Quality Control in Standardized Clinical Trials. CTN 107 “Oh, Say, Can I See Your QC?”

Quality Control in Standardized Clinical Trials

CTN 107

“Oh, Say, Can I See Your QC?”

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.

Presentation Objectives

Regulations & Guidelines about Quality Control of Imaging 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.”

Introduction to the Topic

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

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.

Quality Control: Definition

“ 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. “

“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.”

Declaration of Helsinki

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

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

GET ONE !

Dose Calibrator QC

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

Na-22 Source

PET/CT Daily Quality Control

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

DATERestart Host

Dose Cali. Time Clock / PET

Daily PET QC CT Tube Conditioning CT QC

1-Mar-09     "Success"    

2-Mar-08          

3-Mar-08          

4-Mar-08        

5-Mar-08          

6-Mar-08          

(cont’d)           

WEEKLY          

DATE  System Shut Down

 Air Calibration ( x 3/wk)

RTP LASER ALIGNMENT

3-Mar-08          

10-Mar-08          

17-Mar-08          

24-Mar-08          

31-Mar-08          

MONTHLY -          

DATE   PET UniformityCT Phantom Pins

CT Impulse Response CT Slice Width

24-Mar-08          

PET-CT Quality Control Log

CT Daily QCNormal 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

A CT Protocol is comprised of:

• –Surview ( scout, pilot, scan-o-gram)

• –Helical or Conventional Prescribed Scan

• –Reconstructions

• –MPR’s (sag/coronal)

Are All CTs Created Equal?

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, thesponsor must be notified since it will beconsidered a protocol deviation.

– Document the situation for the sponsor, andinitial and date the note.

– Create a plan within the department to makesure the QC is performed with the studyspecific 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

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.

Considerations for Research 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 processes1. 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

• Dose Calibrators (daily, weekly, annual)

• Gluco- meters (daily)

• PET Scanner (daily, monthly, annual)

• CT Scanner (daily, monthly, annual)

ALWAYS perform QC BEFORE the patientprocedure is started!!!!

Considerations for Research QC

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) 10/22/2008   (qc) 3/20/2009    dmg

QC RequirementInitial &

Monthly

 Initial & QuarterlyInitial & Quarterly

Initial & Pt Acq.

"Test" patient and SUV Phantom

  Initial  

Phantom Used VS (Virtual

Scopics)VS VS VS None VS  

QC Date     (qc) 10/01/2009   (pt1) 10/30/2008   dmg

      (pt) 10/14/2009   (pt1) 12/16/2008    

      (qc) 1/22/2010   (pt2) 12/18/2008    

          (pt3) 12/22/2008    

Site Acceptance LetterFrom: "Mr. Big” <[email protected]>To: xxxxx@ aol.comDate: 1/15/2010 3:49 PMSubject: Novartis ABCD1234 : Site: 0514

Notification of Final Qualification‑ PET

Dear <participant>,Thank you for submitting the First Subject PET‑CT Images on the XXXXXScanner for the Novartis ABCD1234 study. These images have passedour internal Quality Inspection. <Your Institution> has now completed the Final Qualification Processfor PET. We sincerely appreciate you and your site's efforts throughout thisqualification process. Virtual-Scopics is very excited to be working with you. Best regards, Mr. BigAssociate, 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”