Presented at the ACRP Global Conference in Houston in April 2012.

1. “So You Think You Know GCP ...”
Northern California Chapter ACRP
March 21, 2013
1

2. Presenter
Paul Below, MS, CCRA
• Clinical Project Leader, American Medical Systems
• Trainer for ACRP
• Former President Minnesota Chapter ACRP (2004, 2010)
• Adjunct instructor for the St. Cloud State University
Master’s Degree Program in Applied Clinical Research
• Recipient of ACRP’s Leadership in Clinical Research as a
CRA Award in May 2011
• Recipient of ACRP’s Top Speaker Award for the
2012 Global Conference
2

3. Disclosure
• Paul has no relevant
financial relationship
in relation to this
educational activity
3

4. Background
• This presentation was developed to correct
numerous errors and myths about Good Clinical
Practice overheard by the presenter throughout
his clinical
research career
4

5. Are you sure this
Yes, you have to do is right? I’ve
it this way. It’s an never been asked
FDA requirement. to document it
this way before.
5

6. I never heard of this FDA
requirement before but it
must be true. He is the
monitor and he should
know …
I wouldn’t
count on it
6

7. Learning Objectives
• Define Good Clinical Practice (GCP)
• Differentiate between GCP requirements (stated in
regulation) and recommendations (stated in
guidance documents) in several key areas
• Identify several circumstances where “industry
best practices” exist that go above and beyond
what the FDA requires or even recommends
7

8. What is Good Clinical Practice (GCP)?
• Good Clinical Practice (GCP) is a unified standard
for designing, conducting, recording, and
reporting trials that involve human subjects
• GCP is composed of many
parts that cannot be found
in any one book or place
8

9. Other Federal
Regulations
FDA Regulations
(21 CFR) FDA Guidance
Documents
State Law
GCP International
Standards
SampleLaw
Local Title
(Institutional Sponsor
Sample Text
and IRB Policies) SOPs
Industry
Best Practices
9

10. Other Federal
Regulations
FDA Regulations
(21 CFR) FDA Guidance
Documents
• Informed Consent (21 CFR 50)
• State Law
•
GCP
Institutional review boards (21 CFR 56)
Financial disclosure (21 CFR 54)
International
Standards
• Electronics records and signatures (21 CFR 11)
• Investigational new drugs (21 CFR 312) and application to
SampleLaw
Local Title
(Institutional
market a new drug (21 CFR 314) Sponsor
Sample Text
and IRB Policies) SOPs
• Investigational device exemptions (21 CFR 812) & premarket
Industry
approval of medical devicesPractices 814)
Best (21 CFR
10

11. Other Federal
Regulations
FDA Regulations
(21 CFR) FDA Guidance
Documents
• Nuclear Regulatory Commission regulations for the medical
use of radioactive substances (10 CFR 35 and 21 CFR 361)
• Department of Transportation regulations for the shipment
State Law
GCP
of hazardous materials (49 CFR) International
Standards
• HIPAA Privacy Rule (45 CFR 160-164) for the use and
disclosure of protected health information
SampleLaw
Local Title
• “Common Rule” (45 CFR 46) - Human subjects protection
(Institutional Sponsor
rulesSamplefederally funded research
for Text
and IRB Policies) SOPs
Industry
Best Practices
11

12. Other Federal
Regulations
FDA Regulations
(21 CFR) FDA Guidance
Documents
• FDA Information Sheets
State Law
GCP
• ICH Guidelines for Good Clinical Practice (1997)
International
Standards
• Investigator Responsibilities (2009)
• Adverse Event Reporting to IRBs (2009)
Local Law
Sample Title
• Sample Text the Form FDA 1572 (2010) Sponsor
(Institutional
FAQs on
and IRB Policies) SOPs
• Risk-Based ApproachIndustry
to Monitoring (Draft, 2011)
Best Practices
12

13. Other Federal
Regulations
FDA Regulations
(21 CFR) FDA Guidance
• Ethical Doctrines: Documents
 Declaration of Helsinki
 Nuremberg Code
• Clinical Research Guidelines:
State Law
 ICH Guidelines for GCP (E6)
GCP International
Standards
 ICH Guidelines for Safety Reporting (E2A)
 ISO 14155 – Medical Devices
SampleLaw
Local Title
• EU Directives Text
(Institutional
Sample
Sponsor
and IRB Policies) SOPs
• Country-Specific Requirements
Industry
Best Practices
13

14. Other Federal
Regulations
FDA Regulations
(21 CFR) • Age of consent FDA Guidance
Documents
• Legally authorized representatives
• Clinical research registration
• Medical records privacy
State Laws
•
GCP
Gene research International
Standards
• STD/HIV reporting
SampleLaw • Gifts to practitioners
Local Title
(Institutional Sponsor
Sample Text
and IRB Policies) SOPs
Industry
Best Practices
14

15. • Institutional Policies:
 Internal Protocol Review Committee Approval
 Investigational ProductOther Federal
Storage / Dispensing
Regulations
 Personnel Training Requirements
FDA Regulations
• IRB Policies: CFR)
(21 FDA Guidance
Documents
 Protocol Deviation Reporting Requirements
 SAE Reporting Requirements
 Frequency of Continuing Review and Reporting Format
State Law
GCP
 Informed Consent Requirements International
Standards
Local Law
(Institutional Sponsor
and IRB Policies) SOPs
Industry
Best Practices
15

16. • CRF Completion Guidelines
• Other Reporting Requirements
SAE Federal
Regulations
FDA Regulations
• Regulatory Document Organization
(21 CFR) • Sponsor-Specific Form Completion
FDA Guidance
Documents
• Source Documentation Practices
• Investigator Signature Requirements
State Law
GCP
• Investigational Product Storage and
International
Accountability Requirements
Standards
SampleLaw
Local Title
Sponsor
(Institutional
Sample Text
and IRB Policies) SOPs
Industry
Best Practices
16

17. • Good Documentation Practices
Other Federal
Regulations
• GCP Training Requirements
FDA Regulations
• Site SAE Reporting Requirements
(21 CFR) FDA Guidance
Documents
• Investigational Product Storage
• Handling Lost to Follow-Up Subjects
•
GCP Agreement
• Curriculum Vitae Requirements
State Law
Form 1572 and Clinical Investigator
International
Standards
Requirements
Local Law
(Institutional Sponsor
Sample Text
and IRB Policies) Industry SOPs
Best Practices
17

18. Other Federal
Regulations
FDA Regulations
(21 CFR) FDA Guidance
Documents
State Law
GCP International
Standards
SampleLaw
Local Title
(Institutional Sponsor
Sample Text
and IRB Policies) SOPs
Industry
Best Practices
18

19. Learning all of the parts of GCP can take some
time and may seem daunting to those new to the
clinical research industry
19

20. Time to Test Your GCP
Knowledge
20

21. • The following slides are a series of questions to
test your knowledge of GCP
• You will be able to
submit your answers
by text messaging or
through the web
• All answers are
anonymous (no one
is identified by name or phone number)
21

22. How to Vote by Text Message
Example Question: What is your favorite color?
• Red 3544
• Blue 3545
• Green 3546
• Orange 3546
To vote, text the corresponding keyword to 22333
NOTE: Standard carrier text messaging rates apply but there are no additional
22
fees to participate in the quiz

23. Informed
Consent
Questions
23

24. Question
FDA Regulations (21 CFR 50) specify the following:
Question Keyword
The ICF must be signed and dated by the subject 624626
The ICF must be signed and dated by the person obtaining 624627
consent
The ICF must be signed and dated by the Principal Investigator 624628
The ICF must be signed by a child subject if the IRB determines 624651
that assent is required
All of the above 624655
24

25. Question
FDA Regulations (21 CFR 50) specify the following:
Question Keyword
The ICF must be signed and dated by the subject 624626
The ICF must be signed and dated by the person obtaining 624627
consent
The ICF must be signed and dated by the Principal Investigator 624628
The ICF must be signed by a child subject if the IRB determines 624651
that assent is required
All of the above 624655
Text your answer (keyword) to 22333
25

26. Answer
FDA Regulations (21 CFR 50) specify the following:
Question Keyword
The ICF must be signed and dated by the subject 624626
The ICF must be signed and dated by the person obtaining 624627
consent Specified in 21 CFR 50.27a
The ICF must be signed and dated by the Principal Investigator 624628
The ICF must be signed by a child subject if the IRB determines 624651
that assent is required
All of the above 624655
26

27. Explanation
• The ICF must be signed and dated by the person
obtaining consent – Specified by ICH GCP (4.8.8).
• The ICF must be signed and dated by the Principal
Investigator – Not specified by FDA Regulation or
Guidance but sometimes required by IRBs.
• The ICF must be signed by a child subject if the IRB
determines that assent is required – The method of
documenting assent is determined by the IRB (21
CFR 50.55) and does not necessarily have to be by
child signature.
27

28. Question
FDA Guidance (Guide to Informed Consent Info Sheet
& ICH GCP) specifies the following:
Question Keyword
The ICF should be written at a 6th grade reading level 624669
When it is anticipated that consent interviews will be 624727
conducted in a foreign language, a translated ICF should be
prepared
A subject who can understand and comprehend spoken 624773
English, but is physically unable to talk or write, should not be
enrolled in a clinical trial
All study personnel involved in the informed consent process 624774
should be trained in Human Subjects Protection
All of the above 624775
28

29. Answer
FDA Guidance (Guide to Informed Consent Info Sheet
& ICH GCP) specifies the following:
Question Keyword
The ICF should be written at a 6th grade reading level 624669
When it is anticipated that consent interviews will be 624727
conducted in a foreign language, a translated ICF should
be prepared
A subject who can understand and comprehend spoken 624773
However,isthe Guide to Informed Consent indicates that
English, but physically unable to talk or write, should not be
if a non-Englishtrial
enrolled in a clinical speaking subject is unexpectedly
All study personnel involved in the informed consent process
encountered, investigators will not have a written 624774
should be trained in Human Subjects Protection
translation of the ICF and must rely on oral translation.
All of the above 624775
29

30. Explanation
• The ICF should be written at a 6th grade reading level
– No specific grade level requirement is defined.
Instead, the FDA Information Sheets say:
“The IRB should ensure that technical and scientific
terms are adequately explained or that common terms
are substituted. The IRB should ensure that the
informed consent document properly translates complex
scientific concepts into simple concepts that the typical
subject can read and comprehend.”
Similarly, ICH (4.8.6) specifies that the consent
language should be “as non-technical as practical and
should be understandable to the subject.”
30

31. Explanation
• A subject who can understand and comprehend
spoken English, but is physically unable to talk or
write, should not be enrolled in a clinical trial – They
can be enrolled if an impartial witness is present
during the entire informed consent discussion.
• All study personnel involved in the informed consent
process should be trained in Human Subjects
Protection – Required for NIH studies but not
currently specified by FDA.
31

32. Financial
Disclosure
Question
32

33. Question
FDA Regulations (21 CFR 54) specify the following:
Question Keyword
Part- or full-time employees of the sponsor may not participate 624803
as Clinical Investigators in that sponsor’s trials
Clinical Investigators may not have a proprietary interest (i.e., 624804
patents, royalties) in the tested product in a trial
Clinical Investigators may not receive more than $25,000 a year 624812
in “payments of other sorts” (i.e., grants, consulting fees,
speaker honoraria)
In general, financial disclosure is not required for large open 624813
safety studies conducted at multiple sites
None of the above 625046
33

34. Answer
Specified in 21 CFR 54.2e. 54) specify the following:
FDA Regulations (21 CFR Financial disclosure
applies to any study of a drug or device in
Question Keyword
humans submitted inof the sponsor may not participate 624803
Part- or full-time employees a marketing application
that theInvestigators inor FDA relies on to establish
as Clinical applicant that sponsor’s trials
efficacy or any study in which a single (i.e.,
Clinical Investigators may not have a proprietary interest 624804
investigator makestested product in acontribution
patents, royalties) in the
a significant trial
to theInvestigators may not receive more than $25,000 a year 624812
Clinical demonstration of safety.
in “payments of other sorts” (i.e., grants, consulting fees,
speaker honoraria)
In general, financial disclosure is not required for large 624813
open safety studies conducted at multiple sites
None of the above 625046
34

35. Explanation
• Part- or full-time employees of the sponsor may not
participate as Clinical Investigators in that sponsor’s
trials – This is allowed but financial disclosure is
required.
• Clinical Investigators may not have a proprietary
interest (i.e., patents, royalties) in the tested product
in a trial – Same as above.
• Clinical Investigators may not receive more than
$25,000 a year in “payments of other sorts” (i.e.,
grants, consulting fees, speaker honoraria) – Same as
above.
35

36. Explanation
• Sponsors may include individuals as Investigators
who have these financial interests but they have to
explain any steps taken to minimize the potential for
bias resulting from any of the disclosed
arrangements, interests, or payments (21 CFR 54.4a)
• FDA then decides if the steps are adequate to ensure
the reliability of the study (21 CFR 54.5a)
• Interestingly, there is no requirement for financial
disclosure by monitors or other sponsor personnel
who have the capacity to bias the data
36

37. IRB
Question
37

38. Question
FDA Regulations (21 CFR 56) specify the following:
Question Keyword
An IRB must be composed of five (5) members 625047
An IRB must have at least one female member 625048
If an IRB regularly reviews research involving prisoners, a 625049
prisoner representative should be included on the board
An IRB member that has a conflicting interest in a project under 625076
review may not participate in the IRB's review proceedings
None of the above 625077
38

39. Answer
FDA Regulations (21 CFR 56) specify the following:
Question Keyword
An IRB must be composed of five (5) members 625047
An IRB must have at least one female member 625048
If an IRB regularly reviews research involving prisoners, a 625049
prisoner representative should be included on the board
An IRB member that has a conflicting interest in a project under 625076
review may not participate in the IRB's review proceedings
None of the above 625077
39

40. Explanation
• An IRB must be composed of five (5) members –
Must have at least 5 members (21 CFR 56.107a).
• An IRB must have at least one female member – The
FDA Regulations (21 CFR 56.107b) specify:
“Every nondiscriminatory effort will be made to ensure
that no IRB consists entirely of men or entirely of women,
including the institution's consideration of qualified
persons of both sexes, so long as no selection is made to
the IRB on the basis of gender.”
40

41. Explanation
• If an IRB regularly reviews research involving
prisoners, a prisoner representative should be
included on the board – Consideration shall be given
to the inclusion of one or more individuals who are
knowledgeable about and experienced in working
with those subjects (21 CFR 56.107a).
• An IRB member that has a conflicting interest in a
project under review may not participate in the IRB's
review proceedings – These individuals can
participate in order to provide information
requested by the IRB (21 CFR 56.107e).
41

42. Monitoring
Question
42

43. Question
FDA Guidance (ICH GCP) specifies the following:
Question Keyword
A monitoring report should be submitted to the sponsor after 627475
each site visit or trial-related communication
Monitors should not make any notations or corrections on the 627539
CRF pages
Monitors should ensure that all corrections to the CRF are 627540
completed with a single line through the incorrect entry and
initiated and dated by the completer
Monitors should attempt to meet in person with the 627541
Investigator at every visit to discuss the progress of the trial
All of the above 627542
43

44. Answer
FDA Guidance (ICH GCP) specifies the following:
Question Keyword
A monitoring report should be submitted to the sponsor 627475
after each site visit or trial-related communication
Monitors should not make any notations or corrections on the 627539
CRF pages Specified in ICH 5.18.6a
Monitors should ensure that all corrections to the CRF are 627540
completed with a single line through the entry and are initiated
and dated by the completer
Monitors should attempt to meet in person with the 627541
Investigator at every visit to discuss the progress of the trial
All of the above 627542
44

45. Explanation
• Monitors should not make any notations or
corrections on the CRF pages – Sponsors should
have written procedures to assure that changes or
corrections in CRFs made by sponsor's designated
representatives are documented, are necessary, and
are endorsed by the investigator (ICH 4.9.3).
• Monitors should ensure that all corrections to the
CRF are completed with a single line through the
entry and are initiated and dated by the completer –
Any change or correction to a CRF should be dated,
initialed, and explained (if necessary) and should
not obscure the original entry (ICH 4.9.3).
45

46. Explanation
• Monitors should attempt to meet in person with the
Investigator at every visit to discuss the progress of
the trial – There are several sections of ICH that
address the monitors responsibility to communicate
with the Investigator but the frequency of these
communications is not specified (ICH 5.18.4). This is
often specified in sponsor SOPs.
46

47. Source
Documentation
Question
47

48. Question
FDA Regulations (21 CFR 312/812) specify the following:
Question Keyword
It is prohibited to use CRFs (other than questionnaires) directly 625078
as source documents
Each subject’s case history should document that informed 625079
consent was obtained prior to participation in the study
All source documents must be signed by the completer 625089
If a site uses electronic medical records as source documents, 625090
the EMR system must be compliant with 21 CFR part 11
All of the above 625091
48

49. Answer
FDA Regulations (21 CFR 312/812) specify the following:
Question Keyword
It is prohibited to use CRFs (other than questionnaires) directly 625078
as source documents
Each subject’s case history should document that informed 625079
consent was obtained prior to participation in the study
Specified in bothmust CFR 312.62bcompleter
All source documents
21 be signed by the and 812.140a. 625089
“Case uses electronic medical records as source documents,
If a site histories” include CRFs, signed and dated 625090
the EMR system must be compliant with 21 CFR part 11
consent forms, and medical records (physician
All of the above 625091
progress notes, individual's hospital chart and
the nursing notes)
49

50. Explanation
• It is prohibited to use CRFs (other than
questionnaires) directly as source documents –
There is no regulation preventing this practice or
from using copies of CRFs as source documents.
• All source documents must be signed by the
completer – There is no requirement for this but
several FDA Guidances do specify that data should
be “attributable.”
50

51. Explanation
• If a site uses electronic medical records as source
documents, the EMR system must be compliant with
21 CFR part 11 – There is currently no FDA
Regulation or Guidance specifying this. However, a
recent FDA Draft Guidance does indicate:
“For those who use electronic signatures based upon the
use of identification codes in combination with
passwords, the clinical site must employ controls to
ensure the security and integrity of the authorized user
names and passwords (21 CFR 11.300a).”
Draft Guidance on Electronic Source Documentation in Clinical Investigations
(December 2010)
51

52. Investigator
Responsibilities
Question
52

53. Question
FDA Guidance specifies the following:
Question Keyword
A Trial Delegation List should identify the training that 625092
individuals have received that qualifies them to perform
delegated tasks
In device studies, the field clinical engineer’s activities should be 625093
described in the protocol and informed consent (if face-to-face
contact with subjects)
Investigators should develop a plan for the oversight of the 625096
clinical trial that might include the creation of specific SOPs
Investigators conducting studies of drugs with potentially fatal 625097
toxicity should be readily available 24 hours/day and in
reasonably close proximity to study subjects
All of the above 625098
53

54. Answer
FDA Guidance specifies the following:
Question Keyword
A Trial Delegation List should identify the training that 625092
individuals have received that qualifies them to perform
delegated tasks
In device studies, the field clinical engineer’s activities should be 625093
described in the protocol and informed consent (if face-to-face
contact with subjects)
Investigators should develop a plan for the oversight of the 625096
clinical trial that might include the creation of specific SOPs
Investigators conducting studies of drugs with potentially fatal 625097
toxicity should be readily available 24 hours/day and in
reasonably close proximity to study subjects
All of the above 625098
54

55. Study Records
Storage
Question
55

56. Question
FDA Regulations (21 CFR 312/812) and Guidance (ICH
GCP) specify the following:
Question Keyword
It is the Investigator’s responsibility to inquire with the sponsor 625099
when study records no longer need to be retained
In general, study records should be obtained indefinitely 625114
because it is never certain when product development will be
permanently discontinued by the sponsor
Sponsors should pay for the costs of records storage by 625115
Investigators
For device studies, an Investigator may transfer custody of study 625116
records to anyone who will accept responsibility for them
None of the above 625117
56

57. Answer
FDA Regulations (21 CFR 312/812) and Guidance (ICH
GCP) specify the following:
Question Keyword
It is the Investigator’s responsibility to inquire with the sponsor 625099
when study records no longer need to be retained
In general, study records should be obtained indefinitely 625114
because it is never certain when product development will be
permanently discontinued by the sponsor
Specified in 21 CFR 812.140e (however, there is
no comparable language inrecords312) by
Sponsors should pay for the costs of
Investigators Part storage 625115
For device studies, an Investigator may transfer custody 625116
of study records to anyone who will accept responsibility
for them
None of the above 625117
57

58. Explanation
• It is the Investigator’s responsibility to inquire with
the sponsor when study records no longer need to
be retained – Per ICH 4.9.5, it is sponsor’s
responsibility to do so. In addition, ICH 5.5.12,
indicates:
“The sponsor should inform the investigators/ institutions
in writing of the need for record retention and should
notify the investigators/institutions in writing when the
trial related records are no longer needed.”
58

59. Explanation
• In general, study records should be obtained
indefinitely because it is never certain when product
development will be permanently discontinued by
the sponsor – The FDA Regulations and ICH GCP
both have criteria for retention that are well
defined. The current reality is that sites and
sponsors usually plan to hold onto records for many
decades.
59

60. Explanation
• Sponsors should pay for the costs of records storage
by Investigators – There is no FDA Regulation or
Guidance that address this but many experienced
sites now demand this as a line item in their Clinical
Trial Agreements.
60

61. In Conclusion
Yes, you have to do That doesn’t sound
it this way. It’s an right to me. Where
FDA requirement. exactly is that listed in
the CFR?
61

62. In Conclusion
Well, uh …
OK, maybe it’s not a That still doesn’t
regulation but it’s sound right. What
what the FDA guidance document
expects. is that from?
62

63. In Conclusion
I’m not sure but it
doesn’t matter. It’s a
requirement of my
sponsor company.
63

64. In Conclusion
OK, that’s fine. Why didn’t you just say so in
the first place? I’m happy to do it to satisfy
your company policy. You didn’t have to use
those FDA excuses to justify your request.
64

65. Learning Objectives
• Define Good Clinical Practice (GCP)
• Differentiate between GCP requirements (stated in
regulation) and recommendations (stated in
guidance documents) in several key areas
• Identify several circumstances where “industry
best practices” exist that go above and beyond
what the FDA requires or even recommends
65

66. Closing Thoughts
• Much of what we do in clinical research is driven
by our own industry best practices and not by
FDA requirements or even recommendations
• It takes a serious effort to understand all of the
component parts of GCP and to stay up-to-date
with changes
• As sponsor representatives, we often act as
trainers for new site staff and they rely
on us to provide accurate information
66

67. Closing Thoughts
• Be careful when telling an investigator site, “You
have to do this because the FDA requires it”
unless you are certain that it is specified
by regulation – it can seem like a very heavy
handed play if you are wrong
67

68. Thank You
• Thanks for the Northern California Chapter for
the invitation to present
• Thanks also to the chapter leadership for all that
they do for ACRP and the local research
community
• Consider volunteering with the outstanding group
– it is well worth the time!
68

69. • Paul Below, CCRA
paul@pbelow-consulting.com
612-643-5598
You are welcome to use these slides for your own internal training purposes but they remain the
69 copyrighted property of the presenter. Please contact Paul for permission to reuse.