Quality Control in Standardized Clinical Trials

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Quality Control in Standardized Clinical Trials
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Oh, Say, Can I See Your QC?

• CTN 107

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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.

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Regulations Guidelines about Quality Control of
Imaging and Radiopharmacy Equipment
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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.

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• 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
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• QC failure of imaging and radiopharmacy equipment
  represents
• Potential loss of data
• Inability to provide accurate quantification
• Wastes our patients time
• Lack of standardization from site to site
• Energy

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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
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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.

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• 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.

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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.

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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
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Dose Calibrator QC
The Dose Calibrator time clock should ALWAYS
match the PET Scanner time clock.
GET ONE !
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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
  ?-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
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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
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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,
  ATA0e(-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
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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
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Glucometer Quality Control (Daily)
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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.

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Imaging Equipment Quality Control

• If frequency varies from the above, justification
  must be based on scientific data or
  manufacturers recommendation.
• If a less frequent schedule is being used, there
  must be clear documentation of the justification
  (such as based on scientific data).

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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.

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PET/CT QC

• Blank scan - Daily
• Normalization - After a hardware change or per
  manufacturers recommendations
• Absolute Activity Calibration - After a hardware
  change or per manufacturers recommendations
• Preventive Maintenance - Every 6 months, or per
  manufacturers recommendations

Icanl.org
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PET/CT Daily Quality Control
Na-22 Source
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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!
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PET/CT Uniformity Phantom
Required by most manufacturers Monthly and
Annually
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Phantom and Table Must Be Level !!!
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Monthly SUV and Uniformity Validation
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PET-CT Quality Control Log
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CT Daily QC

• Normal operations include the following 3 tasks
  (in order)
• 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.
• 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.
• Uniformity - ROIs distributed in homogeneous
  material should indicate consistent signal (HUs)
  and noise.

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CT Daily Quality Control
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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
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CT Daily QC Scan

• Uniformity ROIs distributed in homogeneous
  material should indicate consistent signal (HUs)
  and noise

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Are All CTs Created Equal?

• A CT Protocol is comprised of
• Surview ( scout, pilot, scan-o-gram)
• Helical or Conventional Prescribed Scan
• Reconstructions
• MPRs (sag/coronal)

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CT Daily QC scan

• Accuracy of Water Calibration
• Image Noise
• Uniformity
• Artifacts

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CT Weekly QC Scan

• HU calibration check
• Water
• Air
• Teflon
• Hounsfield Unit Calibration
• ROI means
• ROI standard deviation range
• - mAs setting accuracy

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CT Weekly QC Scan cont.

• kVp, mAs exercising
• Filament adaptation
• Collimation
• MTF Slice thickness
• Physics layer
• Check error log

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CT Monthly/Semi-Annual QC Scan

• Slice Thickness
• Slice Positioning
• Laser Alignment
• CT Scale
• Resolution
• Low Contrast Resolution
• Dosimitry

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LAP Laser Alignment Phantom
Lasers are mounted on the walls and ceiling of
the scanner room
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Patient Positioning
Inform your vendor if using special appliances
such as flat pallet and wing board for treatment
planning
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Jaszczak/ACR Phantom
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International Conference on Harmonization of Good
Clinical Practices (ICH E6)
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• (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.

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• 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.

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• 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.

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General Responsibilities of Investigators
(21CFR312SEC.312.60)
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• 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.

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• (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.

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• 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.

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• If your departmental QC procedures vary from the
  manufacturers recommendations, provide reference
  documentation for why your procedures are
  adequate.
•  I. The pharmaceutical sponsor may or may not be
  an expert in imaging technology.
•  

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• Investigate image artifacts immediately, before
  releasing the patient. Check for real-time QC
  failures, such as motion artifact, attenuation
  artifact, dose infiltration artifact, etc.
• 1. If corrective actions are taken (such as
  motion correction software), document what was
  done and why.
• 2. Save all original data

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III. Some Differences Between Clinical QC and
Research QC
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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.

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• 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
• .

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• 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

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• G. If the sponsor does not detail specific QC
  requirements but states perform routine QC as
  recommended by the manufacturer, provide
  documentation of the manufacturers QC
  recommendations

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SUV Phantom Vendor Phantom (Monthly) (Bi-Monthl
y)
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• 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
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• Quality Control Data is
• 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.

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Virtual Scopics Research Phantom-Counts
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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!!!!
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(No Transcript)
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Site Acceptance Letter

• From "Mr. Big ltmbig_at_virtualscopics.comgt
• To xxxxx_at_ aol.com
• Date 1/15/2010 349 PM
• Subject Novartis ABCD1234 Site 0514
• Notification of Final Qualification- PET
• Dear ltparticipantgt,
• 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.
• ltYour Institutiongt 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

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QUESTIONS ????
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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