Good Clinical Practice GCP

1
Good Clinical Practice (GCP)

• Kelly Robertson, RN, BSN, CCRP
• Assistant Director, Clinical Research, MHMC

2
Objectives

• Review research and development process
• Review trial design measurements
• IND drugs
• Early stopping rules
• Good clinical practice

3
Research Development Process

• Includes all of the activities required to move
  the Investigational Product from discovery to
  market
• Discovery
• Pre-clinical testing
• Permission to test in humans
• Phase I, II, III testing
• Process interpret the data
• Obtain approval to market the product
• Market the product
• Phase IV testing

4
Key Players in a Clinical Trial

• Sponsor
• Investigation Site Team
• IRB/IEC
• Regulatory Authority/Competent Authority
• Subject/Participant
• Contract Research Organization

5
Trial DesignMeasurements

• Safety
• Efficacy
• Primary endpoint/objective
• Secondary endpoint/objective

6
Trial DesignBlind or Open

• Blind
• Single Blind
• Double Blind
• Open or open-label
• All parties know the identity of the subjects
  treatment

7
Trial DesignRandomization

• Treatment assigned by some element of chance.
• Treatment groups may be stratified (divided) into
  different sub-groups based on characteristics
  such as age, gender, and race.

8
Trial DesignSample Size

• An adequate sample includes a population large
  enough to make generalizations from the data.
• Statisticians will help answer question

9
Clinical TestingTimeline
Total Time to Complete Testing 15 Years
10
IND Requirements

• Must show the drug is safe for clinical trials
• Required for all clinical trials, except
• Drugs not subject to pre-market approval
• Approved drugs

11
Stopping the Clinical Trial

• Development can be stopped at any time
• Safety
• Efficacy
• Business Reasons/
• Clinical trial can be halted at one site or all
• Clinical trial can be halted by the PI, IRB/IEC,
  Sponsor, or the CRO

12
International Conference on Harmonization (ICH)
13
Objectives of ICH guidelines

• Provide a unified standard
• EU US Japan
• To facilitate mutual acceptance of clinical data
• Developed in accordance with existing standards
  in US, EU, Australia, Canada, Nordic Countries,
  and WHO

14
Good Clinical Practice

• Definition
• 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.
• (ICH GCP)

15
GCP is not a wallpaper you paste over your
Clinical Development it is to be built into the
Structure.
16
GCPs
FDA
OHRP
ICH

• International
• Glossary
• Principles
• IRBs
• Investigator
• Sponsor
• Essential Documents

• 45 CFR 46
• IRBs
• Informed Consent
• Women
• Prisoners
• Children

• 21 CFR
• Electronic
• Documents
• Informed Consent
• Financial Disclosure
• IRBs
• IND Regulations

17
Principles of ICH GCP

• Conduct trials according to GCP
• Weigh risks vs. benefits
• Protect the subjects
• Have adequate information to justify trial
• Write a sound protocol
• Receive IRB/IEC approval
• Use qualified physicians

18
Form FDA 1572

• Contract between FDA and the Investigator
• Includes logistics such as names and addresses
• Section 9
• Commitments of the Investigator

19
ICH GCP

• Glossary
• Principles of ICH GCP
• Information regarding
• IRB/IEC
• Investigator
• Sponsor
• Protocol
• Investigators Brochure
• Essential Document

20
GCP-ICH-Glossary Definitions related to clinical
study issues

• Investigator
• Monitoring
• Monitoring report
• Multicenter trial
• Nonclinical study
• Protocol
• Randomization
• Sponsor
• Sponsor-initiated
• Subinvestigator

• Case Report Forms (CRF)
• Clinical study report
• Clinical trial
• Coordinating investigator
• Identification code (of trial subjects)
• Interim clinical study report
• Investigational product
• Subject
• Trial Site

21
GCP-ICH-Glossary Definitions related to safety
issues

• Adverse drug reaction (ADR)
• Adverse events (AE)
• Serious adverse events
• Unexpected adverse drug reaction

22
GCP-ICH-Glossary Definitions related to
regulatory issues

• Amendments
• Applicable regulatory requirement
• Contract Research Organization (CRO)
• Direct access
• Documentation

• Good clinical practice
• Institution (medical)
• Investigator Brochure
• Legally acceptable representative
• Standard operating procedures

23
GCP-ICH-Glossary Definitions related to ethical
issues

• Confidentiality
• Contract
• Impartial witness
• Institutional review board (IRB)

• Independent ethics committee (IEC)
• Informed consent
• Minimal risk
• Opinion
• Vulnerable subjects
• Well-being

24
GCP-ICH-Glossary Definitions related to
compliance/auditing issues

• Audit
• Audit certificate
• Audit report
• Compliance (in relation to trials)
• Inspection
• Quality assurance
• Quality control
• Source data
• Source documents

25
How to comply with ICH GCP

• Use qualified support staff
• Obtain informed consent
• Record information appropriately
• Protect confidentiality
• Handle investigational products appropriately
• Implement quality systems

26
Investigator Responsibilities
27
Investigator Responsibilities

• Ensure the study is conducted according to the
  investigator statement/agreement, protocol and
  regulatory requirements
• Ensure the protection of the participants
  rights, safety and welfare.
• Ensure the control of investigational drug.
• Obtain informed consent
• (21 CFR 312.60 and 312.61)

28
Investigator Responsibilities

• Maintenance of records
• Investigator Qualifications and Agreements
• Adequate Resources
• Medical Care of Subjects
• Communication with IRB
• Compliance with protocol
• Investigational product
• Randomization
• Informed Consent

29
Regulatory Authorities will inquire about

• Source of study subjects
• Did they have the disease under study
• Did the meet the eligibility criteria
• Was the protocol precisely followed
• Were AEs reported appropriately

30
Common Findings via FDA and OHRP

• Failures to adhere to protocol
• Eligibility criteria
• Randomization
• Required efficacy tests
• Changes unauthorized by the sponsor

31
Common Findings via FDA and OHRP

• Failures to maintain adequate/accurate records
• Data changed to could not be verified
• Records destroyed or otherwise missing
• Medical course not documented

32
Common Findings via FDA and OHRP

• Failures to report concomitant therapy
• Failures to maintain drug acct. records
• Failures to obtain proper consent
• Verbal
• Obtained after admission

33
Common Findings via FDA and OHRP

• IRB failed to review the research at a convened
  meeting
• Investigators failed to promptly report
  unanticipated problems involving risks to
  subjects to IRB, OHRP, and sponsor
• Continuing review of research was NOT substantive
  nor meaningful

34
Common Findings via FDA and OHRP

• IRB did not ensure additional protections for
  vulnerable subjects
• IRB members inappropriately participated in new
  and continuing review of protocols of which they
  had a conflicting interest

35
Informed Consent Process
36
Informed Consent

• An agreement between researchers and participants
• A mutual commitment
• Both parties agree to

37
ICH GCP Principles of the Informed Consent Process

• The investigator must comply with all applicable
  regulations
• The investigator must obtain prior written
  IRB/IEC approval of the consent form, and any
  other information given to the participant
• The informed consent process must be free of any
  coercion or undue influence

38
Informed Consent Process

• The investigator must provide want to know
  information to participant, including risks and
  benefits
• Clinical trial information must be presented in a
  way that ensures understanding
• Subjects must have adequate time to ask questions
  and get answers

39
Informed Consent Process

• Subjects must understand that they are able to
  withdraw consent at any time
• The informed consent form/process must contain no
  language that implies the waiver of rights
• The consenting process must be clearly documented
  in the subjects chart

40
Informed Consent Document

• Templates are provided by the sponsor (MH, or
  pharmaceutical companies)
• Templates may be modified by the site to meet the
  local requirements

41
Informed Consent Document

• Must contain elements of informed consent
  relevant to your clinical trial
• Protocol title
• Version date of the consent form
• Page numbers
• Participant signature line

42
Informed Consent Review/Approval

• IRB must approve the form prior to use by any
  subject
• IRB must approve of all information provided to
  participants including written material such as
  handouts or brochures, verbal instruction and
  videotapes

43
Signatures

• Participants must sign and date the most current
  IRB approved form
• The person administering the consent signs and
  dates the form
• The investigator and/or a witness may sign and
  date
• Participants are given a copy of the consent form
  and the originals are filed with the
  participants records

44
Special Circumstances

• Vulnerable participants
• May have a legal representative
• Underage participants
• Must have a parent or legal guardian sign the
  consent form
• Depending on the age of the subject, assent may
  be required
• Problems with literacy
• A witness must be present

45
Common Consenting Errors

• State and local requirements for legally
  authorized representatives are not adhered to
• Informed consent form is not properly signed and
  dated as indicated on the form and according to
  the regulations
• Subject signing informed consents that sections
  of the consent have been crossed out

46
Common Consenting Errors

• Subject not signing informed consent prior to
  administration of protocol required procedures.
• Subjects are provided the informed consent
  document, but are told to read and sign it
  without opportunity to ask questions or obtain
  clarification
• Document not approved by the IRB or is an
  outdated version

47
AE/SAE/EAE Adverse Events/Serious Adverse
Events/Expedited Adverse Events
48
Adverse Events

• What are Adverse Events?
• Any untoward medical occurrence in a clinical
  trial participant who has received test
  article/intervention that may or may not have a
  causal relationship with this treatment

49
Adverse Events

• Why is complete, accurate reporting of AE data
  important?
• Allows timely methodical evaluation of clinical
  safety data for clinical trial participants both
  individually and as a group
• Maximizes individual participation safety
• Develops accurate drug toxicity profiles
• Compliance with regulatory requirements

50
Intensity of the Event

• All adverse events will be assessed by a sponsor
  and/or protocol defined grading system
• The following guidelines are often used to
  quantify intensity
• Mild events require minimal or no treatment and
  do not interfere with the patients daily
  activities
• Grade I

51
Intensity of the Event

• Moderate events result in a low level of
  inconvenience or concern with the therapeutic
  measures. Moderate events may cause some
  interterence with functioning
• Grade II
• Severe events interrupt a patients usual daily
  activity and may require systemic drug therapy or
  other treatment. Severe events are usually
  incapacitating
• Grade III

52
Intensity of the Event

• Life threatening any adverse drug experience
  that places the patient or subject in the view of
  the investigator, at immediate risk of death from
  the reaction as it occurred, i.e., it does not
  include a reaction that had it occurred in a more
  severe form, might have caused death
• Grade IV
• Death
• Grade V

53
Relationship to study products

• All adverse events must have their relationship
  to study product assessed using the following
  terms
• Definitely Related
• Probably Related
• Possibly Related
• Probably Not Related
• Not Related
• Pending (temporary assignment for death)

54
Association with Study Product

• Determination of association with the study
  product must be done by a qualified staff member
• What makes someone qualified to assess
  association with a study product?

55
SAE Definition

• ANY adverse event that at any dose
• Results in death
• Is life threatening
• Requires inpatient hospitalization or prolongs
  hospitalization

21 CFR 312.32
56
SAE Definition

• Results in persistent or significant
  disability/incapacity
• Is a congenital anomaly or birth defect
• Important medical event
• Other conditions as specified in the protocol
  
• 21 CFR
  312.32

57
Reporting Timeframes

• Per MH IRB
• Internal AE unexpected and related-report in 10
  days
• External AE-serious and unexpected and
  related-report in 10 days
• Death-Report within 24 hours of discovery
• Must be reported within 24 hours
• If patient died within 30 days of participating
  and is deemed related to study

58
Resolution of Event

• All AE/SAE should be followed
• Until event has stabilized
• Condition returns to baseline
• Condition is resolved
• Condition no longer meets the SAE criteria

59
Trends

• Adverse events and serious adverse events are
  reviewed throughout the course of all clinical
  trials for potential trends
• Review of these data snapshots allows for
  identification of potential trends which can be
  related to
• Concomitant medications
• Toxicities
• Secondary indications

60
Summary/Investigator Responsibilities

• Report all SAEs per sponsor/protocol defined
  timelines
• Notify IRB of AEs/SAEs per IRB policy
• Comply with all applicable regulatory
  requirements related to the reporting of
  unexpected serious adverse events

61
Source Documentation
62
Working Definition of Source Documents

• All written and printed documents that are
  pertinent to a research participants
• Exposure to the investigational agents
• Exposure to other treatments
• Progress of the disease course
• Response to therapy

63
Definitions

• Source Documents are original documents, data,
  and records and may include
• Hospital records, clinic charts, laboratory
  notes, memoranda, subject diaries, x-rays,
  subject file

ICH 1.52
64
Deviations from Protocol

• Referred to as Protocol Violations and/or
  Protocol Deviation/Departures
• Occur when there is non-adherence to Protocol
• All deviations from Protocol must be addressed in
  clinical trial subject source document
• The documentation should include the reasons for
  the deviation and all attempts to prevent or
  correct them

65
Electronic Medical Records

• Monitors are permitted at MH to have direct
  access into the Epic system if a DRA amendment
  has been approved by the IRB
• Copies of electronic medical records DO NOT need
  to be certified for the sponsors to accept them

66
Verifying Source Documents

• Ensure that source data are complete, accounted
  for, follow a logical sequence of events
• Ensure that source data support entries in CRF

67
Protocol Required Documentation

• All inclusion/exclusion criteria be addressed
• Clinical trial required tests and procedures done
  on time or if not, why not
• Withdrawals, dropouts, lost to follow up
• AEs/SAEs properly documented/reported
• Endpoints of the clinical trial

68
Resources

• 21 CFR 11
• 21 CFR 312.62
• ICH section 4.9,5.5
• FDA form 3500A Medwatch
• 21 CFR 312.32
• ICH section 4.11, 5.16, 5.17 and 7.3
• ICH E2A
• 21 CFR 50
• 21 CFR 312.60
• ICH 4.8
• ICH 5.18.4e
• 45 CFR 46