clinipace worldwide: conducting clinical trials in latin america

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Latin America is Fertile Ground for Clinical Trials: What Every Sponsor Needs to Know

Presented by:

Barb Geiger, BSN, RNExecutive Vice President of Clinical Operations at Clinipace Worldwide



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Conducting Trials in Latin America

Investigators

Sites

Patients

Regulatory Environment

Challenges

Suggestions for Success




Investigators

Experience

• Source: clinicaltrials.gov

Many investigators are trained and experienced in the conduct of trials

Country % Increase No. Trials 2005 No. Trials 2009

Argentina 16 97 112

Brazil 58 153 241

Mexico 49 106 158




Investigators

Training

GCP / ICH courses mandated by some countries for investigators, study coordinators and nurses

Certification may be required by some regulatory authorities for principal investigators

Educational forums at various Universities and Foundations

Investigators Meetings

Study Initiation Meetings

International Conferences




Investigators

Science

High value placed on science and protocol design

Involve the local experts in protocol and study design

Investigator roundtables a great source of input

Enthusiasm for the research process




Sites

Public versus Private

National health care varies in each country

• Impacts your ability to do trials requiring specified treatment, e.g. second line oncology trials

Public versus Private institutions:

• Socioeconomic differences

• Private insurance for some patients

• Differences in Standard of Care

Availability of new commercial drugs

Treatment naïve patients




Sites

Locations

Population in Latin America affects site selection

• 538 million people in the region

• Dense population in major cities

• Ethnic diversity (European, Asian, African)

May have multiple study sites in one large city

Sites may have a religious or ethnic focus that impacts your trial

Considerations for sites outside of the major cities:

• Shipping samples

• Patient accessibility and transportation




Patients

Standard of Care

Public – generics, first line treatment will vary

Private – patient will have access to new treatments

Relationship with healthcare provider

Compliance

Retention

Respect




Patients

Family Support

Altruism

Willingness to participate




Patients

Epidemiology

Ethnic and Genetic Predisposition

• Gastric Cancer – Chile and Peru

• Gallbladder Cancer – Peru

• Cervical Cancer and HPV – throughout the region

Infectious Diseases

• Tropical

• TB, HIV

• Reverse Seasons

Pneumonia

Influenza




The Regulatory Environment

Protect the Welfare and Safety of Study Participants

Based on ICH

Local Regulations mirror ICH

Regulations updated (change) regularly




The Regulatory Environment

Timelines

Process

Informed consent

CTAs

Bioequivalence

Regional Requirements




Timelines

Country Set‐Up/Translation

Ethics Committee

IEC MOH Import Total

Argentina 4 weeks 4‐6 weeks 2 weeks(parallel)

90 business days

1‐2 weeks

5 ½ months

Brazil 4 weeks 4‐6 weeks 90 days 90 days 2‐3weeks

8 ½ months

Chile 4 weeks 4‐6 weeks NA Notifica‐tion only

30 business days

4 months

Mexico 4 weeks 4‐6 weeks NA 45 business days

3 weeks 4 ½ months

Peru 4 weeks 2‐4 weeks NA 60 days 3 weeks 4 ½ months




Process

Site Ethics committees

Generally 4‐6 weeks

Verify membership although they follow GCP / ICH

Investigators often members of EC

Cost approximately $600‐$1,000 USD

Institution specific requirements, especially for Informed Consent will not be negotiable

CRO does submission to Ethics Committee




Process

Independent Ethics Committee

In some countries an IEC will be necessary

Generally 2‐3 weeks

Cost approximately $600 USD

Established to insure patient safety if institution EC not experience, now standard to include

Parallel to site EC




Process

National EC

Brazil CONEP

Will take 3 months or longer

Often have questions about:

• Protocol – e.g. use of placebo will require justification

• Consent – Specific wording will be required

• Patient Follow‐Up – provision of product post‐study

Little leeway for change or negotiation




Process

Ministry of Health

Dossier requirements will be very specific – CRO should provide Sponsor with a detailed list of what is required

• Protocol, IB, C of A etc.

Contact with evaluators will be allowed, generally e‐mail

Evaluators may not always be expert in the field – make sure the submission is very clear

MOH has varying importance in the process depending upon the country

• Argentina – ANMAT is the primary review

• Chile – no MOH approval required other than notification and issuance of import permit




Process

Informed Consent

Provide a template and understand it will be changed

Local language and other languages will be required

Country specific requirements as well as site requirements must be respected

Will be the most difficult aspect of the approval process




Sample Informed Consent Wording

“In the case of research-related side effects or injury, medical care will be provided by your doctor or you will be referred for appropriate medical care, without any costs for you. If you are injured or become sick as a direct result of the proper administration of the investigational drug, xxxxxxx, or of the study procedures adequately conducted by you, by your study doctor and study staff as required in the study plan, the Sponsor will assume the responsibility to provide entire assistance and compensation to treat such medical complications and injuries.

You do not waive any of your legal rights for compensation by signing this form. An insurance policy was provided to cover any injuries related to xxxxxxx used in this study.”





“After study completion, if you have not been taken off of the study drug for any reason (your disease progresses or due to a side effect), your doctor will determine what the best treatment for you will be. If it is determined that the test medication, xxxxxxx, is the best treatment compared to the current available treatments in Brazil, the test medication will be provided by the sponsor to you without any cost.“




Process

Clinical Trial Agreements (CTAs)

Will be required as part of the submission/approval process

• Unlike in US, the EC and MOH sees the site contracts

• Budget / Cost

Don’t assume the cost will be less in Latin America

» Investigator grant and CRO cost may be less

» Oversight, shipping, travel etc. will be more

Same grant across all sites in country is likely

Institution language will be required at many sites – others will sign with no changes

May have a signature by intervening administrator

Negotiations must be done by local representatives (CRO)




Regional Requirements

Provision of Comparators

No cost requirement

Continued Treatment

Pregnancy

Insurance / Indemnification




Provision of Comparators

All comparator agents used in trial must be supplied, even if SOC

May be supplied locally or reimbursed

Consider use of generics and need for standardization

Ancillary products must also be provided, e.g. pregnancy tests

Pain meds, antihistamines, anti‐emetics must be provided as needed

Goal is no cost to patient or institution





“Enough quantity of preventive condom and oral hormonal contraceptive (efficient methods to prevent pregnancy) will be provided at no cost to all study participants (condom for men and condom plus oral contraceptive for women with potential to be pregnant), during the whole study, including the 2 weeks after you complete treatment.”




Continued Treatment

Patient benefit

Protocol design

Investigator discretion

Compassionate use

Commercial availability

What if development is stopped?

Must be in informed consent





“You may be taken off of the study only after the analysis of the reasons by the Ethics Committee that approved the study in the hospital/clinic where you will be treated. This may occur, e.g., whether the study is stopped or your study doctor decides not treat you with the study drug anymore. However, in case of a medical emergency, you may be taken off of the study without a previous analysis by the Ethics Committee due to the reason of protection to your health. This decision will be communicated as soon as possible to the Ethics Committee that approved the study in the hospital/clinic where you will be treated.“




Bioequivalence

Argentina has new BE study regulations which impact drugs that must be conducted as BE studies

Some BE studies will enroll patients rather than normal healthies – when this is the case the assigned evaluator will be from the BE team

Normal healthy studies go to a secondary agency within ANMAT, INAME, for additional review

A BE study would normally have to be conducted at a BE unit that fulfills specific criteria

Sites are inspected by ANMAT as part of the protocol approval process

The protocol itself, must clearly address all the information inherent to PK samples: handling, storage, shipping, etc. (not just a worksheet or manual)




Pregnancy

“If you do become pregnant, you will have to discontinue study treatment, however you will be followed for 30 days after the child is born. You should inform your study doctor if you had any problems during your pregnancy or if your baby had any health problems. Beside the follow up, entire assistance will be assured to you or your partner who becomes pregnant (in case of male participant in the study) and to the child, if applicable, if any of such persons are injured as a direct result of the proper administration of the investigational drug, xxxxxxx, or of the study procedures adequately conducted by you, by your study doctor and study staff as required in the study plan .

Breastfeeding mothers cannot participate in this study.




Insurance

Malpractice insurance not common in public setting

Institutional insurance may be the government

Investigators/Institutions may not be able to indemnify sponsors

“Self Insure” language – may not be a set amount




Sample CTA Insurance Wording

“We do hereby warrant that all investigators in our centre have malpractice insurance for errors and omissions that might arise under this study.”




Challenges

Language

Local Translations

Informed consent

• Multiple languages

• Local dialects and variations

• One Spanish consent is not enough

Regional and Cultural Differences

It is not the United States of Latin America

Changing Regulations

Keeping up can be difficult

Red ink in dossier

Provincial regulations in addition to national





Planning

Don’t underestimate the start‐up time and plan for more

Consider import‐export and customs fees into your budget

Shipping costs for central labs – can you do locally?

Holidays

• National

• Bridge

• Summer





Review Process

Never submit protocol amendment during review cycle

Dossier package must be complete and error free (or restarts the clock) – use the requirement list provided by the CRO

Discuss local regulations with your legal team:

• Informed consent language (belongs to the site, not the sponsor)

• Insurance requirements

• Patient follow‐up





Communication

Always better face‐to‐face

Be careful with email – may be misunderstood

Be clear and polite – demands are not acceptable

Pick up the phone

Speak clearly and without colloquialisms




Culture

Local representative to address regional issues

Speaking Spanish is not enough

Site/Country Informed Consent templates must be respected

Don’t insist on sponsor wording

• It will be rejected






Ethical Considerations

Vulnerable Population?

• Perception of study population as poor, illiterate or without access to healthcare

• Reliance on healthcare provider or family to make decisions

• Indigenous populations will require community leader consent

• Patient payments not allowed




Successful clinical trials rely on a variety of factors

Investigational Teams

Target Patient Population

Patient Retention and Compliance

Standard of Care




Debunking the Myths

Investigators are highly trained and have clinical research experience and staff

There WILL be competition for patients and sites for your trial

Some patients will have health insurance

Not all patients will be treatment naïve

Most facilities are comparable to or better than European and US sites

Language does not have to be a barrier to success

US FDA does accept data from Latin American sites and conducts inspections in the region

Plan ahead and you can manage the timelines for a successful outcome

Latin American sites can help make up for start‐up time with a faster enrollment rate




Q&A

Please submit your questions via the chat feature

Barb Geiger, BSN, RNExecutive Vice President of Clinical Operations at Clinipace Worldwide

[email protected]

www.clinipace.com

mailto:[email protected]

clinipace worldwide: conducting clinical trials in latin america

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