ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
Saturation of clinical trials sites
ICTW Punta del Este, Uruguay
Trends in the globalization of clinical trials
Nature Reviews Drug Discovery 7, 13-14 (January 2008)
ICTW Punta del Este, Uruguay
Top 50 Countries Ranked By Average Relative Annual Growth Rates.
Nature Reviews Drug Discovery 7, 13-14 (January 2008)
ICTW Punta del Este, Uruguay
Trends in globalization, industry perspective
Mass, ASCO 2009
1997 2005
ICTW Punta del Este, Uruguay
Brazil – peculiarities
• Directives 196/96, 251/87, 292/99 and Resolution 404
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
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).
ICTW Punta del Este, Uruguay
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)...
ICTW Punta del Este, Uruguay
Complex regulatory process
Courtesy of Socorro Portella, Novartis Brazil
ICTW Punta del Este, Uruguay
2005
ICTW Punta del Este, Uruguay
Main site selection criteria by investigators
Courtesy of Socorro Portella, Novartis Brazil
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
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…
ICTW Punta del Este, Uruguay
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.
ICTW Punta del Este, Uruguay
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.)
ICTW Punta del Este, Uruguay
Challenges and opportunities
ICTW Punta del Este, Uruguay
Regulatory timelines in Brazil
Translations
Queries
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
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)
ICTW Punta del Este, Uruguay
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)
ICTW Punta del Este, Uruguay
Protocol issues identified by CONEP
Source: CONEP 2000 - 2005
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
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)
ICTW Punta del Este, Uruguay
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
ICTW Punta del Este, Uruguay
BACKUP
ICTW Punta del Este, Uruguay
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.
ICTW Punta del Este, Uruguay
Countries main agencies