Analysis Databases:Analysis Databases:A Regulatory PerspectiveA Regulatory Perspective

2003 FDA/Industry Statistics Workshop 2003 FDA/Industry Statistics Workshop "Statistics: From Theory to Regulatory "Statistics: From Theory to Regulatory

Acceptance“Acceptance“Parallel Session II: Analysis DatabasesParallel Session II: Analysis Databases

Hyatt Regency, Bethesda, Maryland Hyatt Regency, Bethesda, Maryland September 18-19, 2003 September 18-19, 2003

Steve Wilson, DrPHSteve Wilson, DrPHDeputy DirectorDeputy Director

Division of Biometrics II/FDA/CDERDivision of Biometrics II/FDA/CDER

Analysis Databases:Analysis Databases:Let’s Get a Guidance Let’s Get a Guidance

ProntoPronto

2003 FDA/Industry Statistics Workshop 2003 FDA/Industry Statistics Workshop "Statistics: From Theory to Regulatory "Statistics: From Theory to Regulatory

Acceptance“Acceptance“Parallel Session II: Analysis DatabasesParallel Session II: Analysis Databases

Hyatt Regency, Bethesda, Maryland Hyatt Regency, Bethesda, Maryland September 18-19, 2003 September 18-19, 2003

Steve Wilson, DrPHSteve Wilson, DrPHDeputy DirectorDeputy Director

Division of Biometrics II/FDA/CDERDivision of Biometrics II/FDA/CDER

DisclaimerDisclaimer

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

OutlineOutline

• The way we wereThe way we were• The way we areThe way we are• Standards developmentStandards development• The The urgenturgent need for a guidance on need for a guidance on

the submission of analysis filesthe submission of analysis files• New eCTD guidanceNew eCTD guidance• Developing a guidanceDeveloping a guidance• CDISC and ADaMCDISC and ADaM

The Way We WereThe Way We Were• Statistical review focused on efficacyStatistical review focused on efficacy• Data submitted to reviewers (“desk Data submitted to reviewers (“desk

copies”)copies”)– No EDRNo EDR– No archive standards (e.g., Transport 5, No archive standards (e.g., Transport 5,

PDF, …)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 Pharmaceutical development separate

from healthcare. from healthcare.

The Way We AreThe Way We Are• Risk-Benefit / Safety - EfficacyRisk-Benefit / Safety - Efficacy• Medical reviewers “want” data for “analysis”Medical reviewers “want” data for “analysis”• PDUFA limits time and optionsPDUFA limits time and options• Tough realities related to Science (no more Tough realities related to Science (no more

knee-jerk LOCF)knee-jerk LOCF)• Approvable cyclesApprovable cycles• Submission standards (Transport 5, PDF)Submission standards (Transport 5, PDF)• Reviewer templatesReviewer templates• Data “warehouse” – more standards (HL7, Data “warehouse” – more standards (HL7,

Version 3, SDS, CDISC, HIPAA, etc.) Version 3, SDS, CDISC, HIPAA, etc.)

Standards Development : Standards Development : A Sea of Terms & AcronymsA Sea of Terms & Acronyms

JANUS

Version 3

WEBSDM

PPV

SDM

ODM

CDISC

eCTD

ICH

MeDRA

SNOMED

AERS

HIPaa911

RCRIMHL7

ADaM

XML21 CFR 11

Standards DevelopmentStandards Development• ICH E3 – study descriptionICH E3 – study description• eCTD – electronic Common Technical eCTD – electronic Common Technical

Document (submission guidance, Booze-Allen Document (submission guidance, Booze-Allen viewer tools)viewer tools)

• Submission Data Standards (CDISC Version 3, Submission Data Standards (CDISC Version 3, PPV Pilot, Lincoln Tech CRADAs –PPV and PPV Pilot, Lincoln Tech CRADAs –PPV and WEBSDM HL7/RCRIM, JANUS)WEBSDM HL7/RCRIM, JANUS)

• ProtocolsProtocols– ICH E6, E9 and E3ICH E6, E9 and E3– Statistical analysis planStatistical analysis plan

• Consistency – impossible task?Consistency – impossible task?

I Contend That …I Contend That …• It is important that we (statisticians, the It is important that we (statisticians, the

industry, clinical trialists, regulators, industry, clinical trialists, regulators, researchers) need to agree on and use researchers) need to agree on and use standards for describing an analysis standards for describing an analysis database and analyses -- for a study and database and analyses -- for a study and for combined studies. 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 We need to use the guidance to document

and communicate the scientific decisions we and communicate the scientific decisions we make in analyzing datamake in analyzing data

eCTD Draft Guidance: August eCTD Draft Guidance: August 20032003

Guidance for IndustryGuidance for Industry

Providing Regulatory Submissions in Providing Regulatory Submissions in Electronic Format — Human Electronic Format — Human

Pharmaceutical Product Applications Pharmaceutical Product Applications and Related Submissionsand Related Submissions

DRAFT GUIDANCEDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.This guidance document is being distributed for comment purposes only.Comments and suggestions regarding this draft document should be submitted within 60 Comments and suggestions regarding this draft document should be submitted within 60

days of publication in the days of publication in the Federal RegisterFederal Register of the notice announcing the availability of the of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments 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 should be identified with the docket number listed in the notice of availability that publishes in thepublishes in the Federal Register Federal Register..

For questions regarding this draft document contact (CDER) Randy Levin 301-594-5411, or For questions regarding this draft document contact (CDER) Randy Levin 301-594-5411, or (CBER) Robert Yetter at 301-827-0373. (CBER) Robert Yetter at 301-827-0373.

eCTD Draft Guidance: eCTD Draft Guidance: Finding a “Home” for Analysis Finding a “Home” for Analysis

FilesFiles1.1.Study reportsStudy reportsTypically, a single document should be provided for each study Typically, a single document should be provided for each study

report included in this module. However, if you provide the study report included in this module. However, if you provide the study reports as multiple documents, you should confine the subject reports as multiple documents, you should confine the subject matter of each document to a single item in the following list…matter of each document to a single item in the following list…

Individual subject data listings …Individual subject data listings …

-- Analysis datasets-- Analysis datasets- Analysis datasets- Analysis datasets- Analysis programs- Analysis programs- Data definitions- Data definitions

[my emphasis][my emphasis]

Developing Guidance for Developing Guidance for Analysis Databases: Some Analysis Databases: Some

ChallengesChallenges• Keeping Science alive – complexity (The Keeping Science alive – complexity (The

Battle of the Comments)Battle of the Comments)• Improving the Science (data quality; missing Improving the Science (data quality; missing

data – “gets hard real fast” – O’Neill, 2003 data – “gets hard real fast” – O’Neill, 2003 FDA/ASA Biopharm Workshop; safety and FDA/ASA Biopharm Workshop; safety and efficacyefficacy

• Efficient, unambiguous communication Efficient, unambiguous communication (recent experience)(recent experience)

• Everybody already knows what to doEverybody already knows what to do• Include health research enterprise and new Include health research enterprise and new

technologiestechnologies

Regulation GuidanceRegulation GuidanceRegulatory EnvironmentRegulatory Environment

S. Woollen

Guidance Begets Guidance:Guidance Begets Guidance:Be Careful of the Be Careful of the ConsequencesConsequences

• 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

Developing GuidanceDeveloping Guidance• Best advice – reflect best practiceBest advice – reflect best practice• Pay attention to current practice & Pay attention to current practice &

Science (meetings with sponsors) 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 New urgency – guidance on submission

of analysis files of analysis files

Did Get People Together for the Did Get People Together for the First Time to Talk Standard: First Time to Talk Standard:

CDISCCDISC• WorkgroupsWorkgroups

– SDM (submission data)SDM (submission data)– ODM (operational data – XMLODM (operational data – XML– ADaM (analysis data)ADaM (analysis data)– Lab (laboratory data)Lab (laboratory data)

• Challenge – coordinate effortsChallenge – coordinate efforts• ADaM – doing the hard workADaM – doing the hard work• We (FDA) are “observers”We (FDA) are “observers”

ADaM focus – FDA ADaM focus – FDA StatisticiansStatisticians

• ““provide guidelines for the creation of provide guidelines for the creation of files and associated documentation that files and associated documentation that are submitted to the FDA statistical are submitted to the FDA statistical reviewer in support of the primary and reviewer in support of the primary and important secondary study objectives”important secondary study objectives”

• ““statistical analysis data models statistical analysis data models represent consensus across a large represent consensus across a large number of reviewers experienced in number of reviewers experienced in regulatory review”regulatory review”

• A big jump start for us – re. guidanceA big jump start for us – re. guidance

ADaM Models: One PROC AwayADaM Models: One PROC Away

• ““Statistical Analysis Dataset Models”Statistical Analysis Dataset Models”– Change-from-baselineChange-from-baseline– Time-to-eventTime-to-event– CategoricalCategorical– Safety (under construction)Safety (under construction)

• Detailed examplesDetailed examples– Detailed description of data files and Detailed description of data files and

corresponding metadata (SDM)corresponding metadata (SDM)– Example based on real endpointExample based on real endpoint– Display tablesDisplay tables– Test dataTest data

ADaM Models: ADaM Models: The Power of StandardsThe Power of Standards

Are We There Yet?Are We There Yet?More GuidanceMore Guidance

• Statistical Analysis PlansStatistical Analysis Plans• E3 – Appendix 16.1.9 E3 – Appendix 16.1.9

Documentation of statistical Documentation of statistical methods methods

• ProtocolsProtocols

THANK YOUTHANK YOUSee You Next Year!See You Next Year!

wilsons@cder.fda.govwilsons@cder.fda.gov

301-827-5583301-827-5583