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Proposing a framework for classifying all the clinical research related processes and use cases. Some of this work is based on a project at the National Cancer Institute (NCI) many years ago to capture and document all the use cases in clinical research from a Cancer center perspective.  It is in support of Multi-Institutional trials.    Many of these use cases have been fairly well documented based on input from a large number of subject matter experts (SMEs) who actively participate in planning and conducting clinical trials at both coordinating site level and site level.  

Note:  This is proposal to consider for BR&R and a DRAFT. It needs input and feedback from BR&R members.  For the time being, only the Initiate Study use case has been drilled down further to get to the use case currently under discussion in BR&R – Register a Protocol at ClinicalTrials.gov

Majority of the multi-institutional studies have following four business modes: 

 Plan Study

This use case  includes the use cases for developing and maintaining the scientific, regulatory, financial, legal and logistical (includes the protocol processes and resources) aspects of Protocol and managing the Protocol document and related material.

Study Team -- Principal Investigator, Biostatistician, Protocol Coordinator, Review Boards (IRB, NCI, Scientific Board, Department Board)

End of protocol planning - approvals are done, ready to be activated, available for sites to open the study. 

The Plan Study use case can break down as follows:

Plan Study

-Develop Scientific Concept

--Research Existing Work

--Develop Preliminary Scientific Plan

---Determine Logistical Feasibility of the Study/Trial Completion

---Establish Significance of the Study/Trial

--Develop Preliminary Administrative Plan

---Define Professional Qualifications of an Investigator Needed for Study/Trial

----Identify and Contact Study/Trial Team

--Develop Preliminary Safety Plan

---Review Regulatory Constraints

--Develop Preliminary Data Management Plan

---Manage/Evaluate Tech Transfer

--Develop Preliminary Financial Plan

---Explore Possible Funding Opportunities

-Develop Protocol and Associated Materials

--Develop Scientific Plan

---Develop Background & Rationale

---Define Objectives

---Define Measures

----Define Criteria to Evaluate Response (Outcome)

---Define Secondary Studies

----Define Laboratory Methods to be used for Ancillary Studies

----Define Image Methods for Ancillary Studies

---Describe Study Design and Schema

----Develop Eligibility Criteria

----Develop Randomization Plan

----Develop Accrual Plan

-----Describe patient Recruitment Plan

---Develop Statistical Plan

--Develop Operational Plan

---Develop Intervention Plan (as appropriate)

----Define Clinical Intervention Plan (as required)

----Define Behavioral/Psychosocial/Educational Intervention Plan (as required)

----Develop Community Intervention Plan (as required)

---Define Observational/Epidemiologic Plan (as required)

----Define Case STudy Plan (as required)

----Define Case Control Study Plan (as required)

----Define Cohort Study Plan (as required)

----Define Surveillance Research Plan (as required)

---Define Methodologic (Applied) Research Plan (as required)

---Develop Study/Trial Calendar

---Define Participant Enrollment Activities

--Develop Study Specific Data and Safety Monitoring Plan

---Develop Plan for Response Assessment

---Develop Study Specific Adverse Event Reporting Plan

---Develop Study Specific Plan for the Safety, Monitoring and Evaluation of Participants

--Develop Administrative Plan

---Identify Study/Trial Administration Information

---Identify Auditing Entity

---Identify Required Reports

---Identify Participating Sites (Site Identification)

--Develop Study/Trial Specific Data Handling Plan

--Develop Informed Consent Form

--Develop Financial/Contractual Plan

---Gather Funding Information

----Determine the Funding Source

-----Determine Patient Care Funding

---Plan the Study/Trial Budget

----Identify Administrative Costs

----Identify Auxiliary Budget

---Negotiate Budget

----Define Milestones

---Negotiate Contracts

---Financial Compliance Review/Approval

-Review and Approve Study

--Review and Approve Scientific Concept

---Verify Logistical Feasibility of the Study/Trial

--Review and Approve Protocol and Associated Materials

-Define Response Criteria Interpretation Method

--Define DICOM Viewer

--Define Image Annotation Tool

--Define Image Annotation Template

Initiate Study

This use case includes activities associated with activating a study at the coordinating center and opening the study for enrollment at a participating site. In cases where the coordinating center and participating site are the same (e.g., investigator initiated study), some of these activities may be duplicative or performed simultaneously.

End of setup - sites have done what they need to do to open the study for enrollment. 

Conduct Study

This use case includes activities for managing the execution of a study, i.e., from the time the study is made available for enrollment until end of study when data collection in over.

End of conduct - no more data are being collected on the study subjects. 

Report and Analyze (this goes across the first three business modes)

Review collected data in aggregate or detail for a trial to answer operational, primary and secondary objectives as well as the interim analysis questions.

.        planning reporting - Institutional Review boards (IRBs)

·        conduct reporting - Adverse Events (AEs)

·        analysis reporting - review of study data

·        end of analysis – initial results have been published and other publishing is on-going for years


Initiate Study Use Cases

Use Case includes activities associated with  activating a study at the coordinating center and opening the study for enrollment at a participating site. In cases where the coordinating center and participating site are the same (e.g., investigator initiated study), some of these activities may be duplicative or performed simultaneously.

Note:  Not showing the actors for these use cases for now.  The various roles and responsibilities associated with the personnel who perform these activities tend to differ among organizations and focusing on those names is often distracting.


Activate Study at Coordinating Center

Use Case includes activities for making the study available to participating sites, including verifying that everything is ready to activate the study and communicating to all participating sites that the study has been activated.

These activities include:
Registering the protocol with the appropriate organization(s)
Ensuring the availability of drug/device
Developing a study-level regulatory binder
Initializing operational management systems
Making study-specific training available for site personnel
Distributing protocol and associated materials to the participating sites


Initiate Study > Activate Study at Coordinating Center > Register Protocol

Register Protocol Use Case

The use case includes activities associated with registering a protocol or a clinical trial with the appropriate registry/ies.

Actors

·        Research Investigator, or

·        Responsible party depending on center requirements 

Scenario

The lead organization registers the protocol in the appropriate registry/ies. (Need to expand this and write it as  a Storyboard)

For example, NCI supported cancer interventional studies are requested to be registered with the NCI via CTRP, with exception for studies reviewed, approved, and managed by NCI. http://www.cancer.gov/clinicaltrials/ctrp/page7#b 

The FDA requires the registration of Ph II and Ph III FDA regulated interventional clinical trial in the www.clinicaltrials.gov registry which is also accepted by both the World Health Organization and International Committee of Medical Journal Editors. 

ICMJE requires the registration of all intervention studies Ph I – Ph IV.  This can be done in www.clinicaltrials.gov even if the FDA does not require the registration in clinicaltrials.gov.

 Pre-Conditions

1.      Protocol is available, but does not necessarily need to be approved

Basic Flow

1.      Investigator (or designee) goes to the appropriate registry/ies to register the protocol

2.      Investigator (or designee) enters required information into the registry

3.      Investigator completes registration 

Post-Conditions

1.      Protocol is registered in the appropriate registry/ies

2.    Unique study ID assigned by the registry.  E.g., ClinicalTrials.gov assigns a NCT Number


BRIDG and ClincialTrials.gov Harmonization

The data elements of registering a protocol with ClinicalTrials.gov have been harmonized with the BRIDG Model.  These semantics are represented by the subset of BRIDG model view.  

Go to bridgmodel.nci.nih.gov > click "Browse BRIDG Model 5.3"  > Navigate to "Additional Focused Views" package in the Model browser in the left window pane > click on "ClinicalTrials.gov"

BRIDG and HL7 FHIR

The BRIDG model was mapped to FHIR STU 3.0.1 under a US FDA Grant (U01FD005846).

Candidate FHIR Resources that support the semantics of data elements for registering a protocol at CLinicalTrials.gov.  These do not represent all the ct.gov requirements.  There are many elements in ct.gov that are not currently supported by the existing FHIR resources.  They will have to reviewed to discuss and decide which ones need to be added to the base resources and which ones may need to become extensions.

1.      ResearchStudy

2.      PlanDefinition

3.      Observation

4.      Person

5.      ActivityDefinition

6.      Practioner

7.      PractionerRole

8.      Medication/MedicinalProductDefinition

9.      Device

10.   Immunization ??

11.   DocumentReference

12.   Group

13.   Location

14.   TBD


There are a lot of elements in CT.gov that are not supported in existing FHIR resources and were identified as GAPS. 





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