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					Welcome to Durham!
Smart CRF

       Leonard Sacks MD
          Deputy director
 Office of Critical Path Programs
                FDA
     How familiar are you with the CDISC
     CDASH initiative?

1.    Not familiar
2.    Somewhat familiar       11       12
3.    Familiar
4.    Very Familiar
                                   8

                          1
                          1   2    3   4
Do you believe FDA accepts paperless
trials?
 1) Yes
 2) No
                      25
                              17



                       1       2
If your organization works with clinical trials,
what approximate percentage of CRFs are
fully electronic?

1. 0%
2. 1-50%
                                21
3. 51%-99%
4. 100%
                                      10
                            4               5

                            1    2     3    4
How effective would you estimate your current
systems are in detecting investigator fraud (e.g.
fictitious patients)?
1. <25%
2. 26-50%
3. 51-75%                     15
4. 76-99%
5. 100%                             9    8    8

                                                    1
                               1    2    3    4     5
What percentage of clinical monitoring is spent correcting
and completing the CRF (e.g. missing concomitant meds,
missing AE report, missing investigator signature or date)?

1. <25%
2. 26-50%
3. 51-75%                               15
4. 76-99%
                                                   13
                                             10
5. 100%
                                   7


                                   1    2     3     4    5
What percentage of clinical monitoring is spent educating
study staff?

1. <25%
2. 26-50%
3. 51-75%                              19
4. 76-99%
5. 100%
                                 12
                                             5

                                  1     2    3     4    5
Hey what’s this?
And this….
Old system
 Huge bulky paper CRF
 Tedious for investigator- repetition, data transfer,
    consistency
   Tedious for monitors
   Tedious to transport and archive
   All data must be transcribed
   Data cannot be evaluated in real-time
   Unable to capture images etc
   Numerous ancillary functions are needed e.g.
    randomization, informed consent, monitoring
Borrow experience
 Paper records antiquated in clinical practice
 At FDA, electronic submissions
 SPL- searchable labels
 Electronic Adverse Event reports
 Electronic health records in clinical practice
Borrow experience
 Security and privacy-
     Experience from the financial world-online
      banking
     Financial privacy and tax returns
Paper CRF – ? the dinosaur
 Electronic CRF ~50% submissions, limited
  capabilities.
 Smart CRF becomes the platform for clinical
  study
Smart CRF – Two functional tiers

1.       Information entry/archival-
          Interface with point of data entry
              investigator, laboratory, patient (in
               the case of a Patient Reported
               Outcome tool)
          “smart” function
              auto-audits for inconsistencies in
               matching fields
              checks for missing data
              prompts for additional data fields e.g.
               SAE form
              automated carry over of information
               that does not change
              data assembly
Smart CRF – Two functional tiers
2.   Data trafficking
         Input from:
            investigator,
            lab,
            imaging,
            patient (PRO’s)
         Output to:
            Sponsor
            IRB/DSMB
            CRO
            FDA
Smart CRF-trial components
 Envisaged to cater for all the components of a clinical
  trial
      Electronic informed consent/video interface
      Inclusion and exclusion
      Randomization
      Recording study procedures
      Recording clinical findings
      Laboratory data trafficking
      Auto monitoring
      Safety reporting
      Interactive with investigator
      Archival of data, images etc
Smart CRF – the stakeholders/users
 Envisaged to cater for the needs of all the many
  users/stakeholders in a trial:
      Patient
      Health care provider/investigator
      Laboratory services
      Imaging services
      CRO
      Monitors
      IRB/DSMB
      Sponsor
      FDA
Functions tailored for user/stakeholder
 Patient-
       informed consent, real-time results, safety alerts-from lab, from sponsor
 Investigator-
       interactive-informs on data trends
       prompts e.g. SAE forms
       auto transfer of fixed data
        automatic population of lab fields
       auto-monitoring
            consistency e.g. inclusion and exclusion criteria,
            completeness e.g. stop dates for concomitant meds
 Sponsor-
       remote access real-time e.g. overseas sites,
       Immediate data analysis without waiting for transcription
 CRO-
       monitoring function, archiving, communication
 IRB-
       automatic submission and aggregation of SAE reports
 FDA-
       fraud monitoring, investigator training
Other functions
   Fraud detection
        Variance algorithms- e.g. date of birth, variance of lab data, BP measurement
        Corroborative data entry-independent entry from lab- eliminates transcription fraud (cannot
         eliminate fraudulent specimens), independent imaging data entry
        Electronic date and time stamp, unable to change data without an electronic record
   Safety warning-
        Automatic generation of SAE form
        Integration of all SAE reports
        Algorithms for iterative lab safety analysis e.g. threshold number of LFT elevations, threshold
         differences between arms
        Notification of IRB and Sponsors
        They can trigger immediate alerts to investigator and patient
        Investigator interactive reporting of safety trends-e.g.. subcritical rise in LFTs, Creatinine
   Auto-monitoring-
        Prompts for missing data-e.g.. stop dates, start dates informed consent- won’t allow
         investigator to continue
        Consistency check on all dependent fields- e.g. concomitant meds, pill counts
   Imaging
     Smart CRF – Trial Components: Do you
     agree thus far with the Smart CRF as an
     objective?

1.    Yes
2.    No
                        31
3.    Somewhat


                                        6

                         1      2       3
     Are you currently using a ‘Smart CRF’?


1.    Yes
2.    No
                        20     20
3.    Don’t know




                        1       2      3
An interesting corollary-
 Study results can be evaluated without un-
  blinding
 Automated pre-specified analyses can be
  reviewed without knowing which arm is which
 Conclusions can be made on non-inferiority
  or superiority prior to breaking the blind
   Complementary initiatives
 Embedding the case report form in the clinical
  electronic health record so that patients can be
  studied during the course of their clinical care
  (Electronic health Records/Clinical research)
 Data standards- streamlining the format and
  content of data elements so they can be shared
  between different users e.g. laboratory, health
  care provider, investigator, sponsor, pharmaco-
  vigilance investigator
 Ethical initiatives to ensure patient privacy and
  protect patient identity
More on data standards
 CDASH Project
   Clinical Data Acquisition Standards
    Harmonization

 CDISC
   Study Data Tabulation Model (SDTM)
   Standard for Exchange of Nonclinical Data
    (SEND)
   Operational Data Model (ODM)
     Has your organization taken any steps to
     implementing any CDISC standards?

1.    Yes
2.    No
                        33
3.    Don’t know


                                 2
                         1       2       3
     If you have implemented a CDISC
     standard, which one is most valuable to
     your organization?

1.    Lab Standard
2.    SDTM (Study Data
                               27
      Tabulation Model)
3.    ODM (Operational
      Data Model)
                                     6
4.    SEND (Standard       2               1
      for Exchange of
      Non-clinical Data)   1   2     3     4
Clinical Data Interchange Standards
Consortium
 Principles
    Lead development of standards that improve process
     efficiency while supporting the scientific nature of
     clinical research
    Creating flexible, intelligible and navigable submissions
    Importance of data quality structure and content
    Global multidisciplinary functionality
    Emphasize data sharing and minimize duplication
    Provide education on CDISC
    Avoid promoting individual organizations or vendors
CDISC
CDISC
Challenges
 Addressing source documentation as
  required by regulation
 Preventing automatic (default) carryover of
  changeable data e.g. concomitant meds
 Ensure investigator ownership of data- they
  take responsibility
Regulations and Guidances
 21CFR11 “Electronic records, electronic signatures”
 Procedures
    to ensure signer cannot repudiate the signed record as
     genuine
    For validation of accuracy, ability to detect alterations,
     time stamped audit trails
    For limitation of access to, and generation of accurate
     copies of electronic records
    Checks on authority to sign and access records
    To verify identity of electronic signature
Regulations and Guidances
   Guidance: Part 11, electronic records; Electronic signatures-scope and
    application (August 2003)
        Enforce
             Limiting system access to authorized individuals
             Use of operational system checks
             Use of authority checks
             Determination that persons who develop, maintain or use electronic systems
              have the education, training and experience to perform their assigned tasks
             Establishment of, and adherence to written policies that hold individuals
              accountable for actions initiated under their electronic signatures
             Appropriate controls over systems documentation
             Controls for open systems corresponding to controls for closed systems
             Requirement related to electronic signatures
        Enforcement discretion
             Validation of computerized systems
             Requirements related to computer-generated time-stamped audit traisl
             Legacy systems (those in place prior to Aug 97)
             Copies of records and record retention

   Computerized systems used in clinical investigations (May 2007)
DSI- Examples of problems
 Backdating of monitoring reports
 Gaps in performance of source verification
 On site source data not retained at closeout
  of study
 Procedures recorded prior to actual patient
  visit
 Delays in signing electronic data capture
Conclusions
 Smart CRFs offer enormous opportunities to
  expedite clinical trials
 They can be tailored to the needs of all
  parties involved in the clinical trial
 They can perform numerous trial functions
 They can simplify study monitoring
 They can improve safety monitoring through
  real-time surveillance
 They save trees, and space and
  gasoline…..and so on.
Questions
 What still needs to be done to move forward?
 How to we set about determining electronic
  reliability?
 Are there standards that need to be
  articulated for the myriad functions of the
  ECF?
 Other ideas?
     How many years away is a Smart CRF?


1.    <3
2.    3-7
3.    7-10
4.    >10
5.    Not going to
      happen
     Is there market value for the Smart CRF?


1.    Yes
2.    No
3.    Not Sure
     Is SCDM the forum for discussion on the
     development and adoption of Smart CRF
     objective?

1.    Yes
2.    No
3.    Not Sure

				
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