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RACT Revision History

Previous Version Final Version Date SME Responsible


N/A 19-Feb-2013 Cheryl Small and Catherine
Campbell
1.0, 19 Feb 2013 2.0, 11-Apr-2014 Lisa Horne-Lucero; Sue Mullin; Lori
Convy; Jessica Holthuizen; Mireille
Zerola; Tom Kelly; Ethan Diamant
Key Changes
Original

1. Purpose tab added

2. Process overview tab added explaining process related to RACT completion / updates

3. Instructions for use tab added/expanded

4. Addition of columns in the RACT tab:


* Addition of Impact (column F)
* Addition of Probability (column G)
* Addition of Detectability (column H)
* Addition of category weighting (column J)
* Addition of program/protocol level risk (column K)
* Rationale for category risk level assessment (column L)
* Examples of risk level considerations for high, medium, low (columns N, O, P)
* Mitigation/comments for identified risks (column Q)
* Addition of Overall Risk Level

5. Participants tab added for documentation of cross-functional team members involved in RACT discussion/completion

6. Added tab to document critical data and processes

7. Added tab with possible mitigation examples per category question

8. Added drop-down lists tab - the data contained herein are used for drop-down lists throughout the document
Legal Disclaimer:

These materials are intended to facilitate RACT discussions for clinical trial sponsors and others with regards to risk-based monitoring meth
activities, bears full responsibility for its own risk assessment process and accompanying materials to ensure both the accuracy of the mate

By using this RACT, you signify your assent to the below terms of use. If you do not agree to them, you are not authorized to copy, distribut

Disclaimer of Liability : TransCelerate, its staff or its Member Companies shall not be held liable for any improper or incorrect use of this RA
TransCelerate, its staff or its Member Companies be liable for any direct, indirect, incidental, special, exemplary or consequential damages
data, or profits; or business interruption) however caused and on any theory of liability, whether in contract, strict liability or tort (includin
advised of the possibility of such damage. This disclaimer of liability applies to any damages or injury, whether for tortious behavior, neglig

Disclaimer of Warranties/Accuracy and Use of Information : The tabs in this RACT may include technical inaccuracies or typographical error
improvements and/or changes in the products, services and/or job aids described in these materials at any time without notice.

This document is provided 'AS IS' WITHOUT WARRANTY OF ANY KIND, EITHER EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, T
OR NON-INFRINGEMENT. Some jurisdictions do not allow the exclusion of implied warranties, so the above exclusion may not apply to you

Neither TransCelerate, its staff or its Member Companies warrants or makes any representations regarding the use or the results of the use
legality, reliability, or usefulness of the RACT.

The content in this Tool can be modified or adopted to specific company needs.

This is not a validated Tool. Ensure validation as applicable per company requirements.

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. Identify how/by whom the risk will b
that are housed within the overall Integrated Quality Risk Management Plan (IQRMP) (e.g., Data Review Plan, Statistical Analytical Plan, Saf

2. Categorization of the risks which will be managed by and affect the Monitoring Plan (and data review). Category risk scores will be calcu
as guides and are not to be considered all inclusive). Inputs into the calculation of the category risk score are impact, probability and detec
will be determined (categories can be weighted differently, if deemed appropriate).

3. Determination of the baseline level of monitoring activities. The overall risk level score will determine the baseline level of monitoring a

(*) it is recognized that all companies will have their own functional risk plans that will be referenced within the IQRMP.
Process Overview
Applicable
Columns
C, row 1

D, row 1

C
D
E
F

K
L

M
N, O, P

J, row 1
K, row 1

C, row 1

B & C, row 2

A
B
C
Instructions for use

RACT tab

Enter RACT version number (eg. 0.1, 1.0, 1.1)

Enter RACT version date

The RACT tab contains multiple categories (13 categories +1 optional row to be completed); the categories are summarized in blue colo
questions for discussion. The underlying questions can easily be collapsed (+) or expanded (-).
The overall objective for each category is specified in column C.
Questions for discussion should be discussed within the cross-functional team performing the risk assessment categorization.
Additional considerations for the questions are provided to aid in the discussion.
Impact: determine whether the identified risk, should it occur, has a high, medium or low impact on the trial. Determine the potential
data integrity, subject safety and GCP compliance for this trial. A score will be associated with this: high (3), medium (2), low (1). After c
separate questions, an impact score is to be assigned to each category (blue lines) - this does not have to be an average but should be
team discussion considering the importance of the underlying questions specific to this trial.

Probability: determine whether the identified risk has a high, medium or low probability of occurence. A score will be associated with t
(1). After completion of each of the separate questions, a probability score is to be assigned to each category (blue lines) - this does no
should be based on the cross-functional team discussion considering the importance of the underlying questions specific to this trial

Detectability: consider detectability when evaluating a risk. Higher detectability usually means lower risk, eg. risks associated with data
real-time basis will have a lower score than risks associated with data can only be reviewed at the site during an on-site visit.
A score will be associated with this: difficult to detect (3), medium to detect (2), easy to detect (1). After completion of each of the sep
score is to be assigned to each category (blue lines). - this does not have to be an average but should be based on the cross-functional
importance of the underlying questions specific to this trial.

A category risk score is calculated for each of the (13+1 optional) risk categories (blue lines). This is calculated as the product of impact
the category level. A color coding is applied (1-3: green; 4-9: yellow; 10-27: red). - this does not have to be an average but should be b
team discussion considering the importance of the underlying questions specific to this trial.
Weighting: depending on trial-specific requirements, there is an opportunity to rank the importance of the categories by assigning a w
is 1.0. If a certain category is of lesser importance, it can be given a lower weight (ranging from 0.1 to 1.0 - do not enter 0).; e.g. if the
patient carries higher weighting compared to the other criteria, this would remain at 1.0 and other criteria would be weighted lower.

Risks can be identified as program and/or protocol risk. It is recommended to keep program level risks consistent across trials within th
Rationale for separate risk level questions may be documented in this column. Questions not relevant for this program/protocol can b
recommended to enter 'not applicable' in the column 'Rationale for category risk level assessment'
Rationale for the category risk score should be entered on a category level ( blue lines) ; when making this decision, the overall impact
into account.

Specific functional plans that may be impacted by this assessment are to be documented here.
Examples for risk level assessments are given for high, medium, low. These are provided as examples to help guide the discussion and
needs.
Mitigation actions/plans can be enteredfor those categories that appear with the highest category risk score. A non-exhaustive list of m
the tab 'Mitigation examples'. It is recommended to first complete the risk assessment to have an overall view on the final category sc
that categories with the highest scores receive priority for targeted monitoring and mitigation. Note that some individual items might s
put in place. Mitigation can be described on a high level, details will be provided in the different functional plans as they are develop
the functional plans, there are changes, it is recommended to update the RACT. If there is a decision to accept or monitor the risk, t
well.

Overall risk score is calculated from the 13(+1) risk category scores, taking into account the weighting associated with each category ris
Overall risk score is presented as high, medium, low, depending on the value.

Participants
Version of the protocol outline/protocol that was used for this RACT version is to be entered.

Version and version date of the RACT are copied over from the RACT tab
Representatives present during risk assessment categorization tool discussion, along with their role, are to be documented
Last name
First name
Role; it is recommended to identify someone with overall decision making authority in case consensus cannot be obtained in the team
Critical data_processes
Document critical data in accordance with the following definition: Data that is critical to the reliability of the study findings, specificall
primary and key secondary endpoints. Other critical data include data related to subject safety, such as serious adverse events and eve
of treatment.
Document critical processes in accordance with the following definition: Processes that underpin subject safety and ethical treatment
integrity of study data, such as blinding or referring specified events for adjudication.

Mitigation examples
This tab provides a non-exhaustive list of possible mitigation examples. Use these as starting points for the discussion on mitigations fo
categories with highest final scores.

Drop-down lists tab


Grey highlighted areas are used for the various drop down lists in the RACT tab. Names of the various plans can be adapted to compan

Click 1 to collapse

Click 2 to expand
Protected cell

No, to be
completed
No, to be
completed
Yes

Yes
Yes
Yes
No, to be
completed

No, to be
completed

No, to be
completed

Yes, calculation

No, to be
completed (data
validation 0.1 - 1.0)

Yes, drop-down
No, to be
completed

Yes, drop-down
Yes

No, to be
completed

Yes, calculation
Yes, calculation

No, to be
completed
Yes, calculation
RACT version <enter RACT version <enter RACT version date>
number>
Overall Risk Level: #N/A #N/A
Category Category Objective Questions for Discussion Considerations Impact Probability Detectability Total Category Risk Category Weighting Program/protocol risk Rationale for category Functional Plan(s) Impacted Examples for Examples for considering Examples for considering low Mitigation/Comments -
Number 3 point scale 3 point scale 3 point scale Score 0.1 - 1.0 risk level assessment considering high risk medium risk risk possible examples are given
(blue line = category (blue line = (blue line = ( summary rating in the tab 'mitigation
summary) category summary) category summary) only 1.0 is default) examples'

1 Safety Determine any known If your company has standard processes for #N/A
risks for subject safety 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 Medial Surveillance Team (MST) Chair Identified risks from the Medical Surveillance #N/A Identified risks per Potential risks per MST no potential or identified risks
with Medical Leader confirm what is the safety Team which have predetermined rules for MST
risk to the subject? determining safety risk with confirmation from
the Medical Leader

1.2 Safety Is the compound a marketed product? #N/A The compound is not a The compound is a marketed The compound is a marketed
marketed product product but is being studied in product and is being studied
an unapproved indication in an approved indication

1.3 Safety Is the risk greater than or less than the Standard #N/A Markedly higher than Somewhat higher than the No higher than the risk of SoC
of Care(SOC)? the risk of SoC Trials risk of SoC authorized by - using authorized (local
involving IP not local regulatory authority) range of
authorized by local regulatory authority, but using indication, dosage and form,
regulatory authority (a for new indication, studying or off-label use that is
grading lower than substantial dosing established in practice and
HIGH may be modifications, or use in supported by published
justified if there is combinations where evidence
extensive class data or interactions are suspected
pre-clinical and clinical
evidence)

1.4 Safety Is this compound/class known to have any Consider any protocol-specific reporting #N/A Yes more than X? Between X and Y Less than Y
serious side effects/toxicity? Have events of requirements for (S)AEs and endpoints
special interest been identified?
1.5 Safety Are there any specific Health Authority (HA) e.g. Special Protocol Assessment, Post Marketing #N/A Incorrect application Timelines and protocol are There are no specific HA
requirements/ commitments? Requirement of feedback taking specific HA requirements/commitments
requirements/commitments
into account

1.6 Safety Is the compound known to have any significant #N/A Interaction may cause Interactions are related to No drug-drug interactions
interactions with other medications? SAES Cytochrome P450 induction or have been identified
inhibition

2 Study Phase Factor the risks #N/A 1.00


inherent in the study
phase into the trial

2.1 Study Phase Does the Phase of the trial increase the risk? A small sample size (Phase 1) means a lower #N/A Phase IIA Phase IIB-IIIB Phase IV
acceptable error rate
2.2 Study Phase Is this a pivotal trial? #N/A Original application for Supplemental/new indication Supplemental application not
marketing for an approved product requiring a Phase III clinical
authorization requiring a Phase III trial (e.g., post
clinical trial, or a country- marketing commitment) or a
specific labeling trial, or study being conducted for
certain Post-Authorization publication purposes
Safety Study (PASS) studies
upon feedback from team.

3 Complexity Determine how the #N/A 1.00


complexity of the
study impacts risk

3.1 Complexity Does the protocol require any complex or Consider the number of visits, the duration of #N/A Yes many new complex Yes, new procedures, but not No new or complex
uncommon procedures beyond the usual the study, diagnostic testing that is not common procedures. complex, common in some procedures
standard of care? for this subject population. Consider potential regions. No new procedures
impact for both study sites and study subjects; but many procedures.
consider whether subjects will have procedures
performed at home and/or by themselves and
how this impacts risk; consider whether there is
strict timing for certain procedures in the
protocol

3.2 Complexity Will the study collect PK samples? If yes, consider number of time points. #N/A Multiple PK (timed Simple PK; one measurement No PK measurements.
measurements), per day. One reference
complex dosing (e.g. medication. Scheduled visits
multiple reference only
medications).

3.3 Complexity Will the complexity affect subject burden? Consider the possibility of noncompliance or #N/A Subjects must visit An offset facility is used for an No. Visits every 4-6 weeks. No
withdrawal of consent several facilities for assessment during the study subject Report Outcomes
different procedures such as for an MRI or subject (PRO) assessments
such as an MRI, biopsy will be domiciled at least 2 x
or subjects requiring for 24 hours.
domicile visit for
multiple days.

3.4 Complexity Are there events that require adjudication? Consider the number of events to be #N/A Multiple event types Single event type to be No adjudication
adjudicated, amount of documents required as to be adjudicated adjudicated
part of adjudication package, operational
complexity in tracking / follow up of adjudication

3.5 Complexity Does the protocol have sub studies? Consider whether multiple informed consent #N/A >3 sub studies 1-3 sub studies 0-1 sub studies
forms need to be administered and the
associated complexity

3.6 Complexity Does this protocol have a non-standard study #N/A Adaptive design Cross-over study Standard study design
design? and/or complex study
design (multi-arm,
multi-regimen,
OL/SB/DB portions,
control panels, etc.)

3.7 Complexity What is number of subjects required to be On a site level, consider the maximum number of #N/A >3000 or 300-3000 50-300
randomized? subjects that can be enrolled (prior to review of 1-50
data)

3.8 Complexity What is the expected number of sites? #N/A >300 50-300 1-50

4 Subject Population Determine whether #N/A 1.00


the subject population
increases the risk for
the study.

4.1 Subject Population What is the severity of the subject population's Consider the potential for SAEs or subject risk, #N/A subjects on subjects on first line therapy;
condition? co-morbidities, expected outcomes, complexity second/third line initial stages of disease
of disease state. therapy;
life-threatening illness

4.2 Subject Population Is the population considered to be a vulnerable Consider informed consent issues #N/A Yes pediatrics, NA No
population (children, inmates, mentally ill)? geriatrics, subjects
with mental health
problems, acute life-
threatening illness,
etc.

4.3 Subject Population Are there special considerations for Women of Consider dose modifications, difference in #N/A WOCBP must be on WOCBP must be on at least No special considerations for
Childbearing Potential (WOCBP)? Are there other assessments, for example. multiple methods of one form of birth control. WOCBP in the protocol
considerations for special subject populations? birth control - risk of
compliance related to
requirement of
multiple methods.

4.4 Subject Population How specific are the eligibility criteria? Consider ability to document #N/A Multiple aspects of single aspect in medical
requirements/verify inclusion/exclusion criteria. diagnosis to be history to be confirmed
Consider stratification based on subject compiled based on
population. What is required in terms of medical history
documentation for diagnosis? Consider clarity on
central vs. local lab results being acceptable for
inclusion/exclusion ranges.

4.5 Subject Population Will subjects be allowed to be rescreened if they Consider situations to allow rescreening. #N/A Rescreening allowed in No rescreening allowed in Protocol to have clear details
do not pass all eligibility criteria? Consider ways to track subjects that are certain situations - protocol on when rescreening is
rescreened. consider issues with allowed and instructions for
reconsenting and subject ID and reconsenting
subject ID numbers

4.6 Subject Population Are there any requirements/restrictions on Consider mechanism to track status of this #N/A Unclear definitions of Requirements, but very clearly No requirements
sample size from a specific region/race/ethnic requirement throughout the study - e.g. IXRS, ethnic background described and no ambiguity
background? and how to ensure sites are notified of status in
study.

5 Technology What level of #N/A 1.00


technology
competence is required
for a successful study?

5.1 Technology Is there a new tool/device being implemented to Consider ePRO , iPad, vital signs collection #N/A A complex device is The device is relatively new to There is no device being used
capture data? devices, other devices for this assessment. used that is standard of care, but has been or the device is commonly
Consider how difficult the device is to use and complicated to use. used successfully in other used globally as standard of
how much training will be required. Is the new Multiple programs. care.
device being used to capture a languages/time zones
primary/secondary endpoint? involved in the study.
Also consider new technologies such as CTMS,
eTMF etc.

6 Data Collection, CRF Assess the integrity of #N/A 1.00


source the data based on data
collection methods
6.1 Data Collection, CRF Is the data collected manually or electronically? Are there unique complexities associated with #N/A No eDC eDC (non-standard system) eDC (standard system)
source Are there any data collected using eSource the collection of data in this trial that pose risks
(direct data entry)? Are CRF data collected using to data integrity? Are there study-specific edit
EDC? checks that can be introduced to reduce
transcription errors? Consider readiness of the
technology for the data collection (eCRF, ePRO,
Central Reading Center/Imaging/Diagnostic
data ,etc.)

6.2 Data Collection, CRF What is the time lapse between data entry and Consider time necessary for integration of data #N/A Multiple sources All data available for central
source availability for central review? from multiple sources in clinical database. needing integration in review without time delay
backend database;
manual sources, e.g.
Local labs, ePRO. etc.

6.3 Data Collection, CRF Will there be multiple data locks? Consider interim analysis, DMC review. Multiple #N/A Multiple data locks Ongoing central review
source locks can actually mitigate the risk from a data with limited central
quality perspective, but might also require more review
resources.

6.4 Data Collection, CRF Will the subject use an ePRO device or complete Consider what the diary is being used to collect #N/A Data being collected to Collection of study medication No diary being used
source a paper diary? (e.g. study medication) or data being collected to support a primary or
support a primary or secondary endpoint. secondary endpoint
Consider reconciliation of the paper diary
information against the AE page.

6.5 Data Collection, CRF Will multiple data systems be used requiring data Consider the ability to QC data from each vendor #N/A Need to integrate Few systems to integrate One system, no integrations
source transfer and integration? early in the study to identify issues. Will the data multiple systems required
be available on an ongoing basis for review?

6.6 Data Collection, CRF Determine if the amount of data will impact the Consider how low number of subjects, sites or #N/A Less than 5 sites and/ 5-10 sites; >100 and <250 The study has more than 10
source ability to perform central monitoring duration may impact the ability to perform or less than 100 subjects study between 3 sites, more than 250 subjects
central monitoring. subjects and/or less months and 1 year in duration and is greater than 1 year in
than 12 weeks in duration
duration

7 Endpoints Determine if the #N/A 1.00


method for capturing
endpoints will affect
data integrity?

7.1 Endpoints How will the primary and secondary endpoints Consider the risks associated with a 3rd party #N/A Clinical assessments Clinical assessments along Lab/Diagnostic data only
be collected? (e.g. lab, adjudication committee). Is there only, e.g. PI conducting with lab or diagnostic (e.g.,
experience with the vendor? Have there been determination of ECG) data; subject Reported
issues/findings in the past? Is it a subjective nodules size or tumor Outcomes (PRO) data only
endpoint that will require an ePRO. Will assessment
qualification/training be required to perform an
endpoint assessment? Is there potential for bias
in the collection of the endpoint? Consider
requirements for calibration of equipment.

7.2 Endpoints Is it an event driven or outcome study? Consider the issue of missing data due to lost to #N/A Endpoint study or Studies that have a follow-up No follow-up
follow-up or withdrawal of consent? outcome of death visit after discontinuation of
treatment that requires
collection of data

8 Organizational Determine any #N/A 1.00


Experience possible risks in the
organization
coordinating the
program

8.1 Organizational What is the organization's experience with the Consider therapeutic area (TA), indication and #N/A No experience Experience in last 2 years Current experience
Experience compound? other compounds within the class. Consider
experience of team in the industry and TA.

9 Investigational Determine any risks #N/A 1.00


Product/Study associated with IP
Medication administration

9.1 Investigational What is the route of administration? Consider if study medication can only be #N/A Subject self- Oral administration multiple Controlled IV administration in
Product/Study administered in an acute care setting. administration of times/day acute care setting; Oral 1-2
Medication injectable tablets/day

9.2 Investigational Is there a new device associated with medication #N/A Yes No
Product/Study delivery?
Medication
9.3 Investigational Is there any risk related to availability of Consider budget, drug overage, manufacturing #N/A High cost budget, Medium budget, moderately Low cost budget, standard
Product/Study investigational product? time, expiry dates, etc. prolonged/complex complex manufacturing manufacturing process, long
Medication manufacturing requirements, 1 year plus term shelf life
required, e.g. large shelf life
compound, short
shelf-life

9.4 Investigational Is there a comparator/background medication? Consider any safety implications specific to the #N/A Comparator required but no No comparator
Product/Study comparator or background medication(s). safety implications,
Medication Consider the use of the comparator outside the
US, is it considered SOC in the countries selected
for study participation?

9.5 Investigational Is there dose titration or is the preparation of the Consider the algorithm for dose titration or dose #N/A Complex dose Simple dose adjustments (e.g. No dose adjustments, single
Product/Study dose to be calculated/modified based on adjustments; is it clear, what is the potential for adjustments (e.g. based on 1 parameter) or agent
Medication measured parameters (e.g.. weight, renal error? based on 2 parameters dosing algorithm, few drug
function, age)? or more) or dosing regimen
algorithm, multiple
drug regimen

9.6 Investigational Is "rescue" therapy permitted? Consider the algorithm for rescue medication. Is #N/A
Product/Study rescue blinded? Is SOC used for rescue?
Medication
9.7 Investigational Are interruptions/restarts permitted? #N/A
Product/Study
Medication
9.8 Investigational Are there any specific diluents or materials to be Consider how diluents will be provided? (will the #N/A Diluents are needed, Diluents are needed, but not No
Product/Study used? site obtain diluent or will they be provided?). not provided and the provided, but are commonly
Medication Also consider the provision of materials such as availability is not used and easy to obtain
filters and infusion bags. Is there any risk consistent globally globally
regarding onsite compounding of IP?

10 IP Logistics / Supply Determine risk #N/A 1.00


Chain involving logistics and
supply chain

10.1 IP Logistics / Supply What is the known shelf-life of the compound? Consider expiration dates of compound and #N/A
Chain diluents.

10.2 IP Logistics / Supply Are there temperature, light or humidity Does the compound need to refrigerated during #N/A Multiple restrictions Time limitation from Temperature restrictions only
Chain restrictions associated with shipping and transport? Consider temperature requirements for reconstitution, reconstitution to for storage, refrigeration not
storage? for storage of shipped and/or reconstituted study storage and timing for administration required
medication. Is there a limit to the time that a administration
drug is prepared and administered to the
subject. Determine how this information will be
documented to ensure compliance with
restrictions.

10.3 IP Logistics / Supply Do expiration dates present a potential threat to Consider comparators #N/A
Chain maintaining an adequate supply of the product?

10.4 IP Logistics / Supply Is there a manufacturing or handling complexity? #N/A Aseptic/sterile Cold chain products Standard formulation (e.g.,
Chain products; formulation tablets, liquids, stable at
requiring separate room/ambient
unblinding teams (site temperature) not requiring
and/or monitoring); any special handling
study drug is a narcotic

10.5 IP Logistics / Supply Will adequate supplies be available within the Consider available overages (at #N/A
Chain hubs/warehouses or at the sites to adequately hub/warehouse/site levels as applicable). Will
support recruitment. recruitment targets have some flexibility?

10.6 IP Logistics / Supply Are there multiple studies using the same drug Consider ways to clearly identify study specific #N/A
Chain supply at a site? kits

11 Blinding Determine to what #N/A 1.00


degree the type and
execution of blinding
impacts study risk

11.1 Blinding How is the blinding set up? e.g. single blinded bottles, kits. Consider study #N/A Multiple bottles that Kitted study medication. Open-label study medication
design e.g. double dummy, active vs. placebo, are that not kitted. There is a risk of AEs
crossover There is a risk of an (hypoglycemia) associate with
Are there instructions provided regarding what SAE (e.g. stroke) taking the wrong study
to do if the subject is administered the "wrong" associated with taking medication
study medication? the wrong study
medication

11.2 Blinding How are the blinding assignments e.g. IVRS//IWRS? #N/A On-site pharmacist Manual treatment assignment Automated treatment
administered/created? assigns the blind assignment
11.3 Blinding Is the blinded IP created on-site? Consider need for unblinded pharmacist, #N/A On-site pharmacist - Received blinded from
unblinded monitor. creates blinded IP manufacturer

11.4 Blinding What is the risk of unblinding? Consider over encapsulated tablets, size #N/A Actual physical Over-encapsulated tablets; Tablets; Subject receives same
differences between active and placebo? How is difference in Subject receives medication throughout the
the blinding protected? appearance between active/placebo study
active and placebo;
Re-randomization

11.5 Blinding Are there potential ways to unblind a subject Are there lab results that could unblind study #N/A High possibility to Moderate possibility to No other ways
other than through study medication as medication. Are there procedures in place to unblind the subject unblind
described above? ensure labs are not performed that have the through labs/certain
potential to unblind; consider whether single or AEs
multiple results have the potential for
unblinding;
Consider also AEs that might potentially unblind
12 Operational Determine to what #N/A 1.00
Complexity extent the degree and
nature of outsourcing
increase the risk of the
study

12.1 Operational Complexity What is the level of outsourcing? Which activities Consider if only monitoring being outsourced. #N/A Multiple( non- Multiple (preferred) vendors Few vendors involved
are being outsourced? How many vendors are Are there different CROs depending on the preferred) vendors involved for different activities
involved in the same activity? countries? involved in the same
activity, e.g.. multiple
vendors involved in
monitoring activities
across countries;
subcontracting

12.2 Operational Complexity What is the experience level with the vendor? Consider if the vendor is a preferred partner. #N/A No previous Vendor is an approved Vendor is a preferred partner
experience in working partner, but they don't have and procedures for
with a particular experience in the particular collaboration have been
vendor, due diligence therapeutic area or phase, or established
has not yet been they have corrective actions
performed to address

12.3 Operational Complexity Is a central lab or local labs being used? If a central lab is being used, are tests performed #N/A Local lab only Central lab only or both No labs performed
centrally or locally and then harmonized? How local/central lab approach;
will local labs be harmonized? Have there been Local lab data service involved
any previous issues with the lab regarding data
integrity? Consider risk of loss of samples during
storage

12.4 Operational Complexity Determine to what Is there an Academic Research Organization, Consider impact on communication, decision #N/A Lack of experience Established charters and
extent other parties Executive Committee or Steering Committee making and documentation. Consider value of with this type of communication pathways
involved in the conduct involved? Is there an adjudication committee global membership to assess local standard of committee,
of the study impact involved? care and communication. Consider ability to inexperienced
risk track metrics associated with adjudication committee members
process from event identification to adjudication.
Consider experience of committee.

12.5 Operational Complexity What is the complexity of the data Consider collection, sample storage, visits, #N/A Multiple One unknown/young data Known data types
type/biomarker? logistics, testing methods by labs related to these unknown/young data type
samples types (ePRO, LABMISC,
etc.).Unknown
biomarkers (possibly
exploratory or
analyzed). New assay
to be developed for
the study

13 Geography Determine if Risk assessment/mitigation may need to be #N/A 1.00


regulatory/commercial performed on a country by country basis -
considerations impact monitoring plans can be adapted accordingly
the risk

13.1 Geography Are there requirements for this program by Consider regulatory requirements #N/A
specific countries? Is there a need to include
certain countries?

13.2 Geography Are there countries that are restricted from #N/A
participation?

13.3 Geography Determine how the Are there countries/sites involved that might GCP experience, Clinical Investigator experience, #N/A Countries with very Countries with moderate Countries with well
geographical footprint present greater risk to trial conduct? Site infrastructure; consider country specific limited clinical trial clinical trial experience; low established clinical trial
may impact the risk monitoring plan adaptations to address specific experience; large proportion of research naive infrastructure/ experience
needs proportion of research sites involved
naive sites involved

13.4 Geography Is the protocol in alignment with the local Consider how differences between local standard #N/A Many differences Protocol is in line with local
standard of care. of care and the protocol requirements might lead necessitating protocol- standard of care practices
to protocol deviations specific training

13.5 Geography Is the background/rescue comparator medication Consider impact of provision of comparator or #N/A Background/rescue Background/rescue No background/rescue
available in the country? rescue therapy (not currently approved in the comparator comparator medication is not comparator medication
country); there might be risk related to in- medication not approved in a few countries
experience with particular medication approved in most participating in the trial,
administration - to be considered on a country by countries participating requiring provision as IP, and
country basis in the trial, requiring no experience with the
provision as IMP, and product within a particular
no experience with the country
product within a
particular country

13.6 Geography Does the country have issues with import/export Consider impact on endpoints, consider impact #N/A Samples are for a Export issues, but samples are No import/export issues
of blood or other biological samples? on using multiple vendors as part of mitigation primary/secondary not for a primary/secondary
strategy endpoint, and export endpoint
issues exist

13.7 Geography Are there country specific risks to EC/HA * If there is a new device/technology, is there a #N/A Country with complex Country with easy import,
approval, recruitment, data collection? risk it will not obtain HA/EC approval? import requirements, short approval timelines,
*Are the regulations stable or are they known to long approval stable regulatory framework,
change frequently? timelines, unstable all protocol specific
* Will approval timelines restrict target regulatory framework, procedures allowed
recruitment? no PGX collection
*Are there drug manufacturing allowed
requirements/sourcing requirements for use in
the country?
* Are there ethical considerations that need to
be assessed?
* Are there procedures that are not permitted in
the country (e.g.; collection of PGX samples)
* Consider the risks associated with recruiting a
high volume of subjects in a short time.
* Would an import/export VAT tax be prohibitive
to enrollment?

13.8 Geography Is it permissible to collect outcome information Level of risk increases when primary or #N/A Multiple countries not All countries permit collection
for subjects that are lost to follow-up (LTFU) or secondary endpoints depend on follow-up allowing collection of of outcome information when
have withdrawn consent? information outcome information subject withdraws consent or
when subject is LTFU
withdraws consent or
is LTFU

14 <Add any company <Add objective for #N/A 1.00


specific other company specific other
categories> objective>
14.1 <Add questions for discussion for company #N/A
specific other objective>
Enter draft protocol outline, final protocol,
Input for discussion: etc.
RACT version <enter RACT version number> <enter RACT version date>
Participants in RACT discussion
Last name First name Role
Green cells are copied from RACT tab
List critical data (high level) Rationale Source, if applicable and Visable only on site? If
already known already known
List the critical datapoints Describe rationale for datapoint eCRF, central lab, IWRS, Yes/No
being critical, such as: Endpoint- other
primary / Endpoint - secondary
/safety/other (specify); Adding too
many extra secondary, tertiary,
exploratory data could lead to
additional risk and complexiy

List critical processes (high level) Rationale Visable only on site? If


already known
List the critical processes Describe rationale for process Yes/no
being critica, such as relation to:
Endpoint- primary / Endpoint -
secondary /safety/other (specify)
Category Number Category
1 Safety

1.1

1.2

1.3

1.4

1.5

1.6
2 Study Phase

2.1
2.2
3 Complexity

3.1

3.2

3.3

3.4

3.5

3.6
3.7

3.8
4 Technology

4.1
5 Subject Population

5.1

5.2

5.3
5.4

5.5

5.6
6 Data Collection, CRF source

6.1

6.2
6.3

6.4

6.5

6.6
7 Endpoints

7.1

7.2
8 Organizational Experience

8.1
9 Investigational Product/Study
Medication

9.1

9.2

9.3

9.4

9.5

9.6

9.7

9.8
10 IP Logistics / Supply Chain

10.1

10.2
10.3
10.4

10.5

10.6
11 Blinding

11.1

11.2
11.3
11.4

11.5
12 Operational Complexity

12.1
12.2
12.3

12.4

12.5
13 Geography
13.1

13.2

13.3

13.4

13.5

13.6

13.7

13.8
Questions for Discussion

Per the Medial Surveillance Team (MST) Chair with


Medical Leader confirmation what is the risk of safety
to the subject?

Is the compound a marketed product?


Is the risk greater than or less than the Standard of
Care (SOC)?

Have events of special interest been identified?


Are there any specific Health Authority (HA)
requirements/ commitments?

Is the compound known to have any significant


interactions with other medications?

Does the Phase of the trial increase the risk?


Is it a pivotal trial?

Does the protocol require any complex or uncommon


procedures beyond the usual standard of care?

Will the study collect Pharmacokinetic (PK) data?

Will the complexity affect subject burden?

Are there events that require adjudication?

Does the protocol have sub studies?

Does this protocol have a non-standard study design?


What is number of subjects required to be
randomized?

What is the expected number of sites?

Is there a new tool/device being implemented to


capture data?

What is the severity of the subject population's


condition?

Is the population considered to be a vulnerable


population (children, inmates, mentally ill)?
Are there special considerations for Women of
Childbearing Potential?
How specific is the eligibility criteria?
Will subjects allowed to be rescreened if they do not
pass all eligibility criteria?

Are there any requirements/restrictions on sample size


from a specific region/race/ethnic background?

Is the data collected manually or electronically? Are


there any data collected using eSource (direct data
entry)? Are CRF data collected using EDC?
What is the time lapse between data entry and
availability for central review?
Will there be multiple DB locks?

Will the subject use an ePRO device or complete a


paper diary?
Will multiple data systems be used requiring data
transfer and integration?
Determine if the amount of data will impact the ability
to perform central monitoring

How will the primary and secondary endpoints be


collected?

Is it an event-driven or outcome study?


What is the organization's experience with the
compound?

What is the route of administration?

Is there a new device associated with medication


delivery?

Is there any risk related to availability of investigational


product

Is there a comparator/background medication?

Is there dose titration or is the preparation of the dose


to be calculated/modified based on measured
parameters (e.g.. weight, renal function, age)?

Is "rescue" permitted?

Are interruptions/restarts permitted?

Are there any specific diluents or materials to be used?

What is the known shelf life of the compound?

Are there temperature, light or humidity restrictions


associated with shipping and storage?
Do expiration dates present a potential threat to
maintaining an adequate supply of the product?
Is there a manufacturing or handling complexity?

Will adequate supplies be available within the


hubs/warehouses or at the sites to adequately
support recruitment.
Are there multiple studies using the same drug supply
at a site?

How is the blinding set up?


How are the blinding assignments
administered/created?
Is the blinding created on-site?
What is the risk of unblinding?

Are there potential ways to unblind a subject other


than through study medication as described above?

What is the level of outsourcing? Which activities are


being outsourced? How many vendors are involved in
the same activity?
What is the experience level with the vendor(s).
Is a central lab or are local labs being used?

Is there an Academic Research Organization, Executive


Committee or Steering Committee involved? Is there an
adjudication committee involved?

What is the complexity of the data type/biomarker?


Are there requirements for this program to include
specific countries?
Are there countries that are restricted from
participation?
Are there countries/sites involved that might present
greater risk to trial conduct?
Is the protocol in alignment with the local standard of
care.
Is the background/rescue comparator medication
available in the country?

compliance with local laws and regulations, country


selection/allocation adjustment, study redesign
Are there country specific risks to EC/HA approval,
recruitment, data collection?
Is it permissible to collect outcome information for
subjects that are lost to follow-up or have withdrawn
consent?
Potential controls/mitigation actions

medical monitoring of related events and TEAEs


if no, level of scrutiny and frequency of review of safety
data
if yes, same plus PHV

medical monitoring of related events and TEAEs


medical monitoring of related events and TEAEs, AESI,
comparison to IB, site and central monitoring of critical
data

appropriate controls as needed per commitment

if yes, monitoring of SAE, AE, targeted conmed review, I/E


criteria, clear protocol information and training, SDR if
critical, automatic edit fires in eCRF

They are controlled through protocol/study design to limit


exposure to IP/procedure, increased medical monitoring.
no difference in monitoring

if yes, focused training, protocol clarity, appropriate


instructions, add KRI/critical data, targeted monitoring
If yes, potential critical process> collection method
impacts risk (central collection vs. site collection), clear
SOE/training, targeted monitoring
if yes, consider protocol redesign, monitoring drop-out
rate
Adjudication manual and process, communication plan
spec to blinding if applicable, site and staff training around
endpoint, tools and process

training, appropriate instructions, design validation to


ensure appropriate identification of subjects in data base
(increased risk to execution) adjust the monitoring
approach as needed, look at critical data and processes,
reassess risks
validate randomization, stratification schema, IVRS setup
to ensure stoppage
confirm feasibility justification, review recruitment and
retention strategy

critical process and critical data would require targeted


monitoring, appropriate training/testing

informed consent, I/E, safety monitoring, data collection


specific to the subject population's condition,
informed consent process addressing vulnerable
population, clearly defined protocol/I/E/IRB/regulation
compliance
if yes, site and central monitoring of critical data
all, I/E verification, ICF information included
same as above

same as above

same as above

training, appropriate instructions, regulatory compliance,


back up system if needed, data synchronization
data completion manual, contractual agreement with
sites, CRA intervention defined in MP

if yes, focused training, protocol clarity, appropriate


instructions, add KRI/critical data, targeted monitoring
vendor agreements; correlation with IT depts., UATs,
scheduled results review by study team

confirm data validation plans

critical process and critical data would require targeted


monitoring, appropriate training/testing
adjudication committee, follow up, prevention of lost to
follow up strategy
engage with experts, increased training, QbD for
mitigation,

clarity of directions, training/demonstrations, site


qualifications, facility appropriate, process monitoring

clarity of directions, training/demonstrations, site


qualifications, facility appropriate, process monitoring

site facility assessment, temperature monitoring,


accountability process, appropriate planning for supply
chain-quantity, time, temperature (no interruptions of
drug supply to subject), appropriate monitoring of IP from
start to end
clarity of directions, training/demonstrations, site
qualifications, facility appropriate, process monitoring,
availability/logistics,

clarity of directions, training/demonstrations, site


qualifications, facility appropriate, process monitoring
clarity of directions, training/demonstrations, site
qualifications, facility appropriate, process monitoring,
country specific

clarity of directions, training/demonstrations, site


qualifications, facility appropriate, process monitoring

clarity of directions, training/demonstrations, site


qualifications, facility appropriate, process monitoring

appropriate engagement with CTMMS personnel

site facility assessment, temperature monitoring,


accountability process, appropriate planning for supply
chain-quantity, time, temperature (no interruptions of
drug supply to subject), appropriate monitoring of IP from
start to end
site facility assessment, temperature monitoring,
accountability process, appropriate planning for supply
chain-quantity, time, temperature (no interruptions of
drug supply to subject), appropriate monitoring of IP from
start to end
CTMMS planning, less tolerance for waste

from manufacture of IP through shipment to sites process


belongs to IP manufacturing system; monitoring during
study is addressed by: IP logs, accountability, temperature
monitoring/storage, access to supply, supply based on
enrollment,
adequate separation of drug at site, appropriate labeling
at site,

ensuring randomization process is appropriate,


inadvertent unblinding has prevention controls,
monitoring process maintains blind, monitoring of IWRS
for unblinding, training of site staff/pharmacist/PI

statistical plan; IVRS validation

well defined pharmacy manual;

process for blinding of associated lab values; appropriate


training of sites regarding safety assessment and reporting

monitoring transfer of data, monitoring reconciliation,


ensuring processes are documented, oversight of vendors,
training in place, agreements in place
defined vendor contracts, detailed scope of work
certifications UTD, data quality,

Verify process for data transfer/reviews, monitor process


for data collection to prepare for DMC/ensure data is
ready for DMC
validate measurement process of data type/biomarker;
early data review
compliance with local laws and regulations, country
selection/allocation adjustment, study redesign
compliance with local laws and regulations, country
selection/allocation adjustment, study redesign
compliance with local laws and regulations, country
selection/allocation adjustment, study redesign

monitoring for protocol violations

CTMMS planning, country assignment

compliance with local laws and regulations mitigate by


testing locally but then consider lab compatibility (e.g..
China, local testing, ensure harmonization with other labs)
compliance with local laws and regulations; ongoing
consultation with regulatory

statistical plan; well-defined protocol description:


definition of (non)completer; expectation for follow-up
Drop-down categories Drop-down categories Drop-down categories Drop-down categories
for RACT tab, Column F for RACT tab, Column G for RACT tab, Column H for RACT tab, column M
Medical Monitoring
High (3) High (3) Difficult to detect (3)
Plan
Medium (2) Medium (2) Medium to detect (2) Safety Plan
Low (1) Low (1) Easy to detect (1) Data Plan
Statistical Analysis Plan

Monitoring Plan
Training Plan
Quality Plan
Risk Management Log

Communication Plan
Drop-down categories Drop-down categories
for RACT tab, column E for RACT tab, column K 3 point scale

High Program 3
Medium Protocol 2
Low Program/Protocol 1

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