How a Large CRO Has Implemented and Benefitted from CDISC Standards Amy Caison & Jhelum Naik, PPD.

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How a Large CRO Has Implemented and Benefitted from CDISC StandardsAmy Caison & Jhelum Naik, PPD

Challenges of Data Standards

● Implementing Data Standards: A challenging task− Vast and ever increasing− Constantly evolving− Sometimes ambiguous− Continuous training

● For CROs− Every client and their expectations are different− Standards provide a common language− Enable greater focus on the science and less on mundane

data tasks− Organizational standards can support the implementation

of SDTM data standards at each step of the study lifecycle

Data Standards: Carrot and Stick

● Carrot− Regulatory submissions that

are easily interpreted, understood, and navigated by reviewers leading to quicker decisions

− Cost-benefit analysis by Gartner (2009) found greatest return on investment from standards achieved from use of standards throughout the lifecycle of a study

− Enable efficiencies to accomplish more work faster at reduce cost

● Stick− Forthcoming: Statutory

authority to reject non-conforming submissions (PDUFA V)

− Retrospective application of standards often results in greater cost than collecting standardized data from the beginning of a project

Evolution of Standards Implementation

● In the beginning: non-SDTM standards simple mapping

● Implementation of early versions of SDTM as required by sponsors: bespoke programming− Laborious, inefficient

● Development of internal standards for uniform implementation of SDTM across studies

● Generation of tools to support uniform implementation

Maturation of Standards Implementation

● Increase in client requests for SDTM− Each client has its own interpretation drives flexibility in

tools and processes− Emergence of client-specific standards experts from the

larger pool of CDISC experts

● Explosion of engagement with standards− SMEs− Subteams targeting specific tools or processes− Involvement in public review cycles− Active membership on standards committees and

involvement with standards working groups

PPD’s Use of CDISC: Motivation and Benefits

● PPD’s motivation is the same as for the CDISC organization:− Improve time, quality and costs− Allow easier integration of data− Assist regulatory reviewers− Shorten the time to get products to the market

● CDISC was also chosen as PPD’s global standards because:− There was a recognition that regulators would formally request CDISC in the

future− Many of PPD’s clients were also starting to implement CDISC

● PPD has been one of the early adopters which has meant that investment has been made upfront, the benefits though are that we have . . .− Developed our experience− Had time to develop tools to get the job done efficiently− Had time to proactively prepare for future standard releases

Implementation

● Translation of CDISC industry standards by expert groups − Enable ease of use/adoption by project teams at all phases

of a study lifecycle

● Development of tools and processes to support implementation− Includes organizational standards and implementation

guidance

● Ensure adequate and timely project team support and issue/question resolution

● Ensure tools/processes are reviewed and updated as needed when standards evolve

PPD Expert Groups

Industry Standards

Organizational

Standards

Clinical Trial

Industry Standards

Dissemination and Support

Feedback and Questions

Implementation of CDISC PPD Expert Groups

● Steering Committee − Cross functional committee− Responsible for:

− Creation and dissemination of CDISC information at PPD

− Ensuring PPD is current− Identification of key focus

areas− Oversight for expert groups

and all PPD CDISC activities

● Expert Groups (with relevant subteams) in place:− SDTM− ADaM− eCRTs− aCRF− Validation

Implementation of CDISC PPD Expert Groups

● Development of utilities− SDTM macro suite− eCRT Utility− Extensive use of templates (e.g., CRFs, ADaM, mapping specs, etc.)− Data visualizations and dashboards

● Expert groups support teams− Global training for all Biostatistics & Programming staff

● Face-to-face

● WebEx Recordings

● Mentoring on projects

− Support lines for each expert group for rapid issue resolution

● All committees and groups have a responsibility to stay current:− Flag need for utility or material updates− Continue to enhance and develop all utilities and material− Share knowledge across company

Implementation of CDISC Tools & Processes

● Utilities, Templates, & Tools− Effort to do as much as we can with automated tools without losing the

flexibility being a CRO requires− Emphasis is on application of core principles with room for study-specific

adaptation if needed● Example: SDTM spec creation tool

− Creates a spec based on the data that includes the standard SDTM version-specific variables in each domain

− Can programmatically substitute standard SDTM version-specific variables with client-specific variables for each domain

− Modular components, strive to avoid the “black-box”● Programmers have the flexibility to apply only that which is needed/useful for any given

− The standards provide the scaffolding which can be adapted to fit the study design

Implementation of CDISC Tools & Processes

Benefits

● Facilitates training and resource deployment− Learn the standards, tools, and you can work on any study

for any client who uses CDISC-based standards− Dialects of standards

● We may all speak the same language, just somewhat different versions of that same language− “British English” v. “American English” − Myth of “Standard English” = myth of “Standard SDTM”− “Standard SDTM” v. “xSDTM” v. “ySDTM” v. “zSDTM”− Allows for focus on differences, not the totality of each standard

− Less of a learning curve, client to client− Enables focus on content, big picture, rather than minutiae

of technical standards application

Benefits

● Standards facilitate quality− Required, expected, and permissible variable attributes

● easily/quickly identify data or programming issues● Required SDTM variables with missing values obviously point to

an issue

− OpenCDISC validator can enhance independent validation and improve quality

− Familiarity with standards issue investigation can be quickly focused and typical known causes can be quickly explored

Benefits

● More efficient work processes− Tools, utilities, and templates can automate many tedious,

time consuming tasks● Creating hyperlinks in eCRTs● Setting variable attributes in SDTM● Developing specs● Copying specs from one study to another similar study● Applying client standards structures● creating common/typical table shells (particularly safety)

Benefits

● Ensure precision, uniform implementation, and quicker development− Macros which perform common/standard functions across

datasets● Creating supplemental qualifier datasets● Implementing standard algorithms (e.g., xxSEQ, xxDY, xxSTDY)

where a fixed algorithm can be applied to multiple domains● Applying labels● Ordering variables within a domain● Assigning variable lengths

Benefits

● Project Management Trilemma: “Fast, Cheap, Good – pick any 2” is the standard line− You can pick all 3 with mature implementation of data

standards● Can do more work with fewer resources in shorter periods of

time without sacrificing quality if standards are utilized● Template programs and/or macros for ADaM and TLFs can be

developed that make use of expected variable names● Increases the power of copy-over efficiencies● Can undertake projects which would not have been possible

prior to data standards

● If repeatability is planned for, greater and greater efficiencies can be realized

Case Study: Multi-Study Program

● Four long-term Phase III studies with staggered enrollments (with respect to each study)− Similar protocols, estimated 2% difference across studies− Standards applies to all phases of the project lifecycle

● Use of similar vendors providing standardized data structures● Identical CRF setup (except for protocol-specific differences)

− Staggered start lessons learned are relevant to latter studies enabling course corrections to improve performance

● Standards facilitate client communication and understanding− Common language− Improved communication and understanding between the

CRO and the sponsor

● Standards at all stages increase efficiencies− Consistent CRFs across protocols− Vendor data transfer specifications− SDTM standards− Enabled significant efficiencies for following studies after

initial development

● Standards can positively affect resource utilization− Two programmers were assigned to lead four studies

● Never more than 3 support programmers at any given time− Reliance on standards meant quicker implementation by experienced

staff− Net reduction in total number of individuals working on such a large

and complex multi-protocol program− Issues from one study and their resolutions were easily transferred to

other studies since communication is more efficient in smaller teams− Sponsor teams were similarly small and consistent− Results in a collaborative, cohesive team that worked well together

● Standards apply to processes as well− All four studies had critical interim locks which were back-

to-back● Study 1 lock + 30 days = study 2 lock, etc.● Team faced challenges during first lock

− Rapidly generated lessons learned document− Communicated issues through team− Safeguards enacted across other studies− Remaining 3 studies enjoyed lock/turn-around in record time

● Benefits− Client reception

● 2 additional projects awarded outside of the program ● Strong performance would not have been possible without

leveraging of standards throughout the project

− Subsequent out-of-program projects benefitted significantly from multi-study program● Easy to program since standards were still used● Significant team experience and familiarity ensured success

− Increased client trust− Continued strong performance resulted in bolus of

additional awards from this client

Case Study: Fast & Furious

● 100+ to 70+ safety and efficacy tables supporting academic conference submissions and publications, depending on protocol

● Repeats on multiple protocols● Short notice, short turn-around● Development of standard shells

− Standard ADaM specs − Program & validation copy-over efficiencies: ADaM &

Tables− 4 deliveries of different protocols in 6 months− Enables concurrent development, streamlined revision

Case Study: Fast & Furious

● Repeat project implementation then becomes:− Copy shells/specs− Grab new data (SDTM)− Do an initial run of the ADaM to see what, if anything falls

out− Generally minor tweaks to address any data-driven issues− Run of table programs/validations to see baseline status− Generally minor tweaks to address any data-driven issues− Senior review− Delivery, often ahead of timelines

● All possible because of data standards

Impact of Standards Proliferation

● Resource/timeline constraints determined to be not related to any standards-oriented task− Business-oriented details

● Budget and contract approval● Receipt of client materials

− Resource availability for senior and statistical review− Efficiencies are not unlimited; standards can only do so

Impact of Standards Proliferation

● Broad-based standards increasing capacities for CROs more complex and numerous studies− Results in greater project management requirements

● Ensure consistent standards implementation● Coordinate resources● Manage budgets and client communications

− Leads to changing roles/responsibilities for programmers and statisticians

Summary

● Evolution and maturation of standards● Implementation

− Expert Groups (main driver)− Tools & Processes

● Benefits● Case studies

− Long-term, multi-protocol comprehensive program− Targeted post hoc analyses, repeated across multiple

protocols

● Impact of standards− Still a limit to efficiencies− Change in roles and responsibilities

Questions?

Copyright, 2012 by Pharmaceutical Product Development, LLC ("PPD"). All rights reserved. This presentation, including the information contained herein and commentary associated herewith ("materials"), is provided as a service of PPD. These Materials, based on publicly available information as well as the knowledge and experience of PPD's employees, have been prepared solely for informational and educational purposes and should not be relied upon for professional advice. Any further use of these Materials requires the expresswritten consent of PPD.

Copyright, 2014 by Pharmaceutical Product Development, LLC ("PPD"). This presentation, including the information contained herein and any associated commentary, ("Materials") is provided as a service of PPD. These Materials are based on publicly available information as well as the knowledge and experience of PPD's employees at time of drafting; however future accuracy cannot be guaranteed. As such, these Materials should not be solely relied upon without, or used as a substitute for, future consultation with PPD. Any further use of these Materials requires the express written consent of PPD.

How a Large CRO Has Implemented and Benefitted from CDISC Standards Amy Caison & Jhelum Naik, PPD.

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