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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
Outline
25% of clinical trials use patient diaries Paper diaries
Slow completion of clinical trials Fail to meet FDA data standards
Electronic diaries Enhance efficiency and speed trials Meet FDA data standards Allow smaller, more efficient studies
FDA can meet the goals of Critical Path Initiative by: Applying standards for data quality to all diaries Removing doubt about acceptance of electronic diary data
3
Patient Reported Outcomes (PROs)
Subjective states e.g., pain, dizziness
Symptoms observed by the patient e.g., asthma attacks, bowel movements
Collected in 78% of Phase I-IV trials DataEdge, 1994; RB Webber
Included in 31% of approved NDAs 1997-2001; Willke, Burke, & Erickson, 2002
Diaries used in ~ 25% of trials (Phase II-IV) DataEdge, 1998-1999
4
Paper Diaries: Inefficient, Poor Data Quality
Paper diaries Up to 80% of paper diary
cards contain significant
errors (Quinn et al., 2000)
Slows database lock eDiary 98% reduction in data cleaning
Efficient data management
– On-line data edits
Accelerated data lock:
– eDiaries: 1 day after LPO
– Paper diaries: 4+ weeks after LPO
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Paper: Apparent Compliance30 Minute Window
Paper EPD
% C
om
plia
nce 0
20
40
60
80
100
Apparent compliance
Actual compliance
Based on patient time/date entries
Stone et al, BMJ, 2002Stone et al, CCT, 2003
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30 Minute Window
Paper EPD
% C
om
plia
nce 0
20
40
60
80
100
Apparent compliance
Actual compliance
Paper: Test / Verify Apparent Compliance
Verify patient-entered completion times
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Paper: Actual Compliance30 Minute Window
Paper EPD
% C
om
plia
nce
0
20
40
60
80
100
Apparent compliance Actual compliance
Based on instrumented paper diary
Observed back-filling, hoarding, forward-filling
Stone et al, BMJ, 2002Stone et al, CCT, 2003
8
eDiary: Actual Compliance30 Minute Window
Paper ED
% C
ompl
ianc
e
0
20
40
60
80
100
Reported compliance Actual compliance
Based on electronic time stamp
Stone et al, BMJ, 2002Stone et al, CCT, 2003
9
Contribution of eDiary toClinical Development Efficiency
Decreases error Avoidance of back-filling, faked data
Yields more definitive indication of drug effects Increased power Lower error rate
Compared similar studies with paper diary vs. eDiary
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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
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 Approved NDA (Allergan Acular LS)
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
Conclusions
Paper diaries Slow completion of clinical trials Fail to meet FDA data standards
Electronic diaries Enhance efficiency and speed trials Meet FDA data standards Allow smaller, more efficient studies
FDA can meet the goals of Critical Path Initiative by: Applying standards for data quality to all diaries Removing doubt about acceptance of electronic diary
data
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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ALCOA and DiarieseDiaries Paper Diaries
Attributable Patient passwords, code, and device identification
Handwriting?
Legibility Digital recording, human-readable output
Depends upon nature of diary and subject
Contemporaneous Time/date stamping; enforcement of protocol sequencing
Cannot verify; no enforcement of protocol sequencing.
Original Patients cannot change the data once recorded
Not clear if changes made to data.
Accurate Time/date stamping Cannot confirm when completed
* April 1999 FDA Guidance for Computerized Systems Used in Clinical Trials