I remain very interested in modeling Activities in clinical trials. Activities are performed according to Rules that are specified in the Protocol. I am searching how to best model these rules. Here is one thought. All Activities have a Start Rule. Rules are Analyses in our mini-study ontology since one Analyzes the data from other Activities ("Prerequisite Activities") to determine if and when the target Activity can take place.
Let's start with the easiest Activity (from a modeling perspective): Obtaining Informed Consent. It has a Start Rule that says "begin at any time." The Rule is automatically satisfied by default so has a RuleOutcome always set to TRUE. There are no preconditions other than a Subject's willingness to participate in this Activity. The Activity completes with an ActivityOutcome = InformedConsent_GRANTED. The ActivityStatus is now Complete. The RDF looks something like this:
:Person1 :participatesIn :InformedConsent1 .
:InformedConsent1 :hasStartRule :Rule_DEFAULT .
:Rule_DEFAULT :activityOutcome "TRUE"ˆˆxsd:string
:InformedConsent1 :hasPerformedDate "2017-04-01"ˆˆxsd:date; (the date the activity was performed)
:activityStatus :activitystatus_CO; (the Activity is completed)
:activityOutcome :informed consent_GRANTED .
Let's assume it's a simple trial that has only three screening activities: DemographicDataCollection, FastingBloodSugar, and a serum PregnancyTest (if female).
We create a new Rule which says : RuleOutcome is TRUE if the prerequisite activity is complete and has a certain outcome. Generically it looks like this.
:PrerequisiteOutcomeRule rdfs:subClassOf :Rule .
:hasPrerequisite :Activity ;
:hasPrerequisiteStatus :activitystatus_CO; (the prerequisite activity must be complete)
:hasPrerequisiteOutcome :ActivityOutcome . (the prerequisite activity must have a certain outcome)
(there are optional properties one can consider here, like :delay , which specifies a duration that one must wait before the target activity can begin after the prerequisite activity ends.)
The instance data looks like this:
:Person1 :participatesIn :DemographicDataCollection1 .
:DemographicDataCollection1 :hasStartRule :PrerequisiteOutcomeRule1 .
:PrerequisiteOutcomeRule1 :hasPrerequisite :InformedConsent1;
:hasPrerequisiteStatus :activitystatus_CO;
:hasPrerequisiteOutcome :informed consent_GRANTED.
Once this information is recorded, and the rule satisfied, the Activity becomes a PlannedActivity.
An embedded spin:rule can check the PrerequisiteActivity and return a value of TRUE if the conditions are met:
:PrerequisiteOutcomeRule1 :activityOutcome "TRUE"ˆˆxsd:string .
Once the RuleOutcome is evaluated as TRUE, another spin:rule can set the scheduled date of the DemographicDataCollection equal to the date the InformedConsent was done (plus any delay specified in the Rule). The Activity now becomes a ScheduledActivity.
The same Rule can be applied to the FastBloodSugar activity.
PregnancyTest requires a new rule. It can begin with the DemographicDataCollection Activity is Complete and the Outcome is :sex_Female.
Now the very cool part. These same rules can be used to check for Eligibility. Why? Because an eligibility criterion is nothing more than a Start Rule which defines when the RandomizationActivity can begin.
Similarly we can define rules when Visits, Elements, Epochs can begin. The Study now becomes a graph of StudyActivities, all waiting to begin, but only those that have Rules with RuleOutcome=TRUE are ready to go next. I think this paradigm will hold for even the most complex adaptive designs. It is something worth testing.
Finally, an existential question. Is ObtainingInformedConsent a StudyActivity? If a HumanSubject (a Person of Interest) participatesIn the ObtainInformedConsent Activity, but does NOT grant informed consent, is he/she considered to have participated in the Study? If so, what would their disposition be? Screen Failure doesn't seem right since no screening tests were conducted. Is ObtainingInformedConsent a ScreeningActivity? If so, then failure to obtain informed consent could be considered a screen failure.
Please share your thoughts, and especially if you have other ideas on how model activity rules.
Let's start with the easiest Activity (from a modeling perspective): Obtaining Informed Consent. It has a Start Rule that says "begin at any time." The Rule is automatically satisfied by default so has a RuleOutcome always set to TRUE. There are no preconditions other than a Subject's willingness to participate in this Activity. The Activity completes with an ActivityOutcome = InformedConsent_GRANTED. The ActivityStatus is now Complete. The RDF looks something like this:
:Person1 :participatesIn :InformedConsent1 .
:InformedConsent1 :hasStartRule :Rule_DEFAULT .
:Rule_DEFAULT :activityOutcome "TRUE"ˆˆxsd:string
:InformedConsent1 :hasPerformedDate "2017-04-01"ˆˆxsd:date; (the date the activity was performed)
:activityStatus :activitystatus_CO; (the Activity is completed)
:activityOutcome :informed consent_GRANTED .
Let's assume it's a simple trial that has only three screening activities: DemographicDataCollection, FastingBloodSugar, and a serum PregnancyTest (if female).
We create a new Rule which says : RuleOutcome is TRUE if the prerequisite activity is complete and has a certain outcome. Generically it looks like this.
:PrerequisiteOutcomeRule rdfs:subClassOf :Rule .
:hasPrerequisite :Activity ;
:hasPrerequisiteStatus :activitystatus_CO; (the prerequisite activity must be complete)
:hasPrerequisiteOutcome :ActivityOutcome . (the prerequisite activity must have a certain outcome)
(there are optional properties one can consider here, like :delay , which specifies a duration that one must wait before the target activity can begin after the prerequisite activity ends.)
The instance data looks like this:
:Person1 :participatesIn :DemographicDataCollection1 .
:DemographicDataCollection1 :hasStartRule :PrerequisiteOutcomeRule1 .
:PrerequisiteOutcomeRule1 :hasPrerequisite :InformedConsent1;
:hasPrerequisiteStatus :activitystatus_CO;
:hasPrerequisiteOutcome :informed consent_GRANTED.
Once this information is recorded, and the rule satisfied, the Activity becomes a PlannedActivity.
An embedded spin:rule can check the PrerequisiteActivity and return a value of TRUE if the conditions are met:
:PrerequisiteOutcomeRule1 :activityOutcome "TRUE"ˆˆxsd:string .
Once the RuleOutcome is evaluated as TRUE, another spin:rule can set the scheduled date of the DemographicDataCollection equal to the date the InformedConsent was done (plus any delay specified in the Rule). The Activity now becomes a ScheduledActivity.
The same Rule can be applied to the FastBloodSugar activity.
PregnancyTest requires a new rule. It can begin with the DemographicDataCollection Activity is Complete and the Outcome is :sex_Female.
Now the very cool part. These same rules can be used to check for Eligibility. Why? Because an eligibility criterion is nothing more than a Start Rule which defines when the RandomizationActivity can begin.
Similarly we can define rules when Visits, Elements, Epochs can begin. The Study now becomes a graph of StudyActivities, all waiting to begin, but only those that have Rules with RuleOutcome=TRUE are ready to go next. I think this paradigm will hold for even the most complex adaptive designs. It is something worth testing.
Finally, an existential question. Is ObtainingInformedConsent a StudyActivity? If a HumanSubject (a Person of Interest) participatesIn the ObtainInformedConsent Activity, but does NOT grant informed consent, is he/she considered to have participated in the Study? If so, what would their disposition be? Screen Failure doesn't seem right since no screening tests were conducted. Is ObtainingInformedConsent a ScreeningActivity? If so, then failure to obtain informed consent could be considered a screen failure.
Please share your thoughts, and especially if you have other ideas on how model activity rules.
A colleague posted this on LinkedIn: "Very thought provoking. For your existential question, I wonder if there is any industry (ICH perhaps) or regulatory guidance around ObtainingInformedConsent when it is not obtained? Do you know of any? It seems on the surface that investigators would only approach potential study subjects they feel would qualify for the study, and would have at least a reasonable likelihood of passing screening. Nobody likes to waste time. So with that assumption in-mind, it seems reasonable that regulators may want to consider (at least know) if there are any common themes why potential study subjects might be saying no.
ReplyDelete.
ReplyDeleteThanks for your comments, xxx. You add an important twist to the issue...why would a subject recruited for a trial not grant informed consent when formally asked to grant it. Very good question. Assuming they are formally counseled and asked to grant informed consent but they don't, do we want them categorized as Screened and failed screening (reason: Informed Consent not granted) or do we say Not screened (Informed Consent not granted so screening never started). I will look around various ICH sources. If you find anything, please let me know. Cheers!