Electronic Diaries: Impact on Drug Development

Saul Shiffman, Ph.D.

Chief Science Officer

invivodata, inc.Advisory Committee for Pharmaceutical Science

19-20 October, 2004

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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

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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

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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

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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

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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

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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)

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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)

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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

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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