Latin America: Challenges & Opportunities in Clinical Research

Latin America Review

o Wanda Dobrzanski Nisiewicz M.D.

o Directoro 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

1

Physician Led | Therapeutically Focused2

South America Central America

Caribbean

22 independent countries +France, Netherlands and U.S.

dependencies

Population ~ 600 million

Latin America Overview

Physician Led | Therapeutically Focused

Latin America – Clinical Trials by Region

3

Source: clinicaltrials.gov as of March 2015


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 relationshipo Significant availability of naïve patients (both

treatment and trial naïve)

Latin America



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



o Reverse seasons o Established regulatory environment in most of the

countrieso Data quality within the average of the industry o Regular inspections by MoH in certain countrieso Spanish and Portuguese as unique languageso Competitive costs

Latin America


Why Subjects Participate in Clinical Trials

o Zero cost of treatmento “Modern” medication / evaluationso Respect for their doctoro Positive status in the community / familyo Differentiated treatment by hospital staffo Satisfaction on inner needs: valued, appreciated,

listened to, reassured, approved and acknowledgedo Altruistic feelingo Benefit perceived in the family for disease education

Latin America

8 Physician Led | Therapeutically Focused

Getting Epidemiological Information from LAo 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


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


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

Source: 2014 Icahn School of Medicine at Mount Sinai. Annals of Global Health 2014;80:370-377


Other Therapeutic Areas with High Prevalence in Specific Diseaseso 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

Strong enrollment rates, higher patient-compliance and retention

Drop-out rates 50% lower than other regions


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 USo Logistical issues:

Regional/Central laboratories (restriction on some days of the week)

Custom clearances process in each country to import/export supplies

Latin America


Overcoming Challenges o Plan to start with Latin American countries from

the very beginning of the projecto Perform feasibility activitieso Diversify the risk by adding an appropriate

number of countrieso Rely on local knowledge and expertiseo Evaluate potential rather than experience


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


Import Process and Logisticso 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


ArgentinaPopulation distribution

Norte5,795,36314.4%

Mesopotamia6,524,71916.3%

Centro22,575,37256.3%

Argentina total: 40,117,096

Patagonia2,100,1885.2%

Cuyo3,121,4547.8%


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


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 PotentialBrazil population distribution

43.7%

56.3%

Norte

Nordeste

Centro-Oeste

Sudeste

Sul


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


ChilePopulation distribution

21

XV

XII

XI

X

XIV IXVIIIVII

RMVI

V

IV

III

II

INº 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


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


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

MexicoPopulation distribution

INEGI Instituto Nacional de Estadística y Geografía. Censo de Población y Vivienda 2010

http://www3.inegi.org.mx/sistemas/componentes/mapa/default.aspx




Mexico

Mexico37%

Distrito Federal21%

Jalisco18%

Nuevo León11%

Yucatán5%

Chihuahua8%

Main cities

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PopulationMexico 15,175,862Distrito Federal 8,851,080Jalisco 7,350,682Nuevo León 4,653,458Yucatán 1,955,577Chihuahua 3,406,465


Coverage of Other Countries

Peru

Panama

Columbia

Guatemala


Conclusiono 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


Conclusiono 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

Q & A

Wanda Dobrzanski, M.D.,Head of Clinical Operation Latin America

[email protected]

Anibal Calmaggi, M.D.,Senior Medical Director,

Infectious Diseases and [email protected]


Q & A Sessiono 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?


Q & A Sessiono 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?


Q & A Sessiono You mentioned that Political environment has

started to stabilize and significant economic development is occurring. Can you clarify what countries you are referring to?


Q & A Sessiono 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?


Q & A Sessiono 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?


Q & A Sessiono 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?


Q & A Sessiono 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?


Q & A Sessiono 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?


Q & A Sessiono Which recruitment strategies are most commonly

used in the region? How does the countries find their study subjects?


Q & A Sessiono Could you please further explain about your

centralized health-care system in the region? Is there a central database available for subjects’ enrollment?

Date post:	10-Feb-2017
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Latin America: Challenges & Opportunities in Clinical Research

Health & Medicine