Industry Experience in Clinical Trials Management. Catherine Lee Area Head Clinical Operations Asia Pfizer Inc 20 May 2011 Brussels

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1 Industry Experience in Clinical Trials Management Catherine Lee Area Head Clinical Operations Asia Pfizer Inc 20 May 2011 Brussels

2 Stakeholders in clinical research Critical activities to ensure patient safety or well being Proper protocol feasibility Rigorous site selection Close monitoring Amendments to protocols How they do it in EU What does ICH say? Safety reporting in ICH Countries Asia countries example The Role of Ethics committees Outline

3 Stakeholders in clinical research Sponsor Regulatory Authority Monitor/ CRA* Patient IRB Share responsibility * Monitor/ CRA: Clinical Research Associate from Sponsor Investigator

4 Proper Feasibility Process Program feasibility product Protocol input from countries Proper clinical development plan Protocol feasibility study Confirm country allocation Site feasibility site Confirm pt/site no per country PCO conduct pre-trial assessment Confirm individual site participation

5 Rigorous site selection Essential Features Available pt pool/facility Well-established clinical operations infrastructure/site management organization Institution Qualified, dedicated or committed investigators Properly Trained site staffs/low turnover/available time Build in clinical trial process into Hospital procedure to ensure the requirement can be met per protocol Transparent budget management process

6 Close Monitoring Education and Qualification of Monitors CRA Certification Program Protocol specific training/ta training Annual re-certification of monitors/ sharing audit trend Monitoring Process Measuring adherence to investigational plan and protocols Support consistent and prompt monitoring of visit data Monitor Oversight and Controls Implement protocol specific comonitoring visits Improved Escalation plan / documented review MVR Investigator Site Selection Formal Documentation of site ability to meet study requirements Mandate web GCP/Study Training for Investigators 6

7 Amendments to Protocols Why there is a need for protocol amendment(s)? things evolve and change during development phase, Inclusion/exclusion criteria, study visit, tests, change based on trial execution New information related to IP, comparator, disease, procedures or treatment that affect the trial conduction Changes to sample size, statistical analysis based on interim analysis Safety event/information Amendment based on DSMB review comments Administrative change : e.g. study team member change Actual execution Well designed Exploratory nature We try to minimise but not possible to eliminate

8 Sponsor shall notify competent authorities (CA) and EC if protocol amendments are : Substantial amendment & Likely impact on trial subjects or Change the interpretation of the scientific documents or Otherwise significant How do they do it in EU? Sponsor and investigator shall take appropriate urgent safety measures to protect subjects against any immediate hazard and inform the CA and EC at the same time if New event relating to the conduct of the trial or the development of the investigational medicinal product and Likely to affect the safety of subjects Urgent safety measures may be taken without prior notification to the national competent authority. However, the sponsor must inform ex post the national competent authority and the Ethics Committee of the Member State concerned of the new events, the measures taken and the plan for further action as soon as possible.

9 What does ICH GCP say? 4.5 Compliance with Protocol Protocol should be conducted if obtained approval/favourable opinion by regulatory authority and IRB/IEC. Investigator should not implement any deviation from, or changes of the protocol prior review and documented approval/favourable opinion from IRB/IEC except : Where necessary to eliminate an immediate hazard(s) to trial subjects, or The change(s) involves only logistical or administrative aspects of the trial As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted: to the IRB/IEC for review and approval/favourable opinion, to the sponsor for agreement and, if required, to the regulatory authority(ies)

10 Safety Reporting in ICH Countries 5.16 Safety Informa1on: IB, interim analysis, DSMB update The sponsor is responsible for the ongoing safety evalua8on of the inves8ga8onal product(s) The sponsor should promptly no8fy all concerned Inves8gator(s)/ ins8tu8on (s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to con8nue the trial. Increasing SAE/SADR cases of specific trial that might be queried for justification. Safety alert letter globally for a SUSAR, triggered regulatory authority inspection to further determine if patient safety/welfare/ right is still protected and consideration of trial s continued execution Adverse Drug Reac1on Repor1ng : SUSAR update The sponsor should expedite the repor8ng to all concerned inves8gator (s)/ ins8tu8ons(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reac8ons (ADRs) that are both serious and unexpected.

11 Example of IND notification to RA from Asian country Background: study early termination was related with safety concern Sponsor report to regulatory authority on 23 April 2010 with study termination notification letter and Dear Investigator letter 27 April 2010 : Queries from regulatory authority regarding Please submit a detailed reason statement. Please notify the decision of early termination to principal investigators and the IRE at each site promptly. Please check a clinical trial progress so far Please check all serious adverse events in country X Please set up a follow up plan for participating subjects' safety 17 May 2010 : Sponsor report to regulatory with completed response

12 Regulation evolving to smooth the study conduct In Country A, once a protocol has been approved by regulatory authority, if the subsequent protocol change (s) doesn t involve study design or safety aspect, the applicant should only obtain IRB/IEC s approval and with notification of reference to the regulatory authority. Align with ICH requirement in safety reporting Once a protocol has been approved by regulatory authority, PI/Sponsor need to submit SUSAR instead of individual SAE report to RA/EC. Simplified process

13 The role of Ethics Committee and Regulatory Authority Institutional Review Board (IRB) / Independent Ethics Committee (IEC) : ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects Clinical trial review and approval Clinical trial annual progress report and approval renewal EC inspection Continuing review the impact for subject safety and study integrity when there is protocol amendment, protocol deviation, SUSAR, IB update submitted to EC Regulatory Authority (RA) : Bodies having the power to regulate. In the ICH GCP guideline the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections. Clinical trial related regulations management and harmonization with international related regulations Annual IRB/EC review and certification

14 Robust System/ Process Clear metric to deliver Timely feedback Continuous Improvement Commu nication Quality professional staffs/ High Performing Site/PI Training / Certification Site accreditation Excellent Team work Quality embedded into our daily practice to secure pt safety