Monitoring the Progress of Trials and the Safety of Participants

Don Workman, PhD Victor Santana, MD

St. Jude Children’s Research Hospital

A continuous ongoing review of the conduct of the trial

Shared responsibility

– Research Team/Principal Investigator

– Institutional Officials

– Oversight Committees (IRB, DSMB)

Monitoring the Progress of Trials and the Safety of Participants

Partnership in Research

Investigator

IRBInstitutionalOfficials

Participant

A Systematic Approach to the Problem

Defining what needs to be monitored and reported

Defining role of DSMB and role of IRB

Developing infrastructure to report, evaluate and act upon safety concerns in a timely fashion

Monitoring Elements as Summarized in the NCI Clinical Data Update System

Patient-Specific Data – demographics – treatment status (received therapy)

– date of entry – off-therapy reason(s) subgroup on protocol

– eligibility – performance status

– prior therapy – disease code (diagnosis, SNOMED) treatment by course

– Course ID – Start date

– Rx assignment (ph I) – BSA or weight dose of agent

– agent – dose modification – total dose/course adverse even reporting

– type – grade

– attribution – reporting response

– evaluable – best response at time of evaluation

Monitoring Type or Phase

of TrialMonitoring

Interval

Reports to Subcommittee

Number of Patients to be Monitored

Phase I Central Elements Continuously

Missing Data Reports Monthly

Quarterly First 3 patients enrolled, plus 1 patient per dose level

Phase II Eligibility and Consents Continuously

Central Elements Quarterly

Missing Data Reports Quarterly*

AEs Quarterly

Response coding semiannually, or at appropriate protocol time points

Semiannually, or

as required in the protocol

First 2 patients enrolled, plus at least 10% of total patients accrued

Monitoring Type or Phase

of TrialMonitoring

Interval

Reports to Subcommittee

Number of Patients to be Monitored

Phase III Eligibility and Consents Continuously

Central Elements Quarterly

Missing Data Reports Quarterly*

Response coding semiannually

Other primary objectives

Annually

Semiannually, or

as required in the protocol DSMP

First 2 patients enrolled, plus at least 10% of total patients accrued

ST JUDE holds

IND/IDE

Per study-specific monitoring plan Per study phase Per study phase, or study-specific monitoring plan

The Problem of AE/SAE Reporting and IRB Review

Problems in reporting:

– Over-reporting (reporting of anticipated adverse events)

– Increased research in drugs and biologics

– Increased federal scrutiny—OHRP, FDA

– Saturation effects

– Lack of denominators in Safety Reports, lack of normative data for population under study

The Problem of AE/SAE Reporting and IRB Review

Problems in review:

– External events reports often sketchy summaries—no opportunity for questions/clarifications

– IRB is not DMC/DSMB

– IRB is not FDA with single IND file

– IRB needs to rely on local investigator to interpret the meaning of the events reported

PI Reports & Categorizes Adverse

Events

Electronic SubmissionElectronic Submission

IRBOffice of

RA

Office of VP Clinical Trials

External Reporting:

OHRP

CTEP

NIH

FDA

RAC

SPONSORS

Internal Reporting

Other Committees Institutional

(DSMB, CPSRMC)

FeedbackFeedback

Follow-up

An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs

Project Development– 18 months from design to implementation – Began with Implementation of a Form, designed

like screen-shots to include checkboxes and fill-in the blanks

– Development of flow-diagram for Web-based Reporter

– Security versus Access issues– Need for electronic “signature” other title 11

issues

An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs

Project Development– Integration with existing databases

Verifiable identities/access list

Internal reports: subjects/medical record numbers– Links to registered protocols– Information stream to other PIs

External reports: radio buttons for selecting protocol(s) for reporting of events (sometimes multiple studies on single safety report)– E-mail notification to PIs

An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs

Functional Outcomes

– Real-time IRB reporting: time stamping

– Forced choice, smart forms, no incomplete submissions

– Ease of access—any system signed onto intranet

– Ability to generate single-incident reports

– Ability to generate reports entered in specified time period

An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs

Functional Outcomes

– Quicker reporting times

– Ability of IRB Office to generate reports based on protocols, type of events, across subjects

– Able to generate internal denominators

– Use of standardized NCI toxicity tables

– Able to record IRB actions, and updates from Investigators onto previous reports

An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs

Process Improvements

– More timely reporting—able to demonstrate overall compliance

– Better communication between investigators and IRB

– Able to manipulate information into reports

– Improved information summary presentation for reviewers

– Easy access to history of events on any protocol

An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs

Process Improvements– No need for generating additional

correspondence – PI can generate time-stamped “receipt” by IRB

and determinations from the Committee– Requires PI input on judgments re. Seriousness,

relationship (related/not related), and expected/unexpected

– Requires PI judgments regarding need for revision/amendment to consent/protocol

DEMONSTRATION

Dr Teddy Bear

Conclusions

Technology can be used to improve process for collection and review of information regarding adverse events

Web-based applications can facilitate cross-talk between various databases

Well-designed systems may allow for a single report in an inpatient hospital to generate incident reports, ADR reports, medwatch reports, and AE/Safety reports

Acknowledgments

Don Workman, Ph.D., IRB Administrator (2003) Donna Hogan, IRB Office, CIP Mickey Weeks, Clinical Informatics Donald Sanderlin, Clinical Informatics Victor Santana, M.D