Quality Control in Standardized Clinical Trials

1. Quality Control in Standardized Clinical Trials

2. “Oh, Say, Can I See Your QC?” CTN 107

3. 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.

4. Regulations & Guidelines about Quality Control of Imaging and Radiopharmacy Equipment

5. 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.”

6. “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.

7. 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

8. 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

9. 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.

10. “ 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. “

11. 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.”

12. 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

13. Dose Calibrator QC The Dose Calibrator time clock should ALWAYS match the PET Scanner time clock. GET ONE !

14. 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

15. 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

16. 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

17. 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

18. Glucometer Quality Control (Daily)

19. 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.

20. 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).

21. 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.

22. 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

23. PET/CT Daily Quality Control Na-22 Source

24. 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!

25. PET/CT Uniformity Phantom Required by most manufacturers: Monthly and Annually

26. Phantom and Table Must Be Level !!!

27. Monthly SUV and Uniformity Validation

28. PET-CT Quality Control Log

29. 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.

30. CT Daily Quality Control

31. 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

32. CT Daily QC Scan Uniformity – ROIs distributed in homogeneous material should indicate consistent signal (HUs) and noise

33. 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)

34. CT Daily QC scan • Accuracy of Water Calibration • Image Noise • Uniformity • Artifacts

35. CT Weekly QC Scan • HU calibration check – Water – Air – Teflon • Hounsfield Unit Calibration – ROI means – ROI standard deviation range - mAs setting accuracy

36. CT Weekly QC Scan con’t. • kVp, mAs exercising – Filament adaptation – Collimation • MTF & Slice thickness – Physics layer • Check error log

37. CT Monthly/Semi-Annual QC Scan • Slice Thickness • Slice Positioning • Laser Alignment • CT Scale • Resolution • Low Contrast Resolution • Dosimitry

38. LAP Laser Alignment Phantom Lasers are mounted on the walls and ceiling of the scanner room

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

40. Jaszczak/ACR Phantom

41. International Conference on Harmonization of Good Clinical Practices (ICH E6)

42. (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.

43. 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.

44. – 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.

45. General Responsibilities of Investigators (21CFR312:SEC.312.60)

46. 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.

47. (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.

48. 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.

49. 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.

50. 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