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TRIAL RISK ASSESSMENT GUIDANCE
FOR NSLHD SPONSORED
INVESTIGATOR-LED/COLLABORATIVE
GROUP CLINICAL TRIALS
Purpose
This risk assessment guidance is designed to help the
coordinating principal investigator capture the risks posed
by his or her clinical trial over and above standard clinical
care, so that this information can be used to:
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Develop the sections of the trial protocol relating to risk,
either by incorporating the outputs within the protocol or
as an appendix.
Develop proportionate trial management and monitoring
plans.
Address certain questions relating to risk and ongoing
monitoring of risk in the ethics application.
Contents
RISK ASSESSMENT GUIDANCE ........................................................................................ 3
PART 1: DEFINING THE PATIENT JOURNEY.................................................................... 3
PART 2: DEFINING THE ADDITIONAL RISKS ASSOCIATED WITH PARTICIPANTS'
PHYSICAL INTEGRITY AND SAFETY ................................................................................ 4
a)
Risks posed by the intervention(s) being tested .................................................... 4
b)
Risks posed by additional study procedures required by the protocol when
compared with standard care ............................................................................................ 5
c)
Defining plans for the ongoing safety monitoring of the trial................................ 6
PART 3 DEFINING RISKS TO PARTICIPANTS' RIGHTS ................................................... 7
a)
Obtaining appropriate consent................................................................................. 7
b)
Protecting participants' personal data..................................................................... 8
PART 4: DEFINING RISKS TO DATA INTEGRITY ............................................................. 8
a)
Features of a robust design ...................................................................................... 8
b)
Risks to the reliability of results............................................................................... 8
c)
Data collection and handling methods that may help improve data quality ........ 9
APPENDIX I – RISK ASSESSMENT FORM ...................................................................... 11
Risk Assessment Guidance V2 April 2016
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RISK ASSESSMENT GUIDANCE
Risk assessment is the process of identifying the potential hazards associated with a trial and assessing
the likelihood of those hazards occurring and resulting in harm.
The purpose of this guidance is to assist investigators to:

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Clarify the patient journey to ensure accountabilities and liabilities are clearly defined
Define the risks and hazards inherent in a clinical trial protocol
Develop the appropriate risk mitigation plans
This information will help expedite the governance and ethics assessments by providing reassurance
that all appropriate plans are in place
The risk assessment must be documented using the risk assessment form in Appendix I.
PART 1: DEFINING THE PATIENT JOURNEY
NSW Health staff conducting trial activities within a Public Health Organisations are covered by Treasury
Manage Funds. NSW Health staff conducting trial activities at sites outside the control of a Public Health
Organisation (e.g. in private hospitals) are not indemnified by Treasury Managed Funds and should
either be covered by their employer or hold separate insurance/indemnity cover for liabilities that may
arise.
For each clinical trial, in order to assess whether adequate cover is in place and whether the facilities
utilised are fit for purpose, it is important to define the patient journey.
Example Form
DEFINING THE PATIENT JOURNEY
Detail all locations (public or private) where trial related activities will be conducted (e.g. consent,
treatment/intervention, assessment and follow-up)
INTERVENTION
SCHEDULE
Within 2 weeks
prior to first
intervention
Day 1 (+0-2
hrs.)
LOCATION
(Public or private)
DESCRIPTION OF THE PROTOCOL
REQUIRED ACTIVITY AND FACILITIES
Royal North Shore (RNS)
Oncology Outpatients
Trial consent
Dr X trial
team
RNS Private
Patient received pre-med and trial treatment
Emergency resuscitation equipment present in
the treatment room
Dr X or Dr
Y
Patient escorted from the RNS Private to the
RNS Oncology Day Unit
Dr X trial
team
PK blood samples collected over a 16 hr. period
with patient monitoring
Dr X trial
team
Day 1 (2 hrs.)
Day 1 (+2-18
hrs.)
RNS Oncology
Outpatients
Day 1 (+20 hrs.)
Risk Assessment Guidance V2 April 2016
Patient discharged (taxi home)
3
PART 2: DEFINING THE ADDITIONAL RISKS ASSOCIATED WITH PARTICIPANTS'
PHYSICAL INTEGRITY AND SAFETY
a) Risks posed by the intervention(s) being tested
OVERALL RISK CATEGORY FOR THE TRIAL
Drug/Device Clinical Trials
Risk Category
Trials involving a drug entered onto the Australian Register of Therapeutic Goods
(ARTG) if:
-
They relate to the licensed range of indications, dosages and forms, or;
They involve off-label use, if this off-label use is established practice and
supported by sufficient published evidence and/or guidelines (for example in
paediatrics or oncology).
Trials involving a medical device used within its product indications if knowledge
derived from controlled trials already exists.
TYPE A
Risk comparable to
standard medical
care
1) Trials involving a drug entered onto the ARTG if:
-
Such products are used for a new indication (different patient population/disease
group) or;
- Substantial dosage modifications are made or;
- They are used in combinations for which interactions are suspected.
2) Trials involving a drug NOT entered onto the ARTG if:
- The active substance is part of a drug that is entered onto the ARTG.
3) Trials involving a medical device used:
-
Outside the scope of certification or;
Within the scope of certification, but no knowledge from controlled trials exists.
TYPE B
Risk somewhat
higher than standard
medical care
N.B. A ‘TYPE A’ grading may be justified if there is extensive clinical experience with
the product and no reason to suspect a different safety profile in the trial population.
For paediatric trials, the risk category would be determined by an appropriately
qualified individual (TYPE B or TYPE C)
1) Trials involving a drug not entered onto the ARTG.
2) Trials involving a medical device not entered onto the ARTG.
N.B. A grading other than ‘TYPE C’ may be justified if there is extensive class data or
pre-clinical and clinical evidence.
TYPE C
Risk markedly
higher than standard
medical care
Other Interventional Clinical Trials
For other interventional clinical trials, similar principles should be used to identify the risks associated with the trial
intervention(s).
Risks should be assessed relative to the standard of care for the relevant clinical condition (i.e. use of the
intervention meets local or national protocols) and the level of clinical experience with the intervention rather than
the patients’ underlying illness or the recognised adverse effects of the intervention.
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The following considerations will guide the nature and extent of participant safety monitoring that will be
required in the trial:
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The nature of the drug(s)/device/intervention(s)
The potential for known or anticipated toxicities/adverse events
Which body systems may be affected
Phase of development
Study population: healthy volunteers or patients?
Is the intervention being used outside its marketing authorisation, e.g. has the dosage
regimen/route been modified? If so, what are the implications of any modifications for
participants?
What are the known/anticipated safety issues and are they all addressed within normal clinical
practice (standard care)?
If unknown, what are the anticipated risks/other effects based on preclinical data or knowledge
of class of drugs/type of device/intervention?
Is the duration of use compatible with previous experience?
For drugs and biologics, is there a potential risk of dosing errors?
Might concomitant medications increase the risk, i.e. interactions?
For devices, is there a safety impact resulting from the device not being operated properly or
failing to operate?
Example
ADDITIONAL RISKS ASSOCIATED WITH THE USE OF THE DRUG(S)/DEVICE(S) WHEN
COMPARED WITH STANDARD TREATMENT
IP/Device
ABC 123
Body System/Hazard
Metabolic
Hyperglycaemia
GIT
Raised transaminases
CVS
Prolonged QT interval
How will these risks be minimised?
Additional blood glucose monitoring
X hourly
LFTs performed weekly
Digital ECG, Holter monitoring
X hourly
b) Risks posed by additional study procedures required by the protocol when compared with
standard care
Just as for the risks associated with the trial drug/device/intervention, these should be assessed relative
to standard investigations and procedures for the clinical condition of the participants in the trial. For
example, if an invasive procedure (such as a biopsy) is normal practice for good quality care, then its
inclusion in the study protocol would not be an additional risk to participants.
Some issues to be considered in the assessment (this list is not comprehensive):

Does the protocol require additional procedures over and above those which would be expected
from standard care for the participant’s clinical condition – e.g. blood tests, biopsies, x-rays, lumbar
puncture, contrast media scans?
o If so, what is the likelihood and magnitude of the harm that might be caused to the
participant?
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
What measures might reduce either the likelihood or magnitude of harm to the study participants
(for example, qualifications, experience and training of clinical staff at site or the availability of
special facilities or equipment)?
Example
RISKS POSED BY ADDITIONAL STUDY PROCEDURES REQUIRED BY THE PROTOCOL
WHEN COMPARED WITH STANDARD CARE
Risk
Specify concerns
Right heart
catheterisation
Risk of complication:
Excessive e.g.
bleeding,
pneumothorax
How will these risks be minimised?
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Trial sites experienced with the procedure
Contact details of a clinical advisor in protocol
Data Safety Monitoring Committee convened
On-site adverse event monitoring checks
c) Defining plans for the ongoing safety monitoring of the trial
Once the assessment of risk to participant safety has been made, the requirements for safety monitoring
in addition to standard care can be assessed, and risk mitigation strategies can be put into place. A
formal Data Safety and Monitoring Board (DSMB) should generally be considered for all trials but are
not always be necessary. The following is an extract from FDA guidance relating to Data Safety
Monitoring Boards (known as DMCs):
"A fundamental reason to establish a DMC is to enhance the safety of trial participants in
situations in which safety concerns may be unusually high, in order that regular interim analyses
of the accumulating data are performed. We recommend that sponsors consider using a DMC
when:
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The study endpoint is such that a highly favourable or unfavourable result, or even a
finding of futility, at an interim analysis might ethically require termination or redesign of
the study before its planned completion;
There are a priori reasons for a particular safety concern, as, for example, if the
procedure for administering the treatment is particularly invasive;
There is prior information suggesting the possibility of serious toxicity with the study
treatment;
The study is being performed in a potentially fragile population such as children,
pregnant women or the very elderly, or other vulnerable populations, such as those
who are terminally ill or of diminished mental capacity;
The study is being performed in a population at elevated risk of death or other serious
outcomes, even when the study objective addresses a lesser endpoint;
The study is large, of long duration, and multi-center."
In studies with one or more of these characteristics, the additional oversight provided by a DSMB can
further protect study participants. In other studies, such as short-term studies for relief of symptoms (see
2.2 of FDA Guidance) or early studies (see 4.4.2 FDA Guidance), such committees are generally not
practical or warranted.
'For more information, see FDA and EMA Guidance.
Other trial oversight measures that may be appropriate include:

Independent data review: A specifically convened Study Safety Group and/or the appointment
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of a Medical Monitor to look at single cases and aggregate safety data for identification and
verification of safety signals.
Stopping rules and rules for modifying study treatment: E.g. Local clinical review and
decision making with a pre-specified decision making algorithm.

PART 3 DEFINING RISKS TO PARTICIPANTS' RIGHTS
a) Obtaining appropriate consent
The ability of trial participants to give fully informed consent depends on:
i.
Ethical considerations specific to participants as outlined in Section 4 of the National
Statement, including capacity of the study population to consent to research, and;
The consent process. There should be careful consideration to ensure that the optimal
consent process is identified (e.g. numbers of stages or timing).
ii.
Some issues to be considered in the assessment (this list is not comprehensive):
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Does the study population include participants such as those outlined in the National
Statement Section 4 (e.g. children and young people, people in unequal relationships, people
highly dependent on medical care who may be unable to give consent, patients with a mental
illness)? If so, are additional safeguards required to optimise the informed consent process?
Will foreign language translations of all consent documents and/or foreign language
interpretation services be required?
Is it likely there will be some participants unable to give fully informed consent (e.g. severe
pain, cognitive impairment)? Who will decide whether or not a participant is capable of giving
consent, and how (e.g. by a specialist; via a cognitive assessment)?
Does the study fall under the scope of the Guardianship Act, and thus require approval from
the Guardianship Division (GD) of the NSW Civil and Administrative Tribunal and a specific
consent mechanism approved by the GD?
Where appropriate, does the consent process allow sufficient time for the participants to
consider their decision and discuss it with a third party?
What measures might reduce the likelihood that participants may be included in the study
without the appropriate level of consent?
For example:
- Experience and training of clinical staff at site
- Additional training by the CI or delegate
Example
RISKS TO PARTICIPANTS' RIGHTS - The Consent Process
Risk
Specify concerns
Consent Procedure
Children between 4
and 10 years
Failure to obtain
fully informed
parental consent
Risk Assessment Guidance V2 April 2016
How will these risks be minimised?
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Study team with paediatric expertise
Specific training on the consent/assent process
Age-appropriate information sheets reviewed by a patient
group for levels of clarity and understanding
Central monitoring of consent forms by trial centre (with
statement in the information sheet to ensure explicit
consent for this activity)
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b) Protecting participants' personal data
It is essential that personal data collected in the course of any clinical trial, even if collected with the
consent of the individual, are held securely and are only accessed by authorised staff.
Some issues to be considered in the assessment (this list is not comprehensive):
 Are particularly sensitive data being collected?
 Are personal identifiers associated with the data?
 Are data being transferred between organisations?
 Will consent to access and use the data be obtained?
 Are data to be sent outside the Australia? Are data protection laws equivalent?
 Will consent be given to share the data with third parties (if relevant)?
 Are the data security measures appropriate?
 Is there any risk of harm associated with dissemination of results?
Example
RISKS TO PARTICIPANTS' RIGHTS - Protection of Personal Data
Risk
Specify concerns
Breach of
confidentiality
Identifiable data
transferred out of
Australia
How will these risks be minimised?
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Confidentiality agreement in place between the hospital
and the US institution undertaking the analysis
Computer security systems assessed
Patient consent sought - An explicit statement that data
processing will take place in the US added to the
Participant Information Sheet/Consent Form
PART 4: DEFINING RISKS TO DATA INTEGRITY
In general, the more robust the design, the less dependence there is on quality control and assurance
measures to secure reliable results.
Appropriate procedures to manage and monitor each trial should be established during trial design and
documented in trial management, statistical analysis and monitoring plans,1 and, where relevant, in a
DSMB charter.
a) Features of a robust design
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Outcome measures which are objective and simple to assess accurately
Effective masking of the intervention when assessing the outcome (when objective outcome
measures cannot be used)
A properly generated randomisation schedule and robust allocation concealment
A simple intervention that is difficult to apply incorrectly
b) Risks to the reliability of results
Method of randomisation (if applicable):
1
For very simple trials, the trial management and monitoring plans may be incorporated within the protocol
Risk Assessment Guidance V2 April 2016
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Is a robust method in place to generate and periodically confirm the randomisation schedule?
Does the method of random allocation of treatment arm prevent prediction before a patient is
entered into the trial? For example: centralised randomisation by telephone or web; by
allocation of a treatment pack held in pharmacy rather than sealed envelopes stored in clinic;
avoidance of known block sizes, particularly in an open label study
Masking of the intervention (if applicable):
 Who needs to be blinded? For example, participant, clinician, coordinators, outcome assessor.
 Could there be any unwarranted or warranted un-blinding in the course of the trial? Consider
potential impacts of who has access to randomisation schedule, methods for emergency unblinding, etc.
Intervention:
 What is the complexity/potential for error (e.g. complex chemotherapeutic regimen with
multiple drugs, different doses and dose-adjustments)?
 Is the process of dose escalation clear (if applicable)?
 What is the likelihood of non-adherence, and its potential impact?
Outcome measures:
 Degree of objectivity – Is there a potential for standardised assessment with validated
methods?
 Is there a potential for simple external verification (e.g. death certificate, copy of an
investigation report)?
 Is there a potential for unbiased adjudication or review masked to treatment allocation – e.g.
Central, blinded assessment of investigations, Independent Endpoint Review?
Completeness of follow-up:
 What is the duration, intensity and complexity of procedures (i.e. the extent to which they differ
from normal care of the patient group)?
 What is the likelihood of non-adherence, and its potential impact?
c) Data collection and handling methods that may help improve data quality
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Well-designed, unambiguous and tested case report forms (CRFs), whether paper or electronic,
that focus on the essential data required for the particular trial
Procedures that ensure a timely flow of data from investigator sites, and checks of the data, as
they are received
A user-friendly, validated database (e.g. Electronic Data Capture [EDC] system)
Data verification and validation (e.g. a database containing in-built range and consistency checks)
Data management and transfer methods that ensure an audit trail is maintained from the primary
data to the database, and from the database to the analysis files (with changes that are controlled,
attributable, and properly authorised).
Valid analyses using appropriate techniques; this may be facilitated by the development of a
statistical analysis plan that is peer-reviewed and endorsed by the trial oversight committees
Quality control checks of statistical outputs (and publication)
Risk Assessment Guidance V2 April 2016
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Example
RISKS TO DATA INTEGRITY
Risk
Specify concerns
Strict eligibility
criteria and complex
study requirements
Increased risk of
ineligible
participants being
entered/ protocol
violations
How will these risks be minimised?
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Central review of eligibility prior to randomisation by faxed
form containing key de-identified data
Protocol-specific training delivered at start-up meeting
Periodic monitoring visit to include checks of clinical
records of eligibility/endpoint data
Annual investigator meeting with issue resolution session
and top-up training
Guidance adapted with kind permission from the MRC/DH/MHRA Joint Project: Risk-adapted Approaches to the
Management of Clinical Trials
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APPENDIX I – RISK ASSESSMENT FORM
The purpose of this form is to assist Investigators define and map the risks associated with a
proposed clinical trial. It is recommended that this risk assessment is undertaken before the
funding application (if applicable) and in parallel with the development of the trial protocol.
Protocol Name/No:
Investigator:
Sponsor:
PART 1: DEFINE THE PATIENT JOURNEY
Detail all locations (public or private) where trial related activity will be conducted (e.g. consent,
treatment/intervention, assessment and follow-up)
SCHEDULE
LOCATION
(Public or private)
DESCRIPTION OF THE TRIAL RELATED
ACTIVITY AND FACILITIES
Add additional rows as required
Risk Assessment Guidance V2 April 2016
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STAFF
MEMBER
PART 2: DEFINE THE RISK CATEGORY FOR THE MEDICINAL
PRODUCT(S)/DEVICE(S)/INTERVENTION(S) BEING TESTED
Justification
Type A = Risk comparable to
standard medical care
Type B = Risk somewhat higher
than standard medical care
Type C = Risk markedly higher
than standard medical care
Part 2a: DEFINING THE ADDITIONAL RISKS ASSOCIATED WITH THE USE OF THE
DRUG(S)/DEVICE(S)/INTERVENTION(S) WHEN COMPARED WITH STANDARD TREATMENT
Adequate systems in place to deal with the risks associated with the
drug(s)/device(s)/intervention(s) as part of standard care (usually only Type A Trials)
Otherwise, please outline any risks that have been identified and describe the mitigating actions
planned (e.g. availability of emergency resuscitation equipment, additional monitoring etc.)
Drug/Device
Body System/Hazard
How will these risks be minimised?
Add additional rows as required
Part 2b: DEFINING THE RISKS POSED BY ADDITIONAL STUDY PROCEDURES REQUIRED BY
THE PROTOCOL WHEN COMPARED WITH STANDARD CARE
Risk
Specify concerns
How will the risks be minimised?
Add additional rows as required
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Part 2c: FOR DRUG/DEVICE TRIALS ONLY: DEFINING PLANS FOR ONGOING SAFETY
MONITORING
Will a Data Safety Monitoring Board (DSMB) be convened?
Yes
No
If no, please justify and describe any alternative plans for the ongoing safety
monitoring of the drug/device (e.g. independent data review/medical monitor)
PART 3: RISKS TO PARTICIPANTS' RIGHTS
3a The Consent Process
Risk
Specify concerns
How will the risks be minimised?
Add additional rows as required
3b Protection of Personal Data
Risk
Specify concerns
How will the risks be minimised?
Add additional rows as required
PART 4: RISK TO DATA INTEGRITY
Risk
Specify concerns
How will the risks be minimised?
Add additional rows as required
Investigator's signature: ____________________________________
Risk Assessment Guidance V2 April 2016
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Date: ___________________