1. Clinical Trials Registry Susan Koenig, MPP&PA Director, Office of Compliance & Quality University of Missouri-Columbia School of Medicine Compliance & Quality Seminar Series Presents:

2. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 2 Objectives 1.Learn the background and importance of clinical trials registration. 2.Identify clinical trials registration requirements by source and scope. 3.Explore recent and proposed changes in requirements. 4.Review reporting methods including electronic uploads and downloads.

3. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 3 Why is a registry important? WHO: “ A public, complete and readily searchable registry……will –Further good research practice –Assist in making treatment decisions –Help increase public trust in clinical research”

4. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 4 Why is a registry important? FDAAA (Food & Drug Administration Amendments Act) of 2007: The Data Bank (clinicaltrials.gov) will –Enhance patient enrollment –Track subsequent progress –Make the registry publicly available –Ensure the registry is searchable on the Internet

5. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 5 Why is a registry important? NEJM editorial: –“Mandatory registration represents a critical advance in making clinical trials of new treatments public knowledge.” –“A decade ago a clinical trial could be conducted in secret…..” –“With several recent blockbuster drugs…..breakdowns in communication of trial results kept safety concerns from doctors and patients.”

6. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 6 Clinical Trials Registry Chronology November 1997 – FDA Modernization Act mandates registration February 2000 – clinicaltrials.gov available on the Internet September 2000 – Medicare NCD (National Coverage Decision) on routine costs of clinical trials allowed IF trial is registered in proposed HCFA registry October 2003 – WHO begins dialogue on registration September 2004 – ICMJE (International Committee of Medical Journal Editors) endorses WHO initiative November 2004 – Trials Registry Platform recommended during WHO Ministerial Summit on Health Research, held in Mexico City May 2005 – WHO Trials Registry recommendations approved by the world health Assembly

7. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 7 Clinical Trials Registry Chronology January 2006 – AAMC (Association of American Medical Colleges) calls for registration May 2006 – WHO specifies 20 key data elements for clinical trials registries December 2006 – Medicare Coverage Advisory Committee considers using clinicaltrials.gov in lieu of proposed HCFA registry June 2007 – ICMJE (NEJM, June 7, 2007) expands and clarifies definition of types of trials to be registered September 2007 – FDAAA signed into law October 2007 – NEJM reiterates ongoing support for clinical trials registration and the new FDAAA requirements

8. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 8 International Committee of Medical Journal Editors “ICMJE adopts the WHO’s definition of clinical trials as ‘any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.’

9. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 9 International Committee of Medical Journal Editors Health-related interventions include any intervention used to modify a biomedical or health-related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes).

10. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 10 International Committee of Medical Journal Editors Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events. As previously, purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration.”

11. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 11 Food & Drug Administration Amendments Act of 2007 Additional clout for the FDA Pediatric device & pharmaceutical issues Conflict of interest on FDA committees Post-market safety of drugs Clinical trial data bank

12. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 12 FDAAA Major Changes Definition expanded Phase I excluded Data elements expanded Results reporting to be initiated

13. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 13 Applicable Clinical Trial Device –Prospective study of health outcomes –Compare device interventions –Pediatric post-market surveillance studies –Excludes prototype and feasibility studies Drug –Controlled clinical investigation –Drug subject to FDA requirements –Excludes Phase I clinical trial

14. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 14 Responsible Party Sponsor registers one time for ALL sites Investigator who is responsible for conducting the trial

15. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 15 Data Bank Expansion Content expanded –Descriptive information –Recruitment information –Location and contact information –Administrative data

16. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 16 Data Elements Descriptive Information Brief title, intended for the lay public Brief summary, intended for the lay public Primary purpose Study design Study phase (for an applicable drug clinical trial) Study type Primary disease or condition to be studied, or the focus of the study Intervention name and intervention type Study start date Expected completion date Target number of subjects Outcomes, including primary and secondary outcome measures

17. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 17 Data Elements Recruitment Information –Eligibility criteria –Gender –Age limits –Whether the trial accepts healthy volunteers –Overall recruitment status –Individual site status –Whether or not there is expanded access for those who do not qualify for enrollment

18. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 18 Data Elements Location and Contact Information –Name of sponsor –Responsible party by official title –Facility name and contact information City, state, zip code for each location Toll-free number

19. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 19 Data Elements Administrative Data –Unique protocol identification number –Other protocol identification numbers, if any –FDA’s IND/IDE protocol number and record verification date

20. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 20 Timing When to register? Applicable clinical trials register by later of –90 days after enactment (by December 26, 2007) –21 days after first patient enrolled

21. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 21 Posting of Results After Drug or Device Approval Link from clinicaltrials.gov to required information FDA Information, if applicable FDA summary documents Posted FDA assessments of results FDA public health advisories FDA action package of applicable drug Safety and effectiveness of applicable device NIH Links Medline citations NLM database of product labels

22. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 22 Posting of Results One year later, by September 27, 2008 Registry to include data elements and tables –Demographic and baseline data –Primary and secondary outcomes –Point of contact about results –Existence of agreements that restrict release

23. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 23 Posting of Results Three years later, by September 27, 2010 Future guidance Public meeting –18 months after enactment (by March 2009) –for public input on third year rule making.

24. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 24 Adverse Events in Results Data Bank Regulations must be issued by March, 2009 OR Adverse Events must be included by September, 2009 Adverse Events –Serious –Frequent (>5% within any arm) –Anticipated & unanticipated

25. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 25 Federal Grants Funded in whole or in part –DHHS –FDA –NIH –AHRQ Must submit registry data and results Agencies must verify submission before releasing remaining funds

26. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 26 Reporting Methods Web page clinicaltrials.gov PRS (Protocol Registration System)

27. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 27 Account Application Process There are two types of PRS accounts:  Organization accounts multiple users trials conducted at an organization  Individual accounts trials conducted by a single investigator

28. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 28 Reporting Methods Logon –Each institution designates a PRS Administrator –Administrator creates logons –Contact Susan Koenig at koenigse@health.missouri.edu

29. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 29 Reporting Methods Create a Record –Entry is saved, modify as needed –“Complete” –when edits are finished –Modify at any time and mark again as “complete” PRS Administrator will “approve” and “release”

30. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 30 Reporting Methods Clinicaltrials.gov staff will review before entry is available for public view Appear on web site within 2-5 days NCT number assigned at that time

31. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 31 Reporting Methods Electronic Reporting –Records can be uploaded and downloaded –Must be in PRS document format –One upload can contain multiple records –Records with errors are placed in “complete” status –Modify errors by corrected upload or through on-line edit

32. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 32

33. Office of Compliance & Quality, University of Missouri-Columbia School of Medicine 33 Office of Compliance & Quality https://sp.missouri.edu/sites/researchbudgetresources/default.aspx 882-8957 buhrp@health.missouri.edu koenigse@health.missouri.edu