Regulatory issues in PET drug development and standardization of PET imaging

Transcription

1 NSFC/CAS/JSPS International Workshop Frontier of Translational Medicine: Molecular Imaging Dec 6, 2014 Regulatory issues in PET drug development and standardization of PET imaging Michio Senda, MD PhD 千田道雄, Kobe, Japan ( 先端医療中心 ) ( 神戸 ) (Chairman of the JSNM Molecular Imaging Strategic Committee) 1. PET is special. Contents 2. Regulations and challenges in PET drug development in Japan 3. JSNM s activity: standardization and qualification program 1

2 1. PET is special. PET is special PET drugs are short lived. Often manufactured within hospitals or in small labs Manufactured in multiple sites and batches Released and injected before sterility test PET images depend on camera/scanning parameters, which influence Image quality and quantification Image interpretation and diagnostic capability 2

3 Example Measurement of radiochemical purity with radiohplc 11 C-PET drug Radioactivity Radiochemical Impurities? Radiochemical purity =96.8% Retention time PET is special PET drugs are short lived. Often manufactured within hospitals or in small labs Manufactured in multiple sites and batches Released and injected before sterility test Quality standards Quality assurance GMP PET images depend on camera/scanning parameters, which influence Image quality and quantification Image interpretation and diagnostic capability 3

4 Effect of reconstruction parameter upon the images for the identical acquired data FDG-PET in a patient with lung cancer Mediastinal metastasis Tumor SUVmax = 11.1 SUVmax SUVmax = 8.9 = 7.3 Partial Volume Effect Spatial resolution 4mm FWHM 8mm FWHM 12mm FWHM Reconstruction parameter affects image resolution and noise. IBRI PET is special PET drugs are short lived. Often manufactured within hospitals or in small labs Manufactured in multiple sites and batches Released and injected before sterility test Quality standards Quality assurance GMP PET images depend on camera/scanning parameters, which influence Image quality and quantification Image interpretation and diagnostic capability Standardization Harmonization Qualification 4

5 Development of new PET drugs Preclinical study Clinical trial / research Regulatory approval Reimbursement Clinical practice Rules vary from country to country. PET is special. Confusion Obstacle, as drug development is getting global, and as more (therapeutic) drug companies are getting involved. 2. Regulations and challenges in PET drug development in Japan 5

6 PET drug regulations in Japan (i) In-house PET drug is out of regulation as a drug. (ii) Radiosynthesizer for in-house production of a PET drug is subject to approval as a medical device. Other rules in Japan (iii) Approval is closely linked to reimbursement, which covers the entire nation. (iv) Formal clinical trial (Chiken) and investigator-driven clinical research are on strictly different tracks. In-house FDG Cyclotron FDG synthesizer (Approved device) F Device Package Insert, Academia s guideline QC test Non-GMP FDG (In-house drug) Hospital /Clinic Clinical practice PETscan (Reimbursed) Commercially delivered FDG Pharma factory Hospital /Clinic Cyclotron F GMP for commercial drug Clinical practice Drug Package Insert, QC test Delivery Academia s guideline FDG synthesizer FDG Pharma PETscan JP (Approved drug) (Reimbursed) In-house PET drug for investigator sponsored research Cyclotron RI Radiosynthesizer (Unapproved device) (Single or multi purpose) Non-GMP Academia s guideline QC test 11 C-methionine etc PET drug (In-house drug) Hospital /Clinic MHLW Guideline (Ethics review, etc) PETscan Research (ISS) 6

7 Formal clinical trial (Chiken) Usually sponsored by industry Pharmaceutical Affairs Law (PAL) applies. CTN is submitted to / accepted by PMDA. (CTN=Japanese IND, PMDA=Japanese FDA) PET drugs are chiken drugs (IMP), and produced based on GMP. Synthesizers are chiken devices. Clinical trial is done based on GCP. Data are to be used for PMDA approval. GAP Investigator-driven clinical research Academic Research PAL does not apply to in-house made new PET drugs produced with unapproved synthesizers, fitting in with academic research track. Only ethics guideline (2009) applies. Local ethics committee. Informed consent. etc. Data not to be used for PMDA approval. MHLW guideline for microdose (2008) MHLW notice on ICH-M3(R2) consensus preclinical guideline (2010) Investigational drug GMP revised (2008) applicable to lab-based short-lived drugs. Contract manufacturing is permitted. Drugs can be delivered to other sites. Drugs cannot to be delivered to other sites. Transport of radionuclides permitted only under Radionuclide Law. Current situations and challenges As a result of the Japanese regulations, production of PET tracers for in-house use is easy, both for clinical research using unapproved synthesizers and reimbursed diagnostic scans using approved FDG synthesizers, whereas delivery to other hospitals/clinics is difficult due to necessity of GMP and regulatory approval as a drug. Only one commercial production network exists. Number of PET centers in Japan 147 with cyclotron 357 in total (Aug, 2014) { 210 without cyclotron Hotlabs of most PET centers do not comply with GMP. 7

8 Approved PET drugs and synthesizers in Japan (Nov 2014) PET drug approved as a drug: F-FDG PET drugs, for which approved synthesizers are available: 15 O-CO 2, 15 O-O 2, 15 O-CO F-FDG 13 N-NH 3 F-florbetapir July 2014 FDG and FDG synthesizers are approved for oncology, epilepsy, and heart disease, (there are restrictions; details omitted), but not for dementia, infection/inflammation. In-house FDG Cyclotron Designated FDG synthesizer approved (Approved device) synthesizer Rules are changing F Device Package Insert, Academia s JSNM s standards guideline QC test PET FDGdrug (In-house drug) GMP Non-GMP by JSNM Hospital /Clinic Clinical practice PETscan (Reimbursed) Commercially delivered FDG Pharma factory Hospital /Clinic Cyclotron F GMP for commercial drug Clinical practice Drug Package Insert, QC test Delivery Academia s guideline FDG synthesizer FDG Pharma PETscan JP (Approved drug) (Reimbursed) In-house PET drug for investigator sponsored research Cyclotron RI Radiosynthesizer (Unapproved device) (Single or multi purpose) Non-GMP Academia s guideline QC test 11 C-methionine etc PET drug (In-house drug) Hospital /Clinic MHLW Guideline (Ethics review, etc) PETscan Research (ISS) 8

9 3. JSNM s activity: standardization and qualification Japanese Society of Nuclear Medicine JSNM activity 1. Standardization of in-house produced PET drugs and qualification of production sites a. QA guideline for in-house PET drug production (JSNM s GMP) (Oct 2011). b. Standardization of quality specifications and testing methods for specific PET drugs: 11 C-methionine (Feb 2014), F-florbetapir, F-flutemetamol, F-florbetaben (in preparation), upgrading old non-gmp standards. c. Training programs for JSNM s GMP (2012-). d. Site qualification program for in-house PET drug production by QA audit and 3 batch data. NIRS designated as an auditing organization (Apr 2013). Six PET centers/drugs qualified so far. e. Applicable to clinical practice using designated approved synthesizer ( F- florbetapir with NEPTIS) (Aug 2014). Japanese Society of Nuclear Medicine 9

10 JSNM activity 2. Standardization, harmonization of PET scanning and qualification of PET imaging sites/cameras a. Standardization of imaging procedure and harmonization criteria of scanning protocol for specific PET scans: brain 11 C-methionine (Mar 2013), brain FDG and amyloid (Aug 2013), whole-body FDG (public comment version). Standardized procedure covers: subject preparations, standard injected activity, accumulation time, standard scanning time, image interpretation criteria, and phantom criteria for determination of reconstruction parameters for each camera. b. Site and scanner qualification program for specific PET scans by questionnaire, audit and phantom data. IBRI and MICRON designated as auditing organization. Six PET centers/scanners qualified so far. Applicable to clinical practice under pledge to continue maintenance and calibration. c. Training program for scanning standardization and site/scanner qualification. d. Training program for interpretation of brain amyloid images. Japanese Society of Nuclear Medicine Scanner qualification phantom for brain imaging with 11 C-methionine Visualization of 7.5mm sphere Contrast for 7.5mm sphere 13% Resolution RC 10mm >0.45 Quantitative capability for BG ±5% Uniformity for BG ±5% CT PET 38mm 5mm 27mm 16mm 7.5mm 10mm Japanese Society of Nuclear Medicine 10

11 Scanner qualification phantoms for brain FDG and amyloid* (*using 11 C-PiB, F-Florbetapir, F-Flutemetamol) Resolution FWHM 8mm %Contrast 55% Uniformity ±5% Statistical noise 15% Hoffman 3D brain phantom Uniform phantom Japanese Society of Nuclear Medicine Effect of reconstruction parameters (Hoffman phantom) iteration subset

12 Effect of reconstruction parameters (Human FDG image) iteration subset 8 24 Scanner qualification phantom for whole body FDG imaging Visualization of 10mm sphere NEC phantom 10.8 Mcounts Background variability N 10mm <5.6% S/N Q H,10mm / N 10mm > 2.8 Relative RC 10mm > 0.38 (FWHM<10mm) Quantitative capability in BG < ±5% Uniformity in BG area ±10% Public comment version SUV range for each sphere NEMA body phantom (Sphere/BG = 4/1) Japanese Society of Nuclear Medicine 12

13 Conclusions PET is special, but patients are the same. To make PET a universal tool, standardization crucial. To make PET data reliable, quality assurance is essential. JSNM is standardizing the PET drugs and PET scanning and has launched site qualification programs to facilitate regulatory approval and reimbursement. 13