With an established regulatory environment and a strong healthcare infrastructure, Latin America continues to grow as an advantageous landscape for conducting clinical research. Join Medpace experts Anibal Calmaggi, MD, Senior Medical Director, Infectious Diseases and Vaccines, and Wanda Dobrzanski, MD, Director Clinical Operations, Pediatric infectious diseases and Pharmaceutical medicine specialist, as they share their collective 36 years of experience in designing and managing clinical research in Latin America. This presentation discusses: • Advantages and benefits of running trials in Latin America • Challenges and strategies for addressing them • Required procedures and processes • An in-depth look at the most significant Latin American countries for conducting clinical research

1. Latin America Review
o Wanda Dobrzanski
Nisiewicz M.D.
o Director
o March 2016
LATIN AMERICA:
Challenges &
Opportunities in
Clinical Research
HOST:
James Pusey, M.D.
Senior Vice President, Clinical Operations
PRESENTERS:
Wanda Dobrzanski, M.D.
Head of Clinical Operation Latin America
Anibal Calmaggi, M.D.
Senior Medical Director,
Infectious Diseases and Vaccines

2. South America
Central America
Caribbean
22 independent countries +
France, Netherlands and U.S.
dependencies
Population ~ 600 million
Latin America Overview
Physician Led | Therapeutically Focused2

3. Latin America – Clinical Trials by Region
3 Physician Led | Therapeutically Focused
Source: clinicaltrials.gov
as of March 2015

4. Benefits of Performing Clinical Trials
o Growing population: ~ 620 million people, 80% in
urban areas
o Qualified, reliable and committed medical
professionals. Physicians with more time to
dedicate to clinical studies
o Strong patient-doctor relationship
o Significant availability of naïve patients (both
treatment and trial naïve)
Latin America
Physician Led | Therapeutically Focused4

5. Benefits of Performing Clinical Trials
o Incidence/prevalence of certain diseases similar
or higher than the U.S.
o Centralized health-care. Mexico City, (Mexico),
Sao Paulo (Brazil), Buenos Aires (Argentina) and
Rio de Janeiro (Brazil) have together a population
>60 million people
 Allows higher enrollment rates in fewer sites
o A significant portion of the population <14 years
old (27%)
o Ethnic diversity covering most of the world's
population
Latin America
Physician Led | Therapeutically Focused5

6. Benefits of Performing Clinical Trials
o Reverse seasons
o Established regulatory environment in most of the
countries
o Data quality within the average of the industry
o Regular inspections by MoH in certain countries
o Spanish and Portuguese as unique languages
o Competitive costs
Latin America
Physician Led | Therapeutically Focused6

7. Why Subjects Participate in Clinical Trials
o Zero cost of treatment
o “Modern” medication / evaluations
o Respect for their doctor
o Positive status in the community / family
o Differentiated treatment by hospital staff
o Satisfaction on inner needs: valued, appreciated,
listened to, reassured, approved and
acknowledged
o Altruistic feeling
o Benefit perceived in the family for disease
education
Latin America
Physician Led | Therapeutically Focused7

8. Getting Epidemiological Information from
LA
8 Physician Led | Therapeutically Focused
o There is a lack of comprehensive epidemiological data for the
Latin
o American countries in some therapeutic areas. Main reasons:
 Non-mandatory reportability to the Health authorities
 Difficulties to conduct epidemiological research in resource-poor
settings
 Chronic nature of many diseases, multiple causes and correlated
morbidity.
 More data systematically collected for some conditions that require
hospitalization, such as cancer
 Most of the available data is concentrated in the larger economies,
such as Brazil, Mexico, and Argentina. The smaller economies in this
region, such as Peru and Colombia, are largely neglected, and the
epidemiological information is poor for some diseases
• Epidemiological available information must be confirmed, updated and
complemented with data obtained from feasibility studies, studies published
in local language, Minister of Health special reports, enrollment rates from
previous similar studies, etc.
• This search should be approached by a local team as a routine work for
every potential study to be conducted in LA

9. Cardiovascular and Metabolic Disease Trends in LA
o Cardiovascular diseases are the leading cause of death in LA,
with ischemic heart disease as the principal cause in most
countries
o The adaptation to occidental life styles in LA countries has given
rise to an increase in the prevalence of overweight, abdominal
obesity, smoking, hypertension, metabolic syndrome, diabetes
mellitus type 2 and cardiovascular diseases
o Smoking prevalence is still unacceptably high in the region.
Prevalence rates of smoking (defined as having smoked >100
cigarettes and currently smoking) range from 12.8% in Colombia,
15.5% in Brazil, 19.9% in Mexico, up to 32.7% and 33.4% in
Uruguay and Argentina, and as high as 42% in Chile
o Hypercholesterolemia and hypertension are the two most
common cardiovascular risk factor across the LA region. The
increasing prevalence of diabetes is forecast to become
considerably significant in the epidemiology of cardiovascular
disease
A summary
Physician Led | Therapeutically Focused9

10. Oncology Trends in Latin America
o The epidemiological information on cancer in LA originates mainly from
mortality registries and from a limited number of population-based
cancer registries that present reliable data. Therefore, incidence data
are still limited to specific populations
o The patient pool for cancer therapies is rising in LA, a trend primarily
driven by the rising life expectancies across the populations
o Prostate cancer is the most common malignancy developed by men,
and is the second leading cancer-related cause of death in men,
surpassed only by lung cancer
o Lung cancer is the second more frequent malignancy in men. It is
responsible for the greatest number of cancer-related deaths in this
population
o Breast cancer is the most common form of cancer developed by women
and also the leading cause of cancer-related mortality for woman
o Colorectal cancer is the fourth most commonly developed cancer in LA,
after prostate, breast, and uterine cancers. In line with the average age
of the population, colorectal cancer is expected to rise over the forecast
years
A summary
Physician Led | Therapeutically Focused10
Source: 2014 Icahn School of Medicine at Mount Sinai. Annals of Global Health 2014;80:370-377

11. Other Therapeutic Areas with High
Prevalence in Specific Diseases
11 Physician Led | Therapeutically Focused
o Infectious diseases
 Endemic: TB, dengue, malaria, zika
 High prevalence of antimicrobial resistance rates
(carbapenem resistant enterobacteriaceae, HA-
MRSA and CA-MRSA, Acinetobacter spp and P.
aeruginosa MDR)
o Respiratory diseases: COPD, asthma, allergic
rhinitis
o Neurologic diseases: multiple sclerosis, Parkinson
disease, epilepsy, stroke
o Mental disorders: schizophrenia, bipolar disorder,
depression, panic disorder

12. Strong enrollment rates, higher
patient-compliance and retention
Drop-out rates 50% lower than
other regions

13. Challenges to Performing Clinical Trials
o Social, economic or politically volatile environment
in some countries
o Clinical trial regulations in LA are still evolving in
some countries
o Regulatory timelines longer than in the US
o Logistical issues:
 Regional/Central laboratories (restriction on some
days of the week)
 Custom clearances process in each country to
import/export supplies
Latin America
Physician Led | Therapeutically Focused13

14. Overcoming Challenges
14
o Plan to start with Latin American countries from
the very beginning of the project
o Perform feasibility activities
o Diversify the risk by adding an appropriate
number of countries
o Rely on local knowledge and expertise
o Evaluate potential rather than experience
Physician Led | Therapeutically Focused

15. Special Requirements and Tips
o Study documents translation into Portuguese for
Brazil and Spanish for the rest of the countries for
initial submission
o ICF adaptation according to country-specific
requirements
o Notarized transfer of responsibility letters
(delegating submissions/ conduct of the study to the
CRO)
o Global insurance certificate for all countries and
local insurance issued by national insurance company
for Costa Rica
o Labels in local language and including local
requirements
Working in Latin America
Physician Led | Therapeutically Focused15

16. Import Process and Logistics
o Licenses needed for study drugs, devices, lab
kits (in some countries also export permit is
needed for biological samples)
 Complete list of all goods to be imported (and
exported) at the begining of the submission process
o Customs clearance process involved in all LA
countries
o Local depot per country is highly recommended
for storage and distribution
o Requirement for each import event:
 Pro-forma invoices to be reviewed in advance
 Air way bills number needed in advance
Physician Led | Therapeutically Focused16

17. Argentina
Population distribution
17 Physician Led | Therapeutically Focused
Norte
5,795,363
14.4%
Mesopotamia
6,524,719
16.3%
Centro
22,575,372
56.3%
Argentina total: 40,117,096
Patagonia
2,100,188
5.2%
Cuyo
3,121,454
7.8%

18. Renewed Regulatory Commitment
o “ANMAT declares that it adopts a
proactive position to boost the
development of clinical research”
o “Supporting clinical research,
ANMAT is actively working to
update and improve the
evaluation process guidelines,
without relaxing the requirements
for population protection,
especially of the people included
in the study. Besides, it aims at
increasing the collaboration with
other government bodies”
March 2016
Physician Led | Therapeutically Focused18

19. Total population: 202 768 562
North 17 231 027 8,5%
North East 56 560 081 27,9%
Middle West 15 219 608 7,5%
South East 85 115 623 42,0%
South 29 016 114 14,3%
Source: IBGE - Censo Demográfico – Estimative in 2014
Brazil’s Potential
Brazil population distribution
Physician Led | Therapeutically Focused19
43.7%
56.3%
Norte
Nordeste
Centro-Oeste
Sudeste
Sul

20. Perspectives of Changes
Aim: expedite regulatory approvals in Brazil
o Implementation of an accreditation process of
research ethics committees composing the system
CEP/CONEP –Q3/2016 after EC trainings
o Implementation of a resolution to analyze study
protocols according to risk defined by study design
o Minimum risk & Low Risk protocols , only notification
needed or fast track
o Moderate & High Risk protocols, EC approval required
Brazil regulatory environment in 2016 – under discussion
Physician Led | Therapeutically Focused20

21. Chile
Population distribution
21
XV
XII
XI
X
XIV IX
VIII
VII
RM
VI
V
IV
III
II
I
Nº Región Numero %
XV Arica y Parinacota 213,816 1.3%
I Tarapaca 300,021 1.8%
II Antofagasta 547,463 3.3%
III Atacama 292,054 1.8%
IV Coquimbo 707,654 4.3%
V Valparaiso 1,734,917 10.4%
RM Metropolitana 6,685,685 40.2%
VI O’higgins 877,784 5.3%
VII Maule 968,336 5.8%
VIII Bio Bio 1,971,998 11.9%
IX La Araucania 913,065 5.5%
XIV Los Rios 364,592 2.2%
X Los Lagos 798,141 4.8%
XI Aysen 99,609 0.6%
XII Magallanes 159,468 1.0%
Total Chile 16,634,603 100%
Población por Regiones Censo 2012
Fuente: Sintesis de Resultados Censo 2012
Physician Led | Therapeutically Focused

22. Chile
o Reliable timelines: 4-5 months/16-20 weeks from
initial submission
o Each site submits to their local ethic commitee
(there is no central IRB in Chile)
o Short timelines for studies involving Medical
Devices (MD): 8 weeks from initial submission
o Chilean sites
 Highly qualified medical personnel and experienced
investigators
 Excellent patient recruitment and retention
 Experienced on pediatric studies
Strengths & Success factors
22 Physician Led | Therapeutically Focused

23. Total population: 112,336,538
From 7,643,195 to 15,175,862
From 5,779,830 to 7,643,194
From 3,801,963 to 5,779,829
From 1,955,578 to 3,801,962
From 637,026 to 1,955,577
Mexico
Population distribution
Physician Led | Therapeutically Focused23
INEGI Instituto Nacional de Estadística y Geografía.
Censo de Población y Vivienda 2010

24. Mexico
Mexico
37%
Distrito Federal
21%
Jalisco
18%
Nuevo León
11%
Yucatán
5%
Chihuahua
8%
Main cities
24
Population
Mexico 15,175,862
Distrito Federal 8,851,080
Jalisco 7,350,682
Nuevo León 4,653,458
Yucatán 1,955,577
Chihuahua 3,406,465
Physician Led | Therapeutically Focused

25. Coverage of Other Countries
25 Physician Led | Therapeutically Focused
Peru
Panama
Columbia
Guatemala

26. Conclusion
o Highly-motivated and experienced investigators with
availability to recruit subjects in a variety of
therapeutic areas
o The increasing number of clinical research activities in
Latin America is facilitating the outsourcing of trials to
the region
o Political environment has started to stabilize and
significant economic development occurs
o Healthcare has improved and centers with personnel
trained in clinical research have increased
o National clinical trial regulations aligned with
international good clinical practices have been
established
Physician Led | Therapeutically Focused26

27. Conclusion
o Latin America shows a less competitive
landscape, favorable cost, language capabilities,
and robust quality data
o This can help pharmaceutical and biotechnology
companies speed up drug development process
Physician Led | Therapeutically Focused27

28. Q & A
Wanda Dobrzanski, M.D.,
Head of Clinical Operation Latin America
v.dobrzanski@Medpace.com
Anibal Calmaggi, M.D.,
Senior Medical Director,
Infectious Diseases and Vaccines
a.calmaggi@Medpace.com

29. Q & A Session
29 Physician Led | Therapeutically Focused
o Please clarify what you mean by low/medium risk
studies will only require a notification. Do you
mean that low/medium treatment risk protocols
will only require approval from the LEC with a
notification to CEC (CONEP)?
o Who will determine the protocol risk?
o Once this process is fully implemented, what will
be the expected approval timelines in Brazil?

30. Q & A Session
30 Physician Led | Therapeutically Focused
o You mentioned that ANMAT has declared a
proactive position to boost the development of
clinical research by working to update and
improve the evaluation process guidelines and by
increasing the collaboration with other
government bodies. In practical terms, what has
this changed?
o Will these changes expedite regulatory approvals
in Argentina?

31. Q & A Session
31 Physician Led | Therapeutically Focused
o You mentioned that Political environment has
started to stabilize and significant economic
development is occurring. Can you clarify what
countries you are referring to?

32. Q & A Session
32 Physician Led | Therapeutically Focused
o Regarding Rare diseases, do you have any fast
track process to approve these studies?
o In Metabolic and Diabetes, do you have previous
experience to share from Latin America?

33. Q & A Session
33 Physician Led | Therapeutically Focused
o You mentioned in the presentation that data
quality is within the average of the industry.
However, what were the results of the FDA audits
performed in Latin America?
 What countries were audited?

34. Q & A Session
34 Physician Led | Therapeutically Focused
o During your presentation you just mentioned
about the epidemiology for infectious disease,
cardiology & metabolic diseases and oncology.
Which are the diseases with bigger incidence and
prevalence in Latin America?
o Are there potential sites in the Latin American
region to work with endocrine disorders such as
Diabetes, Acromegaly and Cushing disease?

35. Q & A Session
35 Physician Led | Therapeutically Focused
o Some sponsors select LatAm as rescue countries
to be included in the study, do you think this
strategy could be used for the countries in the
region?

36. Q & A Session
36 Physician Led | Therapeutically Focused
o Which are the new proposed timelines for
approvals after the changes in the regulatory
environment for the Argentina and Brazil take
place? How many months do you think it will take
to have the final approval released in these
countries?

37. Q & A Session
37 Physician Led | Therapeutically Focused
o Which recruitment strategies are most commonly
used in the region? How does the countries find
their study subjects?

38. Q & A Session
38 Physician Led | Therapeutically Focused
o Could you please further explain about your
centralized health-care system in the region? Is
there a central database available for subjects’
enrollment?