Retrieve Protocol for Execution

Introduction

This is a draft of the Retrieve Protocol for Execution Profile (RPE) supplement to the Quality, Research, and Public Health (QRPH) Technical Framework. This draft is a work in progress, not the official supplement or profile.

Profile Abstract

The Retrieve Protocol for Execution Profile (RPE) provides an automated mechanism for EHR to retreive a complex set of clinical research instructions (or a protocol) from an EDC system to execute within the EHR.

• RFD scenario teams:
  • Sponsors: Pfizer, Lilly, Novartis, Genzyme
  • EHRs: Cerner, Allscripts, Greenway, Epic
  • eClinical: Outcome Sciences, Nextrials, IPL
• Proposal Editor: Landen Bain (CDISC )
• Profile Editors:
  • Diane Wold (Glaxo Smith Klein - Chair of CDISC’s Trial Design Team )
  • Peter Villiers(SAS - developer of ODM extensions to express Schedule of Activities)
  • Daemon Whittenburg (Greenway Medical Technologies)
• Lisa Chatterjee (DIFZ, chair of CDISC’s Protocol Representation team)
• Dan Levy (Outcome Sciences)
• Jane Griffin (Cerner)
• Amar Das (Stanford Professor)

Meeting Notes

• 12/12/08
  • Discussed Detailed Proposal
• 12/19/08
  • Discussed RPE Use Case Graphic
• 01/09/09
  • Discussed RPE Flow Diagram
  • Transactions from Protocol Manager to Protocol Executor when the study changes
    • AmendProtocolDefinition
  • Studies should be versioned
    • Added to Flow Diagram
  • Check study version transaction
    • Is there a todo here?
  • Add enter patient in study transaction (responses: ACK ENTER, ACK ENROLL, ACK INFORM CONSENT). This would happen before the patient is enrolled into a study.
    • Added to Flow Diagram: UpdateProtocolState (XML Message to EnterPatientRequest/ScreenPatientRequest?)
  • Add Prerequisites/Dependencies
    • (patient ran through inclusion/exclusion criteria, patient signed inform consent, labs, documented signed inform consent, screening etc.)
    • Need to define these in more detail
  • Patients get “screen failed” may or may not be entered into EDC
    • This will be a response from the UpdateProtocolState(EnrollPatientRequest) transaction with instructions on next steps (define next steps)
  • List before/after of enroll
    • No idea what i was trying to accomplish here
  • Changed Enroll Patient to EnrollPatientRequest
    • Added to Flow Diagram
  • Determined that only the "UpdateProtocolManager(EnrollProtocolRequest)" Transaction would be worked for the next publication of RPE.
    • Currently the focus as well as documenting the other items involved in the RPE use case
• 01/16/09
  • Agenda
    • Review RPE wiki
    • Define input/output data elements needed for the UpdateProtocolManager(EnrollPatientRequest) transaction
      • Work will be needed form the EDC side in order to define these data elements
    • Discuss XML standards to be used for message parameter supplied in the UpdateProtocolManager transaction
      • Choosing an XML standard cannot happen until we have defined the data elements needed for the transaction
      • Need to also think about other data elements needed for the other options for this "UpdateProtocolManager" transaction
  • Define the difference between Protocol and Protocol State.
    • ProtocolDefinition
    • ProtocolInstance/ProtocolState
    • From the Trial Design Model (TDM) - 1.2 Separation of Concerns: Trial Design vs. Trial Execution?
    • Three have been proposed...will add to agenda for next meeting
      1. ProtocolDocument – aka ProtocolDoc
      2. ProtocolDesign – aka ProtocolDesign
      3. ProtocolDefinition – aka ProtocolDef
    • New name for UpdateProtocolManager based on this decision?
  • Add AmendProtocol transaction from ProtocolManager to ProtocolExecutor
    • Added an AmendProtocolDefinition transaction to the RPE Flow Diagram
  • Add EnterPatient/PatientInScreening transaction
    • Added an UpdateProtocolState(EnterPatientRequest/ScreenPatientRequest) transaction to the RPE Flow Diagram
  • Add FreezePatient transaction
    • Added an AlertProtocolState(FreezePatient, Unfreeze/Thaw, LockPatient/SignOffOnPatient, Unlock) transaction to the RPE Flow Diagram
  • Add LockPatient/SignOffOnPatient transaction
    • patient is done
    • Added an AlertProtocolState(FreezePatient, Unfreeze/Thaw, LockPatient/SignOffOnPatient, Unlock) transaction to the RPE Flow Diagram
  • Add Unfreeze/Thaw transaction
    • Added an AlertProtocolState(FreezePatient, Unfreeze/Thaw, LockPatient/SignOffOnPatient, Unlock) transaction to the RPE Flow Diagram
  • Add UnLock transaction
    • big issue...more auditable
    • Added an AlertProtocolState(FreezePatient, Unfreeze/Thaw, LockPatient/SignOffOnPatient, Unlock) transaction to the RPE Flow Diagram
  • Discussed the need to clarify why we chose to do the one transaction "UpdateProtocolManager(EnrollProtocolRequest)"
    • Seems to be one of the most needed?
    • The content used for the ProtocolDef will come from the Trial Design Model (TDM), which is not complete
    • The "UpdateProtocolManager(EnrollProtocolRequest)" transaction doesn't need the entire ProtocolDef to be functional, just an identifier for the ProtocolDef
• 01/23/09
  • Agenda
    • RPE wiki changes?
    • Review input/output data elements needed for the UpdateProtocolManager(EnrollPatientRequest) transaction
      • Work will be needed form the EDC side in order to define these data elements
    • [To be done after the input/output data elements are defined] Discuss XML standards to be used for message parameter supplied in the UpdateProtocolManager transaction
      • Choosing an XML standard cannot happen until we have defined the data elements needed for the transaction
      • Need to also think about other data elements needed for the other options for this "UpdateProtocolManager" transaction
    • Add Prerequisites/Dependencies
      • (patient ran through inclusion/exclusion criteria, patient signed inform consent, labs, documented signed inform consent, screening etc.)
      • Need to define these in more detail
    • Define the difference between Protocol and Protocol State
      • ProtocolDefinition
      • ProtocolInstance/ProtocolState
      • From the Trial Design Model (TDM) - 1.2 Separation of Concerns: Trial Design vs. Trial Execution?
      • Three have been proposed
        1. ProtocolDocument – aka ProtocolDoc
        2. ProtocolDesign – aka ProtocolDesign
        3. ProtocolDefinition – aka ProtocolDef
      • New name for UpdateProtocolManager based on this decision?

Open Issues

• Similar issues are addressed in the Performance Measurement Data Element Structured for EHR Extraction white paper. What relation does RPE have with quality initiatives?
• How to deal with protocols amendments taken during the study?
• How does RPE relate to RFD. Is RPE essentially a content profile using RFD infrastructure? Or does RFD create new RFD-like transactions.
• How much automation of protocol events is within grasp? How to executable tasks get conveyed to the Protocol Executor (Enabler? Enactor?)
• Find a correct place for (Actions before Protocol Executor agrees to participate - approval from IRB, Form5272 for investigator, training, contract, site signs NDA with pharma company.
• Change "Enroll in Protocol" transaction to be "Agrees to Participate".
• Remove "Review CRFs for data capture and data entry" from Use Case Graphic
• Add transactions for
  • Study changes, schedule is updated, version each study, check study version transaction
  • Protocol Manager Submit Alert to Protocol Executor
  • Schedule visits transaction (needs to be a seperate transaction after EnrollPatient)
• Move "pre-order labs and other assessments" to "Patient Involvement" in use case graphic

Risks

• Cross-system workflow integration is a relatively new area for IHE.
• The EHRs risk encountering the clinical research regulatory environment 21 CFR part 11.

Summary

Many healthcare sites supplement their core patient care activities by participating in clinical trials. Currently, the tasks required for clinical research participation are served by systems entirely separate from the site's EHR. The ITI profile Retrieve Form for Data-capture (RFD), along with its complementary content profile Clinical Research Data-capture, have set a path towards integrating site-based clinical research workflow into the task manager of an electronic health record. This new profile, Retrieve Protocol for Execution, expands the scope of workflow integration between clinical research and EHR systems.

CDISC's Protocol Representation team intends to develop a standard protocol document, derived from the BRIDG, a RIM-linked data model. This protocol representation includes the Trial Design Model a standard structure for representing the planned sequence of events and the treatment plan of a trial. This planned sequence of events includes many tasks that could be executed by an EHR's workflow engine. The 'schedule of activities' section of the trial design includes clinical trial activities such as interventions (e.g., administering drug, surgery) and study administrative activities (e.g,. obtaining informed consent, distributing clinical trial material & diaries, randomization) as well as assessments. The time is ripe to insert these executable workflow tasks into the EHR for execution within the site's normal way of doing business.

State of systems before RPE

State of systems after RPE

The Problem

Research protocols are complex instruction sets that guide the conduct of trials. A subset of the protocol pertains to the activities of the healthcare provider site that participates in the trial. This instruction set specifies the data to be captured, tests to be ordered, inclusion and exclusion criteria for subjects, number and type of visits, etc. These instructions currently reside in hard copy binders which provide guidance for study coordinators at research sites. What is desired is a way to insert protocol instructions into an EHR for automatic completion.

Volume I

Dependencies

• patient inclusion/exclusion criteria
• patient signed inform consent
• labs
• documented signed inform consent
• screening

Use Case - Investigational New Drug Clinical Trial

In the uses cases below, we describe the before and after effects of implementing the Retrieve Protocol for Execution profile.

• The setting for the clinical trial use case is a physicians’ practice where patient care is delivered side-by-side with clinical research.
• The site, Holbin Medical Group, is a multi-site physician practice, employing over 100 physicians in a variety of specialties.
• Holbin’s CEO encourages the physicians to participate as site investigators for pharmaceutical-sponsored clinical trials.

Before Retrieve Protocol for Execution

Preconditions

1. A Clinical Research Protocol is defined by a clinical trials expert.
2. Holbin provides support for clinical research activities in the form of a Research Department of twelve dedicated study coordinators, mostly RNs, along with clerical and data-entry support personnel.
3. Holbin Medical Group uses an Electronic Health Record (EHR) and a number of sponsor-provided Electronic Data Capture (EDC) systems for documenting clinical trial activities.

Use Case

1. Clinical Research Site's Involvement
   1. Holbin’s involvement in a clinical study begins when the Research Department receives a request for proposal (RFP) from PharmaGen, a biopharma research sponsor.
   2. A Study Coordinator, Patricia Zone, RN, evaluates the RFP for business viability and clinical appropriateness, provides the requested documentation back to the sponsor, and agrees to participate
2. Approved as a site for PharmaGen #1234 trial
   1. After being approved as a site for the PharmaGen #1234 trial, the site Holbin Medical Gruop provides the required regulatory documentation to the sponsor
   2. The physician identified as the Principal Investigator and other study personnel receive protocol-specific training from the sponsor, including training in use of the SynerGen EDC system.
3. During the trial set-up period, Patricia takes a number of steps that require interaction with the EHR. At this juncture, searches are at an aggregate level
   1. Ensures that the appropriate system security is in place for this protocol;
   2. Recruits patients to participate as subjects according to inclusion and exclusion criteria described in the study protocol;
   3. Creates a visit type for 1234 patient visits;
   4. Reviews CRFs for data capture and data entry;
   5. Pre-orders labs and other assessments;
   6. Performs all the attendant financial tasks.
4. Following set up, Patricia contacts Corey Jones, a patient at Holbin, about participating in the trial, and Corey agrees to participate as a subject. A number of tasks deal with this individual patient
   1. Register Corey in the EHR as a subject in trial #1234, using the EHR’s patient index.
   2. She also registers Corey as a subject in the EDC system.
   3. She schedules Corey’s study visits using the EHR scheduling module, and flags the visits as pertaining to the trial #1234.
   4. Initiates clinical trial care and trial-specific documentation.

Postconditions

Holbin Medical Group uses an Electronic Health Record (EHR) and the SynerGen EDC Electronic Data Capture (EDC) system to document the PharmaGen #1234 trial activities.

After Retrieve Protocol for Execution

Precondition

1. A Clinical Research Protocol is defined by a clinical trials expert.

Use Case

1. Clinical Research Site's Involvement
   1. ProtocolExecutor uses the RetrieveProtocolList transaction to obtain a list of protocols from the Protocol Manager
   2. ProtocolExecutor uses the AgreesToParticipate transaction to notify ProtocolManager that the site agrees to participate in the study
   3. ProtocolExecutor uses the RetrieveProtocol transaction to obtain the specific protocol from the ProtocolManager
2. Approved as a site for PharmaGen #1234 trial
   1. ProtocolManager uses the SubmitProtocolApproval transaction to the ProtocolExecutor for a specific protocol
   2. ProtocolExecutor uses the SubmitRegulatoryDocumentation transaction to submit required regulatory documentation to the ProtocolManager
3. Trial Setup
   1. ProtocolExecutor uses the UpdateProtocolManager (patient identified) transaction to let the ProtocolManager know that patients have been identified
4. Patient Involvement
   1. ProtocolExecutro uses the UpdateProtocolManager (request enroll patient) transaction to attempt to enroll the patient into the study
   2. ProtocolExecutor uses the UpdateProtocolManager (schedule patient study visits) transaction to update the ProtocolManager that the study visits have been scheduled

Postcondition

Holbin Medical Group uses an Electronic Health Record (EHR) to document the PharmaGen #1234 trial activities using RFD.

Process/Flow

The flow of transactions between the ProtocolManager and ProtocolExecutor

Actors

• Protocol Executor
  • An entity wanting to access clinical research protocols from a seperate entity that manages clinical research protocols.
  • An example would be an EHR vendor that wants to participate in clinical studies by accessing clinical research protocols.
• Protocol Manager
  • An entity that manages clinical research protocols.
  • An example would be an EDC vendor that wishes to allow access to the list of clinical research protocols contained within the EDC system.

Transactions

• RetrieveProtocolList
  • ProtocolExecutor RetrieveProtocolList ProtocolManager (ProtocolManager PublishProtocol ProtocolExecutor???)
• AgreeToParticipateInProtocol
  • ProtocolExecutor AgreeToParticipateInProtocol ProtocolManager
• RetreiveProtocol
  • ProtocolExecutor RetreiveProtocol ProtocolManager
• SubmitProtocolApproval
  • ProtocolManager SubmitProtocolApproval ProtocolExecutor (ProtocolExecutor RetrieveProtocolApproval ProtocolManager???)
• SubmitProtocolDocumentation
  • ProtocolExecutor SubmitProtocolDocumentation ProtocolManager (maybe use EnrollProtocolRequest?? / UpdateProtocolManager??)
• SubmitRegulatoryDocumentation
  • ProtocolExecutor SubmitRegulatoryDocumentation ProtocolManager
• UpdateProtocolManager
  • ProtocolExecutor UpdateProtocolManager ProtocolManager (XML message for PatientIdentified)
• UpdateProtocolManager
  • ProtocolExecutor UpdateProtocolManager ProtocolManager (XML message for EnrollProtocolRequest)
• UpdateProtocolManager
  • ProtocolExecutor calls UpdateProtocolManager from ProtocolManager (XML message for scheduling activities

Retreive Protocol for Execution Actors and Transactions

Actor	Transaction	Opt.	Section
ProtocolExecutor	RetrieveProtocolList	?	?
	AgreeToParticipateInProtocol	?	?
	RetreiveProtocol	?	?
	SubmitProtocolApproval	?	?
	SubmitProtocolDocumentation	?	?
	SubmitRegulatoryDocumentation	?	?
	UpdateProtocolManager	R	?
ProtocolManager	RetrieveProtocolList	?	?
	AgreeToParticipateInProtocol	?	?
	RetreiveProtocol	?	?
	SubmitProtocolApproval	?	?
	SubmitProtocolDocumentation	?	?
	SubmitRegulatoryDocumentation	?	?
	UpdateProtocolManager	R	?

Volume II

Retrieve Protocol for Execution Content

Standards

Interaction Diagrams

Resources

• RPEUseCaseGraphic.jpg
• RPEUseCaseGraphic.ppt

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