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Regulatory issues in Latin America. Max S. Mano Assist. Prof. Medical Oncology – University of São Paulo (USP/ICESP) Medical Oncology – Hospital Sírio Libanês. Saturation of clinical trials sites. Trends in the globalization of clinical trials.

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regulatory issues in latin america

Regulatory issues in Latin America

Max S. Mano

Assist. Prof. Medical Oncology – University of São Paulo (USP/ICESP)

Medical Oncology – Hospital Sírio Libanês


Trends in the globalization of clinical trials

Nature Reviews Drug Discovery 7, 13-14 (January 2008)


Top 50 Countries Ranked By Average Relative Annual Growth Rates.

Nature Reviews Drug Discovery 7, 13-14 (January 2008)

brazil peculiarities
Brazil – peculiarities
  • Directives 196/96, 251/87, 292/99 and Resolution 404

Special circumstances=mandatory submission to CONEP (central EC)

  • Res.196/96:
  • Human Genetics (Res. 340/04)
  • Human Reproduction (Res. 303/00)
  • New drugs and diagnostic tests (Res. 251/97)
  • New (or not yet granted registration in Brazil) equipments, inputs and devices

Submission also




Special circumstances=mandatory submission to CONEP (central EC)

5. New procedures not consensually accepted by the literature

  • Indigenous populations (Res. 304/00)
  • Projects with issues of biosecurity
  • Research coordinated by other countries or with their participation and research involving shipment of biologic specimens abroad (Res. 292/99)
  • Projects for which institutional ECs judged suitable for evaluation by central EC (CONEP).
brazil peculiarities use of placebo post trial access to treatments
Brazil - peculiaritiesUse of placebo, post trial access to treatments
  • Resolution 404, August 2008
    • Reaction to the 2008 Declaration of Helsinki, especially against 2 “clarifications notes” (on the use of placebo and post trial access to treatments)
    • These clarifications are not acceptable and for the Brazilian regulatory process the content of the 2000 version of the Declaration of Helsinki was retained

In other words:

      • At the end of the study, all patients should be given acess to the treatments that have been proven effective (by the study sponsor)
      • No placebo except in situations where no effective therapy exists

*Confusion (difficult interpretation)


*Rejected studies

*Withdrawals (from sponsors)...

complex regulatory process
Complex regulatory process

Courtesy of Socorro Portella, Novartis Brazil

main site selection criteria by investigators
Main site selection criteria by investigators

Courtesy of Socorro Portella, Novartis Brazil

regulatory flowchart brazil

Agencies inefficient in protocol turnaround times

Unnecessary double (and sequential!) process of EC approval

Regulatory Flowchart Brazil

Long time to dossier preparation

Total Set Up & Approval Process: 8 to 10.5 Months

Time to documents translation into Portuguese after all required documents arrival from sponsor and dossier preparation before submission: 7 - 9 weeks





Local Ethics Committee

Time to IRB/EC approval: 6 - 9 weeks

MoH submission after getting the Local IRB/EC approval: 1 week

National Ethics Committee (CONEP)

Time to MoH approval: 18 - 23 weeks

Import Product

Time to CONEP approval:

18 - 23 weeks

Time to import: 3 - 5 weeks



Import process inefficient

regulatory flowchart chile
Regulatory Flowchart Chile

Total Set Up & Approval

Process: 4.5 to 5.5 Months

Protocol, ICF, IB, local insurance, and required translations

Drug at Site

Time to Submission 2 - 3 weeks

Time to drug at site 1 week

Local/Regional EC

Custom Destination

Time to EC Approval 10 - 12 weeks

2 days

MoH (ISP) Submission

MoH Approval

Time to MOH Approval 6 - 7 weeks

regulatory flowchart mexico
Regulatory Flowchart Mexico

Translation of docs.

2 - 3 weeks

Total Set Up & Approval

Process: 3 to 4 months

Regulatory docs.

from sites

E.C., Hospital, study staff

4 - 6 weeks

Protocol Submission to MOH

MOH Approval

6 - 7 weeks

Import licenses for Study Drug & Lab kits

2 - 3 weeks

Additional submissions to MOH (amendments, additional sites)

Export licenses


Customs release

1 - 2 days

MOH approval

MOH answer

Kendle Mexico WAREHOUSE

brazil recent changes
Brazil – recent changes

Resolution 39 (05 jul 2008)

  • National Ethics Committee (CONEP) and ANVISA (FDA-equivalent) a truly parallel process (potential savings 6-8 weeks for the coordinator site)
  • ANVISA can approve all study sites in one submission (potential savings of up to 6 weeks for subsequent sites)
  • Doubful if these agencies will have sufficient staff to cope with these timelines…
summary of effects of regulatory changes in a growing latam region
Summary of Effects of Regulatory Changes in a Growing LatAm Region
  • * Includes all steps including translations, import license,
  • import process, custom clearance, site contracts, etc.
latin america regulatory processes
Latin America regulatory processes
  • In Latin America in general, the review process is sequential: first EC and then MoH.
    • In the USA, each trial requires IND submission to the FDA and in parallel an IRB approval. The rate limiting step is mainly the IRB submissions and approvals process.
    • In EU, there is a parallel review process, and so submissions to EC’s and Competent Authority (MoH) can be performed simultaneously (i.e: in parallel.)
regulatory timelines in brazil
Regulatory timelines in Brazil




Clinical trials in Brazil


  • Mainly large phase III trials
  • Late entrance
    • SLOW regulatory process
    • “Rescue” for trials with low recruitment and/or acceptance abroad
  • Irrelevant participation in early phases of clinical development (phase 0-I / early phase II).
    • High levels of expertise
    • Outstanding infra-structure
    • Dynamic regulatory process


  • Outcome (one example): lower chance for authorship

Pharmaceutical industry sponsored research – POTENTIAL SOLUTIONS

  • ??Make the Ethics Committee (EC) review process more “professional”. Charge more for this and require more QUALITY
    • Avoid unnecessary queries, many due to inexperience from reviewers
  • Make experienced ECs (local ECs) independent from central national EC (a double – local and central review = waste of time and resourses...)
  • Establish clear timelines (beyond which one can assume that unless otherwise informed the trial has been approved): Belgian experience

Local ECs

  • With growing workload, is the EC review sustainable as a ‘volunteer’ activity?


  • Good EC professionals are increasingly hard to find
    • Certified IRB Professional (US experience)
brazil proposals
Brazil – proposals
  • Under discussion:
    • Regional ECs (CONEP should only arbitrate and advise/control ECs)
      • Doubful if there will be enough qualified staff willing to cope with the review process
  • Under implementation:
    • Fully paper-free dossier (on line submission)
protocol issues identified by conep
Protocol issues identified by CONEP

Source: CONEP 2000 - 2005

academic institutional non sponsored research
Academic (Institutional, Non Sponsored) Research
  • No specific legislation for academic research
  • All CNS directives/resolutions apply
  • Difficult to obtain trial insurance in Brazil (probably in L.A. In general)
    • Non insured research may be dangerous for institutions and investigators, especially as no “sponsor” can be identified
academic institutional non sponsored research1
Academic (Institutional, Non Sponsored) Research
  • The National Health System (SUS) does not cover hospitalizations related to side effects
    • Probably the most limiting aspect of academic clinical research in Brazil
pharmaceutical companies thinking of bringing trials to la
Pharmaceutical companies# Thinking of bringing trials to LA?

Crucial steps:

  • Early planning
  • Select CRO based at and with a good track of experience in the region
    • With native professionals, familiar with local culture and language, regularions etc
  • Good site selection (eg experienced coordinating site in Brazil – makes a major difference)
  • Our regulatory process as a whole can become more efficient
  • Our experience with clinical trials is less than 15 years old and there is goodwill from all parts (academic centres, investigators, regulators and industry representatives) to make continuous improvement
brazil peculiarities1
Brazil – peculiarities
  • RESOLUTION CNS Nº 251/97

I.4 – In any clinical trial and in particularly when potential conflicts of interest with novel compounds may apply, the dignity and well-being of the study subject must prevail over all other interests, whether financial, scientific of communitary.