Observational Study Working Group DIA Clinical Trial Disclosure Community Follow-up to teleconference 06 June 2013 regarding proposed changes to PRS/ClinicalTrials.gov.

Purpose of This Slide Deck To follow up on meeting with Becky Williams and Nick Ide from NIH to propose changes in PRS to better accommodate disclosure of observational studies on 06 June 2013*. Request from NIH was to provide specific examples for each of the 4 issues for which we have requested change. *Meeting minutes:

Guide to Slides ISSUE 1 – Registration Data Element: Enrollment Slide 3 : Original request Slides 4-7 : Proposed revisions with examples ISSUE 2 – Registration Data Element: Study Start Date Slide 9 : Original request Slides 10-11: Proposed revision with example ISSUE 3 – Results Data Element: Outcome Measure Time Frame Slide 12: Original request Slides 13-14: Proposed revision with example ISSUE 4 - Results Data Element: Patient Totals Slide 15: Original request Slides 16-22: Further details of problem provided with examples and proposed considerations

ISSUE 1 - Data Element: Enrollment Retrospective database studies are not enrolling participants. Enrollment of 0 is not accepted for Active not recruiting studies when “Actual” is selected. Proposed alternative is to accept 0 as an enrollment number for Active not recruiting status.

ISSUE 1 - Data Element: Enrollment After reviewing the Data Element Definitions Document, PRS and ClinicalTrials.gov it seems the use of the word ‘enrollment’ is the only conflict for retrospective studies.  Is it possible the following revisions could be made?

ISSUE 1 - Data Element: Enrollment SUGGESTED REVISION 1 - Data Element Definitions

ISSUE 1 - Data Element: Enrollment SUGGESTED REVISION 2 - PRS

ISSUE 1 - Data Element: Enrollment ClinicalTrials.gov ISSUE 1 - Data Element: Enrollment SUGGESTED REVISION 3 – ClinicalTrials.gov

ISSUE 2 - Data Element: Study Start Date

ISSUE 2 - Data Element: Study Start Date SUGGESTED REVISION - Data Element Definitions Study Start Date FDAAA  Definition: Date that enrollment to the protocol begins. Guidance for registry studies: the study start date is related to when the first participant was entered into the registry study. For retrospective studies: the study start date is related to the date of analysis of historical data (i.e., 2013) as opposed to when the study was first conducted and data collected (i.e., 1950).* * Suggest adding some guidance (such as red text, above) in Registration Data Elements Definitionsa regarding study start dates for registry and/or retrospective studies, since this has been an area of confusion for those registering kinds of studies.

ISSUE 2 - Data Element: Study Start Date example record for which suggested guidance would have helped: NCT01906255

ISSUE 3: Data Element: Outcome Measure Time Frame

ISSUE 3: Data Element: Outcome Measure Time Frame SUGGESTED REVISION - Results Data Element Definitions Outcome Measure Time Frame * : Time point(s) at which outcome measure was assessed.  Guidance for cross-sectional studies: the time frame for an outcome measure that may have occurred in an open time frame should be worded to illustrate the procedure per study design. For example, “At the single study visit, performed after at least 12 weeks of treatment with drug x.” * * Suggest adding some guidance (such as red text, above) in Results Data Elements Definitions a regarding time frames for cross sectional studies, since this has been an area of confusion for those reporting results for these kinds of studies.

ISSUE 3 - Data Element: Outcome Measure Time Frame example record for which suggested guidance would have helped: NCT01383005   Measure Title Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Individual Item Scores for the Overall Study Population Measure Description Participant treatment satisfaction was measured using the HIVTSQ, which consists of 10 items (1-Satisfaction, 2-HIV Control, 3-Adverse Effects, 4-Level of Demand, 5-Convenience, 6-Flexibility, 7-Knowledge, 8-Life Habits, 9-Recommendability, and 10-Willingness to Continue). Items are scored from 0 (very dissatisfied) to 6 (very satisfied), other than item 4, which has an inverted score from 6 (very demanding) to 0 (very undemanding). Each single item was considered for the evaluation of the primary outcome. Time Frame At the single study visit, performed after at least 12 weeks of treatment with Kaletra QD  

ISSUE 4 - Results Data Element: Patient Totals

ISSUE 4 - Results Data Element: Patient Totals Problem # 1 Double-counting of participants at participant flow and baseline (applies to “switch” studies or other more complex designs). Warning validation message and not accepted by NIH reviewers.

ISSUE 4 - Results Data Element: Patient Totals Problem # 1 example: NCT01108796

ISSUE 4 - Results Data Element: Patient Totals Problem #1 Solution (reference study NCT01108796): To eliminate multiply counted participants in a row, use applicable qualifications as categories and report correct values across the row “NA” with comment functionality, allowing sponsor to provide explanations directly to applicable field.

ISSUE 4 - Results Data Element: Patient Totals Problem # 1 Solution Example: NCT01108796 (this

ISSUE 4 - Results Data Element: Patient Totals Problem #2 Preferred format when participants "switch" interventions is to use the Period structure in Participant Flow or the relevant information can also be communicated via Milestones; however, such detail of information may not available in observational study reports.

ISSUE 4 - Results Data Element: Patient Totals Problem #2 Solution (reference study NCT01153698): Use 1 group/cohort for participant flow, baseline, outcome measures (all participants), safety data per treatment. Accepted after several discussion rounds with NIH and seem to become a best practice.

ISSUE 4 - Results Data Element: Patient Totals Problem #1 and Problem #2 have been solved in a reasonably efficient way given some recent additional functionality in PRS. For this issue, the subgroup’s suggestion is two-fold: make QA reviewers aware of these kinds of studies and their acceptable solutions to limit the need for too much QA back-and-forth Consider any examples or additions to data element definitions or training NIH-generated training materials that might address the challenges of more complex observational study designs.

THANK YOU KINDLY FOR YOUR CONSIDERATION of THESE ISSUES! Questions or comments regarding this presentation can be emailed to Subgroup Chair Suzanne Heyd at sheyd@snet.net