Bringing your projects to a higher level.

1. Bringing your projects to a higher level.

2. Introductions of Cato Team Company Profile Today’s Presentation Agenda

3. Cato Research Team Andrée Lefebvre, B.Sc. RAC Director, Regulatory Affairs & Assistant Managing Director Cato Research Canada Christine Warrington Global Strategic Sales and Marketing Headquarter Office Durham, NC

4. Company Profile We are a full-service contract research and development organization with global resources dedicated to helping pharmaceutical and biotechnology companies efficiently and expeditiously navigate the drug development process in order to bring new drugs, biologics, and medical devices to the people who need them.

5. Cato Research • Full service financially stable global drug development company headquartered in RTP, NC. Global presence. • Founded in 1988 -20 year anniversary • Over 300 Employees • Project teams lead by Ph.Ds and MDs • Established Cato Research Drug Fellowship Program • Clients include pharmaceutical, biotechnology, venture capital and academia

6. Therapeutic Expertise • Oncology • Neurology/Psychiatry • Cardiology • Gastroenterology • Dermatology • Endocrinology/Metabolic Disorders • Infectious Disease • Immunology • Hematology • Ophthalmology • Nephrology • Pulmonology • Rheumatology • Vascular Disorders • Anesthesiology and Pain • Rare Diseases

7. Collaborations PolandRomania Russia Ukraine India Worldwide Locations Cologne, Germany Riga, Latvia Montreal, Canada Frankfurt, Germany Graz, Austria Boston, MA San Francisco, CA Szeger, Hungary Washington, MD Zagreb, Croatia San Diego, CA Durham, NC Tel-Aviv, Israel Johannesburg, South Africa

8. Clinical Trial Services - Phases 1 to 4 Pharmacovigilance Medical Monitoring Data Management Biostatistics Regulatory Quality Assurance Chemistry, Manufacturing, and Controls (CMC) Nonclinical Strategic Consulting Full Service Development Services

9. Quality Assurance Best Practices in a Good Laboratory Practice Environment

10. First, a few words from the wise… The basic concepts underlying quality systems are quite simple: Say what you do, do what you say, prove it and improve it Janet Woodcook, M.D. Director, Center for Drug Evaluation and Research FDA

11. Why do we need GLP? • In the 1950's, 1960's and 1970's, Industrial Bio-Test Laboratories (IBT) performed about 35-40% of all U.S. toxicology testing • Of 867 audits of IBT performed by the FDA under the 1962 law, 618 studies were invalid due to numerous discrepancies between the study conduct and data • FDA sued and the courts found four IBT managers guilty of fraud • As a result of the IBT incident, the FDA decided to regulate laboratory testing • In 1976, the FDA GLP guidelines were proposed; they were finalized in 1978 and became effective in 1979

12. Good Laboratory Practice for Nonclinical Laboratory StudiesTitle 21 Code of Federal Regulations Part 58 • The goal is to demonstrate SAFETY of test article before use in humans • Do controlled, well-documented laboratory studies • Use prospective and approved protocols • Document testing methods and findings • Provide Quality Assurance review

13. GLP Subpart A –– GENERAL PROVISIONS GLP Subpart B –– ORGANIZATION AND PERSONNEL GLP Subpart C –– FACILITIES GLP Subpart D –– EQUIPMENT GLP Subpart E –– TESTING FACILITIES OPERATION GLP Subpart F –– TEST AND CONTROL ARTICLES GLP Subpart G –– PROTOCOL FOR AND CONDUCT OF STUDY GLP Subparts H-I –– [RESERVED] GLP Subpart J –– RECORDS AND REPORTS GLP Subpart K –– DISQUALIFICATION OF TESTING FACILITIES Organization of GLPs

14. The 10 Commandments of GLP • Thou shalt appoint study directors and quality assurance • Thou shalt be competent, as a result of education, training and experience • Honor thy protocol and thy SOPs • Thou shalt conduct studies in adequate and clean facilities • Thou shalt identify test and control articles and document their use

15. The 10 Commandments of GLP 6. Thou shalt maintain and calibrate equipment according to a specified schedule 7. Thou shalt document and correct all deviations 8. Thou shalt not commit fraud; all thy work thou shalt note, sign and date 9. Thou shalt have archives 10.Thou shalt not turn your back on the FDA

16. A Few Definitions • Nonclinical laboratory study • in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety • NOT studies utilizing human subjects, clinical studies, field trials in animals, basic exploratory studies for utility, for determining physical or chemical characteristics of a test article

17. A Few Definitions (cont.) 4 important parts of a GLP study • Sponsor • Management • Study Director (SD) • Quality Assurance Unit (QAU)

18. A Few Definitions (cont.) • Sponsor • A person who initiates and supports a study with financial or other resources • A person who submits a nonclinical study to FDA • A testing facility, if it both initiates and actually conducts the study

19. A Few Definitions (cont.) • Management • Designates a study director before the study starts • Replaces the study director promptly if necessary during the study • Assures that there is a quality assurance unit • Assures that test and control articles or mixtures are tested for identity, strength, purity, stability, and uniformity

20. A Few Definitions (cont.) • Management (continued) • Assures that personnel, resources, facilities, equipment, materials, and methodologies are available as scheduled • Assures that personnel clearly understand the functions they are to perform • Assures that any deviations from these regulations reported by the quality assurance unit are: • communicated to the study director • and corrective actions are taken and documented

21. A Few Definitions (cont.) • Study Director • Scientist of appropriate education, training and experience • Responsible for overall technical conduct of a nonclinical laboratory study and for the interpretation, analysis, documentation and reporting of results • Assures that all study records are archived at the end of the study

22. A Few Definitions (cont.) • Quality Assurance Unit • any person or organizational element, designated by management to perform the duties relating to QA of nonclinical laboratory studies

23. §58.15 Inspection of a testing facility • A testing facility SHALL permit FDA to inspect the facility and to inspect (and copy) all records and specimens • Except • quality assurance unit records of findings, or corrective actions recommended and taken • FDA will not consider a study for a marketing permit if the testing facility refuses to permit inspection and the applicant still must submit the results of the study to FDA!

24. §58.35 Quality Assurance Unit • Duties • QAU monitors each study to assure management that all systems are in conformance with GLP regulations • QAU shall be entirely independent of personnel conducting a particular study

25. §58.35 Quality Assurance Unit (cont.) • Duties • The quality assurance unit shall: • Maintain a master schedule sheet of all studies, indexed by test article and listing these elements: • test system, nature of study, study initiation date, current status, sponsor identity, and name of the study director

26. §58.35 Quality Assurance Unit (cont.) • Duties • Maintain copies of all GLP protocols • Inspect each nonclinical laboratory study at adequate intervals; maintain written signed records of periodic inspections • Bring to the attention of the study director and management immediately any problems found during an inspection that may affect study integrity

27. §58.35 Quality Assurance Unit (cont.) • Duties • Periodically submit to management and to the study director written status reports on each study, noting problems and corrective actions taken • Determine that no deviations from approved protocols or standard operating procedures were made without authorization and documentation

28. §58.35 Quality Assurance Unit (cont.) • Duties • Review the final study report to assure accuracy in description of methods and Standard Operating Procedures, and that results accurately reflect the raw data of the study • Prepare and sign a statement specifying dates of inspections and when findings were reported to management and study director

29. The QAU SOPs (and related) • Topics: • GLP Training • QA training within the GLP environment • Structure of the QAU, e.g. • Inspection group, archiving group, validation group • QA Reporting Systems, e.g. • To respond to QA findings • To report to management (including trend analysis)

30. The QAU SOPs (and related) • Topics (continued): • Good documentation practices • “Inspection” of computer systems • QA Master Schedule • Archiving procedures (including off site archiving) • Disaster recovery plan • Data Audit

31. Good Documentation Practice • Documentation should permit the complete reconstruction of a study • Record data directly, promptly and legibly in indelible ink (never pencil) • Initial and date all observations and any resulting changes, but do not obscure original data • Initial and date only work you’ve performed • Do not document selectively or in advance of performing the activity

32. Good Documentation Practice • Do not use white-out correction fluid or tape • Do not use ditto marks as raw data • Copy all heat sensitive paper and stamp “exact copy” • Explain why any raw data not used was not used • Verify critical calculations using a second person and document this • Notebook pages requiring a second signature shall be completed with that signature

33. Good Documentation Practice • Properly head all pages, tables, columns; identify units • Describe Statistical & Calculation Procedures used • Sign, Date, and File automated printouts (e.g., QC forms) • Retain all Raw Data (original records) in the Study File • Do not document by exception. Use positive documentation, even if only a check mark.

34. Good Documentation Practice • Documentation must allow another person to be able to accurately reconstruct what you have done • Keep all original observationsincluding those observations recorded directly into a computer • Sign and date all computer printouts • Never back-date anything • Follow SOPs and Protocol

35. Good Documentation Practice • Document all deviations with accompanying explanations • Indicate in the record all applicable units and equipment used

36. Raw Data Correction • All changes to raw data must be made without obscuring the original entry • All changes must be initialed and dated by the person making the change, accompanied by an explanation for the change

37. Abbreviations for Reasons

38. Now, you have selected a CRO…

39. The due diligence starts…

40. Reference:Compliance Program Guidance for FDA Staff • BIMO – Bioresearch Monitoring • 7348.808 Good Laboratory Practice (Nonclinical Laboratories) – FDA version • 7348.808A Good Laboratory Practice Program (Nonclinical Laboratories) – EPA Data Audit Inspection

41. Bottom Line… • 7348.808 Good Laboratory Practice (Nonclinical Laboratories) is FDA’s instruction manual for its inspectors’ use when they “audit” your GLP facility or study(ies) • Be pro-active, and make sure you know what they’ll want to see

42. INSPECTIONALGeneral Instructions • Determine the current state of GLP compliance by evaluating the laboratory facilities, operations, and study performance • Organization Chart - If the facility maintains an organization chart, obtain a current version of the chart for use during your inspection

43. INSPECTIONALGeneral Instructions (cont.) • Facility Floor-plan – • Obtain a diagram of the facility • Identify any areas that are not used for GLP activities • Use the floor plan during the inspection to ensure that it is really up-to-date

44. INSPECTIONALGeneral Instructions (cont.) • Master Schedule Sheet • Obtain a copy of the firm's master schedule sheet • Determine who decides if a study is a GLP study • FDA 483’s • Obtain a copy and review findings

45. Areas of Expertise of the Facility • Testing facilities may conduct one or more types of GLP studies. • Physical-chemical testing • Toxicity studies • Mutagenicity studies • Tissue residue depletion studies • Analytical and clinical chemistry testing • Other studies (specify)

46. SOP Evaluation • Review the SOP index and representative samples of SOPs to ensure coverage of all of the areas identified in GLPs • Verify that only current SOPs are available at the personnel workstations • Review key SOPs in detail and check for proper authorization signatures and dates, and general adequacy with respect to the content (i.e., SOPs are clear, complete, and can be followed by a trained individual)

47. SOP Evaluation (cont.) • Verify that changes to SOPs are properly authorized and dated and that a historical file of SOPs is maintained • Ensure that there are procedures for familiarizing employees with SOPs • Determine that there are SOPs to ensure the quality and integrity of data, including input (data checking and verification), output (data control), and an audit trail covering all data changes

48. SOP Evaluation (cont.) • Verify that a historical file of outdated or modified computer programs is maintained. If the firm does not maintain old programs in digital form, ensure that a hard copy of all programs has been made and stored. • Verify that SOPs are periodically reviewed for current applicability and that they are representative of the actual procedures in use • Review selected SOPs and observe employees performing the operation to evaluate SOP adherence and familiarity

49. If the firm has computerized operations, determine… • Who was involved in the design, development, and validation of the computer system? • Who is responsible for the operation of the computer system, including inputs, processing, and output of data? • Determine whether computer system personnel have training commensurate with their responsibilities, including professional training and training in GLPs.

50. If the firm has computerized operations, also determine… • Whether some computer system personnel are contractors who are present on-site full-time, or nearly full-time • Include these contractors as though they were employees of the firm • Specific inquiry may be needed to identify these contractors, as they may not appear on organization charts • Interview and observe personnel using the computerized systems to assess their training and performance of assigned duties