Quality and GLP for Histology and Pathology of Drug Safety Studies

Transcription

1 Quality and GLP for Histology and Pathology of Drug Safety Studies Roger Alison BVSc MRCVS DiplECVP Consultant Toxicological Pathologist

2 What is Quality Histology? It depends upon the purpose - Answer research questions - Diagnosis - Screening - Support regulatory submissions

3 Quality Regulatory Histology Fitness for the purpose - Acceptability - Reliability - Consistency - Reproducibility - Retrievability

4 Quality Systems - Good Laboratory Practice (GLP) - Others: - Good Clinical Practice (GCP) - Good Manufacturing Practice (GMP) - ISO 9000

5 GLP Definition - GLP is a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, reported and archived.

6 Purpose of GLP - Ensure consistent, reliable standards of safety testing world-wide - Promote the quality and integrity of test data - Improve human and environmental safety

7 Origin of GLP Introduced because of fraud or poor quality work in US in 1970s: - Dead animals reappeared - Tumours disappeared - Inadequate mixing of dose in diets - Inadequate/insufficient documentation - Replacement of animals

8 GLP is necessary... Ethically: prevent fraud, public risk, unnecessary use of animals Economically: avoid waste of time and money Scientifically: avoid acceptance of false results Regulatorily: ensure confidence in regulatory decisions

9 GLP is required for... All studies to assess the safety of: - Drugs and medical devices - Pesticides - Chemicals - Biologicals

10 Personnel Sponsor - Study Monitor Test Facility/Test Site(s) - Management - Study Director/Principal Investigator(s) - Study Personnel - Lead Quality Assurance (facility) - Test Site Quality Assurance Unit(s)

11 Sponsor Commissions and submits GLP work Responsible for: - Ensuring laboratory is GLP compliant - Test material information - Approval of protocol - Archiving if contract laboratory or test facility goes out of business

12 Management Ensure GLP complied with: - Designate a Study Director - Ensure staff are trained and experienced - Ensure adequate resources are available - Approve SOPs - Ensure QA programme exists (and reports to management)

13 Study Director The single point of study control Takes responsibility for the overall conduct of the study and its final report

14 Study Director ensures... - GLP is followed - Adequate trained personnel and suitable equipment - Personnel approve the protocol - Protocol, amendments and SOPs are available to study personnel - Procedures specified in the protocol are followed

15 Study Director ensures... - Unforseen events are noted and assessed - Raw data fully documented - Approves and signs the report - Archives study material promptly on completion of the study

16 Principal Investigator At sites separated from the SD, the PI oversees critical phases of the study - Drafts relevant protocol sections - Ensures work is conducted to GLP and in accordance with protocol and SOPs - Prepares contributing report - Ensures raw data is archived

17 Study Personnel - Know Principles of GLP applicable to their involvement in the study - Ensure their training record is up to date - Follow protocols, SOPs - Report problems, mistakes, unexpected events, and involved in corrective action - Record data promptly, accurately, completely

18 Quality Assurance Independent of study conduct - inspect study at intervals - protocol - in-life data, procedures - report - facilities - Report to management and SD

19 Protocols and SOPs Specify how a study is to be conducted: - What is going to be done - Who will do it - When will it be done - What data will be recorded

20 Protocols and SOPs Protocols (study plans) - Study specific instructions, often linking SOPs and providing timings SOPs: - Standard: routine - Operating: working - Procedures: methods

21 Protocol GLP requires: - A written plan, before start of the study - Verified for compliance by QA - Approved by test facility management (and usually by sponsor) - Approved by dated signature of Study Director

22 Protocol Informs: - Study staff, support staff - Management - Subcontractors, Principal Investigators Confirms responsibilities (by signature): - Study Director - Management - Principal Investigators

23 Protocol Information included: - When animals to be killed - Tissues to be taken at necropsy - Tissues to be processed - Slides made: group, numbers, staining - Slides examined (control, high dose?) - Special techniques - Staff responsible

24 Protocol Deviations Protocol Amendments: (study plans) - Planned changes to the original study design Protocol Deviations: - Omissions or deviations ( errors ) - Should be recorded separately - Not as retrospective amendments - Assessed for significance

25 SOPs Histology SOPs: - Tissue trimming - Sectioning - Staining, including special stains - Equipment maintenance - Records to be kept - Slide shipping - Chain of custody

26 SOPs Guides for organ sampling and trimming in rats and mice:

27 Adrenal Gland Trimming - Through cortex and medulla - 1 per side - Longitudinal

28 Seminal VesicleTrimming - Mid section - 1 per side - TS, with coagulating gland

29 SOPs Benefits: - Consistency (between staff, over time) - Training - Reconstruction of methods used in past - Avoids repetitive documentation of procedures - Problems only have to be solved once

30 Data and Documentation When the study is completed, the data, documentation and samples must completely support what was done It must be possible for a third party to reconstruct the study from what remains

31 Data and Documentation Identifies: - Who did it? - When was it done? - What was done? - What were the results? - Documents that SOPs and protocol were followed

32 Data and Documentation Raw Data: - Original records (or verified copies) of original observations and activities in the study - Recorded directly, promptly, accurately, legibly and identified by who did it.

33 Data and Documentation Raw Data: - Original records (or verified copies) of original observations and activities in the study - Recorded directly, promptly, accurately, legibly and identified by who did it.

34 Histology Documentation - Tissues taken - Tissues trimmed - Tissues in block - Tissues on slide - Staining procedures - QC check done

35 Histology Quality Pathologist s niggles: - Same blocking pattern every time, e.g. ovaries/uterine horns/cervix/vagina - No unnecessary extra sections - No mixing slides of different thickness - Same stain colour for control and treated

36 Histology Materials Specimens (wet tissue, blocks, slides) - Uniquely identified - Retained - Retrievable for future queries

37 Histology Quality Control - Check that activities carried out properly - Check all tissues taken at necropsy - Check slide identification, sectioning, staining - Check tissue on slide - Check data complete, signed - Second person does it! Not QA!

38 Pathology Raw Data - Record of the pathologist s findings for individual animals (when pathology data finalised) - Pathologist s text interpreting the findings - (Possibly) computer file containing study data

39 Pathology Quality Control Peer Review: - Review by a second pathologist of draft report, 10% of animals, all neoplasms, all target organs. - Discussion of Peer Review findings using double header microscope - Final Report with consensus opinion between pathologists

40 Pathology Quality Control Peer Review: - Typically takes two weeks for a carcinogenicity study - Data retained: records of animals and organs examined, consensus achieved - Not about correcting minor variations between pathologists - Best result as a collaborative exercise

41 Pathology Quality Control Pathology Working Group (PWG): - After report finalised, often mouse and rat studies together - Study pathologist, reviewing pathologist, PWG leader, six Experts - Characterise important or controversial findings and assess their significance to humans

42 Study Report - Complete and accurate reflection of protocol and raw data - One study, one report - Reviewed and approved by QA - Signed by responsible people - Date of report and finalisation is date signed by study director

43 Archive - All data and specimens retained after study completion - Secure, limited access - Protected against deterioration - Easily retrievable - Regulations define period of retention, but usually held for useful duration of the compound

44 Computers - Same principles of GLP apply - Suitable for purpose - Raw data defined - Formal validation process of hardware and software before operational use - Maintenance, backup, disaster plan, obsolescence and migration to new system need to be defined

45 Multi-site Studies Multi-site study - Where phases are conducted on more than one site - Phase: a defined set of activities - Test Facility: location of Study Director - Test Sites: locations of other phases - Principal Investigators: carry out duties of study director at test sites

46 Multi-site Studies Protocol - Identify test sites, PI, and phases - How test site data will be included in report SOPs - Selection and monitoring of test site - QA procedures - Chain of custody for data and specimens

47 Multi-site Studies Report - One report for study - Include PI contributions - Include evidence of QA involvement - Define archive location - Indicate degree of GLP compliance - Compliance statement for whole study signed by Study Director

48 Multi-site Studies Practical issues: - Communication (Languages!) - Defining responsibilities - Assessment of test sites - Monitoring and reporting of findings - Chain of custody for samples and specimens

49 Summary GLP is little more than good scientific practice, allowing: - Repeatability - Reconstruction - Peer Review It requires application of the same principles as any good research: - Discipline and Care