Clinical research in Latin America: constraints and opportunities

Clinical research in Latin America: constraints and

opportunitiesEduardo Gotuzzo, M.D. FACP

Instituto de Medicina Tropical “Alexander von Humboldt”Universidad Peruana Cayetano Heredia

Hospital Nacional Cayetano HerediaLima, Perú

Introduction

Until recently, clinical trials were concentrated in developed countries

The number of patients enrolled in international multi-centre clinical trials has increased in some countries of Latin America.

L.A. has been included in early phases of new drug development

Introduction

In 1993 2.1% of clinical trials weredone in Latin America; in 1997, 5.1% and in 2000, 7.5%. (IMS Health)

As a result, there are more sites, investigators, committees, CROs, and research-related staff in pharmaceutical companies

•South America(13 countries), Central America and the countries of theCaribbean.

•Current estimatedpopulation: 490 millionpeople.

•Large and veryheterogeneous ethnicand epidemiologicalprofile

Latin America

http://webhost.bridgew.edu/jhayesboh/musica/latin-america-political-map.jpg

City Population(millions)

Mexico 18,259

Sao Paolo 18,182

Buenos Aires 12,819

Rio de Janeiro 10,756

Lima 7,740

Bogota 6,543

Latin America’s megacities

Source: United Nations World Urbanization

Latin America: general facts• The epidemiological profile in LA is changing as

a result of more sedentary lifestyles (a by-product of urbanisation), smoking, drinking and obesity)

• Between 1980 and 2000:number of deaths from infectious diseasesmortality rates for cancer, heart disease and strokesincidence of diabetes

Mortality rates by cause, at the start of the 1980s and the end of the 1990s for selected

countries in Latin America

Mortality rates per 100,000 population,

Mexico Brazil Argentina Colombia

80 90 80 90 80 90 80 90Infectiousdiseases

137.3 29.9 96.1 38.3 44.9 49.6 39.3 26.3

Cancers 24.4 32.7 33.9 42.1 87.6 88.3 37.8 42.0

Diabetes 22.7 42.9 10.7 19.6 16.9 21.0 9.0 13.7

Heartdiseases & strokes

54.8 81.7 129.8 127.5 81.9 142.7 105.4 109.9

LA: a dynamic market for clinicalresearch

• Between 1995 and 2000, the number oftrials executed in the region rose by a factor of ten.

• Certain Latin American markets, suchas Brazil, Mexico and Argentina haveseen a 1000 percent increase in clinicaltrials between 1995 and 2000.

Clinical trials in Latin America: advantages

• The majority of the general population istreatment naïve (not on other medicationsthat could interfere with experimental treatments).

• Heart disease, arthritis, cancer, and infectionsare as prevalent as in the United States.


• The number of clinical trials in Latin America isincreasing at a faster rate than other regions.

• As market conditions are favorable, an increase ofas much as tenfold can be expected over the nextfive years.

• In the past few years, PPD, Quintiles, Covance, ClinTrials, Latin Trials,MDS,Kendle, ICON, and others have opened offices in Latin America tohelp support their efforts in this area.


• The number of qualified health personnelcompares favourably with that in otherdeveloping regions.

• The standard of medical training is generallyhigh, and knowledge of the guidelines laid downby the International Conference on Harmonisation and Good Clinical Practice iswidespread

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Argentin

aVene

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Mexico

BrazilChil

eColo

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aIndiaUSA UK

Source: Eurostat, OECD, CIA World Factbook

Qualified health personnel in LA comparedwith other regions

Physicians/100 population Hospital bed/1000population


• Reverse seasons (it is summer in LA when it is winter in the US) allow companies to test drugs for seasonal induced diseases year-round (diarrhea and respiratory diseases)

• The potential trial-subject population in LA isin large part located in several major cities, allowing recruitment via hundreds of multi-center sites in several countries at the sametime.


• Drop-out rates in the region are about half of those in Europe.

• La investigators have increase in proficiencyand improve standards of operation.

• Individual Latin American governments are also becoming more formalized in theirhandling of clinical research.


• Latin America represents also a potentialmarket for pharmaceutical drugs

• The Compound Annual Growth Rate of the combined market is expected to be 7.3% peryear on average, spurred in part by newproduct patent-protection regulation and enforcement, which makes the region more appealing to multinational companies

Clinical trials in Latin America(1966-2003)

Country Total CT Total registries

%CT/total registries

(per country)

%CT/total registries(region)

Brazil 1496 40106 3.7 35.7Mexico 862 16566 5.17 20.6Argentina 621 17101 3.63 14.8Chile 425 8112 5.23 10.1Venezuela 151 3371 4.5 3.6Cuba 140 2185 6.4 3.3Colombia 109 1642 6.6 2.6Peru 93 837 11.1 2.2

Source: Medline, August 25th, 2003 Adapted from: Cañedo et al. 2004

Clinical Research in Latin America: advantages

• A new form of economic investment withscientific impact.

• In the last decade, the annual investment in theAndean Region has increased from 3-4 US million to more than 50M per year.

• In the same period, clinical research has promoted over 2500 works and a similar numberof additional re puestos de trabajo y promovido

Clinical trials in Latin America (2006)

Phase 1 Phase 2 Phase 3 Phase 4

Brazil 20 34 66 17

Mexico 76 50 167 48

Argentina 15 46 75 15

Chile 5 14 26 7

Peru 38 73 70 31

Source: www.clinicaltrials.gov (US National Institutes of Health)Includes only information of recruiting centers

http://www.clinicaltrials.gov/


Inf.Dis Oncolog CV Resp

Brazil 37 34 20 20

Mexico 26 21 17 17


Chile 16 12 9 11

Peru 19 19 2 11




Industry NIH University Other

Brazil 133 12 26 4

Mexico 140 3 10 0


Chile 57 2 8 0

Peru 47 11 15 1



Clinical trials in Latin America• The successful experience with:

– Capsofungin: all centers in Latin America participated in phase II and phase III studies.

– Linezolid: more than 25-35% of the total studied patients in phase I and phase II trials were from Latin America

– Atazanavir: international approval occurred 1 year earlier than expected due to the performance of investigators in Chile and Peru.

Clinical trials in Latin America• The successful experience with:

– Rotavirus vaccine

– Papillomavirus vaccine

– HIV vaccine

Clinical research: advantages fromthe LA perspective

• Promotes a new style to improve patients´ health care.

• Stimulates the knowledge of ethic aspects of medical practice.

• Stimulates the creation, development and improvement of Institutional Review Boards.

• Provides new options for professional development.

• Fosters collaborative relationships with international leaders.

• Provides alternatives for financial support, training in research, access to bibliographic data-bases, advanced technology, etc.

Clinical trials in Latin America: disadvantages

• At health facilities, there is a widespreadmisunderstanding of the economic issues relatedto clinical trials, which might generate certaintensions with the non participating staff.

• The regulations governing clinical trials in LA are still evolving, in some cases they change rapidlywithout notice and in some other cases they do not yet exist.

• Importing and exporting drugs can be a veryexpensive, length process.

Clinical trials in Latin America: disadvantages

• Some countries in the region suffer from considerable social, economical or political unrest.– After the 2001 crisis, there was a considerable shortfall of

clinical trials in Argentina.– Despite economic achievements, Venezuela is not considered

an attractive site due to current political instability.– General violence affected Peru (in the 90’s) and more recently

Colombia.

• Other than Chile and Uruguay, most LA governmentshave low scores in the latest TI Corruption Perceptions Index.

Clinical trials in Peru

• Ethics Committee and Ministry of Health (MoH) approval take 12-16 weeks. However, there is no need for an additional drug importation license.

• Increasing training in research ethics, as well as GCP.

• Progressively, participation in clinical trials has become an attractive alternative for young health professionals.

Clinical trials in Peru

• The Industry as well as FDA have been inspecting clinical trials conducted in Peru (FDA since 1996). Since 2000 there have been several inspections, all with positive results.

• Access to specialized patient populations to test vaccines: most patients are treatment naïve and many diseases that have been eradicated in the US and Europe still exist in Peru.

Urban legends with regard to Clinicalresearch in Latin America

• “Lots of money involved and available”

• Positive results are “bought”

• Research includes drugs that have no interestfor our countries

• “Money is the major concern for the researchers”

• “Clinical research has no benefit for our country”

Transcultural issues and clinicalresearch in LA

• Ethical standards, just as the scientific ones, shouldnot be compromised based on local traditions.

• A core of human principles are meant to be honoreduniversally, despite local varations in their superficial aspects.

• Local sensitivities should be respected andresearchers must therefore make appropriateaccomodations to local custom.

Angell M. New England Journal of Medicine 1988: 1081-83

Clinical trials in Latin America: hidden threats

• Financial constrains and lack of universal social security systems may induce patients to participate in clinical trials because they can then get access to innovative new drugs and coverage of health expenses they could not otherwise obtain.

• Because of cultural issues, the medical-patient relationship in many LA countries is very paternalistic, which may limit at a certain point the free will of patients.

Particular challenges for clinicalresearch in Latin America

• In many LA countries, there are widesocio-economical disparities; extended health security systems are not alwaysavailable.

• Target populations often lack access toregular health care, political power andan understanding of research.


• Related with ethical aspects of transculturalresearch

– Cultural differences between doctors and patients, researchers and subjects are greater than those seen in developed countries.

– Socially accepted Doctor-patient relationshiptends to be “paternalistic”


• Because of these reasons, situations whereclinical research might potentially exploitpopulations represent a major concern fordeveloping than for developed countries.

• “Exploitation”: a situation where an unfair level of benefits is received by some of two or more parties that interact

Fair benefits for Research in Developing Countries. Science 298 (2002):2133-34.

Reasonable availability requirement

“ As a general rule, the sponsoring agency should agree in advance of the research that any product developed through such reseach will be made reasonably available to the inhabitants of the host community or country at the completion of successful testing”.

Council for International Organizations of Medical Sciences. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva,Switzerland: CIOMS; 2002.

The Fair Benefits Framework

Benefits to Participants during the Research1.Improvement to health and health care2. Collateral health services unnecessary for research study

Benefits to Population during Research3. Collateral health services unnecessary for research study4. Public health measures5. Employment and economic activity

Benefits to Population after Research6.Reasonable availability of effective intervention7. Research and medical care capacity development8. Public health measures9. Long-term research collaboration10. Sharing of financial rewards from research results


The Fair Benefits Framework

Collaborative Partnership1. Community involvement at all stages2. Free, uncoerced decision-making by population

bearing the burdens of the research

Transparency1. Central, publicly accesible repository of benefits

agreements2. Process of community consultations


Requirements for determiningwhether a research trial is Ethical

Requirement Justifying ethical value

Social or scientific value Scarce resources and nonexploitation

Scientific validity Scarce resources and nonexploitation

Fair subject selection Justice

Favorable risk-benefit ratio Nonmaleficence, beneficence, and nonexploitation

Emanuel et al. JAMA. 2000;283:2701-2711

Requirements for determiningwhether a research trial is Ethical

Requirement Justifying ethical value

Independent review Public accountability; minimizing influence of potential conflicts of interest

Informed consent Respect for subject autonomy

Respect for potential andenrolled subjects

Respect for subject autonomyand welfare

Emanuel et al. JAMA. 2000;283:2701-2711

What is being done?1995: Guidelines for GCP for Trials on Pharmaceutical Products (WHO)ICDRA recommendations (Madrid 2004)– Member countries should implement the document– Member countries should guarantee the informed

consent process – Biological Samples in Genetics Studies should follow

GCP guidelines – Gene Therapy is a new area of medicine requiring

rigorous implementation of GCPs and ethics – WHO was asked to explore options for providing

experts to strengthen the R.A. of countries with limited resources

What is being done?International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)– E6: Good Clinical Practices– E2a, E2b, E2c, E2ca, E2d, E2e: Clinical safety data Management – E3: Structure and content of Clinical Study Report– E5: Ethnic Factors in the acceptability of foreign clinical data– E7: Geriatrics: General Considerations for Clinical Research– E9: Statistical Principles for Clinical Research– E10: Choice of Control Groups – E11: Clinical Investigation of Medicinal Products for Pediatrics

Population

Active response from LA

– Meeting of Experts on GCP (1999, Bs As)– II Pan American Conference on Drug

Regulatory Harmonization, established the GCP WG (1999)

– Assessment of GCP situation in the area (2000)

– Mission and Objectives of the GCP WG were defined

International Ethical Committees

• Universidad Peruana Cayetano Heredia• Instituto de Investigación Nutricional• Asociación Benéfica Prisma• Asociación Civil Impacta Salud y Educacíón• Hospital Nacional Dos de Mayo• Instituto de Ciencias Neurológicas “Oscar Trelles

Montes”• Instituto de Medicina Tropical de la UNMSM• Instituto Materno Perinatal• Vía Libre

• Instituto Nacional de Salud• Universidad de San Martín de Porres• Instituto de Salud del Niño• Hospital Nacional Edgardo Rebagliati• Hospital General María Auxiliadora• Instituto de Enfermedades Neoplásicas• Hospital Nacional Guillermo Almenara• Sociedad Peruana de Medicina Interna, Filial

Arequipa

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Clinical research in Latin America: constraints and opportunities

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