Workshop on Electronic Submissions of Biologics: eCRFseCRTs and the eBLA, ePLAELA

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Workshop on Electronic Submissions of Biologics
eCRFs/eCRTs and the eBLA, ePLA/ELA

• Mary A. Buesing, M.D.
• CBER, FDA
• May 22, 1998

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Agenda

• Important milestones
• Organization content of an eBLA
• CRTs
• CRFs
• roadmap.pdf
• readme.pdf
• cover.pdf
• Demo

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Important preparation milestones

• Ideally 8-10 months before submission notify an
  offices CALA coordinator
• 4-6 months ahead of time, plan to demo the
  submission structure, content and navigational
  capability
• 30 days - provide a mock-up version for testing
  on the network
• on day of submission provide all of the
  certifications and cover.pdf information

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Critical success factors

• Simultaneous receipt of paper and electronic
  portions
• still a major problem due to underestimations of
  the time needed to put together a PDF CALA
• A fully navigational, viewable and printable
  submission
• CBER recommends that you test these features
  using our DSP standards before submission
• Limit scanned documents submitted (e.g.
  CRFs,pubs,C.V.s)

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Organizational Structure

• Harmonized form 356h backbone of the
  e-submission
• for the eBLA embed 356h in a pdf file under
  cover.pdf
• for ePLA embed the appropriate licensed
  application form - eg 3212 for a vaccine
• until regs change and everything becomes a BLA
• for eELA embed a filled out 3210 as pdf file(s),
  or use the guidance - item 15

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19 Subsections of the Harmonized form 356h

• 10. Statistical Section
• 11. Case Report Tabulations
• 12. Case Report Forms
• 13. Patent information
• 14. Patent certification
• 15. Establishment Description
• 16. Debarment certification
• 17. Field copy certification
• 18. User fee cover sheet
• 19. Other (specify)

• 1. Index
• 2. Labeling
• 3. Summary
• 4. CMC
• 5. Nonclinical Pharmacology
• 6. Human Pharmacokinetics
• 7. Clinical Microbiology
• 8. Clinical Data
• 9. Safety Data Update

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Folder or pdf file names corresponding to each
item

• clinical
• update
• stats
• safety
• crt
• crf

• labeling
• summary
• cmc
• pharmtox
• cpbio
• micro

• estab
• patinfo.pdf
• patcert.pdf
• userfee.pdf

Exceptions items 13,14,16 amd 18 are pdf files
and do not need folders. Item 17 -field copy
certificaton is not applicable
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The BLA or PLA/ELA is a collection of individual
documents

• Convert each document to a PDF file
• Place all files for each item into its
  appropriate folder

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Organizing the folders

• Please label the folders to facilitate
  easy identification for downloading of
  files from the network

10
The BLA or PLA/ELA is a collection of individual
documents

• Place all folders into a main folder with the
  submissions number

B000000 (or I000000) Amendments B0000000.001
thru B0000000.999
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Each items folder may contain

• Subfolders
• The item PDF files
• A table of contents file
• An index (PDX) file

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Each items folder includes a TOC

• Hypertext linked to each subfolders content pdf
  files
• It includes the location of the file

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and may include bookmarks...

• If the pdf files are large they may also contain
  bookmarks for easy navigation - eg batch records
  often require bookmarks
• If some of the items material is in paper,
  include the location of the paper by volume
  number if possible

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Example
Item folder
CMC
CMCtoc.pdf
CMC.pdx
substan
product
invest
enviro
batch
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e-TOC includes

• BLA TOC
• located in the main folder
• lists all items in the e-submission
• hypertext links to each items TOC
• Items TOC
• located in the items folder
• lists all documents in the items folder
• hypertext links to each document
• Documents TOC
• located in the documents PDF file
• lists all sections/subsections
• bookmarks link to the sections

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For each document provide hypertext links to

• annotations
• related sections
• references
• appendices
• tables
• figures
• embedded forms

Note Please do not try to use hypertext linking
across CD-ROMs
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For large technical sections include a text index
(pdx) file

• An index is not a table of contents but provides
  a search function
• Index all file text and document information
  fields
• An Index consists of an index file (PDX) and
  associated files contained in a single folder

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Identify the document in the PDF Document
Information Title Field
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eCRTs

• Can be provided in 2 types of formats
• Domain profiles
• Patient profiles

Please consult with the product office
re preferences for submisison
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eCRTs- domain

• Also known as data listings
• Consist of all data for a CRF domain
• such as demographics, vital signs, labs, etc
• Provide a table for each CRF domain
• display the variables as column headings
• results per patient per row

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eCRTs - domain

• Provide a single PDF file for each CRF domain
• All domain profiles for a single study should be
  placed in a subfolder identified with the study
  number
• Place all subfolders within a single folder
  domain

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eCRTs - domain

• A table should be provided for each CRF domain
  that displays variables as column headings and
  results for each patient in rows
• Datasets can be submitted in lieu of PDF files if
  reviewing office agrees
• submitted as SAS Transport files under the
  statistical section

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eCRTs - domain

• The title field of the document information field
  for adverse events in study 2001 would be
• dp, study 2001, adverse events

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eCRTs - patient profiles

• Consist of one or more pages that contain all of
  the study data collected for an individual
  patient
• A table should be included for each CRF domain
  for each patient - such as vital signs,
  demographics, labs, efficacy measures
• the organization of tables should be oragnized by
  time and consistent across domains and patients

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eCRTs - patient profiles

• 3 approaches depending on size and navigational
  function
• each patients profile can be provided as a
  single PDF file
• all patient profiles for a single site in one
  file
• all patient profiles for a study in one file
• place all study subfolders into a folder named
  crt

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eCRTs - patient profiles

• The title field of the document information field
  for patient 001 in study 2001 at site 003 would
  be
• pp, study 2001, site 003, PID 2001-003-001

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crt
domain
dptoc.pdf
domain.pdx
Aes.pdf labs.pdf vs.pdf include.pdf exclude.pdf co
nmeds.pdf
study 2001
site 3
site 1234
profile
pptoc.pdf
profile.pdx
study 2001
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eCRFs

• Usually scanned documents
• use 300-600 dpi
• make sure they are legible printable
• please test these on computers with CBERs
  current DSP settings (800 x 600)
• Each patients CRF should be provided as a single
  PDF file, or if small (usually 50 MB) place all
  patients CRFs per site/study as a single folder
• All CRFs for a single site should be placed in a
  subfolder with the site number within the study
  folder

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eCRFs

• Each patients CRF should provide a bookmark link
  to each study visit with each CRF domain - such
  as demographics, vital signs, labs ,etc
• Alternaitvely, a TOC could be provided as page 1
  of each patients CRF, listing the page location
  of all CRF domains collected at each study visit

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eCRFs

• The title field of the Document Information
  dialogue should contain
• the study number
• the site number
• the unique PID
• For example, for patient 001 in study 2001 at
  site 003 would be entered as
• crf,study2001, site 3, PID 2001-3-1

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eCRFs
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Clinical Study Reports

• One Study One PDF File

study003.pdf
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3 Important Contents of an Application Folder
B9800000
roadmap.pdf
readme.pdf
cover.pdf

• tables 2-5

365h
any certifications
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roadmap.pdf

• Used to establish links between the applications
  main toc (blatoc.pdf) and the respective files
  and folders of the submission
• Also, it is a means of chronologically linking
  subsequent applications to each others
  blatoc.pdf files thereby, creating a growing toc
  for all components of the submission

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roadmap.pdf

• It is unique for every submission
• It is replaced/updated using the replace file
  command under Document menu option
• see Table 1 of the guidance document

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readme.pdf

• contains directions for installing, configuring
  and navigating through the submission
• the roadmap.pdf file and the blatoc.pdf should be
  hypertext linked to the readme.pdf file

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cover.pdf

• A description of the submission
• A table summarizing which portions of the
  submission are in electronic vs. paper format
• A table summarizing the submission size and format

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cover.pdf

• A virus verification table
• A table of a sponsors points of contact
• a completed 356h form
• any certifications

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DEMO