ANMAT). Draft guidance discussion for pediatric clinical investigation, http://www.anmat.gov.ar/publicaciones/BPC-Investpediatrica.pdf.
12. Mexico, General Law of Health Pertaining to Clinical Research. Title 5: Investigation for Health, http://www.salud.gob.mx/unidades/cdi/legis/lgs/index-t5.htm.
13. M.A. Castellanos and R. Chiprut, "Clinical Research in Mexico: An Overview," Applied Clinical Trials, 11 (6) 64-68 (2002), http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/Global+Trials/Clinical-Research-in-Mexico-An-Overview/ArticleStandard/Article/detail/83803.
14. IDRACÒ The single source global regulatory database, http://www.idrac.com. For this research the following IDRAC documents were consulted: 73911, 27324, 26812, 26775, 26225, 29097, 29098, 28986, 29010, 26606, 28040, 27960, and 27218.
15. TariusÒ A global one-stop resource, http://tarius.com.
16. International Compilation of Human Research Protections 2009 Edition: Compiled by Office of Human Research Protections U.S. Department of Health and Human Services, http://www.hhs.gov/ohrp/international/HSPCompilation.pdf.