Transcript Developing e-Standards for Clinical Trials Data and Analyses

Developing e-Standards for
Clinical Trials Data and Analyses
Steve Wilson
Division of Biometrics II, CDER, FDA
22nd Spring Symposium
New Jersey Chapter of the American Statistical Association
International Harmonization and Electronic Submission
Embassy Suites, 121 Centennial Ave, Piscataway, NJ
Wednesday, June 6, 2001
Disclaimer
Views expressed in this presentation
are those of the speaker and not,
necessarily, of the Food and Drug
Administration
Acknowledgements
John Clark, Center for Drug Evaluation
and Research (CDER), FDA
Michael Fauntleroy, Center for
Biologics Evaluation and Research
(CBER), FDA
Randy Levin, Center for Drug
Evaluation and Research (CDER), FDA
Outline
Background / motivation
 Statistical review
 Electronic submission
Developing guidance for e-standards
 Clinical data
 Documenting analyses
 CTOC and the eCTD
Other data-related issues
 Too much data? Thinking parsimoniously
 The right data? Quality assurance and safety
 Non-clinical data? Stability and Carcinogenicity
The Big Picture: Electronic Submissions -Data Repository -- Review Tools
Background / Motivation
Statistical review
Electronic submission
Regulation
Guidances
MAPPs
Background/Motivation
Statistical Review
Assess compliance with protocol / blinded
analysis plans -- conduct of the study
Check appropriateness of statistical
models and conclusions
Verify results reported in the NDA
Answer review questions
Modify models and assess robustness /
sensitivity of the results
Background/Motivation
Statistical Review
Modify data sets and reanalyze
Examine the trial and data for potential
bias:
Results by center
Baseline predictors
Important subgroups (sex, age, race, etc,)
Assess impact of audits
Due diligence
The Way We Were
Statisticians requested data, program files and
documentation (PROC Contents, annotated CRF,
description of derived variables, etc.) at PreNDA meetings
To assist review, sponsors submitted these
electronic files to reviewers as “desk copies” -- no
formal archive
Possibly a number of data and program requests
during review cycle
Background/Motivation
Electronic Submission: Regulation
21 CFR Part 11
Electronic Records; Electronic Signatures;
Final Rule
Electronic Submissions; Establishment of
Public Docket; Notice
August 20, 1997
www.fda.gov/ora/compliance_ref/part11/Default.htm
Regulation: 21 CFR Part 11
...electronic records as equivalent to paper
records...
...apply to all FDA program areas...
... intended to permit the widest possible use
of electronic technology, compatible with
FDA's... responsibility to promote and
protect public health...
Regulation: 21 CFR Part 11
...The use of electronic records as well as their
submission to FDA is voluntary...
...docket No. 92S-0251 ... identify specifically
what types of documents or parts of
documents are acceptable for submission in
electronic form without paper records...
...consult with the intended agency receiving
unit for details
Electronic Submission: NDA
Electronic equivalents to paper
Text and CRFs
PDF (Adobe’s portable document format)
organized in specified folders
“Navigate” with bookmarks and hyperlinks
CRTs -- the Data
Version 5 SAS transport SAS Institute (SAS
technical support TS-140.
Business Case: replace CRTs format...open
format published by the -- save trees, already
giving it to the statisticians
Electronic Submission: Guidance
NDA -- Case Report Tabulations
...provide a single transport file for each
dataset. ...
...less than 25MB per file...
...data definition tables ...variable name, a
description of the variable, the type of variable
(e.g., number, character, date), and codes...
derived variables...method of deriving the
variable
Electronic Submission: Guidance
NDA -- Case Report Tabulations
...Variable names are limited to 8 characters...
...Descriptive name up to 32 characters...
...Further recommendations...for each specific
submission type...
...discuss the content of the datasets with the
review division prior to submission.
Appendix 2: Example Content of
Specific Clinical Datasets
The following lists contain suggested data
elements for the individual datasets.
... serve as a starting point for discussion between
you and the review division on the content and
organization of the datasets and, therefore, is not
all inclusive.
... refining these data elements ...
...data needed for each indication varies… specific
information ... at the time of the pre-NDA meeting
or earlier ...
Appendix 2: Example Content of
Specific Clinical Datasets
... programs that you used in your statistical
analysis ... final analysis for principal efficacy
and safety data...placed in the appropriate
subfolder of the crt folder.
...The programs should contain sufficient
detail to allow the reviewer to follow the
logical flow of the program...
Appendix 2: Example Content of
Specific Clinical Datasets
 Demographics
 · Age






· Sex
· Race
· Weight
· Height
· Country
· (Consult the review division
…)
 Inclusion criteria
 · Vary by protocol – consult ...
 Exclusion criteria
 · Vary by protocol – consult ...
 Concomitant medications









· Drug name
· Drug start date
· Drug stop date
· Drug started before study
(yes/no)
· Drug type
· Dose
· Reason for medication
· (Consult the review
division...)
...
Appendix 2: Example Content of
Specific Clinical Datasets
Medical history
Microbiology data
Disposition
Physical examination
Drug exposure
Adverse events
Efficacy results
Vital signs
Human pharmacology
and bioavailability /
bioequivalence data
ECG
Labs
Electronic Submission: CBER
REVISED Guidance for Industry: Providing
Regulatory Submissions to the Center for
Biologics Evaluation and Research (CBER) in
Electronic Format - Biologics Marketing
Applications [Biologics License Application
(BLA), Product License Application (PLA) /
Establishment License Application (ELA) and
New Drug Application (NDA)] 11/12/99
www.fda.gov/cber/guidelines.htm
CDER MAPP 7600.6
Requesting and Accepting Non-Archivable
Electronic Records for New Drug
Applications
…cannot be accepted in lieu of the
archivable electronic record as outlined
in the guidance.
SAS transport file to the EDR.
Mid-Course Review
Regulation: 21 CFR 11
Guidances
General considerations
NDA
CBER
MAPP
www.fda.gov/cder/regulatory/ersr
Regulation
Vs.
Guidance
The Way We Are
Electronic submissions becoming
routine for some
Still dealing with paper for a number of
others
Statistical reviewers caught in the
middle -- CRTs and analysis files
Confusion on both sides
Developing Guidance for e-Standards
Leveraging / observing
Standardizing clinical data
Documenting analyses
Leveraging /Observing
Leveraging is the creation of relationships and/or
formal agreements with others outside the FDA
that will ultimately enhance FDA's ability to meet
its public health mission.
CRADA -- Cooperative Research And
Development Agreement ...appropriate only with
collaborators who will make significant
intellectual contributions.
Observing -- we can look, but we can’t touch
Developing Guidance for e-Standards
Standardizing Clinical Data
Recognized need / advantages
CDISC -- Clinical Data Interchange
Standards Consortium
Agency working group -- guidance
Safety data and patient profiles
Cautionary note
CDISC
CDISC (Clinical Data Interchange
Standards Consortium) -- an open,
multidisciplinary, non-profit organization
committed to the development of industry standards
to support the electronic acquisition, exchange,
submission and archiving of clinical trials data and
metadata for medical and biopharmaceutical product
development.
www.cdisc.org
Ref.:
CDISC
CDISC Goals
 Nearly seamless exchange of data within a company,
between collaborating companies, and with regulatory
agencies – across protocols, companies and compounds
 Effortless archiving of data and metadata for future
review or regulatory audit
 Integration of data from a wide variety of applications
and systems
 Facilitated reviews of regulatory submissions
 Improvements in data quality; ‘cleaner data faster’
Ref.:
CDISC
The CDISC Approach
to Submission Standards
• Follow the lead of the FDA Submission Guidelines
 Consider Regulatory Reviewer(s) as primary customer(s)
• Define basic safety metadata standards to guide
dataset organization -- not rigid structures
 Aim for 80% of domains and 80% of variables
• Use representative examples rather than hard rules
 Allow flexibility for science and sponsor differences
• Start with 12 safety domains; then develop a library
for therapeutic areas over time
• Post standards openly and encourage ongoing input
by all.
Ref.:
CDISC
CDISC: Metadata Description
Specified in Guidelines
 Domain Dataset Name (e.g., DEMO)
 Description (Demographics)
 Location (crt/datasets/1234/demo.xpt)
Metadata model proposes adding Structure
 Defines the key structure and unit of analysis for
a row or observation
 Useful when multiple datasets are needed for the
same clinical domain
 Differentiates crt datasets from redundant
analysis datasets.
Ref.:
CDISC
CDISC Metadata Example:
Dataset Redundancy
 Is the lab value normal? (1 rec/pat/visit/lab test)

Did the lab value change over time? (1 rec/pat/visit)
Ref.:
CDISC
CDISC: Submission Dataset
Definition
Dataset
Description
Location
Structure
Purpose
Keys
Demo
Demographics and
Subject
Characteristics
Concomitant
medication
Demo.xpt
1 Rec/patient
CRT
STUDYID
Conmed. xpt 1 Rec/patient/
medication
CRT
Adverse Events
Adv.xpt
CRT
Conmed
AE
Chem
Chemsum
SUBJID
1 Rec/patient/
STUDYID
SUBJID, MED
STUDYID
adverse event
SUBJID,EVENT
1 Rec/patient/visit/ CRT
measurement
STUDYID
Labs – chemistry
detail
Chem..xpt
Labs – chemistry
summary
Chemsum.xp 1 Rec/patient/visit
t
Analysis
SUBJID, VISIT, LAB
STUDYID, SUBJID,
VISIT
Ref.:
CDISC
CDISC and HL7
The Associate Charter Agreement signed
by HL7 and CDISC calls for the creation
of a Clinical Trials Special Interest
Group (CTSIG) within HL7 that will
convene jointly with representatives
from the existing CDISC Working
Teams.
Ref.:
CDISC
Developing Guidance for e-Standards
Documenting Analyses: Analysis
Dataset Models (AdaM)
DRAFT: Guidelines for the Creation of
Analysis Files and Associated
Documentation for Submission to the FDA
PURPOSE: 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 objectives
Ref.:
CDISC
eIND, eCTD and CTOC
eIND -- electronic Investigational New
Drug
CBER Pilot
eCTD -- electronic Common Technical
Document
CTOC -- Cumulative Table of Contents
XML
Pilots
Other Data-Related Issues
Too much data?
Oncology clinical trials
The right data?
Quality Assurance
Safety
Non-clinical data?
Carcinogenicity
Stability
Too Much Data?
Thinking Parsimoniously
A Proposal for Oncology Trial Data
Draft Guidance:
Cancer Drug and Biological Products —
Clinical Data in Marketing Applications
Contact: Grant Williams, CDER
www.fda.gov/cder/guidance/3983dft.htm
Too Much Data?
Thinking Parsimoniously
A Proposal for Oncology Trial Data
Investigator to sponsor: “Why all these data?”
Answer:
“FDA might want it.”
Sponsor to FDA: “How much data do you need?
Answer: “Good question, we’ve never been asked.”
Grant Williams, May 2001
Too Much Data?
Oncology Proposal
“The Agency recognizes that the collection,
quality control, and entry of data in a
database is an expensive and timeconsuming process…In fact, many of these
data may not be called for in a marketing
application for therapy…We therefore
encourage discussion of specific data
requirements at end-of-phase-2 meetings to
minimize unnecessary data collection”
Draft Guidance for Industry: Cancer Drug and Biological Products
-- Clinical Data in Marketing Applications
Too Much Data?
Benefits of data reduction
Decrease cost
Increase numbers of patients in trials
Improve quality of important data
Decrease audit citations
Grant Williams, May 2001
The Right Data
Quality Assurance
Safety
The Right Data?
Metrics for Data Monitoring and
Data Management -- A Proposal
Extremely difficult during review to assess the
impact of data monitoring and data management
on the reported results of the trial.
May lead to inefficiencies in the review process
Government trial experiences -- time was spent
thinking and worrying about this issue
The Right Data?
Describing Data Monitoring and Management
Sample “Confidence Codes”
I
Empty field --
imputed value
E
Empty field --
filled-in after check with source
documents / investigator
C
Failed edit check -- confirmed as actual value
R
Failed edit check -- value was replaced when checked
against source documents/investigator
P
Failed edit check --
suspicious and not able to confirm as
correct / retained
S
Failed edit check --
not able to confirm / imputed
The Right Data?
Describing Data Monitoring and Management
STUDYID SITEID INVID USUBJID TRTCD FILENAME VARNAME ORIGVAL FINVAL CONFCODE PROCESS
ST014
12 H54321
12
1 MEDHIST1
VISITDY
12/18/98
C
DM
ST014
12 H54321
12
1 MEDHIST1 MHBODSYS
PULM
I
DM
ST014
12 H54321
15
2
AE1
AESTDT
1/4/99
E
MON
ST014
12 H54321
15
2 MEDHIST1
VISITDY 10/2/98 10/12/98
R
MON
ST014
12 H54321
25
2
DEMO1
WEIGHT
55
121
R
DM
ST014
12 H54321
29
3
DEMO1
HEIGHT
96
96
C
DM
ST014
12 H54321
32
1
AE1
AESEV SEVERE
MILD
R
MON
ST014
12 H54321
33
2
PE1
PEREAS
BE
SR
R
DM
ST014
22 Q55626
2
2
PE1
PESTAT
ABN
NRM
R
MON
ST014
22 Q55626
6
1 MEDHIST1 MHBODSYS
CARD
E
DM
ST014
22 Q55626
20
1
PE1
PESTAT
ABN
NRM
R
MON
ST014
26 W33445
13
3
AE1
AESTTM
12:00
12:00
P
DM
ST014
36 F62341
12
1
PE1 PEACTDY
4/2/99
E
DM
ST014
36 F62341
14
2
DEMO1 DMACTDT 10/4/98 10/4/98
C
DM
ST014
36 F62341
14
2
PE1
PESTAT
NE
E
DM
ST014
38 N34598
20
1
AE1
AESTTM
20:00
I
DM
ST014
38 N34598
24
3
AE1
AESEV SEVERE
MILD
R
MON
ST014
38 N34598
32
2 MEDHIST1
VISITDY
9/6/98 10/11/98
R
MON
Non-Clinical Data?
Carcinogenicity
Stability
Carcinogenicity
NDA Electronic Submission Guidance:
Appendix 1: Example Nonclinical
Pharmacology AndToxicology Datasets And
Data Elements
Guidance for Industry: Statistical Aspects
of the Design, Analysis, and Interpretation
of Chronic Rodent Carcinogenicity Studies
of Pharmaceuticals
www.fda.gov/cder/guidance/815dft.pdf
Electronic Submissions -- Data Repository -- Review Tools
Esub Submission
metadata
Documents
Product
information
Investigator Clinical
Information trials
Drug
registration
and listing
EDR Submission
metadata
Clinical
data
Nonclinical
Clinical
Data
metadata
Documents
Data
repository
Product
information
Admin
Investigator
Metadata
Listing
Clinical
trials
Site
Review
environment
COTS
tools
Admin
viewer
CTOC
viewer
Nonclinical
data
Document
viewer
Stability
data
viewer
From Randy Levin, CDER, FDA
Dataset
viewer
PI
viewer
Metadata
viewer
Investigator
viewer
Listing
viewer
Site
viewer
Clinical
trial
viewer
CA tool
Profile
viewer
PK tool
Bioequivalence
tool
THANK YOU
[email protected]
301 827-5583