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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.

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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.



Introduction to the Topic and Radiopharmacy Equipment

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.”


“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 of imaging equipment is fundamental to the goal of image standardization in imaging and therapy trials.


QC failure of imaging and radiopharmacy equipment represents:

Potential loss of data

Inability to provide accurate quantification

Wastes our patient’s time

Lack of standardization from site to site

Energy


General qc protocol info
General QC Protocol Info represents:

  • 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 represents:

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 to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

“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 info1
General QC Protocol Info to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • 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 to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

The Dose Calibrator time clock should ALWAYS match the PET Scanner time clock.

GET ONE !


Constancy
Constancy to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • 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 to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • 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 to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • 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 to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • 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) to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “


Imaging equipment quality control
Imaging Equipment to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “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 control1
Imaging Equipment Quality Control to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • 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 control2
Imaging Equipment to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “ 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
PET/CT QC to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • 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 to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

Na-22 Source


Phantom Integrity to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

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 to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

Required by most manufacturers:

Monthly and Annually


Phantom and Table Must Be Level !!! to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “


Monthly SUV and Uniformity Validation to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “


PET-CT Quality Control Log to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “


Ct daily qc
CT Daily QC to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

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.


CT Daily Quality Control to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “


CT Daily QC Phantom to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

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
CT Daily QC Scan to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

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


Are All CTs Created Equal? to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

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 scan1
CT Daily QC scan to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • Accuracy of Water Calibration

  • Image Noise

  • Uniformity

  • Artifacts


Ct weekly qc scan
CT Weekly QC Scan to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • HU calibration check

    – Water

    – Air

    – Teflon

  • Hounsfield Unit Calibration

    – ROI means

    – ROI standard deviation range

    - mAs setting accuracy


Ct weekly qc scan con t
CT Weekly QC Scan con’t. to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • kVp, mAs exercising

    – Filament adaptation

    – Collimation

    • MTF & Slice thickness

    – Physics layer

    • Check error log


Ct monthly semi annual qc scan
CT Monthly/Semi-Annual QC Scan to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

  • Slice Thickness

  • Slice Positioning

  • Laser Alignment

  • CT Scale

  • Resolution

  • Low Contrast Resolution

  • Dosimitry


LAP Laser to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “Alignment Phantom

Lasers are mounted on the walls and ceiling of the scanner room


Patient Positioning to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “

Inform your vendor if using special appliances such as flat pallet and wing board for treatment planning


Jaszczak acr phantom
Jaszczak/ACR Phantom to perform adequate quality control for research protocols, but the need for excellence is implied in many of the good clinical practice documents. “



(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. handled, and stored in a way that allows its

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 handled, and stored in a way that allows its

initial and date the note.

– Create a plan within the department to make

sure the QC is performed with the study

specific guidelines.


General responsibilities of investigators 21cfr312 sec 312 60
General Responsibilities of Investigators handled, and stored in a way that allows its (21CFR312:SEC.312.60)


The investigator is responsible for and agrees to: handled, and stored in a way that allows its

  • 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.


(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 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.

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.


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.


  • 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


Iii some differences between clinical qc and research qc
III. Some Differences Between Clinical QC and Research QC the patient. Check for “real-time” QC failures, such as motion artifact, attenuation artifact, dose infiltration artifact, etc.


Considerations for Research QC the patient. Check for “real-time” QC failures, such as motion artifact, attenuation artifact, dose infiltration artifact, etc.

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.


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



SUV Phantom Vendor Phantom but states “perform routine QC as recommended by the manufacturer”, provide documentation of the manufacturer’s QC recommendations

(Monthly) (Bi-Monthly)


Clinical Trial Phantom but states “perform routine QC as recommended by the manufacturer”, provide documentation of the manufacturer’s QC recommendations

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


Quality Control Data is: but states “perform routine QC as recommended by the manufacturer”, provide documentation of the manufacturer’s QC recommendations

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 but states “perform routine QC as recommended by the manufacturer”, provide documentation of the manufacturer’s QC recommendations


Considerations for Research QC but states “perform routine QC as recommended by the manufacturer”, provide documentation of the manufacturer’s QC recommendations

ALWAYS perform QC BEFORE the patient

procedure is started!!!!

Dose Calibrators (daily, weekly, annual)

Gluco- meters (daily)

PET Scanner (daily, monthly, annual)

CT Scanner (daily, monthly, annual)


Site acceptance letter
Site Acceptance Letter but states “perform routine QC as recommended by the manufacturer”, provide documentation of the manufacturer’s QC recommendations

From: "Mr. Big” <[email protected]>

To: [email protected] 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
QUESTIONS ???? but states “perform routine QC as recommended by the manufacturer”, provide documentation of the manufacturer’s QC recommendations


Resources for pet and pet ct qc
Resources for PET and PET/CT QC but states “perform routine QC as recommended by the manufacturer”, provide documentation of the manufacturer’s QC recommendations

  • 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”


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