4/28/2015

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Joel Finkle

Advisor, Emerging Practices

CSC Life Sciences BPS

Steps to RPS Adoption

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What are the Steps?

Understand how we got here

Issue Implementation Guides

Build Compliant Tools

Build 2-Way Communication Infrastructure

Benefit from the improvements

eCTD 4 History

You may ask yourself,

“Well, how did I get here?”

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History

RPS Release 1

• Approved, Ignored

RPS Release 2 Iterations

• Slowly closed on the requirements

RPS Release 2 Normative

• Fall 2014 Approval at HL7

HL7 Remaining Tasks

File Normative ballot resolutions with ANSI

Start ISO process – 12-18 months

• Originally required for EU and Japan to participate

• Decision at ICH to proceed without ISO

• Will happen eventually

Implementation Guide

• Doesn’t say how to make a submission

• Only how to make implementation guides that say

how to make a submission

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ICH Remaining Tasks

Implementation Guide

• Currently in Step 2 Draft

Master Set of Context of Use Codes

Internationally-Controlled Vocabularies

Regional Tasks

Restrictions/Additions to ICH lists

Vocabularies for

• Application Types

• Submission (Regulatory Activity) Types

• Submission Unit (Sequence) Types

• Other Region-Specific Codes

Set up 2-Way Communications

• Technology

• Business Processes

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Current Status

Consultation Phase for Draft Guidance

• ICH

• US, EU, Japan

Some problems in guides

• ‘Leftovers’ from earlier editions of RPS (EU)

• Possible misinterpretation of how to assign content to specific

countries/agencies (EU)

• Can’t change content and metadata at once? (ICH)

• Not enough detail on 2-way communications (US, EU)

• English translation of Japanese guide just arrived (JP)

Where to find drafts?

ICH:• http://www.ich.org/products/electronic-standards.html

EU:• http://esubmission.ema.europa.eu/eCTD%20NMV/eCTD.html

US:• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/

FormsSubmissionRequirements/ElectronicSubmissions/ucm309911.htm

JP: • http://www.pmda.go.jp/int-activities/

int-harmony/ich/0004.html

Consultation periods end May 22

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Who else can play?

Other Countries for Drug Submissions

• ICH “Observers” just need an implementation guide

• Other formats (ASEAN, etc.) can be adopted from

RPS but would benefit from eCTD 4’s work

Non-drug submissions can have different rules

• IMDRF for devices

• No sequence numbers

• Allows multiple Submission Units per message

• Tobacco

• Veterinary

Implementation Guides

You are the reason

I've been waiting so long

Somebody holds the key

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Implementation Guide Tasks

For HL7

• How to create specific implementations

For ICH

• How to reproduce the CTD in RPS

For Authorities

• How to deliver each submission type

For Sponsors and their Vendors

• Figure out what it all means!

The Vocabulary Stack

ISO/HL7: Countries, Languages, Status Codes

ICH: Context of Use, Keywords, Species, RoA, Duration, Submission Type,

Submission Unit Type

US CDER: More CoU, Keywords, Application

Types, Statuses

Sponsor/MAH: Document & CoU IDs, Study IDs and Names,Product, Substance,

Excipients…

EMA : Similar to US, plus Review Procedure-related, Mode, Territories

Sponsor/MAH: Document & CoU IDs, Study IDs and Names,Product, Substance,

Excipients…

IMDRF, etc.

CDRH

similar to CDER

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Context of Use Codes

ICH Layer

• Covers CTD Modules 2-5

• Should there be suggested ‘universal’ Module 1 items?

Regional Layer

• Covers CTD Module 1

• Additional M2-5 items?

• Removal of certain M2-5 items?

Submission-specific Layer?

• Additional restrictions on the region’s set

• Example: No Summary of Efficacy on an IND or CTA

• Example: Only cover letter, label on labeling submissions

Standards-Based Controlled Vocabularies

HL7 standards determine basic wiring

• Status Codes

• Actions such as New, Delete, Replace, Update

• Types of things such as telecommunications,

organizations

• Confidentiality codes

• Rules: How to create an RPS message

ISO codes for a few things

• Languages

• Countries

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ICH Vocabularies

Context of Use• The Table of Contents

• Does not include Module 1

Keyword Definition Types• Public lists: Species, Route of Administration,

Duration, Type of Control…

• Sponsor lists: Indication, Manufacturer, Study ID…

• Document Type: Like STF file-tag, but many more

Submission Type

Submission Unit Type

Other product types will need their own lists

ICH Rules

Implementation guide specifies which Contexts

get which Keywords

Some items in RPS Standard not to be used

• Example: Document Keywords

“How to” instructions

• Example: changing metadata

“Transition Sequence”

• More on this later

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Local Controlled Vocabularies & Rules

Each region specifies• Unique application, submission, submission unit types

• Additional Context of Use (Module 1)

• Additional Document Type Keywords (labeling, ad/promo)

EU uses• Review Procedure, Procedure Role, Countries, Authorities

to support CP, MRP, DCP

• Submission Mode (Grouped, Workshare)

US uses• Submission unit Categories

• Form Type

• Submitter and Contact categories

• Review Time

Building eCTD 4 Tools

I make all the money, hauling coal by the tonBut when Saturday goes around I'm too tired for havin' fun

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Tools: Updated Submission Compiler

User Experience Mostly Unchanged

“Transition Sequence” to move old applications

Output in New Format

New Life Cycle Options

Grouped Submissions/Workshare Support

More Metadata

User Experience Mostly Unchanged

Deep down, it’s still just a CTD

Same set of documents

Same PDF requirements

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Transition Sequence

How to continue an application from eCTD 3• Roll up all existing eCTD sequences

• Issue new Context of Use IDs

• Reference leaf IDs in Document objects using special ID

Don’t re-send content• Just instructions how to find it

• and how it will be referred to

Vendor community not happy with this idea• Essentially another submission format to support

• Consensus is that the sequence is not needed

• New eCTD 4 sequences can just refer to leafs in the Document object

• Only advantage of Transition is for Agency migration

New Output Format

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Not that complicated

Five Easy Pieces1. Message “wrapper”

and Submission Unit

2. Context of Use

3. Submission (Regulatory Activity) and Application Details including Review and Product

4. Documents

5. Keyword Definitions

New Life Cycle

Documents are Forever, Context Changes

No more Append

• It’s new content

• But related to old content

Granularity Changes

• One document replaces many

• Many documents replace one

Metadata changes

• Update keywords (e.g. manufacturer name)

• Previously must delete and re-add

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Grouping and Sharing

Current tools already have to deal with

• US Bundled Supplements (as of M1 v2.3)

• EU Grouped Variations and Worksharing

eCTD 4 / RPS makes it more consistent

• Specify multiple Regulatory Activities

• (each with its own Sequence within the Application)

• Exclude some content from particular Activities

Later sequences do not have to be grouped

More Metadata

Module 1 or Application Forms data• Countries

• Contacts

• Procedures

• Categorization of • Application

• Regulatory Activity

• Sequence

Review Information• Received from Regulatory Authority

• Product, Ingredients, Status

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Tools: ID Maintenance

Most IDs will be sponsor-specified

maintained by the Submission Compiler

• Application / Submission / Submission Unit

• Context of Use

• Review IDs come from agency

Documents

• Maintain IDs in Submission Compiler?

• Maintain IDs in Repository?

Contacts and Organizations

• Get to know your DUNS Numbers

Challenge: Interpreting RPS

No Hierarchical Structure• Must be poured through a CTD-shaped sieve

Grouped submissions challenging todisplay and navigate

Can’t depend on item order for viewing• Don’t expect a simple Web Style Sheet

• But then, style sheet viewing is only good for single sequences anyway

Order isn’t obvious:• For M3.2.S, typical display groups by

Substance, then by items within 3.2.S

• For 5.3 Clinical Study Reports, no subsidiary Contexts, but group by indications, then study IDs

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Solution: Machine-Readable Implementation Guides

Specifies which code sets• Example: US NDA = ICH + US M1 – IND-specific

Hierarchy Order of Context of Use (parent/child)

Specifies Keyword (metadata) usage

Specifies valid range of values for each type of submission• Application type limits Submission Type, etc.

Validation Rules• Which application/submission/submission unit codes are

appropriate for which submission types

• Cardinality: “Only one cover letter”

• Metadata: “5.3.5.3 Clinical Study Report must have Indication and Study ID”

Alternative: eCTD-only Tool

Hard-code structure

Probably easier for tools vendors to upgrade,

since the eCTD structure already exists

Just translate published items to eCTD 4 and

interpret receipts back into the eCTD viewer

But this means vendors must make new

software for every region, submission type,

industry, etc.

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2-Way Communications

I want to tell you something you've known all along

Don't leave me hangingon the telephone

2-Way Communication: Infrastructure

Current Web Interfaces

• Not set up for returned content

• Not set up for notifications

Will agencies spruce up web interface?

• Need to support email ‘pickup slips’

• Need to support service providers

Sponsor-run servers

• Automatic receipt and routing

• Automatic processing into Submission Management

• Automatic generation of press release!

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2-Way Communication: Tools

Current interfaces based on AS2

• Agency web servers

• Some publishing tools support it directly

XEVMPD uses AS2 for two-way communication

Probably biggest upgrade for eCTD 4 tools

Benefits of eCTD 4 Realized

So, you can go out on the street and take your chances

But if you do, you better do it right

Or you won't feel the benefit

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Return on Investment

Category Sponsor Vendor Regulator

Tool Flexibility ✔ ✔ ✔

Tool Longevity ✔ ✔ ✔

Ability to Make

Corrections to

Metadata

✔ ✔

Improved

Communications✔ ✔

Tool Flexibility

Origin of RPS was for a common tool at FDA

• Support more than just drugs

• No need for unique software for review at any division

• Common file format

A data-driven publishing tool

• Could support devices, veterinary, etc.

• Could support changes to submissions with just a

configuration file

Lower costs for support, licensing, etc. if only one

tool has to be implemented

Justify development costs across multiple industries

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Tool Longevity

If submissions can be updated with a

configuration file…

• Fewer software implementations (benefits sponsor)

• Fewer software patches (benefits vendor)

More effort can be spent on business process,

integrations than just keeping up with the

Regulatory Authorities

Metadata Corrections

Current eCTD 3.2 does not permit changes

• If you’ve mis-typed a Manufacturer name

a. Leave it as-is and mention the error in a cover letter

b. Delete everything in 3.2.S (for example) and re-submit

eCTD 4 just requires an update to each

Context of Use entry using that Keyword

• Specify existing ID

• Specify keyword value with an “Update” code

Also applies to contacts, submission metadata

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Communications

Speed of response• Direct results versus having to wait for letter, fax, etc.

Improved Correspondence• Connection of Questions to Answers is possible

• But not yet part of the implementation

Record of regulatory action helps integrate• Submission Publishing

• Submission Tracking

• Correspondence Management

Implementation Guides need more detail• Life Cycle: Received, Validated, Accepted, Approved

• No ‘How-To’ yet

And if we don’t change?

eCTD 3.x is likely to still be accepted

for years to come

However

• Will competitors beat you to market?

• better communications

• better business processes

• Would you have more upgrades on eCTD 3 software?

Try to see it my wayOnly time will tell if I am right or I am wrongWhile you see it your wayThere's a chance that we may fall apart before too long

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Thank you

Joel Finkle

Advisor, Emerging Practices

CSC Life Sciences BPS

www.linkedin.com/in/joelfinkle

jfinkle@csc.com

@joelfinkle_csc

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