Transcript TransCelerate RBM Information Materials Module Activities

How to Complete
THE TRANSCELERATE RISK ASSESSMENT
& CATEGORIZATION TOOL
These materials were last updated on 13-March, 2015
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These materials are intended to facilitate and reduce the
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with regard to risk-based monitoring methodologies. Each
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Overview
THE RACT PROVIDES A CONSISTENT APPROACH
TO RISK ASSESSMENT AND DOCUMENTATION
OF MITIGATION AND MONITORING STRATEGIES
The Transcelerate RACT is based on Excel
2010 and certain features may not function
in earlier versions.
There are 9 tabs in the RACT.
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Saving the RACT
Make sure to use the
xlsm extension
e.g. XX123456RACT.xlsm
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What Not To Do When Using the RACT
DO NOT move tabs
DO NOT move
columns
DO NOT change
column widths
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RACT
Walkthrough
RACT-Table of Contents
TAB CONTENT
ADDITIONAL DETAILS
1
Version History
Documentation of the changes to the version of the RACT
2
Purpose of RACT/Legal disclaimer
See Slide 1 and Slide 7
3
Process Overview
See Slide 8-10
4
Instructions for Use
See Slide 11
5
RACT Assessment
See Slides 14-16
6
Participants
See Slides 17
7
Critical Data and Processes
See Slide 18-19
8
Mitigation Examples
See Slide 20
9
Drop-down lists
See Slide 21
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Tab 2 – Purpose of the RACT
THE PURPOSE OF THE RISK
ASSESSMENT AND
CATEGORIZATION TOOL
(RACT) IS TO FACILITATE RISK
ASSESSMENT AND RISK
MITIGATION BY THE
FOLLOWING:
1. Identification of the risks which
could affect patient safety, data
integrity or regulatory compliance
2. Categorization of the risks which will
be managed by and affect the
Monitoring Plan (and data review)
3. Determination of the baseline level
of monitoring activities
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Tab 3 – Process Overview
Draft
protocol
synopsis
Cross-functional
team discussion
to complete
RACT
RACT tab:
Document
RACT version
RACT tab: Discuss questions
underlying each category;
determine impact,
probability and detectability
and indicate whether
associated risk is related to
protocol or program level
Complete summary lines
in RACT tab (blue lines) –
assign each category risk
the impact, probability
and detectabiliy scores,
then add rationale
Add a weighing
for category as
necessary
(1.0 is default)
Summary Risk
Level
calculated
Completed
RACT
Input into
IQRMP
(including thresholds
and risk indicators)
Input into
various
functional plans
Input into
other
processes
Define mitigation for
categories with highest
category risk score
(e.g. Resourcing,
investigator
meetings, etc.)
Participants tab:
Document
participant
Critical data
and processes
tab: Determine
and document
critical data
and processes
Refine/
update RACT
Develop final
protocol/
protocol
amendments
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Tab 3 – Process Overview
Draft
protocol
synopsis
Cross-functional
team discussion
to complete
RACT
RACT tab:
Document RACT
version
RACT tab: Discuss questions
underlying each category;
determine impact, probability
and detectability and
indicate whether associated
risk is related to protocol or
program level
Complete summary lines
in RACT tab (blue lines) –
assign each category risk
the impact, probability
and detectabiliy scores,
then add rationale
Define mitigation for
categories with highest
category risk score
Participants tab:
Document
participant
Critical data and
processes tab:
Determine and
document
critical data and
processes
Refine/
update RACT
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Tab 3 – Process Overview
Add a weighing
for category as
necessary
Summary Risk
Level calculated
Completed
RACT
(1.0 is default)
Input into IQRMP
(including thresholds
and risk indicators)
Input into various
functional plans
Input into other
processes
(e.g. Resourcing,
investigator
meetings, etc.)
Develop final
protocol/
protocol
amendments
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Tab 4 - Instructions for Use
This tab provides overall
instructions for use of the tool. It
is aligned with this presentation.
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Tab 5 – RACT
Navigation and Functionality
COLLAPSED VIEW
EXPANDED
VIEW
Category
1 Safety
Expand and collapse
categories to see all
questions in a category
Objective
Determine any known
risks for subject safety
Questions for Discussion
If your company has standard
processes for determination of
potential or identified safety
risks, then this can serve as input
to the overall risk category
instead of below the separate
questions
1.1 Safety
Per the Medical Surveillance
Team (MST) Chair with Medical
Leader confirm what is the safety
risk to the subject?
1.2 Safety
Is the compound known to have
any significant interactions with
other medications?
2 Study Phase
Factor the risks inherent
in the study phase into
the trial
2.1 Study Phase
Does the Phase of the trial
increase the risk?
2.2 Study Phase
Is this a pivotal trial?
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Tab 5 – RACT
Navigation and Functionality
Expand and collapse
columns to view
examples of risk
EXPANDED
VIEW
Detectability
Total Category Risk Category Weighting 0.1 Program/ Protocol or
3 point scale (3=difficult Score (= mean of all - 1.0
(
Risk
to detect)
total risk scores
summary rating only
(blue line = category within each category)
1.0 is default)
summary)
0
1.00
"What is the Risk"
Functional Plan(s) Impacted
Mitigation/Comments - possible
examples are given in the tab
'mitigation examples'
COLLAPSED
VIEW
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Determination Factors for Risk Scoring
IMPACT
PROBABILITY
DETECTABILITY
What if the risk turns
into an issue, how will
it impact the study?
What is the likelihood
that the risk will
become an issue?
Can the risk be detected
in time before it becomes
a systemic issue?
LOW
issue will not impact primary or
secondary endpoints or
subject safety
LOW
rarely occurred
EASY
can be detected immediately
and is available
MEDIUM
issue will impact an
exploratory endpoint
HIGH
issue will impact primary or
secondary endpoints, subject
safety or GCP compliance
MEDIUM
has occurred, but not
frequently
HIGH
has frequently occurred
MEDIUM
can be detected,
but not immediately
DIFFICULT
very difficult to detect centrally
or may not be detected until
the end of the study
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Risk Examples – IP Administration
EXAMPLE: Oncologic IP administered every 4 weeks at the investigator site
Route of Administration:
Controlled IV administration
in acute care setting; Oral
1-2 tablets/day
Oral administration
multiple times/day
Subject self-administration
of injectable
RISK: If IP is not administered appropriately, it could impact subject safety and
exposure and ultimately efficacy.
IMPACT: If medication is not given appropriately it
would have a high impact on subject safety and
possibly efficacy.
PROBABILITY: IP is administered in the clinic by
experienced, skilled personnel, the probability that it
will be administered incorrectly is low.
RISK SCORE
Impact High = 3
Probability Low = 1
Detectability Easy = 1
DETECTABILITY: Since subjects come into the clinic, it is
known by the site that the subject did not receive the
medication so the detectability is easy.
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Additional Columns
Use the dropdown
menu to identify
the risk as a
protocol or
program level risk
Program/protocol risk
Document the risk
(e.g. the wrong
subject will be
enrolled) may include
additional rationale for
the chosen risk level
Rationale for category risk
level assessment
Use dropdown menu
to document the
functional plan(s) that
will mitigate or monitor
the risk
Functional Plan(s) Impacted
There are currently many
Investigator Brochure, Informed
indications for this compounds Consent
that is currently in Phase III.
Document the mitigation
or monitoring strategy at
a high level, including
activities that are not
documented in a plan
Mitigation/Comments - possible examples are
given in the tab 'mitigation examples'
Also see DSUR. There will be a DMC for this
study.
No Drug/Drug Interactions
(DDI) have been identified for
this compound. As a biologic,
the potential for DDIs is low.
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Tab 6 – RACT Participants
• Team members that contributed to the assessment and development of mitigation
strategies should be documented on this page.
• All functions are expected to contribute to the assessment of risk and the
development of mitigation and monitoring strategies.
• The RACT should be housed in a central location for all to review.
Enter draft protocol outline,
final protocol, etc.
Input for discussion:
RACT version
<enter RACT version number>
<enter RACT version date>
Participants in RACT discussion
Last name
First name
Role
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Tab 7 – Critical Data and Processes
Critical Data
Critical Processes
Data that support primary and key
secondary objectives
Processes that underpin safety or
quality
Rationale: why is it critical?
Rationale: why is it critical?
• Endpoint - primary or secondary
• Safety - SAEs, events leading to
discontinuation of treatment
• Other (specify)
Avoid OVER-identification to avoid
increased risk/complexity
• Safety/ethical treatment - seeking
appropriate medical consultation,
investigating clinically significant findings
• Data quality – blinding, event
adjudication, controlling inter-rater
variability
Document data source
eCRF, central lab, IXRS, other
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Examples of Critical Data/Critical Processes*
THERAPEUTIC
AREA
ENDPOINT
CRITICAL DATA
CRITICAL PROCESSES
Metabolic
Change in baseline HbA1C at
Week X
HbA1C
Collection, storage and shipment of
labs
Cardiovascular
Number of CV events
between treatment groups
per adjudication committee
AEs of stroke, MI,
death
Reporting and collection of AEs
Collection and submission of source
information to adjudication
committee
Anti-infection
SVR 12
HCV RNA
Collection, processing and
shipment of labs
Oncology
Progression Free based on
RECIST 1.1 criteria per
Independent radiology
review committee (IRRC)
Tumor measurements
Performance of scans to collect
tumor measurements
Assessment of RECIST 1.1 criteria
Submission of scans and source
information to IRRC
All
Safety
AEs/SAEs
Collection and reporting of
AEs/SAEs
*note these are only examples and may not be applicable to all studies in a therapeutic area
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Tab 8 – Sample Mitigation and Monitoring
Strategies
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Tab 9 – Drop Down List
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Saving the RACT to PDF for Electronic Study Files
NOTE: Some screen shots on this slide
may differ from your version of Excel.
1.
Choose File -> Print
NOTE: You won’t actually be printing the RACT, but
saving it as a PDF using the Adobe printer function
2.
Click on current Printer name or
icon and change Printer to Adobe
PDF
NOTE: You may need to scroll your list of printers
left/right or up/down to locate and click on the
Adobe PDF printer in your list.
3.
Ensure your print Settings are set to
Print the entire workbook
4.
Click Print
5.
Save the RACT to a desired file
location
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Sample Protocol
Sample Protocol Title and Objectives
Protocol Title
CA123-456: A Randomized, Double-Blind, Phase 3 Trial of NuTherapy versus Standard
of Care (SOC) in previously treated or metastatic Non-Small Cell Lung Cancer
(NSCLC)
PRIMARY OBJECTIVE
To compare the Progression Free
Survival (PFS), based on Independent
Radiology Review Committee (IRRC)
assessment of NuTherapy
monotherapy with SOC in subjects
with Stage IV or recurrent NSCLC
SECONDARY OBJECTIVES
•
•
To compare Overall Response Rate
(ORR), based on IRRC assessment
of NuTherapy monotherapy with
SOC chemotherapy in subjects
with Stage IV or recurrent NSCLC
To compare Overall Survival (OS) of
NuTherapy monotherapy with SOC
chemotherapy in subjects with
Stage IV or recurrent NSCLC
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Sample Protocol Safety Evaluations
NuTherapy
Standard of Care
Identified Events
Identified Events
• Infusion reactions
• Infusion reactions
• Gastrointestinal events
• Gastrointestinal events
• Thrombocytopenia
Drug/Drug Interactions (DDIs)
• None identified
DDIs – none identified
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Sample Protocol Study Design
Subjects will be randomized in a 1:1 ratio to either NuTherapy or SOC.
NuTherapy
alternating
with Placebo
Screening
Randomize
Progression
or
Discontinuation
Follow-up
SOC
Treatment
Phase
Every 2
Weeks
Overall
Survival
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Sample Protocol Study Design
Enrollment Projection
EXPECTED DURATION OF THE
TRIAL IS 3 YEARS
600 subjects
150 sites
Requires 10% African American/
10% Asian subject population
15 countries
40%
30%
30%
US
EU (Germany, France,
Italy, Poland and Spain)
Canada, Mexico,
Argentina, Brazil, China,
Korea, Taiwan, Israel and
Russia
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Sample Protocol Patient Population
Eligibility Criteria
INCLUSION
EXCLUSION
Subjects 18 to 70 years old
ECOG status ≥ 2
Male or Female
Prior treatment with SOC
Histology confirmed Stage IV or Recurrent
NSCLC (squamous or non-squamous)
Pregnant or breastfeeding
Measurable disease by CT or MRI per
RECIST 1.1 criteria
One time rescreening is permitted
for abnormal labs
Subjects must have experienced disease
recurrence or progression during or after
one prior platinum-containing doublet
chemotherapy regimen for advanced
or metastatic disease
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Sample Protocol Procedures
Every 2 weeks
CBC with diff, serum chemistry, biomarkers
Assessment of AEs and Concomitant Medications
Every 4 weeks
Pregnancy test (WOCBP)
Population PK
Every 6 weeks
Radiographic Tumor Assessments
Results will be uploaded electronically to a website for review
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Sample Protocol Investigational Product
DRUG
ADMINISTRATION
NuTherapy alternating with
matching placebo will be
administered every 2
weeks IV starting with
NuTherapy
SOC will be administered
every 2 weeks IV
Dose modifications,
interruption and/or
discontinuation criteria will
be specified for events of
special interest
BLINDING
Study blind will be
assigned by IVRS
Study blind will be
created by the
Pharmacist
RECONSTITUTION
& DOSING
D5W or normal saline
required as diluents, filters
required for infusion for
both NuTherapy and SOC.
Previous errors in using
incorrect filters have not
resulted in AEs
Dosing for NuTherapy
based on weight, dosing
for SOC based on body
surface area
SUPPLY
CHAIN
All study medication will be
supplied globally and shelf-life
for NuTherapy is 2 years and
for SOC 3 years
NuTherapy and SOC require
cold chain refrigeration,
stable for 12 hours at room
temperature after
reconstitution.
Roll-out of Study medication
scheduled to support multiple
studies, process is stable, no
recent issues have occurred.
SOC purchased directly from
pharma company. Contract
signed, first shipment
received. Will be purchased
to support roll-out. Have not
had previous issues obtaining
drug.
3 hubs are providing IP
regionally (US/CA/LA, EU, AP)
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Sample Protocol Vendors
A central lab will be used to collect and distribute biomarkers to the
appropriate specialty lab
Safety labs will be performed by local labs
Sites will enter the local lab values and normal ranges in the eCRF
An IRRC will assess PFS using Recist 1.1 criteria
A DMC will review overall risk benefit
Two CROs will perform monitoring across all countries
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Revision History
Version Number
Version Date
SME Responsible
Key Changes
1.0
13 March 2015
Sue Mullin
Original
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