Ethics and Human Subject Issues in Research: Data and Safety Monitoring in Clinical Studies. Data and Safety Monitoring

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1 1 Ethics and Human Subject Issues in Research: Data and Safety Monitoring in Clinical Studies Roger J. Lewis, MD, PhD Department of Emergency Medicine Harbor-UCLA Medical Center Torrance, California, United States and Immediate Past President Society for Academic Emergency Medicine Data and Safety Monitoring Definition: concurrent, prospective oversight of an ongoing clinical study. Protects patient from avoidable risk and harm during the conduct of the study. Three components of ethical study conduct: An ethical study design (before); Data and safety monitoring (during); Complete and unbiased reporting (after). Data Safety and Monitoring Boards (DSMBs) vs Monitors A DSMB is a group of independent experts who perform data and safety monitoring (review accumulating patient data and adverse event reports; determine when or if a study should be continued, modified, or stopped). A monitor is a one-person DSMB.

2 2 Purposes of Data and Safety Monitoring To protect research subjects from avoidable and often unforeseen risks of participation. To ensure the research is: (1) ethical; (2) scientifically valid; (3) worthwhile; and (4) feasible, throughout the duration of the study. To ensure that the trial is stopped as soon as a reliable conclusion can be drawn from the data. Philosophy You must be prepared for unexpected events and effects. In designing a clinical trial you never know as much as you think you do! Study populations do not behave like general patient populations (common to see lower event rates). Minor adverse events may be very important. Safety Monitoring Focuses on: Tracking, tabulation, and interpretation of adverse events (AEs); Communication of safety data to and from institutional review boards (IRBs) or ethics committees (ECs), the sponsor, and regulatory agencies.

3 3 Data Monitoring Focuses on: Recruitment, follow up, completion, and drop out rates; Critical patient characteristics (covariates) and frequency of endpoints; Evidence of benefit or harm of an experimental treatment, or futility of the study. Example DCLHb Efficacy Trial Hypotensive adult trauma patients (predicted mortality of 40%). Randomized to (1) receive all standard therapy including blood products or (2) all standard therapy, including blood products, and DCLHb. Endpoint: reduction in 28-day mortality (all cause) from 40% to 30%. Most patients enrolled with a waiver of informed consent.

4 4 DSMB Deliberations Meeting December 8, 1997: Committee informed of unequal mortality in the two treatment groups under the assumption of equal enrollment. DMC votes to unblind themselves. Action deferred until December 11 pending additional data on mortality, enrollment by treatment group, and additional patient characteristics. DSMB Deliberations Conference call December 11, 1997: Mortality 8/38 saline; 17/45 DCLHb; p value.098; Individual fatalities reviewed; Parallel European trial data considered; No recommended action. Conference call December 29, 1997: Mortality 8/41 saline; 21/49 DCLHb; p value.018. DSMB Deliberations Conference call January 1, 1998: Additional data on mechanism, infusion status and mortality; European data considered; Mortality 9/44 saline; 24/53 DCLHb; p value.010. Recommendations: (1) stop patient enrollment; and (2) complete all planned data collection on enrolled patients. Hold implemented by sponsor immediately.

5 5 DSMB Deliberations Conference call March 17, 1998: Complete case report form (CRF) and injury severity (ISS) data available. Raw survival data: 28-day mortality; Saline: 8/46 (17%); DCLHb: 24/52 (46%); p value.006. Kaplan-Meier analyses and multivariate modeling all suggest harm from DCLHb. Futility: Probability of ultimately achieving a positive trial result: ~ 1 in DSMB Deliberations March 17, 1998 Recommendation: terminate study Results: March 31, 1998: Sponsor announces termination of DCLHb Efficacy Trial. June 2, 1998: Sponsor announces decision to terminate similar European trial. September 16, 1998: Sponsor abandons DCLHb development, takes $75 million charge against earnings. Safety Monitoring

6 Goals of Safety Monitoring Detection of intervention-associated AEs against background rates in the population. Identification of unanticipated interventionassociated AEs. Identification of subgroups at increased risk of AEs. Verification that expected AEs are not occurring more often than expected. International Conference on Harmonisation Joint project of the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions. Purpose: to make recommendations on ways to achieve greater harmonisation in the requirements for product registration. ICH Guidelines cover virtually all aspect of clinical trials with pharmaceuticals. [see Guideline E2A]. event (AE): Any untoward medical occurrence in a subject administered a pharmaceutical produce and which does not necessarily have to have a causal relationship with this treatment. (ICH Guideline E2A) An adverse drug reaction (ADR) is an AE that occurs after the patient is given a drug (ICH E2A and 21 CFR ). An adverse device effect is an AE in a device trial (21 CFR 812.3). 6

7 7 Serious Event (SAE) An AE that results in any of the following: Death; A life-threatening adverse drug reaction; Inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability/incapacity; Congenital anomaly/birth defect. (ICH E2A and 21 CFR ) Other important medical events may also be SAEs, based on medical judgment. Unexpected Event (UAE) An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., s Brochure for an unapproved investigational medicinal product). (ICH E2A) Severity and Attribution events are further characterized by severity and attribution: Severity usually based on a protocol-specific grading scheme (don t use serious ); Attribution is the investigator s judgment regarding causality. In general, SAEs require expedited reporting, while AEs and UAEs are tabulated and reported at the time of interim analysis by the DSMB.

8 8 Data Monitoring Purpose of Data Monitoring The purposes of data monitoring are to: Assess trial accrual rates and follow up rates; Verify demographic assumptions; Verify patient characteristics with respect to critical covariates; Monitor rates of endpoint(s); Assess evidence for benefit or harm of the experimental treatment; Assess possible futility. Statistical Aspects of Data Monitoring Interim data analyses are generally conducted at a few predetermined points throughout the trial to determine if the trial should be stopped because of demonstrated benefit or harm. The nominal α (maximum significant p value) at each analysis are reduced so that the overall risk of a false positive result, if no treatment effect, is 0.05.

9 9 Group Sequential Trial with Three Interim Analysis and a Final Analysis Begin Enrollment Maximum Sample Size Attained First Interim Analysis Second Interim Analysis Third Interim Analysis Final Analysis α 1 α 2 α 3 α 4 Flow of Information in Monitored Clinical Trials

10 10 IRB or EC, Blind Randomization Code Unblinded or Statistician IRB or ED, Blind Randomization Code Unblinded or Statistician IRB or EC, Interim Data and Safety Report

11 11 Blind Randomization Code Unblinded or Statistician IRB or EC, Interim Data and Safety Report Monitor or DSMB Blind Randomization Code Unblinded or Statistician Recommendation Regarding Study Conduct or Modification IRB or EC, Interim Data and Safety Report Monitor or DSMB Blind Randomization Code Unblinded or Statistician Recommendation Regarding Study Conduct or Modification IRB or EC, Interim Data and Safety Report Monitor or DSMB

12 12 Blind Randomization Code Unblinded or Statistician Recommendation Regarding Study Conduct or Modification IRB or EC, Interim Data and Safety Report Monitor or DSMB Interim Report Outline Data on trial progress (number enrolled, completed, lost to follow up). Information on data quality and completeness. Consistency of data with trial assumptions: Key patient characteristics (covariates); Aggregate rates of principal endpoint(s). Data on primary and secondary endpoints, generally by treatment group (efficacy analysis). event information (SAEs, UAEs, AEs): By treatment group; With assessments of attribution and severity. Any external information. Additional Report Issues Trial is not frozen and some information may be preliminary (e.g., endpoints not adjudicated). Confidentiality: From interested parties (PI, sponsor, etc.); For the patients (no patient initials). Blinding: Keep all interested parties blinded; Do not blind the monitor or DSMB.

13 13 Data Safety Monitoring Boards (DSMBs) DSMBs Independent Data Safety and Monitoring Boards (DSMBs) are usually charged with interpreting interim reports for multicenter phase III trials. When appropriate, a single monitor can perform the same function. Blind Randomization Code Unblinded or Statistician Recommendation Regarding Study Conduct or Modification IRB or EC, Interim Data and Safety Report Monitor or DSMB

14 DSMB Membership DSMBs must include members with a wide range and depth of expertise. Members should include: Expert in underlying science or pharmacology; Clinical expert; Biostatistical expert. Members may include: Ethicist; Patient representatives or advocates. Standard Operating Procedures Membership, including replacement of members; Authority to call and hold meetings; Meeting conduct (open and closed); Information to be reviewed (SAEs, reports, etc.); Requirements for making decisions and recommendations; Protocols for communication of queries and recommendations; Data monitoring plans and guidelines for stopping (often in study protocol). Closed vs Open Sessions Open Sessions: General information on trial progress; Patient accrual; Information from investigators, sponsor, contract research organization (CRO); Questions from DSMB to sponsor, CRO. Closed Sessions: Interim data reports (aggregate and separated by treatment group); All discussions regarding interim data; Discussion of any possible actions or recommendations. 14

15 15 Recommendations Generally, the DSMB may make the following types of recommendations to the principal investigator or sponsor: To continue the trial without modification; To modify the study protocol and continue; To suspend patient enrollment, pending additional information; To terminate the trial.