Regulatory issues in Latin
America
Max S. Mano
Assist. Prof. Medical Oncology – University of São Paulo (USP/ICESP)
Medical Oncology – Hospital Sírio Libanês
[email protected]
[email protected]
ICTW Punta del Este, Uruguay
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.
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Nature Reviews Drug Discovery 7, 13-14 (January 2008)
Trends in globalization, industry
perspective
1997
2005
Mass, ASCO 2009
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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
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Submission
also
to
ANVISA
Special circumstances
=mandatory submission to CONEP (central EC)
5. New procedures not consensually accepted by the
literature
6. Indigenous populations (Res. 304/00)
7. Projects with issues of biosecurity
8. 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 - peculiarities
Use 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:
*Confusion
(difficult
interpretation)
*Delays
*Rejected studies
*Withdrawals
(from sponsors)...
• 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
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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
Total Set Up &
Approval
Process: 8 to
10.5 Months
Kendle
Long time to
dossier
preparation
Time to documents translation into
Portuguese after all required documents
arrival from sponsor and dossier preparation
before submission: 7 - 9 weeks
Investigator
MoH
(ANVISA)
Agencies
inefficient in
protocol
Time to MoH approval:
turnaround
18 - 23 weeks
times
Import Product
Time to import: 3 - 5
weeks
Import
process
inefficient
MoH submission
after getting the
Local IRB/EC
approval: 1 week
Study
Start
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Local Ethics
Committee
Time to IRB/EC
approval: 6 - 9 weeks
Unnecessary
double (and
sequential!)
National Ethics
process of EC
Committee
approval
(CONEP)
Time to CONEP approval:
18 - 23 weeks
Regulatory Flowchart Chile
Protocol, ICF, IB, local
insurance, and required
translations
Total Set Up & Approval
Process: 4.5 to 5.5 Months
Time to Submission
2 - 3 weeks
Drug at Site
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
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Regulatory Flowchart Mexico
Translation of docs.
Regulatory docs.
from sites
E.C., Hospital, study
staff
4 - 6 weeks
2 - 3 weeks
Protocol Submission to
MOH
Total Set Up & Approval
Process: 3 to 4 months
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
Kendle Mexico WAREHOUSE
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Additional submissions
to MOH (amendments,
additional sites)
MOH answer
Brazil – recent changes
Resolution 39 (05 jul 2008)
• National Ethics Committee (CONEP) and ANVISA (FDAequivalent) 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 biologic
6 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
Fonte: http://conselho.saude.gov.br/comissao/conep/relata.ppt
60%
• Mainly large phase III trials
• Late entrance
– SLOW regulatory process
– “Rescue” for trials with low recruitment
and/or acceptance abroad
P ro je to s G ru p o I
1 4%
7%
1 9%
F ase I
F a s e II
F a s e III
• 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
 Outcome (one example): lower chance for authorship
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F a s e IV
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
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Regulatory timelines in Brazil