NonLinear Mixed Effects Consortium

1
NonLinear Mixed Effects Consortium

• Consortium Activities and Objectives
• 15th November 2007

2
Objectives of the NLMEc

• Enable and facilitate the development of MS
  methodologies and software tools that meet
  pharmaceutical industry requirements
• Define and gain wide acceptance for a complete
  User Requirements Specification (URS)
• A comprehensive common standards that enable the
  storage and machine-to-machine interchange of
  data, models and related metadata in the area of
  pharmacometrics
• An interoperable framework system that allows
  seamless interaction between the various software
  tools that are currently used in isolation of
  each other
• An increasingly growing membership of
  pharmaceutical companies that are aligned with
  the goals of the consortium

3
NLME Consortium Achievements to date

• Published high level User Requirements
  Specification (December 2006)
• Published detailed User Requirements
  Specifications (April 2007)
• Consulted with multiple providers/experts in
  Paris during June 2007
• Discussed various approaches to achieving the
  capabilities set out in the detailed URS. The
  attendees included
• Monolix Mango Solutions
• Pharsight Uppsala University
• Insightful RFPK
• The Mathworks ICON
• Approached CDISC with to consider a collaboration
  in creating standards for Modelling and
  Simulation
• The NLMEc are committed to integrating with the
  CDISC framework
• CDISC board are very interested in working with
  the NLMEc.
• The NLMEc has Presented at PAGE, PKUK
• On the Agenda to present at AAPS and ACoP in 2008

4
URS

• The URS represents a wish to unite three major
  functionalities in one system
• Model Estimation
• Model Interpretation including graphics package
• Trial Simulation
• The three modules to be fully integrated
• Share data
• Share models
• The URS documents are published on the NLME
  Consortium forum http//nlme.org/smf/index.php?to
  pic7.0

5
URS Overall Workflow
Entire workflow to be encapsulated in one system
6
Concept of Interoperability Framework
NLME Framework
Universal Model Reader
Universal Data file reader
models
Data Files
Simple User Interface Workflow Management Traceabi
lity (on/off) Model/Data input Validation Scriptin
g Capability Output Reports Graphical Displays
NLME Interoperability Engine
Monolix Module
S-Plus Module
S-Plus
Monolix
NONMEM Module
BUGS Module
NONMEM
BUGS
Any system can be incorporated into the framework
as a module (i.e. NPEM, R, S, PopED, SPK, etc)
7
NLMEc Roadmap

• To achieve the remaining stated objectives, the
  NLMEc has devised a roadmap for the activities
  that need to be completed in pursuit of those
  objectives
• This roadmap is diagrammatically illustrated on
  the next slide, and the plans for each Track
  shown on the roadmap is discussed in more detail
  on the following slides

8
NLME Consortium Plan
PoC Defined
PoC Process Vendor Faciliation
PoC Review
PoC Launched
PoC Presentations
Go/No Go Decision
Standards Definition - Initial draft for
Publication
Manage Feedback
Working Group Formed
Standards v1.0 Published
Standards Refined
Integration with CDISC
Advisory Board Set up
Standards v2.0
Interest?
Work with interested parties to secure membership
Invitation sent
Potential New Member Orientation
Formalise Agenda
Secure Speakers
Agenda Set
Send Invitations
Prepare for Symposium
Hold Symposium
9
Track 1 Proof of ConceptCurrent Situation

• In Parallel to the URS and Standards work, the
  NLMEc is also embarking on a Proof of Concept for
  the Framework approach. The Objective is to
• Confirm the viability of the Framework as a
  software tool base
• Enable the consolidation of independent modules
  onto one platform
• Use eXtensible Markup Language (XML) as a
  standard format for models, data and documents.
• Complete by February 2008

10
Proof of Concept
Data
Model
Can possibly use CDISC XML definitions for the
data
Can possibly use RFPK or PopED XML definitions
for the model

• Proof of concept Step 1
• Using an existing or a custom set of XML
  definitions, translate the data and model files
  associated with modelling and simulation into an
  XML file

11
Proof of Concept
Data
Model
XML Reader For Monolix
XML Reader For NONMEM
Monolix
NONMEM

• Proof of concept Step 2
• Using the output of Step 1 (Model and Data file
  XML definitions), create a mechanism for reading
  the XML data into at least 2 existing software
  systems (NONMEM and Monolix are examples). Both
  XML files must be read.

12
Proof of Concept
Data
Model
XML Reader For Monolix
XML Reader For NONMEM
NONMEM Output
Monolix
Monolix Output
NONMEM
XML Reader For NLME

• Proof of concept Step 3
• After successfully running the model in the
  chosen tool, convert the output to an XML format
  and develop a mechanism to generate output
  reports and graphical displays

test simulation rresults
Output Reports
Graphical Displays
13
Proof of Concept Post April 2008 Activities

• The NLMEc is engaged with a number of
  software/service providers who are participating
  in the PoC
• Once the Proof of Concept process is complete,
  the consortium will decide on a direction based
  on the outcome. Outcomes include
• No successful PoC
• Re-evaluation of the URS and approach to the
  development of Software
• One or more Successful PoCs
• Present successful PoCs at a Symposium in April
  2008
• Tender a Request for Proposal
• Set up the Consortium as a formal organisation
  with legal status and source of funding secured
• Sponsor development

14
Track 2 StandardsThe Current Situation

• The consortium has realised a unique opportunity
  to define standards for model and data definition
  which would enable users to migrate these between
  different software systems
• The NLMEc has formed a small and focused working
  group on Standards
• This working group will focus on the development
  of a common standard for the storage and
  machine-to-machine interchange of data, models
  and related metadata in the area of
  pharmacometrics.
• In Parallel the NLMEc has been in discussion with
  CDISC to see how we could best integrate the NLME
  effort within the overall CDISC framework.

15
Track 2 CDISCCurrent Situation

• The consortium is in discussion with CDISC to
  create a working group to join the efforts of the
  NLMEc with CDISC
• The Consortium propose the formation of a CDISC
  working group for Modelling and Simulation
  standards
• CDISC are interested in a collaboration, having
  discussed the NLMEc at board level
• The NLMEc are developing an action plan,
  strategy, and milestones to ensure this high
  priority initiative is achieved as soon as
  possible.

16
Track 2 CDISCNext Steps

• The Consortium will continue discussions with
  with CDISC on forming a Modelling and Simulations
  working group
• It will then be possible to utilize the CDISC
  methodology and infrastructure to further define
  MS standards
• Merging into the CDISC framework will provide the
  NLMEc standards with affiliation to generally
  accepted existing standards and will allow
  greater integration with related standards.

17
Track 2 StandardsNext Steps

• As a priority the NLMEc Standards Working Group
  will first focus on system-to-system language
  standards (similar to CDISC for clinical data)
• Once the common standard for data storage and
  interchange is adequately established, an XML
  model definition language will be developed
• The NLMEc will then look for feedback from
  industry, vendors, academia, and other such
  groups to review and feedback whether the
  standards proposed encompass all the critical
  elements that need to be defined

18
Track 3 New MembersCurrent Situation

• The NLME has currently 5 Members, with a 6th
  pending
• GSK, Novartis, Novo Nordisk, Pfizer, Servier
• Eli Lilly has committed to join
• The NLMEc is committed to transparency and
  inclusiveness.
• Currently inviting new corporate members
• Meetings - one day a month
• Annual fee covering project management
• Non Corporate interested parties will be invited
  to participate in advisory boards and working
  groups
• This will effectively be a non corporate
  membership, where no fee is charged for
  participation

19
Track 3 New MembersNext Steps

• Companies are welcome to join the consortium
• Members of the consortium have contacted known
  industry peers and explain the activities and
  objectives of the consortium
• In Addition, a general Invitation to join has
  been published
• Potential new members were invited to a NLME
  Consortium meeting to discuss the Consortium in
  more detail (Barcelona, 26-Nov-2007)
• The NLMEc will invite non-corporate membership
  for academia and others in the near future (2008)

20
Track 4 SymposiumCurrent Situation

• The NLMEc plans to hold a Symposium in April 2008
• The purpose of this Symposium includes
• Open forum for industry, academic, regulatory,
  software providers, and service providers to
  discuss progress of the NLMEc
• Opportunity for attendees to view Proof of
  Concept software demonstrations
• Discuss Progress on standards and gauge whether
  there is acceptance of the initiative
• Discuss the further plans of the NLMEc

21
Track 4 SymposiumNext Steps

• The Agenda for the Symposium has been drafted
• Potential Speakers from the FDA and CDISC are
  being contacted
• Invitations will be sent to all known interested
  parties, as well as all those signed up on the
  NLMEc Forum
• The Symposium location and venue will be selected
  and plans for the symposium finalized
• A full list of attendees and materials for the
  symposium will be published prior to the start
• It is anticipated the symposium be a one day
  event
• The cost of the symposium will be shared between
  the participants

22
Other information about the NLMEc
23
How the Consortium is currently set up

• Legal
• The Consortium is run as a group of companies
• There is no consortium agreement in place at this
  time
• Costs
• Each member company contributes towards the cost
  of a project manager
• Currently cost approx 45k EUR / 30k GBP per
  annum
• Each member company sends a representative to a
  monthly Consortium Meeting

24
Consortium Operation

• The representatives at each monthly meeting make
  joint decisions about the direction and
  priorities of the Consortium
• Individual members volunteer to undertake various
  activities, such as update sections of a document
  or do some required research

25
Frequently Asked Questions

• Why did the NLMEc form?
• The consortium is concerned with the progress of
  standards, methodologies and tools within the MS
  field. The current technical landscape is
  lacking in many ways and the NLMEc sees the best
  way of addressing this as collaborating with
  industry partners to help drive the advances and
  changes needed to arrive at a situation where MS
  departments have state of the art tools and a
  stable and integrated environment in which to work

26
Frequently Asked Questions

• How will the consortium handle commercial aspects
  of this undertaking?
• The consortium has not yet decided whether it
  will be funding any initiatives at all. This
  will depend on a number of factors and will be
  evaluated at the appropriate time.
• A number of options are open to the consortium
  should all members agree that a joint funding
  initiative should be undertaken, and any new
  arrangements will be fully approved by each
  companies legal department.