1. Electronic Diaries: Impact on Drug Development Saul Shiffman, Ph.D. Chief Science Officer invivodata, inc. Advisory Committee for Pharmaceutical Science 19-20 October, 2004

2. 2 Outline  25% of clinical trials use patient diaries  Paper diaries n Slow completion of clinical trials n Fail to meet FDA data standards  Electronic diaries n Enhance efficiency and speed trials n Meet FDA data standards n Allow smaller, more efficient studies  FDA can meet the goals of Critical Path Initiative by: n Applying standards for data quality to all diaries n Removing doubt about acceptance of electronic diary data

3. 3 Patient Reported Outcomes (PROs)  Subjective states n e.g., pain, dizziness  Symptoms observed by the patient n e.g., asthma attacks, bowel movements  Collected in 78% of Phase I-IV trials n DataEdge, 1994; RB Webber  Included in 31% of approved NDAs n 1997-2001; Willke, Burke, & Erickson, 2002  Diaries used in ~ 25% of trials (Phase II-IV) n DataEdge, 1998-1999

4. 4 Paper Diaries: Inefficient, Poor Data Quality  Paper diaries n Up to 80% of paper diary cards contain significant errors (Quinn et al., 2000) n Slows database lock  eDiary n 98% reduction in data cleaning n Efficient data management –On-line data edits n Accelerated data lock: –eDiaries: 1 day after LPO –Paper diaries: 4+ weeks after LPO

5. 5 Paper: Apparent Compliance Based on patient time/date entries Stone et al, BMJ, 2002 Stone et al, CCT, 2003

6. 6 Paper: Test / Verify Apparent Compliance Verify patient- entered completion times

7. 7 Paper: Actual Compliance Based on instrumented paper diary Observed back-filling, hoarding, forward-filling Stone et al, BMJ, 2002 Stone et al, CCT, 2003

8. 8 eDiary: Actual Compliance Based on electronic time stamp Stone et al, BMJ, 2002 Stone et al, CCT, 2003

9. 9 Contribution of eDiary to Clinical Development Efficiency  Decreases error n Avoidance of back-filling, faked data  Yields more definitive indication of drug effects n Increased power n Lower error rate  Compared similar studies with paper diary vs. eDiary

10. 10 Reduced Noise, Increased Validity = More Efficient Clinical Development eDiaries yielded (McKenzie et al, 2004; Pearson et al, 2004) :  33% reduction in variability =  50% reduction in sample size  Smaller trials  Fewer Trials More efficient, faster, cheaper clinical development

11. 11 Science, Technology & Regulation are In Place & Proven  Science: Improves validity, enhances power; >100 published studies  Technology: Over 18 years field experience in clinical research  Regulation: ALCOA, predicate rules n Approved NDA (Allergan Acular LS)

12. 12 What Is Needed?  Apply data quality regulations consistently to paper and eDiary data  Promote adoption of modern, efficient, scientifically valid methods for collection of PROs  Make clear statement RE: acceptance of electronic diary data (remove FUD)

13. 13 Conclusions  Paper diaries n Slow completion of clinical trials n Fail to meet FDA data standards  Electronic diaries n Enhance efficiency and speed trials n Meet FDA data standards n Allow smaller, more efficient studies  FDA can meet the goals of Critical Path Initiative by: n Applying standards for data quality to all diaries n Removing doubt about acceptance of electronic diary data

14. 14 Innovation “That it will ever come into general use, notwithstanding its value, is extremely doubtful because its beneficial application requires much time and gives a good bit of trouble, both to the patient and to the practitioner because its hue and character are foreign and opposed to all our habits and associations.” The Source: The London Times, 1834 The Subject: The Stethoscope Reporting Platforms

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16. 16 ALCOA and Diaries eDiariesPaper Diaries A ttributable Patient passwords, code, and device identification Handwriting? L egibility Digital recording, human-readable output Depends upon nature of diary and subject C ontemporaneous Time/date stamping; enforcement of protocol sequencing Cannot verify; no enforcement of protocol sequencing. O riginal Patients cannot change the data once recorded Not clear if changes made to data. A ccurate Time/date stampingCannot confirm when completed * April 1999 FDA Guidance for Computerized Systems Used in Clinical Trials