The number of patients enrolled in international multi-centre clinical trials has increased in some countries of Latin America. Eduardo Gotuzzo, M.D. FACP

1. Clinical research in Latin
America: constraints and
opportunities
Eduardo Gotuzzo, M.D. FACP
Instituto de Medicina Tropical “Alexander von Humboldt”
Universidad Peruana Cayetano Heredia
Hospital Nacional Cayetano Heredia
Lima, Perú

2. 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

3. Introduction
In 1993 2.1% of clinical trials were
done 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

4. Latin America
•South America(13
countries), Central
America and the
countries of the
Caribbean.
•Current estimated
population: 490 million
people.
•Large and very
heterogeneous ethnic
and epidemiological
profile

5. Latin America’s megacities
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
Source: United Nations World Urbanization

6. 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 diseases
mortality rates for cancer, heart disease and
strokes
incidence of diabetes

7. Mortality rates by cause, at the start of the
1980s and the end of the 1990s for selected
countries in Latin America
Mexico Brazil Argentina Colombia
80 90 80 90 80 90 80 90
Infectious 137.3 29.9 96.1 38.3 44.9 49.6 39.3 26.3
diseases
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
Heart 54.8 81.7 129.8 127.5 81.9 142.7 105.4 109.9
diseases &
strokes
Mortality rates per 100,000 population,

8. LA: a dynamic market for clinical
research
• Between 1995 and 2000, the number of
trials executed in the region rose by a
factor of ten.
• Certain Latin American markets, such
as Brazil, Mexico and Argentina have
seen a 1000 percent increase in clinical
trials between 1995 and 2000.

9. Clinical trials in Latin America:
advantages
• The majority of the general population is
treatment naïve (not on other medications
that could interfere with experimental
treatments).
• Heart disease, arthritis, cancer, and infections
are as prevalent as in the United States.

10. Clinical trials in Latin America:
advantages
• The number of clinical trials in Latin America is
increasing at a faster rate than other regions.
• As market conditions are favorable, an increase of
as much as tenfold can be expected over the next
five years.
• In the past few years, PPD, Quintiles, Covance,
ClinTrials, Latin Trials,MDS,Kendle, ICON, and
others have opened offices in Latin America to
help support their efforts in this area.

11. Clinical trials in Latin America:
advantages
• The number of qualified health personnel
compares favourably with that in other
developing regions.
• The standard of medical training is generally
high, and knowledge of the guidelines laid down
by the International Conference on
Harmonisation and Good Clinical Practice is
widespread

12. Qualified health personnel in LA compared
with other regions
5
4
3
2
1
0
SA
ico
K
ru
a
il
ne a
C hile
M a
na
a
az
di
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Ve n tin
el
bi
Pe
ex
U
hi
In
zu
Br
om
C
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ge
ol
Ar
Physicians/100 population Hospital bed/1000population
Source: Eurostat, OECD, CIA World Factbook

13. Clinical trials in Latin America:
advantages
• 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 is
in large part located in several major cities,
allowing recruitment via hundreds of multi-
center sites in several countries at the same
time.

14. Clinical trials in Latin America:
advantages
• Drop-out rates in the region are about half of
those in Europe.
• La investigators have increase in proficiency
and improve standards of operation.
• Individual Latin American governments are
also becoming more formalized in their
handling of clinical research.

15. Clinical trials in Latin America:
advantages
• Latin America represents also a potential
market for pharmaceutical drugs
• The Compound Annual Growth Rate of the
combined market is expected to be 7.3% per
year on average, spurred in part by new
product patent-protection regulation and
enforcement, which makes the region more
appealing to multinational companies

16. Clinical trials in Latin America
(1966-2003)
Country Total CT Total %CT/total %CT/total
registries registries registries
(per country) (region)
Brazil 1496 40106 3.7 35.7
Mexico 862 16566 5.17 20.6
Argentina 621 17101 3.63 14.8
Chile 425 8112 5.23 10.1
Venezuela 151 3371 4.5 3.6
Cuba 140 2185 6.4 3.3
Colombia 109 1642 6.6 2.6
Peru 93 837 11.1 2.2
Source: Medline, August 25th, 2003 Adapted from: Cañedo et al. 2004

17. Clinical Research in Latin America:
advantages
• A new form of economic investment with
scientific impact.
• In the last decade, the annual investment in the
Andean 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 number
of additional re puestos de trabajo y promovido

18. 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
Includes only information of recruiting centers
Source: www.clinicaltrials.gov (US National Institutes of Health)

19. Clinical trials in Latin America (2006)
Inf.Dis Oncolog CV Resp
Brazil 37 34 20 20
Mexico 26 21 17 17
Argentina 32 34 21 20
Chile 16 12 9 11
Peru 19 19 2 11
Includes only information of recruiting centers
Source: www.clinicaltrials.gov (US National Institutes of Health)

20. Clinical trials in Latin America (2006)
Industry NIH University Other
Brazil 133 12 26 4
Mexico 140 3 10 0
Argentina 135 3 17 0
Chile 57 2 8 0
Peru 47 11 15 1
Includes only information of recruiting centers
Source: www.clinicaltrials.gov (US National Institutes of Health)

21. 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.

22. Clinical trials in Latin America
• The successful experience with:
– Rotavirus vaccine
– Papillomavirus vaccine
– HIV vaccine

23. Clinical research: advantages from
the 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.

24. Clinical trials in Latin America:
disadvantages
• At health facilities, there is a widespread
misunderstanding of the economic issues related
to clinical trials, which might generate certain
tensions with the non participating staff.
• The regulations governing clinical trials in LA are
still evolving, in some cases they change rapidly
without notice and in some other cases they do
not yet exist.
• Importing and exporting drugs can be a very
expensive, length process.

25. 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 governments
have low scores in the latest TI Corruption Perceptions
Index.

26. 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.

27. 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.

28. Urban legends with regard to Clinical
research in Latin America
• “Lots of money involved and available”
• Positive results are “bought”
• Research includes drugs that have no interest
for our countries
• “Money is the major concern for the researchers”
• “Clinical research has no benefit for our country”

29. Transcultural issues and clinical
research in LA
• Ethical standards, just as the scientific ones, should
not be compromised based on local traditions.
• A core of human principles are meant to be honored
universally, despite local varations in their superficial
aspects.
• Local sensitivities should be respected and
researchers must therefore make appropriate
accomodations to local custom.
Angell M. New England Journal of Medicine 1988: 1081-83

30. 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.

31. Particular challenges for clinical
research in Latin America
• In many LA countries, there are wide
socio-economical disparities; extended
health security systems are not always
available.
• Target populations often lack access to
regular health care, political power and
an understanding of research.

32. Particular challenges for clinical
research in Latin America
• Related with ethical aspects of transcultural
research
– Cultural differences between doctors and patients,
researchers and subjects are greater than those
seen in developed countries.
– Socially accepted Doctor-patient relationship
tends to be “paternalistic”

33. Particular challenges for clinical
research in Latin America
• Because of these reasons, situations where
clinical research might potentially exploit
populations represent a major concern for
developing 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.

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.

35. The Fair Benefits Framework
Benefits to Participants during the Research
1.Improvement to health and health care
2. Collateral health services unnecessary for research study
Benefits to Population during Research
3. Collateral health services unnecessary for research study
4. Public health measures
5. Employment and economic activity
Benefits to Population after Research
6.Reasonable availability of effective intervention
7. Research and medical care capacity development
8. Public health measures
9. Long-term research collaboration
10. Sharing of financial rewards from research results
Fair benefits for Research in Developing Countries. Science 298 (2002):2133-34.

36. The Fair Benefits Framework
Collaborative Partnership
1. Community involvement at all stages
2. Free, uncoerced decision-making by population
bearing the burdens of the research
Transparency
1. Central, publicly accesible repository of benefits
agreements
2. Process of community consultations
Fair benefits for Research in Developing Countries. Science 298 (2002):2133-34.

37. Requirements for determining
whether 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

38. Requirements for determining
whether 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 and Respect for subject autonomy
enrolled subjects and welfare
Emanuel et al. JAMA. 2000;283:2701-2711

39. 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

40. 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

41. 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

42. 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

43. • 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