Averion, Inc. Presentation Data Monitoring Committee (DMC) Establishment and Management

Averion, Inc. PresentationData Monitoring Committee (DMC) Establishment and Management April 14, 2005

Overview Of Presentation • The Current Environment • Challenges/Problems in DMC implementation • Need for an external DMC • Specific Tasks for DMC? • Sponsors demands in a DMC • DMC interactions with IRB • Selected Literature Resources © 2005 Averion Inc., All Rights Reserved

The Current Environment • Heightened awareness about drug safety and human protection in clinical trials (i.e., Vioxx, Tysabri) • Spotlight on FDA to be a more effective watchdog for patient safety • Recognition that overall system and processes are not standardized and needs better coordination • Investor “intrusion” into clinical trials • Need for risk management approach to protect against litigation © 2005 Averion Inc., All Rights Reserved

Challenges in Protecting the Safety of Participants (Califf, 2003) • System is inefficient • Overemphasis on the monitoring ability of some groups (e.g., IRB), and underemphasis on DMCs and Sponsors • Confusion about responsibilities; communication gaps • Lack of standards for DMCs • Sponsors over-reliance on data audits; slowness in disseminating safety data in a coherent summary • Lack of consistent GCP compliance in Investigators/staffs • Lack of regulatory policy harmonization © 2005 Averion Inc., All Rights Reserved

Recommendations for System Improvement(Califf, 2003) • Well-designed monitoring plans • Centralized review of large multi-site studies • Closer local scrutiny of single institution studies • Greater sponsor attention to monitoring AE • Performance standards in GCP and formal training programs for investigators, staff and IRB. • Standardized DMC composition and function • Harmonization of regulations • Establish guidelines for monitoring Phase I and II trials © 2005 Averion Inc., All Rights Reserved

When Is an External DMC Required? (FDA Guidance, 2001) • NIH: DMC for all Phase III trials • FDA Guidance • Long term trials with mortality or major morbidity outcomes • SAE are expected • Novel and/or potentially high-risk treatments; very little prior information • At risk population (elderly, pediatric). • Multi-center, long-duration study © 2005 Averion Inc., All Rights Reserved

When Is an External DMC Not Required? • Early phase trials (exception: gene therapy trials) • Symptom-only endpoint trials • Short-term trials (except when symptoms occurs in an at-risk population (e.g., pain-relief in late-stage cancer patients) © 2005 Averion Inc., All Rights Reserved

Criteria for the Need and Value of a DMC (Ellenberg et al., 2003) • Will trial provide definitive information (i.e., pivotal)? • Prior data to suggestive of potential for toxicity? • Is mortality a major endpoint, such that inferiority of one has safety and/or effectiveness implications? • Is it ethically important to stop the trial early if the primary questions definitely answered? © 2005 Averion Inc., All Rights Reserved

Four Fundamental Principles of Data Monitoring (Ellenberg et al., 2003) • Safeguarding patient safety is primary responsibility • Others: preserve the integrity and credibility of the trial • Ensure that results are available in a timely way • Multidisciplinary representation • Members free of apparent significant conflicts of interest, • DMC members only receive unblinded safety or efficacy data from the data analysis center © 2005 Averion Inc., All Rights Reserved

Initial review of protocol Review procedures to ensure quality of study conduct Review ongoing study conduct Assess safety and efficacy data Termination due to risk-benefit assessment Termination due to inability to answer study questions Continuation of ongoing trial Modifying sample size based on event rates Reviewing final results Specific Tasks of IRB (Ellenberg, 2003) © 2005 Averion Inc., All Rights Reserved

Data Quality is Vital to the DMC • Sources of data • CRFs, SAE data, Randomization codes • Up-to-date enrollment information • Protocol violations/exemptions • Special assays/lab tests that could unblind sponsor • Last-minute endpoint or mortality data prepared via endpoint sweep • Timely data more important than totally clean data © 2005 Averion Inc., All Rights Reserved

What Do Sponsors Want? • A la carte to full-service • As much information as they can get as early as possible • A “buffer” of responsibility for safety issues • Unbiased professional guidance • DMC will maintain confidentiality, and not go directly to FDA • DMC will let Sponsor have final say on stopping a trial, and will not recommend endpoint change unless a compelling reason © 2005 Averion Inc., All Rights Reserved

Sponsor Access to Interim Data for Planning Purposes • Desire is understandable . . . but may render trial results uninterpretable by Agency • Sponsor should discuss with FDA in advance • Potential for unanticipated extreme finding of effectiveness, which might create an ethical imperative to stop the trial • Sponsor should see minimal information • Formulate written questions, in ‘yes/no’ format • Sponsor should receive only on questions posed • SOP to identify “need to know” individuals © 2005 Averion Inc., All Rights Reserved

Stopping Rules • Data demonstrate clearly that it is unlikely results would change if trial continued • Important safety concern identified • Highly unlikely to show a statistically significant benefit (“futility curtailment” or lack of efficacy) • Stopping for favorable efficacy shortchanges potential safety data (e.g., Tysabri) • If stopping for safety issues, be sure of high quality cases (esp. if benefit is high), and understand potential confounding factors © 2005 Averion Inc., All Rights Reserved

What If A Major Change is Recommended by the DMC • Who should be notified? Do they have authority? • How will FDA, Investigators, Sponsor, IRBs, Subjects be notified? • Who at the Sponsor can see unblended data? • If publicly traded company, how will financial market reaction be handled? © 2005 Averion Inc., All Rights Reserved

Data Monitoring Plan Strategy • Spend the time up front • Review protocol carefully, particularly previous safety experience • Review natural history of disease studied • Review safety information for similar drug class (if applicable) • Likely a focused subset of analysis plan © 2005 Averion Inc., All Rights Reserved

Data Monitoring Plan Elements • Interim analysis frequency and timing • Stopping Rule Boundary • Adjudicated versus non-adjudicated data (locked or draft) • Blinded, partially unblinded versus unblinded • Specific endpoints of DMC interest • Recommendation versus binding decision © 2005 Averion Inc., All Rights Reserved

Sample Table of Contents DMP • Study objective • Study design • Study safety parameters • Statistical considerations • Populations • Analysis of safety parameters • Standard Heading & Computing environment • Tables, Listings and Figures © 2005 Averion Inc., All Rights Reserved

IRB Pushback re: SAE Reporting • Consortium of Independent Review Boards (CIRB) calling for more restrictive definition of suspected AE • Over-reporting reflective of litigation concerns • IRB should only receive “probably or definitely’ related • New draft “Tome” calls for notification of IRB is AE is “at least possibly related” (low bar) • Desire for clear federal guidance • Responsibility for evaluating events lies with Sponsor and Investigator © 2005 Averion Inc., All Rights Reserved

Relationship Between IRBs and DMCs • Concern that overtaxed IRBs spent more time with ongoing reviews and less on initial • No consistent mechanism for interaction • In some cases, Sponsor decides if information warrants sharing with Investigator and IRB • DMC better equipped to manage ongoing safety in trial, esp. a multi-center trial • Helpful if key recommendations of DMC (e.g., open session) are circulated to IRB © 2005 Averion Inc., All Rights Reserved

Training Programs • NIH requires that key personnel have formal training in protection of human research participants • Curriculum has not been developed at a national level • Topics should include: • Basic Issues in research ethics • Elements of GCP • Practical aspects of clinical trial management • Recordkeeping and documentation • NIH Internet based training (<http://ohsr.od.nih.gov/.>) © 2005 Averion Inc., All Rights Reserved

References • Data Monitoring Committees in Clinical Trials: A Practical Perspective (Ellenberg, Fleming, DeMets, Wiley, 2003). • DeMets D. et al. Issues in regulatory guidelines for data monitoring committees. Clinical Trials 2004;1:162-169. • Guidance on the Establishment and Operation of Clinical Trial Data Monitoring Committees, FDA, Nov 2001. • Califf RM et al. Toward protecting the safety of participants in clinical trials. Controlled Clinical Trials 2003;24:256-271. • Hemmings R, Day S. Regulatory perspectives on data safety monitoring boards: protecting the integrity of data. Drug Safety 2004;27(1):1-6. • Whitehead J. On being the statistician on a data and safety monitoring board. Statistics in Medicine 1999;18:3425-3434. © 2005 Averion Inc., All Rights Reserved

Contact Information Averion • Stephen Schmitz, MD, MPH (Director, Medical and Regulatory Affairs) • Phone: 508-416-2816 • Sean Darcy, RN (Director, Medical Affairs) • Phone: 508-416-2724 © 2005 Averion Inc., All Rights Reserved

Key Ingredients to Success • Understanding FDA DMC Guidelines (November 2001) • DMC Management • Charter/SOPs • Recruitment • Sessions (open, closed, closed executive) • Central File (audit standard) • Sponsor Expectations © 2005 Averion Inc., All Rights Reserved

FDA DMC Guidance Document Understanding • Membership must be broad enough to include oncology, biostatistics, and clinical trials experts • DMC must meet regularly to review safety; lack of efficacy is considered to be a safety issue • DMC must exercise independence and flexibility • DMC must document processes and decisions Reference: Draft Guidance for Clinical Trial Sponsors on the Establishment and Operation of Clinical Trial Data Monitoring Committees (November 2001) © 2005 Averion Inc., All Rights Reserved

DMC Management Requirements • Recruitment strategies (experts, availability, potential conflicts) • Meeting coordination (initial, face-to-face vs telecons) • Timeline management (data transfers, analyses, binders) • Meeting management (agenda, unblinding, minutes) • Processes and documentation (Charter/SOP, central files, minutes, FDA audit potential) © 2005 Averion Inc., All Rights Reserved

Sponsor Expectations • DMC members do not develop conflicts of interest • DMC lets the Sponsor make the decisions to modify or to stop the study • DMC will not change study eligibility or endpoints or go in a different analysis direction from the Sponsor; this may impact labeling or introduce interpretation inconsistencies • DMC will maintain confidentiality • DMC will not call the FDA © 2005 Averion Inc., All Rights Reserved

Procedures for DMC Organization • DMC Organization - Document generation - Member recruitment - Create analysis plan / report format - Central file set-up • Initial Meeting - Charter / SOP approval - Report format approval - Meet and greet - Protocol specifics © 2005 Averion Inc., All Rights Reserved

Procedures for DMC Organization (continued…) • Data Review Meeting Preparation - Data transfer (optional) - Data cleaning (optional) - Report generation (optional) - Binders sent to DMC members Meeting - Open / Closed / Executive sessions - Minutes - Binders / Shredding - Timeline future meetings • Central Files © 2005 Averion Inc., All Rights Reserved

DMC Chair: Voting member who chairs all DMC meetings. Usually appointed by Sponsor but may be elected by DMC. DMC Manager: Non-voting member who provides support and guidance regarding DMC procedures and responsibilities. Responsible for recruitment, meeting arrangements, meeting facilitation, any DMC related communication, etc. Supported by DMC Administrator. DMC Biostatistician: Voting and/or non-voting biostatistician(s) who analyze data for the DMC report and provide statistical expertise at the DMC meetings. DMC Players © 2005 Averion Inc., All Rights Reserved

Necessary Documents • DMC Charter/SOP • Confidentiality Agreement [CA] • Contract/Letter of Agreement [LOA] with the DMC member to be signed by either the Sponsor or DMC Management Organization • Conflict of Interest [COI] • Analysis Plan/DMC Report Format © 2005 Averion Inc., All Rights Reserved

Documents to Sign • Confidentiality Agreement [CA] - All DMC members and DMC support staff (non-voting members or support staff may be covered under a company confidentiality contract) • Conflict of Interest Forms [COI] - All DMC members (voting and non-voting) • Contract/Letter of Agreement [LOA] - All voting DMC members © 2005 Averion Inc., All Rights Reserved

DMC Start-Up Logistics The DMC Manager: • prepares Charter/SOP, CA, COI, and member contracts • sends drafts to the Sponsor for review and approval • obtains CA, COI, and LOA signatures from DMC members • circulates Charter/SOP and draft AP to DMC members for approval The DMC Administrator: • organizes the initial meeting • tracks document preparation • takes minutes • sets up Central Files © 2005 Averion Inc., All Rights Reserved

DMC Data Analysis Options • DMC biostatistician conducts independent analyses • Sponsor provides validated SAS code; Averion runs fixed analyses • Sponsor provides clean data; Averion runs analyses • Sponsor provides data “as is”; Averion cleans and runs analyses • Results may need to be rerun following adjudication © 2005 Averion Inc., All Rights Reserved

DMC Analysis Plan Development • DMC biostatistician prepares initial analysis plan (AP) draft • includes shell tables, listings, and graphs • Includes blinding dimensions (efficacy, safety) • includes stopping rules • needs to be consistent with Sponsor SAP • AP is initially forwarded to the Sponsor for input. • DMC will review the AP at the initial DMC meeting. • DMC may modify the AP as results warrant. © 2005 Averion Inc., All Rights Reserved

Initial DMC Meeting Agenda Sponsor representatives and DMC members (voting and non-voting) attend the meeting as appropriate. The meeting objectives are to: • Identify the DMC Chair • Review, revise and approve the DMC Charter • Review and approve AP report format for future meetings • Review study protocol (Sponsor presentation) • Complete any specific activities requested by the Sponsor (current thinking, eligibility, safety issues, stopping rules, etc.) • Formulate study stopping rules (when appropriate) • Allow DMC members to meet and establish a working relationship. © 2005 Averion Inc., All Rights Reserved

Data Review Meetings • Frequency stated in the DMC Charter subject to study accrual. • If a meeting date was not established at the previous meeting, the DMC Administrator will contact DMC members and the Sponsor to identify a mutually acceptable date for the meeting and will then make all necessary arrangements. • Once a meeting date is established, the DMC Biostatistician and Data Management personnel will be asked to supply a timeline for preparation of the DMC report. © 2005 Averion Inc., All Rights Reserved

Data Review Meeting Binder • DMC Administrator prepares and sends binders to meetingattendees containing the following at least one week prior to the meeting: - Meeting agenda - Updated documents (e.g. protocol amendments) - Study Update or other information provided by the Sponsor - Meeting-specific instructions - Meeting minutes from the previous DMC meeting - Data for review (blinded/grouped, per the DMC Charter/SOP) - Any supplemental information related to the data (e.g. SAE reports) • An abbreviated binder, without data, is also sent to the Sponsor. © 2005 Averion Inc., All Rights Reserved

Open Session • Data Review Meetings begin with an Open Session attended by the Sponsor and both voting and non-voting members • previous Open Session meeting minutes are reviewed and approved • Study status (progress, enrollment, protocol amendment(s), etc.) is provided • Potential dates and locations for the next meeting are discussed • Any issues the Sponsor wishes to present/discuss with the DMC. © 2005 Averion Inc., All Rights Reserved

Closed Session • Voting and non-voting members only (no Sponsor representatives) • Data are reviewed and discussed • Recommendations to the Sponsor are formulated and documented (Note: Written documentation of DMC recommendations may be generated at or after the meeting within the time period specified in the DMC Charter. The DMC Chair will convey recommendations to the Sponsor.) © 2005 Averion Inc., All Rights Reserved

Executive Closed Session • Attendance is limited to voting DMC members only (the Sponsor and the non-voting DMC members are excluded from this session) • Unblinding of data - both the decision to break the blind and the actual unblinding - may be restricted to this session • Further analyses, adjudication, or follow-up may be requested • Recommendations to the Sponsor will be discussed © 2005 Averion Inc., All Rights Reserved

DMC Central Files • Membership File:DMC Member names, telephone #, fax #, address, e-mail address, and any additional information or special instructions on how to contact that member. • Charter: All versions • Protocol: Including all amendments • Investigator’s Brochure / Package Insert • Individual DMC Member Folder containing: CV, CA, COI, LOA, correspondence (e-mails, letters, faxes, etc.), copies of all expense reports/payments. • Sponsor Correspondence • Meeting Minutes (primary reason why Sponsor cannot do it!) © 2005 Averion Inc., All Rights Reserved

Closing Thoughts • Multiple DMC models exist, but independence is required. • Not all DMCs are the same; they all need a Charter, a Chair, active members, and a plan customized to the study needs. • Lines of communication between the Sponsor, DMC, and FDA need to be established up front; open and closed sessions supported by minutes and conference calls can keep all parties informed. • Ensure that unblinding procedures are in place to allow safety data to be assessed separately from efficacy data. • Experience counts! © 2005 Averion Inc., All Rights Reserved

Averion, Inc. Presentation Data Monitoring Committee (DMC) Establishment and Management