Regulatory issues in Latin America
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Transcript of Regulatory issues in Latin America
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Max S. ManoAssist. Prof. Medical Oncology – University of São Paulo
(USP/ICESP)Medical Oncology – Hospital Sírio Libanês
Regulatory issues in Latin America
[email protected]@hsl.org.br
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Saturation of clinical trials sites
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Trends in the globalization of clinical trials
Nature Reviews Drug Discovery 7, 13-14 (January 2008)
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Top 50 Countries Ranked By Average Relative Annual Growth Rates.
Nature Reviews Drug Discovery 7, 13-14 (January 2008)
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Trends in globalization, industry perspective
Mass, ASCO 2009
1997 2005
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Brazil – peculiarities
• Directives 196/96, 251/87, 292/99 and Resolution 404
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Special circumstances =mandatory submission to CONEP(central EC)• Res.196/96:1.Human Genetics (Res. 340/04)2.Human Reproduction (Res. 303/00)3.New drugs and diagnostic tests (Res.
251/97)4.New (or not yet granted registration
in Brazil) equipments, inputs and devices
Submission also
toANVISA
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Special circumstances =mandatory submission to CONEP(central EC)5. New procedures not consensually accepted
by the literature6.Indigenous populations (Res. 304/00)7.Projects with issues of biosecurity8.Research coordinated by other countries or
with their participation and research involving shipment of biologic specimens abroad (Res. 292/99)
9.Projects for which institutional ECs judged suitable for evaluation by central EC (CONEP).
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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)*Delays*Rejected studies*Withdrawals (from sponsors)...
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Complex regulatory process
Courtesy of Socorro Portella, Novartis Brazil
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2005
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Main site selection criteria by investigators
Courtesy of Socorro Portella, Novartis Brazil
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Regulatory Flowchart Brazil
Investigator
MoH(ANVISA)
Local Ethics Committee
National Ethics Committee (CONEP)
Study Start
Import Product
Time to import: 3 - 5 weeks
Total Set Up & Approval
Process: 8 to 10.5 Months
MoH submission after getting the Local IRB/EC approval: 1 week
Kendle Time to documents translation into Portuguese after all required documents arrival from sponsor and dossier preparation before submission: 7 - 9 weeks
Time to CONEP approval: 18 - 23 weeks
Time to MoH approval: 18 - 23 weeks
Time to IRB/EC approval: 6 - 9 weeks
Long time to dossier preparation
Unnecessary double (and sequential!) process of EC approval
Agencies inefficient in protocol turnaround times
Import process inefficient
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Regulatory Flowchart Chile
Total Set Up & ApprovalProcess: 4.5 to 5.5 Months
Protocol, ICF, IB, local insurance, and required
translations
Time to Submission 2 - 3 weeks
Time to EC Approval 10 - 12 weeks
Local/Regional EC
MoH (ISP) Submission MoH Approval
Time to MOH Approval 6 - 7 weeks
Custom Destination
2 days
Drug at Site
Time to drug at site 1 week
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Regulatory Flowchart Mexico
Translation of docs.
2 - 3 weeksRegulatory docs.
from sitesE.C., Hospital, study
staff4 - 6 weeks
Protocol Submission to MOH
MOH Approval
6 - 7 weeks
Export licenses(Tissues)
MOH approval
Import licenses for Study Drug & Lab kits
2 - 3 weeks
Customs release
1 - 2 days
Additional submissions to MOH (amendments,
additional sites)
MOH answer
Kendle Mexico WAREHOUSE
Total Set Up & Approval Process: 3 to 4 months
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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…
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Summary of Effects of Regulatory Changes in a Growing LatAm Region
Country Current average time from Protocol & other required documents available to
SIV (months) *
Effect of recent Changes on CT
growth
Argentina 5.5 – 6.5 Continued
Brazil 8 – 10.5 Accelerated
Chile 4.5 – 5.5 Continued
Colombia 4 – 4.5 Accelerated
Mexico 3 – 4 Continued
Peru 5 if not biologic6 if biologic
Accelerated
* Includes all steps including translations, import license, import process, custom clearance, site contracts, etc.
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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.)
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Challenges and opportunities
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Regulatory timelines in Brazil
Translations
Queries
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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
Requirements
Projetos Grupo I
7%19%
14%
60%
Fase I Fase II Fase III Fase IV
Outcome (one example): lower chance for authorship
Fonte: http://conselho.saude.gov.br/comissao/conep/relata.ppt
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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
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Local ECs
• With growing workload, is the EC review sustainable as a ‘volunteer’ activity?
NO!
• Good EC professionals are increasingly hard to find – Certified IRB Professional (US
experience)
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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)
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Protocol issues identified by CONEP
Source: CONEP 2000 - 2005
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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
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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
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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)
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Conclusions
• 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
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BACKUP
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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.
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Countries main agencies