Highlights from ExL Pharma's 5th Data Monitoring Committees

Philadelphia, PA February 22-23, 2010 Highlights from ExLPharma’s 5th Data Monitoring Committees/DSMB

The Role of DMCs/DSMBs in Adaptive Trials:The Impact of DMCs/DSMBs on Decisions for Dosage Changes or Changes in Sample Size 2

DSMB/DMC 3 Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) as defined in FDA Guidance “Establishment and Operation of Clinical Trial Data Monitoring Committees”: a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials. DMC advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.

DSMB/DMC 4 DSMB periodically inspects “interim looks” at the data (prior to all planned patients being treated and followed) and makes recommendations about trial design/conduct based on these “interim looks” including: Continue trial as initially planned. Safety: Potentially stop the trial early if reasonable evidence of harm of new product (or dose) or control product Often based on incidence of AEs or serious AEs DMC safety recommendations not necessarily based on formal statistical rules

DSMB/DMC 5 Example of DSMB Safety Recommendation Double-blinded trial (randomized): Placebo versus Experimental treatment in high risk population Patients scheduled to be treated over several months After the first 40 patients were enrolled (20 in each treatment group) and treated for 1 day to several weeks, DSMB inspected unblinded data: Experimental treatment had 4 life threatening serious adverse events (SAEs) Placebo group had none P-value=0.1060 DSMB Recommendation was to terminate study despite “non-significant” safety p-value

DSMB/DMC 6 Example of DSMB Safety Recommendation (cont’d) DMC Recommendation to stop trial was not easy Perhaps benefit of drug outweighed the risk? Tough to tell at this early stage, but it was thought perhaps it was best not to wait to find out. Sponsor does not necessarily need to follow DSMB recommendation E.g., Sponsor may decide: Continue trial as is Temporarily halt trial until further investigation Discuss with DSMB/DMC & regulatory agency reason for not following recommendation

DSMB/DMC 7 Example of DSMB Safety Recommendation (cont’d) Sponsor does not necessarily need to follow DSMB recommendation (cont’d) Potential issue if trial continues: Sponsor was made aware of the 4 experimental group SAEs during DSMB deliberations Will this “awareness” affect subsequent study conduct (even unintentionally), causing bias in remaining safety data? Perception of bias? Suppose SAE prevalence “evened out” at end of study?

DSMB/DMC 8 DSMB periodically inspects “interim looks” at the data (prior to all patients being treated and followed) and makes recommendations about trial conduct including: Efficacy (“Adapt the trial”) (cont’d): Change primary endpoint (not common -- in my experience) Remove non-efficacious dose(s) (for multi-dose trials); Requires formal statistical rules in order to: Not increase “Type I Error” rate or “significance level” (chance of a false positive trial) Minimize “Type II Error” rate (chance of false negative trial) DSMB/DMC unblinded or “partially” unblinded

DSMB/DMC Committee Composition 9 Discussed in Section 4.1 of FDA Guidance Sponsor/Steering Committee appoints DMC CRO also sometimes asked by Sponsor to appoint DMC Members consist of At least 2 clinicians At least 1 statistician May also have other members; e.g., Ethicist for high risk/vulnerable populations Non-scientist; e.g., consumer rep; patient (not in trial)

DSMB/DMC Committee Composition 10 Ideally, DSMB/DMC members should have Experience in indication being studied Clinical trials experience DSMB/DMC experience Especially important for statistician on DSMB/DMC All members may not have all 3 Opinion: Especially important for Statistician to have at least b and c; Clinician/physician to have at least a (and b);

DSMB/DMC Committee Composition 11 Statistician should also have: Experience in statistical methods for clinical trials Experience in statistical rules for “adapting” design Members should be independent from Sponsor Not a sponsor employee Not an investigator No involvement in the study conduct or analysis planning No serious conflicts of interests All potential conflicts disclosed prior to each meeting

DSMB/DMC Committee Composition 12 Each DSMB/DMC has a chair. Chosen by sponsor and other DSMB/DMC members FDA Guidance: chair capable of “facilitating discussion/integrating different points of view”. Chair provides DSMB/DMCs recommendation of future study conduct to sponsor or steering committee After inspection of interim data, DSMB/DMC members “vote” on a recommendation for future conduct of study Works best if “odd” number of DSMB/DMC voting members

Statisticians in DSMBs Often 3 statisticians involved in the DSMB/DMC process DSMB/DMC Statistician Voting member of DSMB/DMC; helps interpret statistical aspect of results to other voting members, especially adaptive results and statistical repercussions of adapting the design. Analysis Statistician Generates interim results (often not a Sponsor employee) Unblinded to treatment group for each patient “Independent Statistician” Presents results to DSMB/DMC; answers DSMB/DMC statistical questions Non-voting “Go-between” between DSMB and Analysis Statistician All statisticians are not to be involved in analysis of final data or analysis planning

“Fixed” Design “Fixed” clinical trial design (2 treatments) Compare “cure” rate across two anti-infectives: Specify an appropriate (superiority) null and alternative hypothesis: H0: πE = πC H1: πE ≠ πC where πE and πCare the true sensitivities of the experimental and control diagnostic, respectively. To calculate sample size, make assumption of the true πE, πC Determine sample size required to yield adequate power to reject H0 in favor of H1 at a given significance level 14

“Fixed” Design “Fixed” clinical trial design example (cont’d) For determining sample size, assume πE =0.80 and πC =0.70 Two-sided 0.05 level of significance (false positive rate) Desire 80% Power 1:1 Treatment Allocation Sample size per group (using two-sample z-test for proportions): 294 per group 15

Adaptive Trial Designs 16 Adaptive designs allow for re-designing the trial at some point during the trial, usually based on interim look(s) at aggregate efficacy data Stop trial for “futility” of experimental diagnostic Stop trial for overwhelming efficacy Increase sample size to ensure adequate (conditional) power by end of study Decrease sample size if (conditional) power >>original power Remove non-efficacious dose in dose-finding study Change primary endpoint

Adaptive Trial Designs 17 The interim “look” at the data can be blinded or unblinded. Adapting the design of the study often has statistical repercussions, especially if re-design is based on an unblinded analysis Here, we will focus on adapting trial based on an unblinded interim analysis. Also may have operational repercussions

Issues to Consider 18 Once DSMB gives recommendations arrive, could bias in final results occur? If DSMB says “increase the sample size by xx”: if Sponsor follows recommendation, study personnel may realize the product may be efficacious, and just needs a little more sample size to prove its efficacy with good confidence. Cause bias in future study conduct? If Sponsor does not follow recommendation, does Sponsor feel product then has small chance of being efficacious and bias remainder of study? E.g., may move resources off study, slowing study down or reducing quality?

Issues to Consider 19 Once DSMB gives recommendations arrive, bias could result If DSMB/DMC recommends “continue the study as is”, Study personnel who may not understand the requirement for overwhelming efficacy, may think the product is not efficacious, otherwise study would have stopped for efficacy? Causes bias on remaining study personnel?

Dosage Change 20 Most “pivotal” (Phase III) drug/biologic trials contain one dose of the experimental treatment and a control group Some Phase III may contain more than one dose of experimental however (especially those that may “skip” Phase II to get product to market faster in case of serious illness, e.g., ALS) Many Phase II’s have multiple doses of experimental to determine the dose of study in future pivotal Phase III

Dosage Change 21 Suppose we have a trial with multiple doses of experimental treatment, and one control group Formal efficacy rules can be built in to “drop” inefficacious dose after interim analysis; E.g., drop dose(s) with CP<20% when compared to control Maybe use a more liberal (higher) threshold, especially in Phase II, if other doses showing more promise. Increase enrollment in doses with CP<80% but showing promise? In Phase II, control of false positive rate may not be as much of concern In Phase II, may not necessarily have to show treatment effect at 0.05 level of significance Perhaps calculate CP at 0.10 level of significance.

Dosage Increase 22 Many Phase I trials are non-randomized, dose-escalating Enroll first k patients into lowest dose Follow for safety DSMB inspects safety results and gives the “OK” to move on to next dose Next set of k patients enrolled to next (higher) dose Continue through pre-planned doses

Primary Endpoint Change 23 Medical device clinical trial example: Efficacy endpoint is survival at 30 days. DSMB/DMC performed formal pre-planned interim efficacy/futility analysis on endpoint Assessed if trial could be stopped early for overwhelming efficacy, futility, and sample size recalculation as necessary. DSMB/DMC also decided to inspect CP for “3-month survival” outcome at interim stage Not in DSMB/DMC charter Not Necessarily a problem, depending on what DSMB/DMC plans to do with this info Less patients available than at 30 days

Primary Endpoint Change 24 Medical device clinical trial example (cont’d): Reason for request unclear: DSMB/DMC considering recommending change in primary endpoint? Data-driven decision? May increase chance of false positive study Sponsor requested to see interim 3 -month data Strongly recommend against that Data-driven decision and potential introduction of bias into trial Possible approach with no real repercussions: Use 3-month data to plan another study with 3-month outcome as primary endpoint.

Conclusion 25 DSMBs/DMCs consist of experienced clinicians and at least one experienced statistician DSMBs/DMCs responsible for subject safety and scientific merit of study DSMBs/DMCs make recommendations on study design and conduct issues while the trial is ongoing Such recommendations may have repercussions and may introduce bias in remainder of study Important for DSMBs/DMCs to consider such issues Important to minimize such bias

Acting on a DMC/DSMB Recommendation:How to prepare for and respond to DMC/DSMB recommendations

1. Identifying the need for DMCs/DSMBs - 1 1998 - NIH Policy For Data and Safety Monitoring 2001 - Draft FDA Guidance for Clinical Trial Sponsors: Establishment and operation of clinical trial data monitoring committees 2003 - Draft CHMP Guideline on Data Monitoring Committees 2004 - NEJM Data Safety and Monitoring Boards 2004 – Small group processes relevant to data monitoring committees in controlled clinical trials: an overview of reviews 2005 - Issues in data monitoring and interim analysis of trials - DAMOCLES Study Group 2006 - Final CHMP Guideline on Data Monitoring Committees 2006 - Final FDA Guidance for Clinical Trial Sponsors: Establishment and operation of clinical trial data monitoring committees 2008 - JAMA commentary: When should data and safety monitoring committees share interim results in cardiovascular trials? Clear expectations Increased focus on the DMC Evolving role of the DMC

1. Identifying the need for DMCs/DSMBs - 2 Changing Characteristics of Development Portfolios ,[object Object]

Greater HA scrutinyIncreasing Complexity of Development Programs ,[object Object]

Large multi-site, multi-national clinical trials

Multiple simultaneous indicationsPotential for Variation in DMC Interactions ,[object Object]

Interpretation of roles and responsibilities

Alliance partnershipsGreater need for DMCs Importance of clear DMC decisions Opportunity for improvement

1. Identifying the need for DMCs/DSMBs - 3 2006 Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 2. Determining Need for a DMC All clinical trials require safety monitoring, but not all trials require monitoring by a formal committee that may be external to the trial organizers, sponsors and investigators. 2.1 What is the Risk to Trial Participants? A fundamental reason to establish a DMC is to enhance the safety of trial participants in situations in which safety concerns may be unusually high, in order that regular interim analyses of the accumulating data are performed. We recommend that sponsors consider using a DMC when: ,[object Object]

There are a priori reasons for a particular safety concern, as, for example, if the procedure for administering the treatment is particularly invasive;

There is prior information suggesting the possibility of serious toxicity with the study treatment;

The study is being performed in a potentially fragile population such as children, pregnant women or the very elderly, or other vulnerable populations, such as those who are terminally ill or of diminished mental capacity;

The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser point;

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