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ICTW Punta del Este, Uruguay Max S. Mano Assist. Prof. Medical Oncology – University of São Paulo (USP/ICESP) Medical Oncology – Hospital Sírio Libanês.

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Presentation on theme: "ICTW Punta del Este, Uruguay Max S. Mano Assist. Prof. Medical Oncology – University of São Paulo (USP/ICESP) Medical Oncology – Hospital Sírio Libanês."— Presentation transcript:

1 ICTW Punta del Este, Uruguay Max S. Mano Assist. Prof. Medical Oncology – University of São Paulo (USP/ICESP) Medical Oncology – Hospital Sírio Libanês Regulatory issues in Latin America

2 ICTW Punta del Este, Uruguay Saturation of clinical trials sites

3 ICTW Punta del Este, Uruguay Trends in the globalization of clinical trials Nature Reviews Drug Discovery 7, (January 2008)

4 ICTW Punta del Este, Uruguay Top 50 Countries Ranked By Average Relative Annual Growth Rates. Nature Reviews Drug Discovery 7, (January 2008)

5 ICTW Punta del Este, Uruguay Trends in globalization, industry perspective Mass, ASCO

6 ICTW Punta del Este, Uruguay Brazil – peculiarities Directives 196/96, 251/87, 292/99 and Resolution 404

7 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 to ANVISA

8 ICTW Punta del Este, Uruguay 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).

9 ICTW Punta del Este, Uruguay 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: 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)...

10 ICTW Punta del Este, Uruguay Complex regulatory process Courtesy of Socorro Portella, Novartis Brazil

11 ICTW Punta del Este, Uruguay 2005

12 ICTW Punta del Este, Uruguay Main site selection criteria by investigators Courtesy of Socorro Portella, Novartis Brazil

13 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: 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: weeks Time to CONEP approval: weeks Time to MoH approval: weeks Time to IRB/EC approval: weeks Long time to dossier preparation Unnecessary double (and sequential!) process of EC approval Agencies inefficient in protocol turnaround times Import process inefficient

14 ICTW Punta del Este, Uruguay Regulatory Flowchart Chile Total Set Up & Approval Process: 4.5 to 5.5 Months Protocol, ICF, IB, local insurance, and required translations Time to Submission weeks Time to EC Approval weeks Local/Regional EC MoH (ISP) SubmissionMoH Approval Time to MOH Approval weeks Custom Destination 2 days Drug at Site Time to drug at site 1 week

15 ICTW Punta del Este, Uruguay Regulatory Flowchart Mexico Translation of docs weeks Regulatory docs. from sites E.C., Hospital, study staff weeks Protocol Submission to MOH MOH Approval weeks Export licenses (Tissues) MOH approval Import licenses for Study Drug & Lab kits weeks Customs release days Additional submissions to MOH (amendments, additional sites) MOH answer Kendle Mexico WAREHOUSE Total Set Up & Approval Process: 3 to 4 months

16 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…

17 ICTW Punta del Este, Uruguay Summary of Effects of Regulatory Changes in a Growing LatAm Region CountryCurrent average time from Protocol & other required documents available to SIV (months) * Effect of recent Changes on CT growth Argentina5.5 – 6.5Continued Brazil8 – 10.5Accelerated Chile4.5 – 5.5Continued Colombia4 – 4.5Accelerated Mexico3 – 4Continued Peru5 if not biologic 6 if biologic Accelerated * Includes all steps including translations, import license, import process, custom clearance, site contracts, etc.

18 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 ECs and Competent Authority (MoH) can be performed simultaneously (i.e: in parallel.)

19 ICTW Punta del Este, Uruguay Challenges and opportunities

20 ICTW Punta del Este, Uruguay Regulatory timelines in Brazil Translations Queries

21 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 Outcome (one example): lower chance for authorship Fonte:

22 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

23 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)

24 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)

25 ICTW Punta del Este, Uruguay Protocol issues identified by CONEP Source: CONEP

26 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

27 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

28 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)

29 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

30 ICTW Punta del Este, Uruguay BACKUP

31 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.

32 ICTW Punta del Este, Uruguay Countries main agencies


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