1. Good Laboratory Practices & Good Clinical Practices

2. Good Laboratory Practices.

3. Contents: Introduction History Objective Rules and regulation
Noncompliance

4. GLP: GOOD LABORATORY PRACTICE
GLP is an FDA regulation.
Definition: GLP embodies a set of principles that provides a framework within which laboratory studies are planned , performed, monitored, recorded, reported and archived.
GLP is sometimes confused with the standards of laboratory safety like wearing safety goggles.

5. GOOD LABORATORY PRACTICE
GLP applies to nonclinical studies conducted for the assessment of the safety or efficacy of chemicals (including pharmaceuticals).
GLP helps assure regulatory authorities that the data submitted are a true.

6. HISTORY
The formal regulatory concept of “Good Laboratory Practice” (GLP) originated in the
USA in the 1970’s.
The FDA’s publication of Proposed Regulations on GLP in 1976, with establishment of the Final Rule in June 1979 (21 CFR 58).
In 1981 an organization named OECD produced GLP principles that are international standard.

7. WHY WAS GLP CREATED?
In the early 70’s FDA became aware of cases of ( PLP ) poor laboratory practice all over the United States.
FDA decided to do an in-depth investigation in 40 toxicology labs.
They discovered a lot fraudulent activities and a lot of poor lab practices.
Examples of some of these ( PLP ) poor lab practices found were
Equipment not been calibrated to standard form , therefore giving wrong measurements.
Incorrect/inaccurate accounts of the actual lab study
Inadequate plan

8. FAMOUS EXAMPLE
One of the labs that went under such an investigation made headline news.
The name of the Lab was Industrial Bio Test. This was a big lab that ran tests for big companies such as Procter and Gamble.
It was discovered that mice that they had used to test lotion and deodorants had developed cancer and died

9. Industrial Bio Test lab threw the dead mice and covered results deeming the products good for human use.
Those involved in production, distribution and sales for the IBT lab eventually served jail time.

10. OBJECTIVES OF GLP
GLP makes sure that the data submitted are a true reflection of the results that are obtained during the study.
GLP also makes sure that data is traceable.
Promotes international acceptance of tests.

11. MISSION OF GLP Test systems Archiving of records .
Apparatus, material and reagent facilities.
Quality assurance programs.
Performance of the study.
Reporting of study results.
Standard operating procedures (SOP)

12. 21 CFR Part 58: Non-Clinical Laboratory Studies
Subpart A: General Provisions
Subpart B: Organization and Personnel
Subpart C: Facilities
Subpart D: Equipment
Subpart E: Testing Facilities Operation
Subpart F: Test and Control Articles
Subpart G: Protocol for and Conduct of a Non-Clinical Laboratory Study
Subpart J: Records and Reports
Subpart K: Disqualification of Testing Facilities

13. GLP Regulations: Rules and Tools
Chemical and sample inventory, expiration dates
TEST, CONTROL, AND REFERENCE SUBSTANCES
Timely reporting, storage of raw data and reports
RECORDS AND REPORTS
Standard operating procedures
FACILITY OPERATION
Calibration, logbooks of use, repair, and maintenance
EQUIPMENT
Maintain adequate space/separation of chemicals from office areas
FACILITIES
Training records, CVs, GLP training
ORGANIZATION AND PERSONNEL
Documentation (Tools)‏
GLP Regulations (Rules)‏

14. Organization and Personnel
(a)“Each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study shall have education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions.”
(b)“Each testing facility shall maintain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study.”

15. Organization and Personnel
58.33 Study Director
Quality Assurance Unit
“A testing facility shall have a quality assurance unit which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part. For any given study, the quality assurance unit shall be entirely separate from and independent of the personnel engaged in the direction and conduct of that study.”
“For each nonclinical laboratory study, a scientist or other professional of appropriate education, training, and experience, or combination thereof, shall be identified as the study director. The study director has overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation, and reporting of results, and represents the single point of study control.”

16. Facilities
General
“Each testing facility shall be of suitable size and construction to facilitate the proper conduct of nonclinical laboratory studies. It shall be designed so that there is a degree of separation that will prevent any function or activity from having an adverse effect on the study.”
Animal care facilities
Animal supply facilities
Facilities for handling test and control articles
Laboratory operation areas
Specimen and data storage facilities

17. Equipment 58.61 Equipment Design 58.63 Maintenance and Calibration
“Equipment used in ... shall be of appropriate design and adequate capacity ...”
Maintenance and Calibration
(a) “The written standard operating procedures ...”
(b) “Written records shall be maintained ...”
Log book
Fit for use
Not for GLP use.

18. Verification (Testing): external check of equipment accuracy (e. g
Verification (Testing): external check of equipment accuracy (e.g. check balance accuracy against weights at laboratory- no adjustment)‏
Calibration: equipment is adjusted based on comparison to certified or known reference materials (e.g. balance adjusted after comparison to certified weights by trained professional)‏
Standardization: comparison with similar equipment (e.g. use two thermometers of similar design to compare readings)‏
Equipment
Verification?? ??
Calibration ?
Standardization?

19. Protocol , Reports and Records
“Each study shall have an approved written protocol that clearly indicates the objectives and all methods for the conduct of the study.”
Conduct of a Non-clinical Laboratory Study
“The nonclinical laboratory study shall be conducted in accordance with the protocol”
Reporting of Non-clinical Laboratory Study Results
“A final report shall be prepared for each nonclinical laboratory study ...”
Storage and Retrieval of Records and Data
“All raw data, documentation, protocols, final reports, and specimens ... shall be retained.”

20. Raw Data
Definitions. “’Raw data’ means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a study and are necessary for the reconstruction and evaluation of the report of that study.”
If anyone scribble some notes on a scrap of paper, are those notes considered raw data?

21. Raw Data examples of raw data:-
Logbooks (to record temperatures or equipment use, repair, and maintenance)‏
Field or laboratory notebooks
Forms (for field or laboratory observations, chain-of- custody, sample or chemical receipt)‏
Training reports
Computer printouts
Recorded data from automated instruments
Question:
What happens if you make a mistake?
Do not obscure original data!! Instead, draw a single strikeout, then add reason code, initials, and date of change.

22. Standard Operating Procedures (SOP)
40 CFR Part 160 (EPA GLP regulations)‏
“Section Standard operating procedures. (a) A testing facility shall have standard operating procedures in writing setting forth study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study.”
Written procedures for a laboratories program.
They define how to carry out protocol-specified activities.
Most often written in a chronological listing of action steps.
They are written to explain how the procedures are suppose to work

23. Standard Operating Procedures (SOP)
SOPs should accurately reflect how routine tasks are performed
Routine inspection, cleaning, maintenance, testing and calibration.
Actions to be taken in response to equipment failure.
Reviewed on regular basis.

24. What happens if a workplace does not comply with federal Good Laboratory Practice standards?

25. Possible Violations
Falsifying information for permit, registration or any required records
Falsifying information related to testing~ protocols, ingredients, observations, data equipment, ect.
Failure to prepare, retain, or submit written records required by law.

26. Consequences of Noncompliance
The FDA states the following consequences of noncompliance:
The commissioner will send a written proposal of disqualification to the testing facility
A regulatory hearing on the disqualification will be scheduled
If the commissioner finds that after the hearing, the facility has complied, then a written statement with an explanation of termination of disqualification will be sent to the facility
Thus, if it can be shown that such disqualifications did not affect the integrity and outcome of the study itself, or did not occur at all, then the study may be reinstated at the will of the commissioner

27. Upon Disqualification…
If the commissioner finds that the facility showed a noncompliance, any of the grounds after the hearing, then a final order of noncompliance will be sent to the facility with explanations
If a testing facility has been disqualified, any studies done before of after the disqualification will need to be determined as essential to a decision (acceptable or not)
If the study is determined unacceptable, then the facility itself may need to show that the study was not affected by the noncompliance that led to the disqualification
Once finally disqualified, the facility may not receive or be considered for a research or marketing permit and the study is rejected.

28. Upon Disqualification…
The commissioner may notify the public and all interested persons, including other federal agencies the facility may have contacted
The FDA may ask the other agencies to consider whether to support the facility or not under the disqualification
Civil or criminal proceedings may occur at the discretion of the commissioner
Fines of up to $50,000 if one knowingly commits crime and/or 1 year imprisonment~ for registration applicants and producers
Fines up to $5,000 all others~ civil penalty after failing to improve after a minor violation warning was issued~ only those involved in testing will be given civil penalties
Those involved in the distribution or sales will be assessed more heavy penalties, such as criminal penalties

29. Upon Disqualification…
The FDA may turn it over to the federal, state or local law enforcement
The facility’s sponsor may terminate or suspend the facility from doing any non- clinical study for a permit
The sponsor is required to notify the FDA in writing within 15 working days that the facility is to be suspended or terminated and why

30. Reinstatement of a Disqualified Facility
The commissioner will inspect the facility and determine if it shall be reinstated
If it is reinstated, the commissioner is required to notify all persons that were notified of the disqualification including the facility itself

31. Good Clinical Practice

32. Contents Glossary Principles of GCP IEC/IRB Responsibilities
Investigator Responsibilities
Sponsor Responsibilities
Protocols and Amendments
Investigator’s Brochure
Essential Documents

33. Glossary Adverse drug reaction (ADR) Serious Adverse Event (SAE) Audit
Blinding/masking
Investigator
Protocol
Sponsor

34. History of Good Clinical Practice
Prior to an actual set of guidelines to follow for good clinical practice, clinical studies were dangerous and could result in serous disease, or possibly death.
The Nuremburg Code of 1947
Experiments performed in Germany during WWII opened the eyes of the world for guidance for clinical testing on humans.
The code did set ethical guidelines, but it lacked legislation to back it up.
Declaration of Helsinki
In 1964, the World Medical Association established recommendations guiding medical doctors in biomedical research involving human subjects. These guidelines influenced national legislation, but there was no set standard between nations.

35. GOOD CLINICAL PRACTICE
FDA
ICH
21 CFR
International
Electronic Docs.
Inf. Consent
Financial Disclosure
IRBs
IND regs.
glossary
principles
IRBs
Investigator
Sponsor
Essential Docs

36. ICH Guidelines ICH Guidelines are divided into 4 main topics:
Quality Topics – relate to chemical and pharmaceutical quality assurance
e.g. Q1 Stability Testing
Safety Topics – relate to preclinical studies
e.g. S1 Carcinogenicity Testing
Multidisciplinary Topics – cross-cutting topics
which don’t fit into one of the other categories
e.g. M1 Medical Terminology
Efficacy Topics – relate to clinical studies in human subjects
e.g. E6 Good Clinical Practice;
e.g. E2A Clinical Safety Data Management:
e.g. E9 Statistical Principles for Clinical Trials

37. FDA Regulations
21 C.F.R. Part 312, Subpart D (Duties of Sponsors, Investigators)
– 21 C.F.R. Part 50 (Informed Consent)
– 21 C.F.R. Part 56 (Institutional Review Boards)
– 21 C.F.R. Part 54 (Investigator Financial Disclosure)

38. What is GCP ?
Good Clinical Practice (GCP) is defined as a ‘standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected’

39. GCP
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human patients.
Compliance with this standard provides public assurance that the rights, safety and well-being of trial patients are protected and clinical trial data are credible.

40. GCP
Are mainly focused on the protection of human rights in clinical trial.
Provide assurance of the safety of the newly developed compounds.
Provide standards on how clinical trials should be conducted.
Define the roles and responsibilities of -
Clinical Sponsors,
Clinical Research Investigators,
Clinical Research Associates, And
Monitors.

41. Principles of ICH GCP
Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirements.
Before a trial is initiated, foreseeable
risks and inconveniences should be
weighed against the anticipated benefit
for the individual trial subject & society.
A trial should be initiated and continued only if the anticipated benefits justify the risks.
Benefits
RISKS

42. Principles of ICH GCP Continued
The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science & society.
The available non-clinical & clinical information on an investigational product should be adequate to support the proposed clinical trial.
Clinical trials should be scientifically sound, and describe in a clear, detailed protocol.
A trial should be conducted in compliance with the protocol that has received prior IRB (or IEC) approval.

43. Principles of ICH GCP Continued
The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective tasks.
Freely given informed consent should be obtained from every subject prior to clinical trial participation.

44. Principles of ICH GCP Continued
All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.
The confidentiality of records that
could identify subjects should be
protected, respecting the privacy
and confidentiality rules in accordance
with the applicable regulatory
compliance.

45. Principles of ICH GCP Continued
12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol 13.Systems with procedures that assure the quality of every aspects of the trial should be implemented.

46. Institutional Review Board (IRB), Independent Ethics Committee (IEC)
A formally designated group that oversees research involving human subjects.
Approves and disapproves human subject research.
According to the standards of the community or the institution, the IRB/IEC may require modifications to a protocol to ensure patient safety.

47. IRB Function
•The primary function of an IRB/IEC is to safe guard the rights ,safety ,and well being of all trial subjects. This is accomplished by initial, continuing and annual review.
•An IRB should consist of members who collectively have the qualifications and experience to review and evaluate the science , medical aspects, and ethics of the proposed trial.

48. IRB Members 1.A minimum of five (5) members.
2.One member whose concern is not scientific.
3.One member who has no personal or familial relationship to the institution or trial site.
4.Any member with a conflict of interest may not participate in any part of the review or vote (except to provide requested information).
5.Individuals with special expertise may be invited to assist with areas of unique or complex nature. These will not be voting members.
6.A list of IRB/IEC members and their qualifications should be maintained.

49. IRB/Ethics Committee
All studies must be approved prior to recruiting participants
IRB must review all documents given to participants
Reporting AEs and Deviations from protocol to the IRB
Maintenance of Records
Maintain records for 3 years after the completion of the trial

50. Investigator Responsibilities
Adequate Resources
Recruitment
Time
Qualified Staff
Facilities
Training

51. Investigator Responsibilities
Medical Care
A qualified MD (or dentist) responsible for trial-related medical decisions
Provide adequate medical care for AEs or other significant medical condition
Inform PCP about participation in trial
Make a reasonable effort to ascertain why participant withdrawals from study

52. Investigator Responsibilities
Compliance with Protocol
Investigator should sign off on protocol
Investigator should not implement deviations from protocol
If deviations occur, they should be documented and reported at once to the sponsor, the IRB and other regulatory authorities

53. Investigator Responsibilities
Progress Reports
Written summary of trial status to the IRB
Written reports to the sponsor or regulatory authority of any changes affecting the trial
Safety Monitoring
SAEs should be reported immediately
AEs should be reported according to sponsor guidelines
Supply sponsor & IRB with requested materials on participant deaths

54. Investigator Responsibilities
Premature Termination or Suspension
Promptly inform trial subjects
Assure appropriate therapy & follow-up
Inform sponsor, regulatory authorities & IRB
Final Reporting
Inform IRB of study completion & a summary of the trial’s outcome
Provide sponsor & regulatory authorities with all required reports

55. Investigator’s Brochure
Defined as a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects.

56. Clinical Trial Protocol
General Information
Background Information
Trial Objectives & Purpose
Trial Design
Selection & Withdrawal of Participants
Treatment of Subjects
Assessment of Efficacy
Assessment of Safety

57. Sponsor Responsibilities
Quality Assurance & Quality Control
Provide written SOPs
Secures agreement between all parties
Data handling
Contract Research Organization (CRO)
Hired by the sponsor to implement trial-related duties
Medical Expertise
Designated medical personnel to advise on trial-related medical questions and problems

58. Sponsor Responsibilities
Trial Design
Designs CRFs
Planning analyses
Trial Management, Data Handling, Recordkeeping, & Independent Data Monitoring Committee (DMC)
Qualified personnel to supervise overall conduct of the study
DMC assesses the progress of the clinical trial
Maintain SOPs for electronic data processing
Inform Investigator of guidelines for record retention

59. Essential Documents for the Conduct of a Clinical Trial
Preclinical trial commencement
During clinical conduct of trial
After completion or termination of trial

60. Storage of Essential Documents
Sponsor Rule: refer to study protocol
FDA Rule: 2 options
2 years following marketing of the drug or,
2 years after IND application is withdrawn if drug was not marketed

61. References

62. References http://www.fda.gov/oc/gcp/guidance.htm
Handbook: good laboratory practice (GLP): quality practices for regulated non-clinical research and development -2nd ed., WHO Library Cataloguing-in-Publication Data, 2nd ed., 7,15-20.

63. References
OECD Principles of Good Laboratory Practice (as revised in 1997)". OECD Environmental Health and Safety Publications (OECD)
Schneider, K (1983(Spring)). "Faking it: The case against Industrial Bio-Test Laboratories". Amicus Journal (Natural Resources Defence Council): . 

64. References
Tweedale, AC (2011). "Uses of ‘Good Laboratory Practices’ by regulated industry and agencies, and the safety of bisphenol A". J Epidemiol Community Health (BMJ Group) Online First: 15 February doi: /jech  
Webster, Gregory K. et al. (2005). "JALA Tutorial: Considerations When Implementing Automated Methods into GcP". Journal of the Association for Laboratory Automation (Elsevier) 10 (3): 182–191. doi: /j.jala

65. .
Question????

66. Thank you……….