regulatory issues in latin america

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


Saturation of clinical trials sites


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)


Trends in globalization, industry perspective

Mass, ASCO 2009

1997 2005


Brazil – peculiarities

• Directives 196/96, 251/87, 292/99 and Resolution 404


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


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).


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)...


Complex regulatory process

Courtesy of Socorro Portella, Novartis Brazil


2005


Main site selection criteria by investigators

Courtesy of Socorro Portella, Novartis Brazil


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


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


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


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

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.


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.)


Challenges and opportunities


Regulatory timelines in Brazil

Translations

Queries


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


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?

NO!

• Good EC professionals are increasingly hard to find – Certified IRB Professional (US

experience)


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

Source: CONEP 2000 - 2005


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) 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?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)


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


BACKUP


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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regulatory issues in latin america

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