Regulatory issues in Latin America Max S. Mano Assist. Prof. Medical Oncology – University of São Paulo (USP/ICESP) Medical Oncology – Hospital Sírio Libanês max.mano@gmail.com max.mano@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 1997 2005 Mass, ASCO 2009

Brazil – peculiarities Directives 196/96, 251/87, 292/99 and Resolution 404

Special circumstances =mandatory submission to CONEP (central EC) Res.196/96: Human Genetics (Res. 340/04) Human Reproduction (Res. 303/00) New drugs and diagnostic tests (Res. 251/97) New (or not yet granted registration in Brazil) equipments, inputs and devices Submission also to ANVISA

Special circumstances =mandatory submission to CONEP (central EC) 5. New procedures not consensually accepted by the literature Indigenous populations (Res. 304/00) Projects with issues of biosecurity Research coordinated by other countries or with their participation and research involving shipment of biologic specimens abroad (Res. 292/99) Projects for which institutional ECs judged suitable for evaluation by central EC (CONEP).

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)...

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 Long time to dossier preparation Total Set Up & Approval Process: 8 to 10.5 Months Kendle Time to documents translation into Portuguese after all required documents arrival from sponsor and dossier preparation before submission: 7 - 9 weeks Investigator MoH (ANVISA) Local Ethics Committee Unnecessary double (and sequential!) process of EC approval Time to IRB/EC approval: 6 - 9 weeks Agencies inefficient in protocol turnaround times MoH submission after getting the Local IRB/EC approval: 1 week Long time to dossier preparation Unnecessary double (and sequential!) process of EC approcal (local – central EC) Agencies inefficient in protocol turnaround times Import process inefficient Time to MoH approval: 18 - 23 weeks National Ethics Committee (CONEP) Import Product Time to CONEP approval: 18 - 23 weeks Time to import: 3 - 5 weeks Study Start Import process inefficient

Regulatory Flowchart Chile Total Set Up & Approval Process: 4.5 to 5.5 Months Protocol, ICF, IB, local insurance, and required translations Drug at Site Time to Submission 2 - 3 weeks Time to drug at site 1 week Local/Regional EC Custom Destination Time to EC Approval 10 - 12 weeks 2 days Ethics cleared at site (or regional) level Central agency relatively efficient Relatively straightforward process MoH (ISP) Submission MoH Approval Time to MOH Approval 6 - 7 weeks

Regulatory Flowchart Mexico Translation of docs. 2 - 3 weeks Total Set Up & Approval Process: 3 to 4 months Regulatory docs. from sites E.C., Hospital, study staff 4 - 6 weeks Protocol Submission to MOH MOH Approval 6 - 7 weeks Import licenses for Study Drug & Lab kits 2 - 3 weeks From site approvals (EC) to central agencies – no paralel processes Central agency efficient Licenses released fast Additional submissions to MOH (amendments, additional sites) Export licenses (Tissues) Customs release 1 - 2 days MOH approval MOH answer Kendle Mexico WAREHOUSE

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 Colombia 4 – 4.5 Mexico 3 – 4 Peru 5 if not biologic 6 if biologic * 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 Fonte: http://conselho.saude.gov.br/comissao/conep/relata.ppt 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

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: Under implementation: 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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