Transcript Quality Control for Standardized Clinical Trials

Quality Control in Standardized Clinical Trials
“Oh, Say, Can I See Your QC?”
CTN 107
Presentation Objectives
At the conclusion of this discussion, participants
will be able to:
 Describe why accurate documentation of QC
procedures is important in clinical trials.
 List three differences between routine and clinical
QC and QC used for a clinical trial.
 Create a list of questions about QC that should be
answered by the sponsor or trial organizers prior
to patient enrollment.
Regulations & Guidelines about Quality Control
of Imaging and Radiopharmacy Equipment
Introduction to the Topic
Quality Control of imaging and
radiopharmacy equipment is important to
sponsors, FDA, IRB, and our patients.
“The Food and Drug Administration also
reviews study plans before the trial begins, as
well as during the trial.
The FDA and ethics committees have neither
fame nor fortune at stake and can shut down
clinical trials if the risk for participants
becomes greater than expected.”
QC of imaging equipment is fundamental to the goal of
image standardization in imaging and therapy trials.
“Only 50% of submitted imaging data in a large
industry trial was able to used because of poor quality
and sites making changes to the protocol”
QC failure of imaging and radiopharmacy equipment
represents:
a) Potential loss of data
b) Inability to provide accurate quantification
c) Wastes our patient’s time
d) Lack of standardization from site to site
e) Energy
General QC Protocol Info
• To ensure standardized operation the facility must have
and follow site-specific written protocols that accurately
describe the details for all procedures performed within
the facility.
Icanl.org
Quality Control: Definition
The operational techniques and activities
undertaken within the quality assurance system
to verify that the requirements for quality of the
trial related activities have been fulfilled.
“ There is NOT a specific regulation that requires
sites to perform adequate quality control for
research protocols, but the need for excellence
is implied in many of the good clinical practice
documents. “
Declaration of Helsinki
“Medical research involving human subjects must
conform to generally accepted scientific
principles, be based on a thorough knowledge of
the scientific literature, other relevant sources of
information, and adequate laboratory and, as
appropriate, animal experimentation.”
General QC Protocol Info
• Protocols must be organized for easy use (such as in
notebook form with a table of contents) and be readily
accessible to appropriate staff members during
operational hours.
• Where appropriate, records must be maintained to
document compliance with protocols. (e.g.
radiopharmaceutical receipt/disposal records, spill records
etc.).
• Availability of protocols in digital format is desirable.
Icanl.org
Dose Calibrator QC
The Dose Calibrator time clock should ALWAYS match
the PET Scanner time clock.
GET ONE !
Constancy
• Constancy is performed daily by the nuclear medicine
technologist and assesses instrument reliability from day to
day.
– A Cesium-137 sealed radiation vial (or other γ-emitting sealed
radiation source) greater than 50 µCi is placed in the calibrator well.
• The radionuclide activity is recorded by the technologist and
compared with prior day activities and the decayed accuracy
readings to ensure acceptability.
– The daily constancy readings should be between ± 5% of the decay
corrected accuracy readings.
www.eradimaging.com
Linearity
• Linearity procedures assess the instrument's ability to
measure a range of low-activity doses to high-activity
doses accurately and are performed quarterly.
– A dose of a high-activity, short-lived radionuclide is used and
assayed over a given period. Actual measures are compared
with calculated decayed activities and should be within ± 5%.6
• The Cali check System may also be used to perform the
linearity procedure in a shorter period of time.
– With the Cali check System, lead attenuation sleeves are used
to simulate decay of the radionuclide.
www.eradimaging.com
Accuracy
• Accuracy is a quality control measure performed annually,
and is an assessment of the validity of the calibrator's activity
reading compared with the activity of a calibrated sealed
source.
– Two sealed radiation sources greater than 50 µCi and one with an
energy between 100 to 500 keV are assayed 3 times each and
averaged.
• The average activity readings for the sources are compared
with the decay corrected calibrated activity.
– The decay equation is used for the correction, AT=A0e(-0.693T/T1/2);
AT = activity after time T, A0 = initial activity, T = elapsed time, and
T1/2 = half-life. The calculated activity and the average activity
reading should be within ± 5% of each other.
www.eradimaging.com
Geometry
• Geometry is a quality control procedure performed during
installation and only performed during acceptance testing or if
the calibrator is relocated or repaired.
– Geometry ensures the ability of the instrument to accurately measure
activities in different configured containers such as a syringe, vial, or pill.
• A given amount of radionuclide is assayed in a syringe and the
activity is recorded. Next, small increments of saline are added
to the syringe to increase the volume and the activity is
measured.
– The activity should remain fairly consistent regardless of the changing
volume, again within ± 5%.6 Often, this procedure is performed with all
the dose configurations used in the department.
www.eradimaging.com
Glucometer Quality Control (Daily)
Imaging Equipment
Quality Control
• If imaging equipment is physically moved from
site to site, (other than planar mobile gamma
cameras or non-PMT mobile planar/SPECT
cameras used within a building) these items
must be repeated after each move and prior to
equipment use.
Imaging Equipment Quality Control
• If frequency varies from the above, justification
must be based on scientific data or
manufacturer’s recommendation.
• If a less frequent schedule is being used, there
must be clear documentation of the justification
(such as based on scientific data).
Imaging Equipment
Quality Control
• Energy peaking and uniformity testing must be
appropriate for the energy of the radioisotopes
being imaged (e.g. low energy and medium
energy).
• Initial acceptance results should be retained and
used for comparison.
PET/CT QC
• Blank scan - Daily
• Normalization - After a hardware change or per
manufacturer’s recommendations
• Absolute Activity Calibration - After a hardware change or
per manufacturer’s recommendations
• Preventive Maintenance - Every 6 months, or per
manufacturer’s recommendations
Icanl.org
PET/CT Daily Quality Control
Na-22 Source
Phantom Integrity
No Cracks !!
No Dents
!!
No Glue
!!!
Any & All Phantom integrity
issues MUST be reported to the
manufacturer and the Vendor
during clinical trials!
PET/CT Uniformity Phantom
Required by most manufacturers:
Monthly and Annually
Phantom and Table Must Be Level !!!
Monthly SUV and Uniformity Validation
PET-CT Quality Control Log
Restart
Host
DATE
Dose Cali. Time
Clock / PET
1-Mar-09
Daily PET QC
CT Tube Conditioning
CT QC
Air Calibration ( x
3/wk)
RTP LASER ALIGNMENT
CT Impulse Response
CT Slice Width
"Success"
2-Mar-08
3-Mar-08
4-Mar-08
5-Mar-08
6-Mar-08
(cont’d)
WEEKLY
System Shut
Down
DATE
3-Mar-08
10-Mar-08
17-Mar-08
24-Mar-08
31-Mar-08
MONTHLY -
DATE
PET Uniformity
24-Mar-08
CT Phantom
Pins
CT Daily QC
Normal operations include the following 3 tasks (in order):
1. Tube Warm-up- A built-in prep scan that gradually increases heat loading
in the X-ray tube in order to prevent thermal cracking and eliminate the
potential for an arc to occur. It includes a series of exposures made at
incrementing kVp.
2. Daily Air Cals- A built-in prep scan that performs a series of exposures at
varying techniques in order to normalize the detector response using air
as the attenuating media. These scans essentially adjust the detector
gains to achieve a uniform response.
3. Uniformity - ROIs distributed in homogeneous material should indicate
consistent signal (HUs) and noise.
CT Daily Quality Control
CT Daily QC Phantom
Linearity - Linear attenuation coefficients tracked linearly with a specific material
density
The mean CT numbers of air (-1000 HU), water (0 HU), and acrylic (120 HU) displayed
within an ROI should be consistent with the defined value +/- manufacture specified
tolerance
CT Daily QC Scan
Uniformity – ROIs distributed in homogeneous material
should indicate consistent signal (HUs) and noise
Are All CTs Created Equal?
A CT Protocol is comprised of:
• –Surview ( scout, pilot, scan-o-gram)
• –Helical or Conventional Prescribed Scan
• –Reconstructions
• –MPR’s (sag/coronal)
CT Daily QC scan
• Accuracy of Water Calibration
• Image Noise
• Uniformity
• Artifacts
CT Weekly QC Scan
• HU calibration check
– Water
– Air
– Teflon
• Hounsfield Unit Calibration
– ROI means
– ROI standard deviation range
- mAs setting accuracy
CT Weekly QC Scan con’t.
• kVp, mAs exercising
– Filament adaptation
– Collimation
• MTF & Slice thickness
– Physics layer
• Check error log
CT Monthly/Semi-Annual QC Scan
•
•
•
•
•
•
•
Slice Thickness
Slice Positioning
Laser Alignment
CT Scale
Resolution
Low Contrast Resolution
Dosimitry
LAP Laser Alignment Phantom
Lasers are mounted on the walls
and ceiling of the scanner room
Patient Positioning
Jaszczak/ACR Phantom
(2.10) All clinical trial information should be
recorded, handled, and stored in a way that
allows its accurate reporting, interpretation, and
verification.
(2.13) Systems with procedures that assure the
quality of every aspect of the trial should be
implemented.
The research patient is in your department.
You discover the sponsor specific QC procedure
that was supposed to be performed within five days
of the participants imaging session was instead
performed at ten days. What do you do?
Even if the calibration value was normal, the
sponsor must be notified since it will be
considered a protocol deviation.
– Document the situation for the sponsor, and
initial and date the note.
– Create a plan within the department to make
sure the QC is performed with the study
specific guidelines.
The investigator is responsible for and agrees to:

Ensure an investigation is conducted according
to the signed investigator statement

The investigational plan

Apply regulations for protecting the rights,
safety, and welfare of subjects under the
investigator's care

Control of drugs under investigation.
2.
(Form FDA 1572): “I agree to conduct the
study(ies) in accordance with the relevant,
current protocol(s) and will only make changes
in a protocol after notifying the sponsor, except
when necessary to protect the safety, rights, or
welfare of subjects.
3. Following the protocol, including requirements
for quality control, is key to image
standardization between sites.
Investigator record keeping and record retention
21CFR312 Sec. 312.62
(c)Record retention. An investigator shall retain records
required to be maintained under this part for a period
of 2 years following the date a marketing application is
approved for the drug for the indication for which it is
being investigated;
or, if no application is to be filed or if the application is not
approved for such indication, until 2 years after the
investigation is discontinued and FDA is notified.
H. If your departmental QC procedures vary from
the manufacturer’s recommendations, provide
reference documentation for why your
procedures are adequate.
I. The pharmaceutical sponsor may or may not be
an expert in imaging technology.
J. Investigate image artifacts immediately, before
releasing the patient. Check for “real-time” QC
failures, such as motion artifact, attenuation
artifact, dose infiltration artifact, etc.
K.
1. If corrective actions are taken (such as
motion correction software), document what
was done and why.
2. Save all original data
Considerations for Research QC
A. If you are not able to sit in on the PI Training Module then
read the protocol thoroughly. Ask the sponsor, if not
specified, “Are there additional QC procedures?”
B. Document QC performed for each patient study, and
archive the daily and weekly QC with the patient data so
it can be retrieved easily if there is a question.
C. Carefully document deviations from the QC required by the
protocol, or deviations to your usual departmental QC.
D.
In the radiopharmacy, document routine QC on
instrumentation, or document where it can be located for
an FDA audit.
E. Use proper record-keeping and documentation processes
1. Record primary data on source document records;
sign and date all entries
2. Do not erase, use white-out, or otherwise cause an
entry to be illegible.
3. All errors should be indicated with a line-through the
entry, the correct entry written to the right or above the
original, and the initials and date of the person who made
the correction
.
F. Some research protocols will require more than usual QC
(for example, uniformity floods more frequently than required
by camera manufacturer, or additional acquisitions to
determine detector sensitivity or resolution)
1. If a specific quantification protocol will be used
2. If imaging data is being sent to a central reader
3. If the isotope used in unusual or if standard
radiopharmacy QC protocols do not assure quality of the
investigational product
• G. If the sponsor does not detail specific QC
requirements but states “perform routine QC as
recommended by the manufacturer”, provide
documentation of the manufacturer’s QC
recommendations
SUV Phantom
Vendor Phantom
(Monthly)
(Bi-Monthly)
Imaging Quality Control is required as part of the
clinical protocol, QC data may be submitted to the
FDA as part of the New Drug Application Process
Clinical Trial Phantom
Quality Control Data is:
B. Subject to potential audit by the FDA if it is collected as part of
the research protocol.
C. Considered a protocol violation, if not performed properly,
which are detailed in the final study report; depending upon
the seriousness of the omission, the patient data may not be
evaluable.
D. Some research protocols will not require more QC procedures
than are routinely performed by the imaging department. In
that case, detailed records should be kept of all QC that
pertains to the patient being imaged on study.
Virtual Scopics Research Phantom-Counts
Considerations for Research QC
• Dose Calibrators (daily, weekly, annual)
• Gluco- meters (daily)
• PET Scanner (daily, monthly, annual)
• CT Scanner (daily, monthly, annual)
ALWAYS perform QC BEFORE the patient
procedure is started!!!!
Clinical Trials Research Quality Control Log
MCGHI PET-CT DEPT
Clinical Trial
ACRIN
NOVARTIS - A
NOVARTIS - B
Novartis - C
Infinity - A
AUY
CCRU RN
R.C.
J.W.
R.C.
J.W.
C.S.
J.W.
Pathology Type
Lung
Lymphoma
NHL
Melanoma
NSCLC
Solid Nodule
Initial Date
(qc)
QC Requirement
Initial &
Monthly
Initial & Quarterly
Phantom Used
VS (Virtual
Scopics)
VS
QC Date
10/22/2008
(qc)
dmg
3/20/2009
Initial & Quarterly
Initial & Pt
Acq.
"Test" patient and
SUV
Phantom
VS
VS
None
(qc)
10/01/2009
(pt1) 10/30/2008
(pt)
10/14/2009
(pt1) 12/16/2008
(qc)
1/22/2010
(pt2) 12/18/2008
(pt3) 12/22/2008
Initial
VS
dmg
Site Acceptance Letter
From: "Mr. Big” <[email protected]>
To:
xxxxx@ aol.com
Date:
1/15/2010 3:49 PM
Subject: Novartis ABCD1234 : Site: 0514
Notification of Final Qualification- PET
Dear <participant>,
Thank you for submitting the First Subject PET-CT Images on the XXXXX
Scanner for the Novartis ABCD1234 study. These images have passed
our internal Quality Inspection.
<Your Institution> has now completed the Final Qualification Process
for PET. We sincerely appreciate you and your site's efforts throughout this
qualification process. Virtual-Scopics is very excited to be working with you.
Best regards,
Mr. Big
Associate, Site Management
QUESTIONS ????
Resources for PET and PET/CT QC
• Manufacturers’ manual
• NEMA NU-2 Publications 2007, 2001 & 1994 AAPM rpt.
72 ACR
• Karp J.L. et. al., JNM 32 (12), 1991
• Buchert R. et. al., JNM 40 (10), 1999
• Geworski L., JNM 43 (5), 2002
• Bailey et. al. “Positron Emission Tomography – Basic
Science”
• Cherry SR & Dahlbom M, in Phelps ME “Molecular
Imaging”