3Trends in the globalization of clinical trials Nature Reviews Drug Discovery 7, (January 2008)
4Top 50 Countries Ranked By Average Relative Annual Growth Rates. Nature Reviews Drug Discovery 7, (January 2008)
5Trends in globalization, industry perspective 19972005Mass, ASCO 2009
6Brazil – peculiarities Directives 196/96, 251/87, 292/99 and Resolution 404
7Special 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 devicesSubmission alsotoANVISA
8Special circumstances =mandatory submission to CONEP (central EC) 5. New procedures not consensually accepted by the literatureIndigenous populations (Res. 304/00)Projects with issues of biosecurityResearch 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).
9Brazil - peculiarities Use of placebo, post trial access to treatments Resolution 404, August 2008Reaction 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 retainedIn 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)...
10Complex regulatory process Courtesy of Socorro Portella, Novartis Brazil
12Main site selection criteria by investigators Courtesy of Socorro Portella, Novartis Brazil
13Regulatory Flowchart Brazil Long time to dossier preparationTotal Set Up & Approval Process: 8 to 10.5 MonthsKendleTime to documents translation into Portuguese after all required documents arrival from sponsor and dossier preparation before submission: weeksInvestigatorMoH(ANVISA)Local Ethics CommitteeUnnecessary double (and sequential!) process of EC approvalTime to IRB/EC approval: weeksAgencies inefficient in protocol turnaround timesMoH submission after getting the Local IRB/EC approval: 1 weekLong time to dossier preparationUnnecessary double (and sequential!) process of EC approcal (local – central EC)Agencies inefficient in protocol turnaround timesImport process inefficientTime to MoH approval: weeksNational Ethics Committee (CONEP)Import ProductTime to CONEP approval:weeksTime to import: weeksStudyStartImport process inefficient
14Regulatory Flowchart Chile Total Set Up & ApprovalProcess: 4.5 to 5.5 MonthsProtocol, ICF, IB, local insurance, and required translationsDrug at SiteTime to Submission weeksTime to drug at site 1 weekLocal/Regional ECCustom DestinationTime to EC Approval weeks2 daysEthics cleared at site (or regional) levelCentral agency relatively efficientRelatively straightforward processMoH (ISP) SubmissionMoH ApprovalTime to MOH Approval weeks
15Regulatory Flowchart Mexico Translation of docs.2 - 3 weeksTotal Set Up & ApprovalProcess: 3 to 4 monthsRegulatory docs.from sitesE.C., Hospital, study staff4 - 6 weeksProtocol Submission to MOHMOH Approval6 - 7 weeksImport licenses for Study Drug & Lab kits2 - 3 weeksFrom site approvals (EC) to central agencies – no paralel processesCentral agency efficientLicenses released fastAdditional submissions to MOH (amendments, additional sites)Export licenses(Tissues)Customs release1 - 2 daysMOH approvalMOH answerKendle Mexico WAREHOUSE
16Brazil – 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…
17Summary 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 growthArgentina5.5 – 6.5ContinuedBrazil8 – 10.5AcceleratedChile4.5 – 5.5Colombia4 – 4.5Mexico3 – 4Peru5 if not biologic6 if biologic* Includes all steps including translations, import license,import process, custom clearance, site contracts, etc.
18Latin 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.)
20Regulatory timelines in Brazil TranslationsQueries
21Clinical trials in Brazil Fonte:Mainly large phase III trialsLate entranceSLOW regulatory process“Rescue” for trials with low recruitment and/or acceptance abroadIrrelevant participation in early phases of clinical development (phase 0-I / early phase II).High levels of expertiseOutstanding infra-structureDynamic regulatory processRequirementsOutcome (one example): lower chance for authorship
22Pharmaceutical industry sponsored research – POTENTIAL SOLUTIONS ??Make the Ethics Committee (EC) review process more “professional”. Charge more for this and require more QUALITYAvoid unnecessary queries, many due to inexperience from reviewersMake 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
23Local ECsWith growing workload, is the EC review sustainable as a ‘volunteer’ activity?NO!Good EC professionals are increasingly hard to findCertified IRB Professional (US experience)
24Brazil – 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 processUnder implementation:Fully paper-free dossier (on line submission)
25Protocol issues identified by CONEP Source: CONEP
26Academic (Institutional, Non Sponsored) Research No specific legislation for academic researchAll CNS directives/resolutions applyDifficult 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
27Academic (Institutional, Non Sponsored) Research The National Health System (SUS) does not cover hospitalizations related to side effectsProbably the most limiting aspect of academic clinical research in Brazil
28Pharmaceutical companies # Thinking of bringing trials to LA? Crucial steps:Early planningSelect CRO based at and with a good track of experience in the regionWith native professionals, familiar with local culture and language, regularions etcGood site selection (eg experienced coordinating site in Brazil – makes a major difference)
29ConclusionsOur regulatory process as a whole can become more efficientOur 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
31Brazil – peculiarities RESOLUTION CNS Nº 251/97I.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.