CRP 106 Lecture 12 Flashcards
Inspections: Health Canada purpose
Main purpose of inspection is to ensure compliance with
regulations, to ensure clinical trial conducted according to
approved protocol, data generated are accurate, participants not
exposed to undue risk and trial conducted according to GCP.
Audit vs Inspection
Audit: “a systematic and independent examination of trial related activities and
documents to determine whether the evaluated trial related activities were
conducted, and the data were recorded, analysed and accurately reported according
to the protocol, sponsor’s standard operating procedures (SOPs), Good Clinical
Practice, and the applicable regulatory requirement(s)”
* Inspection: “The act by a regulatory authority (authorities) of conducting an
official review of documents, facilities, records and any other resources that are
deemed by the authority (ies) to be related to the clinical trial and that may be
located at the site of the trial, at the sponsor, and/or Contract Research Organization
(CRO) facilities, or other establishment deemed appropriate by the regulatory
authority(ies).”
Notice of Inspection and Duration
Scheduled inspection: provided notice typically 1 to 2 weeks in
advance
* For cause (unscheduled) inspection: will show up at site
unannounced
* Inspections typically last 1 week (M-F) but can last longer if issues
identified
* Typically 1 inspector, but may have more if larger study or
inspector is in training
* Once notice provided, will be given a pre-inspection package
Remote Compliance Verification
- These are a new method of oversight conducted by Health Canada.
- Provide virtual access to study information for review.
- Unrated but can lead to an actual inspection if issues observed.
Site Selection
Number of trials being conducted at study site
* Status of trials being conducted at site (active vs. closed)
* Note a strategic difference between Health Canada and FDA
* Number of participants enrolled in the trial
* The drug(s) involved in the trial(s)
* Number of sites where the trial(s) is being conducted (single site vs.
multisite)
* If the sponsor/qualified investigator/contract research organization has
been previously inspected and compliance history
Inspector’s Review
- Identify key personnel and delegated responsibilities and review
their training, education and experience - Review correspondence with Health Canada and REB to ensure
- REB has provided approval of the trial
- REB has approved all amendments to study documents
- Review informed consent form
- Ensure risk/benefit listed as requested by Health Canada and REB
- Ensure all required items are included in ICF
- Ensure all ICFs are signed by participant (or legally responsible individuals)
and person obtaining consent prior to being enrolled in the study - Ensure appropriate version of ICF was signed by all participants
- Review documents to ensure investigator has adhered to
protocol/amendments and appropriately reviewed by Health Canada
and REB - Ensure that participants enrolled met inclusion/exclusion criteria listed in
protocol - Ensure appropriate transcription of source data to CRFs
- Ensure all adverse events recorded, managed and reported as
required - Review of all IP information to ensure accurate
- Ensure appropriate supervision of medical care is provided by
qualified investigator - Ensure medication stored and handled according to GMP
requirements, labelled appropriately - Review monitor correspondence to ensure all observations are
addressed - NB: more items than listed can be reviewed. This is not an
exhaustive list. - Equipment preventative maintenance and calibration records
Locations of Inspections
- Inspection can occur at numerous different sites where research is
conducted/supported including - Sponsor
- Qualified Investigator (clinical trial site)
- Sponsor/Investigator
- Research Ethics Board
- Contract Research Organization
- Can also occur at Site Management Organization, testing laboratory,
other location as deemed necessary - Inspections are done in person
- Remote compliance verification are occurring online.
During Inspection
Inspector will typically request a tour / walk through of facility. This
is typically the path the participant would take in the study.
* Will review documents pertinent to the conduct of the study
* Will meet with key personnel to verify their role in the study and
answer questions they may have
* Visit any key facilities eg: Pharmacy, Clinical Lab, etc
* Observations will be made as deviations from Division 5
Inspection Observations
- Each observation made will be confirmed in writing during exit
notice/meeting - Each observation made classified as
- Critical (Risk 1)
- Major (Risk 2)
- Minor (Risk 3)
Critical Observations (Risk 1)
- Observation of situations that result in fatal, life-threatening, or
unsafe conditions for participants enrolled in study - Presents immediate or latent risk to rights, health or safety of
participants - Conducting unauthorized studies, adulteration, misrepresentation,
and falsification of records
Critical Observations - Examples
- Sponsor imported drug for purpose of clinical trial without having
received authorization from Health Canada to import (ie: obtained NOL) - Failure to notify Health Canada after amendment implemented in cases
where the clinical trial endangered the health of trial participants or
other persons - Sponsor withholding data (eg: for purposes of deception)
- No record of serious adverse drug reactions which occurred inside
and/or outside of Canada - No records maintained with respect to drug being used in a clinical trial
- No record with respect to enrollment of clinical trial participants
Major Observations (Risk 2)
- Constitutes a marked deviation or deficiency, other than a critical
one, that may result in undue health risks to the clinical trial
participant or other persons or could invalidate the data - NB: Major observations can be reclassified as critical depending on
nature or extent of observation
Examples of upgraded findings - Widespread deficiencies eg:
- Lack of evidence that informed consent was obtained for most participants
enrolled in the clinical trial - Significant deviations from inclusion/exclusion criteria that could endanger
health of participants - Isolated issues would remain as major observations
Major Observations - Examples
REB issues – eg: voting members not independent of QI, major
amendments only provided expedited review, no written guidance as
per GCP, no continuing review
* Amendment implemented (not for safety) prior to obtaining
authorization
* QI does not have appropriate qualification to conduct study
* Medical care and decisions not under supervision of QI
* Failure to obtain REB approval or protocol and ICF prior to initiation of
trial
* Informed consent not obtained prior to enrollment or after major
amendment to informed consent form
* Sponsor did not notify QIs of SUADRs occurring at other sites
* QI did not notify sponsor and/or REB in timely manner of SUADRs
* Significant clinical endpoints not collected in timely fashion, not
correctly recorded, not accurately transcribed to CRF
* Inadequate systems to maintain drug accountability
* Storage or handling controls for IP were inadequate
* Inadequate monitoring of clinical trial site by sponsor
* Those conducting study do not have appropriate training,
education, experience to conduct assigned tasks
* Electronic systems were not validated and no security procedures
in place for systems and no audit trails
Minor Observations (Risk 3)
- Observations not classified as critical or major but which indicate
deficiency and/or deviation from Division 5
Minor Observations (Risk 3) examples
- Delay in notification by sponsor within 15 of change that requires
notification - Incomplete delegation/signature log
- Corrections not initialled and dated
- Minor errors in transcription from source to CRF
- Source documents stored in unsecure location
- Labelling does not comply with Division 5
