“So You Think You Know GCP ...”
Professional Development
Session S049
Sunday, 15 April 2012
1
Presenters
• Jill Matzat, RN, BSN, CCRA , CCRT
– President, Medical Research Management,
Inc. and CRA Solutions, Inc.
• Paul Below, MS, CCRA , CCRT
– Contract Clinical Project Leader, American
Medical Systems, Inc.
– Principal, P. Below Consulting, Inc.
and GCP Training Specialists
2
Disclosure
• Neither Jill nor Paul
have a relevant
financial relationship
in relation to this
educational activity
3
Background
• This presentation was developed to correct
numerous errors and myths about Good Clinical
Practice overheard by the presenters throughout
their clinical
research careers
4
Yes, you have to do
it this way. It’s an
FDA requirement.
5
Are you sure this
is right? I’ve
never been asked
to document it
this way before.
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
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
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
Other Federal
Regulations
FDA Regulations
(21 CFR)
State Law
FDA Guidance
Documents
GCP
Local Law
Sample
Title
(Institutional
and IRB Policies)
Sample Text
9
Industry
Best Practices
International
Standards
Sponsor
SOPs
FDA Regulations
(21 CFR)
Other Federal
Regulations
FDA Guidance
Documents
• Informed Consent (21 CFR 50)
GCP
Financial disclosure (21 CFR 54)
Law
• State
Institutional
review boards (21 CFR 56)
•
International
Standards
• Electronics records and signatures (21 CFR 11)
Local Law
• Investigational
new drugs (21 CFR 312) and application to
Sample
Title
Sponsor
(Institutional
market
a new
Sample
Text drug (21 CFR 314)
and IRB Policies)
10
SOPs
Industry (21 CFR 812) & premarket
• Investigational device exemptions
Best Practices
approval of medical devices
(21 CFR 814)
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
of hazardous materials (49 CFR)
International
GCP
Standards
• HIPAA Privacy Rule (45 CFR 160-164) for the use and
disclosure of protected health information
Local Rule”
Law
Sample
Title (45 CFR 46) - Human subjects protection
• “Common
Sponsor
(Institutional
Sample
Text
rulesand
forIRB
federally
funded
research
SOPs
Policies)
Industry
Best Practices
11
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
(Institutional
• Sample
FAQs
on the Form FDA 1572 (2010) Sponsor
Text
SOPs
and IRB Policies)
• Risk-Based ApproachIndustry
to Monitoring (Draft, 2011)
Best Practices
12
Other Federal
Regulations
FDA Regulations
(21 CFR)
FDA Guidance
Documents
• Ethical Doctrines:
 Declaration of Helsinki
 Nuremberg Code
GCP
StateResearch
Law
• Clinical
Guidelines:
 ICH Guidelines for GCP (E6)
 ICH Guidelines for Safety Reporting (E2A)
 ISO 14155 – Medical Devices
Local Law
Sample
Title
(Institutional
• EU Directives
Sample Text
and IRB Policies)
• Country-Specific RequirementsIndustry
Best Practices
13
International
Standards
Sponsor
SOPs
Other Federal
Regulations
FDA Regulations
•
(21 CFR)
Age of consent
FDA Guidance
Documents
• Legally authorized representatives
• Clinical research registration
State Laws
• Medical records privacy
•
GCP
Gene research
International
Standards
• STD/HIV reporting
Local Law
Sample
Title • Gifts to practitioners
(Institutional
and IRB Policies)
Sample Text
14
Industry
Best Practices
Sponsor
SOPs
• Institutional Policies:
 Internal Protocol Review Committee Approval
 Investigational ProductOther
Storage
/ Dispensing
Federal
Regulations
 Personnel Training Requirements
•
FDA Regulations
(21 CFR)
IRB Policies:
FDA Guidance
Documents
 Protocol Deviation Reporting Requirements
 SAE Reporting Requirements
 Frequency of Continuing Review and Reporting Format
State Law
 Informed Consent Requirements
International
GCP
Standards
Local Law
(Institutional
and IRB Policies)
15
Industry
Best Practices
Sponsor
SOPs
• CRF Completion Guidelines
FDA Regulations
(21 CFR)
• Other
SAE Reporting
Requirements
Federal
Regulations
• Regulatory
Document Organization
FDA Guidance
• Sponsor-Specific Form
Completion
Documents
• Source Documentation Practices
• Investigator Signature Requirements
State Law
GCP
• Investigational Product Storage and
International
Accountability Requirements
Standards
Local Law
Sample
Title
(Institutional
Sample Text
and IRB Policies)
16
Sponsor
SOPs
Industry
Best Practices
• Good Documentation
Practices
Other Federal
Regulations
• GCP Training Requirements
•
FDA Regulations
(21SAE
CFR)Reporting Requirements
Site
• Investigational Product Storage
FDA Guidance
Documents
• Handling Lost to Follow-Up Subjects
GCP
Form 1572 and Clinical Investigator Agreement
State
• Law
Curriculum Vitae Requirements
•
International
Standards
Requirements
Local Law
(Institutional
Sample Text
and IRB Policies)
17
Industry
Best Practices
Sponsor
SOPs
Other Federal
Regulations
FDA Regulations
(21 CFR)
State Law
FDA Guidance
Documents
GCP
Local Law
Sample
Title
(Institutional
and IRB Policies)
Sample Text
18
Industry
Best Practices
International
Standards
Sponsor
SOPs
Learning all of the parts of GCP can take some
time and may seem daunting to those new to the
clinical research industry
19
Time to Test Your GCP
Knowledge
20
• 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
How to Vote by Text Message
Example Question: What is your favorite color?
• Red
(72612)
• Blue
(72613)
• Green
(72614)
• Orange
(72615)
To vote, text the corresponding keyword to 22333
22
NOTE: Standard carrier text messaging rates apply but there are no additional
fees to participate in the quiz
How to Vote Through the Web
Example Question: What is your favorite color?
• Red
• Blue
• Green
• Orange
23
To vote, go to:
PollEv.com/ACRP2012
NOTE: Standard carrier data usage
charges apply but there are no
additional fees to participate in the quiz
Informed
Consent
Questions
24
Question
FDA Regulations (21 CFR 50) specify the following:
Question
25
Keyword
The ICF must be signed and dated by the subject
118968
The ICF must be signed and dated by the person obtaining
consent
118969
The ICF must be signed and dated by the Principal Investigator
118970
The ICF must be signed by a child subject if the IRB determines
that assent is required
118972
All of the above
118973
Question
FDA Regulations (21 CFR 50) specify the following:
Question
26
Keyword
The ICF must be signed and dated by the subject
118968
The ICF must be signed and dated by the person obtaining
consent
118969
The ICF must be signed and dated by the Principal Investigator
118970
The ICF must be signed by a child subject if the IRB determines
that assent is required
118972
All of the above
118973
Text your answer (keyword) to 22333 or go to
PollEv.com/ACRP2012 to vote
Poll Results
27
Answer
FDA Regulations (21 CFR 50) specify the following:
Question
28
Keyword
The ICF must be signed and dated by the subject
118968
The ICF must be signed and dated by the person obtaining
Specified in 21 CFR 50.27a
consent
118969
The ICF must be signed and dated by the Principal Investigator
118970
The ICF must be signed by a child subject if the IRB determines
that assent is required
118972
All of the above
118973
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.
29
Question
FDA Guidance (Guide to Informed Consent Info Sheet
& ICH GCP) specifies the following:
Question
30
Keyword
The ICF should be written at a 6th grade reading level
41600
When it is anticipated that consent interviews will be
conducted in a foreign language, a translated ICF should be
prepared
41604
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
41704
All study personnel involved in the informed consent process
should be trained in Human Subjects Protection
41740
All of the above
41871
Poll Results
31
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
41600
When it is anticipated that consent interviews will be
conducted in a foreign language, a translated ICF should
be prepared
41604
A subject who can understand and comprehend spoken
41704
However,
Guide
to Informed
Consent
that
English, but isthe
physically
unable
to talk or write,
should notindicates
be
in a clinical trial
ifenrolled
a non-English
speaking subject is unexpectedly
All study personnelinvestigators
involved in the informed
consent
process
encountered,
will not
have
a written41740
should be trained in Human Subjects Protection
translation of the ICF and must rely on oral translation.
All of the above
32
41871
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.”
33
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.
34
Financial
Disclosure
Question
35
Question
FDA Regulations (21 CFR 54) specify the following:
Question
36
Keyword
Part- or full-time employees of the sponsor may not participate
as Clinical Investigators in that sponsor’s trials
47817
Clinical Investigators may not have a proprietary interest (i.e.,
patents, royalties) in the tested product in a trial
47914
Clinical Investigators may not receive more than $25,000 a year
in “payments of other sorts” (i.e., grants, consulting fees,
speaker honoraria)
47915
In general, financial disclosure is not required for large open
safety studies conducted at multiple sites
48364
None of the above
48393
Poll Results
37
Answer
FDA Regulations
CFR 54)
specify
the following:
Specified
in 21 CFR(21
54.2e.
Financial
disclosure
applies
Keyword
Questionto any study of a drug or device in
humans
submitted
inofathe
marketing
Part- or full-time
employees
sponsor mayapplication
not participate
47817
as Clinical
that
sponsor’s
trials
that
theInvestigators
applicantinor
FDA
relies
on to establish
efficacy
or any study
which
a single
Clinical Investigators
may notin
have
a proprietary
interest (i.e.,
47914
patents, royalties) in the tested product in a trial
investigator
makes a significant contribution
Clinical
may not receive
more than $25,000 a year
47915
to
theInvestigators
demonstration
of safety.
in “payments of other sorts” (i.e., grants, consulting fees,
speaker honoraria)
38
In general, financial disclosure is not required for large
open safety studies conducted at multiple sites
48364
None of the above
48393
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.
39
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
40
IRB
Question
41
Question
FDA Regulations (21 CFR 56) specify the following:
Question
42
Keyword
An IRB must be composed of five (5) members
9820
An IRB must have at least one female member
9855
If an IRB regularly reviews research involving prisoners, a
prisoner representative should be included on the board
9858
An IRB member that has a conflicting interest in a project under
review may not participate in the IRB's review proceedings
10017
None of the above
10265
Poll Results
43
Answer
FDA Regulations (21 CFR 56) specify the following:
Question
44
Keyword
An IRB must be composed of five (5) members
9820
An IRB must have at least one female member
9855
If an IRB regularly reviews research involving prisoners, a
prisoner representative should be included on the board
9858
An IRB member that has a conflicting interest in a project under
review may not participate in the IRB's review proceedings
10017
None of the above
10265
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.”
45
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).
46
Monitoring
Question
47
Question
FDA Guidance (ICH GCP) specifies the following:
Question
48
Keyword
A monitoring report should be submitted to the sponsor after
each site visit or trial-related communication
92521
Monitors should not make any notations or corrections on the
CRF pages
93121
Monitors should ensure that all corrections to the CRF are
completed with a single line through the incorrect entry and
initiated and dated by the completer
93342
Monitors should attempt to meet in person with the
Investigator at every visit to discuss the progress of the trial
93345
All of the above
93348
Poll Results
49
Answer
FDA Guidance (ICH GCP) specifies the following:
Question
50
Keyword
A monitoring report should be submitted to the sponsor
after each site visit or trial-related communication
92521
Monitors should not make any notations or corrections on the
CRF pages Specified in ICH 5.18.6a
93121
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
93342
Monitors should attempt to meet in person with the
Investigator at every visit to discuss the progress of the trial
93345
All of the above
93348
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).
51
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.
52
Source
Documentation
Question
53
Question
FDA Regulations (21 CFR 312/812) specify the following:
Question
54
Keyword
It is prohibited to use CRFs (other than questionnaires) directly
as source documents
186220
Each subject’s case history should document that informed
consent was obtained prior to participation in the study
186239
All source documents must be signed by the completer
186240
If a site uses electronic medical records as source documents,
the EMR system must be compliant with 21 CFR part 11
186241
All of the above
186242
Poll Results
55
Answer
FDA Regulations (21 CFR 312/812) specify the following:
Question
It is prohibited to use CRFs (other than questionnaires) directly
as source documents
186220
Each subject’s case history should document that informed
consent was obtained prior to participation in the study
186239
All source documents must be signed by the completer
Specified
in both 21 CFR 312.62b and 812.140a.
If a site uses
electronicinclude
medical records
source documents,
“Case
histories”
CRFs,assigned
and dated
the EMR system must be compliant with 21 CFR part 11
consent forms, and medical records (physician
All of the above
progress notes, individual's hospital chart and
the nursing notes)
56
Keyword
186240
186241
186242
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.”
57
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)
58
Investigator
Responsibilities
Question
59
Question
FDA Guidance specifies the following:
60
Question
Keyword
A Trial Delegation List should identify the training that
individuals have received that qualifies them to perform
delegated tasks
187191
In device studies, the field clinical engineer’s activities should be
described in the protocol and informed consent (if face-to-face
contact with subjects)
187193
Investigators should develop a plan for the oversight of the
clinical trial that might include the creation of specific SOPs
187214
Investigators conducting studies of drugs with potentially fatal
toxicity should be readily available 24 hours/day and in
reasonably close proximity to study subjects
187219
All of the above
187241
Poll Results
61
Answer
FDA Guidance specifies the following:
62
Question
Keyword
A Trial Delegation List should identify the training that
individuals have received that qualifies them to perform
delegated tasks
187191
In device studies, the field clinical engineer’s activities should be
described in the protocol and informed consent (if face-to-face
contact with subjects)
187193
Investigators should develop a plan for the oversight of the
clinical trial that might include the creation of specific SOPs
187214
Investigators conducting studies of drugs with potentially fatal
toxicity should be readily available 24 hours/day and in
reasonably close proximity to study subjects
187219
All of the above
187241
Study Records
Storage
Question
63
Question
FDA Regulations (21 CFR 312/812) and Guidance (ICH
GCP) specify the following:
Question
64
Keyword
It is the Investigator’s responsibility to inquire with the sponsor
when study records no longer need to be retained
187650
In general, study records should be obtained indefinitely
because it is never certain when product development will be
permanently discontinued by the sponsor
187653
Sponsors should pay for the costs of records storage by
Investigators
187671
For device studies, an Investigator may transfer custody of study
records to anyone who will accept responsibility for them
187672
None of the above
187677
Poll Results
65
Answer
FDA Regulations (21 CFR 312/812) and Guidance (ICH
GCP) specify the following:
Question
It is the Investigator’s responsibility to inquire with the sponsor
when study records no longer need to be retained
187650
In general, study records should be obtained indefinitely
because it is never certain when product development will be
permanently discontinued by the sponsor
187653
Specified in 21 CFR 812.140e (however, there is
Sponsors should pay for the costs of records storage by
no
comparable language in Part 312)
Investigators
66
Keyword
187671
For device studies, an Investigator may transfer custody
of study records to anyone who will accept responsibility
for them
187672
None of the above
187677
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.”
67
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.
68
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.
69
In Conclusion
Yes, you have to do
it this way. It’s an
FDA requirement.
70
That doesn’t sound
right to me. Where
exactly is that listed in
the CFR?
In Conclusion
Well, uh …
OK, maybe it’s not a
regulation but it’s
what the FDA
expects.
71
That still doesn’t
sound right. What
guidance document
is that from?
In Conclusion
I’m not sure but it
doesn’t matter. It’s a
requirement of my
sponsor company.
72
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.
73
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
74
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
75
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
76
Your Chance to
Ask Us Questions
77
• Jill Matzat, RN, BSN, CCRA
[email protected]
• Paul Below, CCRA
[email protected]
• Complete poll results are available at:
www.pbelow-consulting.com/gcp.html
78
You are welcome to use these slides for your own internal training purposes but they remain the
copyrighted property of the presenters. Please contact Paul or Jill for permission to reuse.
Thank You!
79
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“So You Think You Know GCP ...”