1. Bringing your projects to a higher level.
Add the company between the green lines. You can just type their name if they don’t have a website. Open by
Bringing your projects to a higher level.

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

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
Now that we have had a opportunity to formally introduce ourselves, let’s talk a look specifically at your project and the opportunities that exist between our two organizations.

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.
Established in 1988, Cato research has established themselves as a full service integrated drug development company that offers innovative and creative regulatory strategies as well as all phases of clinical development in both US and International Clinical trials. The Cato Family is comprised of 320 employees worldwide that have provided our high caliber customized services throughout the industry. Our highly qualified project tams of ph.d’s and mds consistently exhibit an adaptable structure within Cato to allow for the flexibility and responsiveness the sponsor needs. Cato Research is a full-service contract research and development organization with international resources dedicated to helping pharmaceutical and biotechnology companies efficiently and expeditiously navigate the regulatory approval process in order to bring new drugs, biologics, and medical devices to the people who need them. We are proud of our company and its role in helping sponsors achieve success in creating better health for people everywhere, and we would like to share more information about Cato Research with you.

5. Cato Research
Full service financially stable global drug development company headquartered in RTP, NC. Global presence.
Founded in 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
62 Employees in europe south Africa and Israel 82 professionals in CTO with 8 MD’s on our staff. Cato Reseach was established
Cato research was established in 1988 as a full service integrated drug development company that offers innovative and creative regulatory strategies as well as all phases of global clinical drug development .
The Cato Family is comprised of over 300 employees worldwide that provide high caliber customized services throughout the industry. Our highly qualified project teams of ph.d’s and mds consistently exhibit an adaptable structure within Cato to allow for the flexibility and responsiveness the sponsor needs.
At Cato Research our people are dedicated to helping pharmaceutical and biotechnology companies efficiently and expeditiously navigate the regulatory and drug development approval process in order to bring new drugs, biologics, and medical devices to the people who need them.
Of particular interest to the success of our people is the Cato Drug Development Fellowship Program where over 600 applicants have produced some of the best trained individuals working within Cato but also some of our strongest ambassadors in the healthcare community for our organization.
We are proud of our company and its role in helping sponsors achieve success in creating better health for people everywhere, and we would like to share very specific examples of our work.

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
We have successfully conducted to date over 350 trials successfully utilizing our full international capabilities.. We

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

8. Full Service Development Services
Clinical Trial Services - Phases 1 to 4
Pharmacovigilance
Medical Monitoring
Data Management
Biostatistics
Regulatory
Quality Assurance
Chemistry, Manufacturing, and Controls (CMC)
Nonclinical
Strategic Consulting
From early development through late-phase trials, CATO offers the entire range of integrated product development services you need. No matter where your point of entry in to our resources, CATO will craft a customized program providing seamless access to our full range of development services to meet your specific needs.

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. The goal is to demonstrate SAFETY of test article before use in humans
Good Laboratory Practice for Nonclinical Laboratory Studies Title 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. Organization of GLPs 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

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 observations including 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
Notation
Meaning
Definition EE
Erroneous Entry
Entry of a wrong number or incorrect word SP
Spelling Error
Entered word is misspelled RD
Repeated Data
Data are already correctly entered elsewhere MC
Miscalculation
Number shown is the result of a miscalculation NL
Not Legible
Entry is illegible or has been overwritten
OE-OK
Original Entry OK
Ignore single line cross-off
STET

38. Now, you have selected a CRO…

39. The due diligence starts…

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

41. Bottom Line…
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. INSPECTIONAL General 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. INSPECTIONAL General 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. INSPECTIONAL General 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

51. Equipment Computers
For computer systems, assess that the following procedures exist and are documented:
Validation study, including validation plan and documentation of the plan's completion
Maintenance of equipment, including storage capacity and back-up procedures
Control measures over changes made to the computer system, which include the evaluation of the change, necessary test design, test data, and final acceptance of the change

52. Equipment Computers (cont.)
Evaluation of test data to assure accurate transmission and proper handling when analytical equipment is directly interfaced to the computer
Procedures for emergency back-up (e.g., battery system and data forms for recording data in case of computer failure or power outage)

53. Storage and Retrieval of Records
Determine how and where computer data and backup copies are stored, that records are indexed in a way to allow access to data stored on electronic media, and that environmental conditions minimize deterioration

54. Storage of Computer Records
Determine to what electronic media such as tape cassettes or ultra high capacity portable discs the test facility has the capacity of copying records in electronic form
Report names and identifying numbers of both copying equipment type and electronic medium type to enable agency personnel to bring electronic media to future inspections for collecting exhibits

55. Assess the procedures by which the study director:
Is assigned and replaced
Assures the protocol and any amendments have been properly approved and are followed
Assures that all data are accurately recorded and verified
Assures that data are collected according to the protocol and SOPs

56. Assess the procedures by which the study director also:
Documents unforeseen circumstances that may affect the quality and integrity of the study and implements corrective action
Assures that study personnel are familiar with and adhere to the study protocol and SOPs
Assures that study data are transferred to the archives at the close of the study

57. QAU Operations Ratio QA employees to all employees (5 to 8%)
Review and verify QAU SOPs to assure that they cover all methods and procedures for carrying out the required QAU functions, and confirm that they are being followed:
Maintenance of a master schedule sheet
Maintenance of copies of all protocols and amendments
Scheduling of its in-process inspections and audits

58. QAU Operations (cont.)
Inspection of each nonclinical laboratory study at intervals adequate to assure the integrity of the study, and maintenance of records of each inspection
Immediately notify the SD and management of problems likely to affect the INTEGRITY of the study
Submission of periodic status reports on each study to the SD and management

59. QAU Operations (cont.) Review of the final study report
Preparation of a statement to be included in the final report that specifies the dates inspections were made and findings reported to management and to the SD
Inspection of computer operations
Training

60. More scrutiny of QAU
Verify that, for any given study, the QAU is entirely separate from and independent of the personnel engaged in the conduct and direction of that study
Evaluate the time QAU personnel spend in performing in-process inspection and final report audits
Determine if the time spent is sufficient to detect problems in critical study phases and if there are adequate personnel to perform the required functions

61. Facilities
Document any conditions that would lead to contamination of test articles or to unusual stress of test systems
Determine that computerized operations and archived computer data are housed under appropriate environmental conditions (e.g., protected from heat, water, and electromagnetic forces)

62. Equipment (other than computers)
For representative pieces of equipment check the availability of the following:
SOPs and/or operating manuals
Maintenance schedule and log
Standardization/calibration procedure, schedule, and log
Standards used for calibration and standardization

63. Testing Facilities Operations
Determine if the testing facility has established and follows written SOPs necessary to carry out study operations in a manner designed to ensure the quality and integrity of the data (including method validation)
Determine if the testing facility has appropriate controlled storage for study samples
Determine if the testing facility maintains and calibrates instrumentation as per SOPs

64. Animal Care
Purpose: To assess whether animal care and housing are adequate to minimize stress and uncontrolled influences that could alter the response of test system to the test article
Inspect typical animal room(s) that will be housing your study

65. Animal Care (cont.)
Review pest-control procedures and documentation of the chemicals used. Identify individuals responsible for the program. When a contractor provides the pest control, determine if someone from the laboratory accompanies the exterminator at all times.
Determine whether the facility has an Institutional Animal Care and Use Committee (IACUC). Obtain and submit a copy of the Committee's SOPs and most recent committee minutes to verify committee operation.

66. Test and Control Articles
Characterization and Stability of Test Articles - The responsibility for carrying out appropriate characterization and stability testing may be assumed by the facility performing the study or by your company
If you intend to perform the test article characterization and stability testing, verify that the test facility has the procedure in place to document that this testing will have been conducted according to GLP (or GMP)

67. Archiving
Determine the number of archive locations – waterproof? Fireproof?
Determine who is the individual assigned as archivist
Verify method of indexing and the time period when documents/slides/computer data are archived after completion of the study

68. Your audit report Classify your findings
Critical, major, minor or observations
Provide a compliance assessment statement
Summarize your audit and request a response within 30 days

69. Remembering an FDA Inspection…

70. A Big…
Thank you