1. Analysis Databases: A Regulatory Perspective 2003 FDA/Industry Statistics Workshop "Statistics: From Theory to Regulatory Acceptance Parallel Session II: Analysis Databases Hyatt Regency, Bethesda, Maryland September 18-19, 2003 Steve Wilson, DrPH Deputy Director Division of Biometrics II/FDA/CDER

2. Analysis Databases: Lets Get a Guidance Pronto 2003 FDA/Industry Statistics Workshop "Statistics: From Theory to Regulatory Acceptance Parallel Session II: Analysis Databases Hyatt Regency, Bethesda, Maryland September 18-19, 2003 Steve Wilson, DrPH Deputy Director Division of Biometrics II/FDA/CDER

3. Disclaimer Views expressed in this presentation are those of the speaker and not, necessarily, of the Food and Drug Administration

4. Outline The way we wereThe way we were The way we areThe way we are Standards developmentStandards development The urgent need for a guidance on the submission of analysis filesThe urgent need for a guidance on the submission of analysis files New eCTD guidanceNew eCTD guidance Developing a guidanceDeveloping a guidance CDISC and ADaMCDISC and ADaM

5. The Way We Were Statistical review focused on efficacyStatistical review focused on efficacy Data submitted to reviewers (desk copies)Data submitted to reviewers (desk copies) –No EDR –No archive standards (e.g., Transport 5, PDF, …) The luxury of time (pre-PDUFA)The luxury of time (pre-PDUFA) Less workloadLess workload Delayed decisionsDelayed decisions Encourage, but not insistEncourage, but not insist Every study a new challengeEvery study a new challenge Routine analysesRoutine analyses Pharmaceutical development separate from healthcare.Pharmaceutical development separate from healthcare.

6. The Way We Are Risk-Benefit / Safety - EfficacyRisk-Benefit / Safety - Efficacy Medical reviewers want data for analysisMedical reviewers want data for analysis PDUFA limits time and optionsPDUFA limits time and options Tough realities related to Science (no more knee- jerk LOCF)Tough realities related to Science (no more knee- jerk LOCF) Approvable cyclesApprovable cycles Submission standards (Transport 5, PDF)Submission standards (Transport 5, PDF) Reviewer templatesReviewer templates Data warehouse – more standards (HL7, Version 3, SDS, CDISC, HIPAA, etc.)Data warehouse – more standards (HL7, Version 3, SDS, CDISC, HIPAA, etc.)

7. Standards Development : A Sea of Terms & Acronyms JANUS Version 3 WEBSDM PPV SDM ODM CDISC eCTD ICH MeDRA SNOMED AERS HIPaa 911 RCRIM HL7 ADaM XML 21 CFR 11

8. Standards Development ICH E3 – study descriptionICH E3 – study description eCTD – electronic Common Technical Document (submission guidance, Booze-Allen viewer tools)eCTD – electronic Common Technical Document (submission guidance, Booze-Allen viewer tools) Submission Data Standards (CDISC Version 3, PPV Pilot, Lincoln Tech CRADAs –PPV and WEBSDM HL7/RCRIM, JANUS)Submission Data Standards (CDISC Version 3, PPV Pilot, Lincoln Tech CRADAs –PPV and WEBSDM HL7/RCRIM, JANUS) ProtocolsProtocols –ICH E6, E9 and E3 –Statistical analysis plan Consistency – impossible task?Consistency – impossible task?

9. I Contend That … It is important that we (statisticians, the industry, clinical trialists, regulators, researchers) need to agree on and use standards for describing an analysis database and analyses -- for a study and for combined studies.It is important that we (statisticians, the industry, clinical trialists, regulators, researchers) need to agree on and use standards for describing an analysis database and analyses -- for a study and for combined studies. This is true for Science and regulationThis is true for Science and regulation We need a guidance.We need a guidance. We need to use the guidance to document and communicate the scientific decisions we make in analyzing dataWe need to use the guidance to document and communicate the scientific decisions we make in analyzing data

10. eCTD Draft Guidance: August 2003 Guidance for Industry Providing Regulatory Submissions in Electronic Format Human Pharmaceutical Product Applications and Related Submissions DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact (CDER) Randy Levin 301-594-5411, or (CBER) Robert Yetter at 301-827-0373.

11. eCTD Draft Guidance: Finding a Home for Analysis Files 1.Study reports Typically, a single document should be provided for each study report included in this module. However, if you provide the study reports as multiple documents, you should confine the subject matter of each document to a single item in the following list… Individual subject data listings … -- Analysis datasets - Analysis datasets - Analysis programs - Data definitions [my emphasis]

12. Developing Guidance for Analysis Databases: Some Challenges Keeping Science alive – complexity (The Battle of the Comments)Keeping Science alive – complexity (The Battle of the Comments) Improving the Science (data quality; missing data – gets hard real fast – ONeill, 2003 FDA/ASA Biopharm Workshop; safety and efficacyImproving the Science (data quality; missing data – gets hard real fast – ONeill, 2003 FDA/ASA Biopharm Workshop; safety and efficacy Efficient, unambiguous communication (recent experience)Efficient, unambiguous communication (recent experience) Everybody already knows what to doEverybody already knows what to do Include health research enterprise and new technologiesInclude health research enterprise and new technologies

13. Regulation Guidance Regulatory Environment S. Woollen

14. Guidance Begets Guidance: Be Careful of the Consequences Providing Regulatory Submissions in Electronic Format NDAs Provided advice on submitting CRT (case report tabulation) data Details on safety data and demographics lists contain suggested data elements for the individual datasets. This listing is meant to serve as a starting point for discussion between you and the review division on the content and organization of the datasets Our advice led to confusion

15. Developing Guidance Best advice – reflect best practiceBest advice – reflect best practice Pay attention to current practice & Science (meetings with sponsors)Pay attention to current practice & Science (meetings with sponsors) Talk to customers – series of meetingsTalk to customers – series of meetings Ask experts – Dave Christiansen, SGEAsk experts – Dave Christiansen, SGE Coordinate with other guidances – HL7Coordinate with other guidances – HL7 We need to do it – eStat GroupWe need to do it – eStat Group Provide draft for commentsProvide draft for comments Not regulation – comment: very fuzzyNot regulation – comment: very fuzzy New urgency – guidance on submission of analysis filesNew urgency – guidance on submission of analysis files

16. Did Get People Together for the First Time to Talk Standard: CDISC WorkgroupsWorkgroups –SDM (submission data) –ODM (operational data – XML –ADaM (analysis data) –Lab (laboratory data) Challenge – coordinate effortsChallenge – coordinate efforts ADaM – doing the hard workADaM – doing the hard work We (FDA) are observersWe (FDA) are observers

17. ADaM focus – FDA Statisticians provide guidelines for the creation of files and associated documentation that are submitted to the FDA statistical reviewer in support of the primary and important secondary study objectivesprovide guidelines for the creation of files and associated documentation that are submitted to the FDA statistical reviewer in support of the primary and important secondary study objectives statistical analysis data models represent consensus across a large number of reviewers experienced in regulatory reviewstatistical analysis data models represent consensus across a large number of reviewers experienced in regulatory review A big jump start for us – re. guidanceA big jump start for us – re. guidance

18. ADaM Models: One PROC Away Statistical Analysis Dataset ModelsStatistical Analysis Dataset Models –Change-from-baseline –Time-to-event –Categorical –Safety (under construction) Detailed examplesDetailed examples –Detailed description of data files and corresponding metadata (SDM) –Example based on real endpoint –Display tables –Test data

19. ADaM Models: The Power of Standards

20. Are We There Yet? More Guidance Statistical Analysis PlansStatistical Analysis Plans E3 – Appendix 16.1.9 Documentation of statistical methodsE3 – Appendix 16.1.9 Documentation of statistical methods ProtocolsProtocols

21. THANK YOU See You Next Year! wilsons@cder.fda.gov 301-827-5583