Clinical Research Guidelines and Regulations Overview

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v2.0  -  2013-03-26
ICH E6 Good Clinical Practice Guidance and
45 CFR 46: Protection of Human Subjects
Note that this is a general slide presentation designed for a
broad audience of clinical researchers.
Accordingly, some sections may not apply to your protocol.
Information that may not be applicable for all studies is
indicated via 
blue italics
.
3
4
Examples include references to:
Investigational Product (IP), the Investigator’s Brochure (IB),
or a study pharmacist
Safety reporting and adverse events
Randomization and unblinding procedures
Regulatory authorities
Clinical treatment (for a behavioral or study or a registry)
Information that may be helpful but does not come
directly from ICH or 45 CFR 46 is identified by this
icon.
Good Clinical Practice (GCP) Guidelines (ICH-E6)
Widely accepted international research standards
Title 45 Code of Federal Regulations (CFR) Part 46
Applies to federally funded research
Federal regulations to protect human subjects
Subpart A: The Common Rule
IRB roles and responsibilities/Informed Consent
5
Additional sections of the Code of Federal
Regulations apply to clinical trials
21 CFR 11: Electronic Records/Electronic Signatures
21 CFR 50: Protection of Human Subjects
21 CFR 54: Financial Disclosure by Clinical Investigators
21 CFR 56: Institutional Review Boards
Additional Guidance
FDA Information Sheets
6
A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and
reporting of clinical trials [studies],
that provides assurance that the data and reported
results are credible and accurate,
and that the rights, integrity, and confidentiality of
study subjects are protected.
7
8
Sets minimum quality standards for the conduct of
clinical research
Compliance with GCP
Ensures that the rights, safety, and well-being of study
participants are protected
Ensures the integrity of the data submitted for approval
Sets standards for a system of mutual accountability
among sponsors, regulatory authorities,
investigators, and IRBs
9
The regulations and guidelines concerning the
establishment of good clinical practice apply to all
studies involving human subjects
Applies to
Interventional studies, including studies without an
investigational product
Observational studies (specimen collection studies, natural
history, etc.)
Device studies
10
Specific to research involving human subjects
conducted or funded by the DHHS
Federal Policy for the Protection of Human Subjects
Designed to make uniform human subject protection
across all federal agencies and departments
Properly qualified to assume responsibility for
conduct of the study
Thoroughly familiar with the investigational product
(IP), and its appropriate use
Willing to comply with GCP and applicable
regulations and be prepared for audits and
monitoring
Maintain a Delegation of Responsibilities log
11
Ability to recruit in sufficient numbers and on time
Sufficient time to complete the study
Adequate number of qualified staff and adequate
facilities to complete the study
Staff who are well informed about the protocol, 
the
IP,
 and their study responsibilities
12
Ensure that all trial-related medical decisions are
made by an investigator who is a qualified physician
Provide adequate medical care for participants who
experience adverse events
Notify the participant’s primary physician of his/her
participation (as appropriate)
Make an effort to learn why participants withdraw
13
Obtain written approval before the study begins
Provide the IRB with the current Investigator’s
Brochure
Provide the IRB/IEC with all documents subject to its
review throughout the trial
14
Conduct the trial in compliance with the protocol
Deviate only with agreement from the sponsor and
prior review/approval from the IRB/IEC
There can be exceptions – see next slide!
Document and explain all deviations
15
The investigator may deviate from the protocol
before obtaining agreement from the sponsor and
review/approval from the IRB/IEC 
only:
When the changes are logistical/administrative, or
To eliminate an immediate hazard to study subjects.
This  requires immediate submission to:
the IRB
the sponsor
regulatory authorities (if required)
16
Responsible for the product, its usage, and its
storage
May delegate to a Pharmacist under the PI’s
supervision
Maintain IP records
Store as specified by the sponsor and in accordance
with applicable regulatory requirement(s)
Use IP in accordance with the protocol
17
Follow the study randomization procedures
Ensure that the randomization code is only broken in
accordance with the protocol
Promptly document and notify the sponsor of any
unblinding 
(for blinded trials)
18
19
These 
require the same
basic
 
elements of consent.
Regulations and Guidance
ICH 4.8
45 CFR 46
45 CFR 46 must be followed for research involving
human subjects that is conducted, supported, or
otherwise subject to regulation by any federal
department or agency.
Adhere to GCP and the ethical principles that have
their origin in the Declaration of Helsinki
Update consent document when new information
becomes available
Avoid:
Coercion or undue influence
Language that causes the participant to waive any legal
rights
20
21
Fully inform participant of all pertinent aspects of
the trial
Use lay and non-technical language
Should be understandable to the subject
8th grade reading level
Translated to native language as applicable (IRB must approve
translations)
Provide enough time for participant to review the
consent document and ask questions
22
The consent document must be signed and dated
Obtain consent prior to start of any study-related activities.  Initial
phone screening can precede consenting.
If a participant or representative is unable to read, a
witness should be present during the consenting
process
Provide the participant with a copy of the signed and
dated consent form
The informed consent discussion and the consent
document should include all essential and additional
elements
Essential elements include:
Statement that the study involves research
Statement that participation is voluntary
Information about purpose, duration, and procedures
23
Essential elements (continued):
Number of subjects involved in the study
Description of risks, benefits, and alternatives
Information about compensation/care for injury
Statement regarding confidentiality of records
Description of possible unforeseen risks
24
Essential elements (continued):
Circumstances for termination without subject consent
Consequences of withdrawing from the study
Additional costs that may result from participation
Statement that new research findings will be shared
Contact information for questions/concerns
25
Additional elements from Title 45 CFR 46:
Subpart B: Additional protections for pregnant women,
human fetuses, and neonates
Subpart C: Additional protections for prisoners
Subpart D: Additional protections for children
26
Explain the study to the extent it can be understood
by participants who can only be enrolled with the
consent of a legally acceptable representative (LAR)
Follow guidelines for nontherapeutic trials (trials in
which there is no anticipated direct clinical benefit to
the participant)
If participant and LAR can’t provide consent, follow
measures described in the protocol
27
ICH 4.9 (Records and Reports)
ICH 4.10 (Progress Reports)
28
Data must be ALCOA (
A
ccurate, 
L
egible,
C
ontemporaneous, 
O
riginal, and 
A
ttributable) and
complete
How and where the data is recorded is key!
If it is not documented, it does not exist
Data on CRFs should match the source documents
(raw data)
29
All changes to a CRF must be dated and signed such
that the original data is not obscured
Retain essential documents for at least 2 years after
the last approval of a marketing application
Provide monitors, auditors, IRB/IEC, 
or regulatory
authorities
 with direct access to trial records
30
31
Record UP/SAE events thoroughly
Meets criteria
PI to determine causality
Follow-up information
Make records available to monitors, auditors and inspectors
Record retention
Institutional requirements
ICH GCP – 2 years after last approval of marketing application in an ICH region
Follow protocol, NIH, and local institutional requirements
Longest requirement should be followed
32
Essential Documents
Permit evaluation of the conduct of the study and the
validity of the data
ICH GCP E6 section 8.0 provides a table of essential
documents, the purpose of the document, and the location
broken down according to the stage of the study
Approved documents maintained at centralized location
with copies (protocol, MOP) at satellite locations
Reviewed for completeness and accuracy
33
Essential Documents (Examples)
Investigator of Record (IoR) 
or 1572
CVs for PI and Sub-Investigators
Licenses, as appropriate
Training records for all study personnel
Protocol / amendment signature page
IRB membership list or roster
IRB approvals – of protocol, consents, ads, handouts
Communication – with IRB, sponsor, CRO, if applicable
Submit a written report at least annually and in
accordance with the IRB’s request
Submit a written report if there are changes that
might significantly change the conduct of the trial
and/or increase risk to subjects
34
ICH 4.11 (Safety Reporting)
ICH 4.12 (Premature Termination or Suspension of a
Trial)
35
Immediately report all SAEs to the sponsor; follow-up
with a written report
EXCEPTION: SAEs identified in protocol as not requiring
immediate reporting
Identify study participants using codes rather than
personal identifiers
Comply with applicable regulatory requirement(s)
related to the reporting of unexpected serious
adverse drug reactions to the regulatory
authority(ies) and the IRB/IEC
36
Report AEs and/or lab abnormalities critical to safety
evaluations to the sponsor per protocol
Provide the sponsor and IRB with additional
requested information
Autopsy report in the event of a death
EKG or other supporting documentation
37
38
* 
Notify in writing
39
*Where applicable
At study completion, the investigator should
provide:
40
Insufficient evidence of Investigator involvement/oversight
No documented delegation of responsibility/scope of work
Failure to adhere to protocol requirements
Inadequate source documents
Changes made to original records without audit trail of when,
why, by whom
Failure to report UPs/SAEs appropriately
Participants not signing most current version of consent form
Inadequate product accountability records
41
Non-compliance runs the gamut from simple
mistakes to fraud.
Even simple mistakes can be costly!
Consent
Specimen handling and processing (labeling, etc.)
Consequences can range from:
Loss of data (Subject, Site, or Study data considered invalid)
Professional/reputational risk for PI and institution
42
Understanding is key to protecting subject safety and
integrity of data
Monitoring and quality management help ensure
compliance
Ultimately, it is the PI’s responsibility
Q&A
Resources
NIDCR Forms
43
44
45
Electronic Code of Federal Regulations
http://www.ecfr.gov/cgi-bin/text-idx?c=ecfr&tpl=%2Findex.tpl
Office for Human Research Protections (OHRP)
http://www.hhs.gov/ohrp/
ICH E6 Guideline
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelin
es/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf
46
NIDCR Investigator of Record Agreement
Delegation of Responsibilities Log
Training Log
Site Screening and Enrollment Log
Subject Code List
Adverse Event Forms
Monitoring Visit Log
These forms and other tools are available through NIDCR’s
Toolkit for Clinical Researchers:
 
  
http://nidcr.nih.gov/research/toolkit
47
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Clinical research encompasses various guidelines and regulations to ensure the protection of human subjects and the credibility of study results. Key aspects include Good Clinical Practice (GCP) standards, Title 45 of the Code of Federal Regulations (CFR) Part 46, and additional CFR sections for clinical trials. These regulations cover informed consent, electronic records, protection of human subjects, financial disclosure, and institutional review boards. Adherence to these standards is essential for the successful design, conduct, and reporting of clinical trials.


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  1. ICH E6 Good Clinical Practice Guidance and 45 CFR 46: Protection of Human Subjects CROMS NIDCR National Institute of Dental and Craniofacial Research National Institutes of Health National Institute of Dental and Craniofacial Research C Clinical Research Operations and Management Support Rho, Inc., Federal Division v2.0 - 2013-03-26

  2. Note that this is a general slide presentation designed for a broad audience of clinical researchers. Accordingly, some sections may not apply to your protocol. Information that may not be applicable for all studies is indicated via blue italics. 3

  3. Examples include references to: Investigational Product (IP), the Investigator s Brochure (IB), or a study pharmacist Safety reporting and adverse events Randomization and unblinding procedures Regulatory authorities Clinical treatment (for a behavioral or study or a registry) Information that may be helpful but does not come directly from ICH or 45 CFR 46 is identified by this icon. 4

  4. Good Clinical Practice (GCP) Guidelines (ICH-E6) Widely accepted international research standards Title 45 Code of Federal Regulations (CFR) Part 46 Applies to federally funded research Federal regulations to protect human subjects Subpart A: The Common Rule IRB roles and responsibilities/Informed Consent 5

  5. Additional sections of the Code of Federal Regulations apply to clinical trials 21 CFR 11: Electronic Records/Electronic Signatures 21 CFR 50: Protection of Human Subjects 21 CFR 54: Financial Disclosure by Clinical Investigators 21 CFR 56: Institutional Review Boards Additional Guidance FDA Information Sheets 6

  6. A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials [studies], that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of study subjects are protected. 7

  7. Sets minimum quality standards for the conduct of clinical research Compliance with GCP Ensures that the rights, safety, and well-being of study participants are protected Ensures the integrity of the data submitted for approval Sets standards for a system of mutual accountability among sponsors, regulatory authorities, investigators, and IRBs 8

  8. The regulations and guidelines concerning the establishment of good clinical practice apply to all studies involving human subjects Applies to Interventional studies, including studies without an investigational product Observational studies (specimen collection studies, natural history, etc.) Device studies 9

  9. Specific to research involving human subjects conducted or funded by the DHHS Federal Policy for the Protection of Human Subjects Designed to make uniform human subject protection across all federal agencies and departments 10

  10. Properly qualified to assume responsibility for conduct of the study Thoroughly familiar with the investigational product (IP), and its appropriate use Willing to comply with GCP and applicable regulations and be prepared for audits and monitoring Maintain a Delegation of Responsibilities log 11

  11. Ability to recruit in sufficient numbers and on time Sufficient time to complete the study Adequate number of qualified staff and adequate facilities to complete the study Staff who are well informed about the protocol, the IP, and their study responsibilities 12

  12. Ensure that all trial-related medical decisions are made by an investigator who is a qualified physician Provide adequate medical care for participants who experience adverse events Notify the participant s primary physician of his/her participation (as appropriate) Make an effort to learn why participants withdraw 13

  13. Obtain written approval before the study begins Provide the IRB with the current Investigator s Brochure Provide the IRB/IEC with all documents subject to its review throughout the trial 14

  14. Conduct the trial in compliance with the protocol Deviate only with agreement from the sponsor and prior review/approval from the IRB/IEC There can be exceptions see next slide! Document and explain all deviations 15

  15. The investigator may deviate from the protocol before obtaining agreement from the sponsor and review/approval from the IRB/IEC only: When the changes are logistical/administrative, or To eliminate an immediate hazard to study subjects. This requires immediate submission to: the IRB the sponsor regulatory authorities (if required) 16

  16. Responsible for the product, its usage, and its storage May delegate to a Pharmacist under the PI s supervision Maintain IP records Store as specified by the sponsor and in accordance with applicable regulatory requirement(s) Use IP in accordance with the protocol 17

  17. Follow the study randomization procedures Ensure that the randomization code is only broken in accordance with the protocol Promptly document and notify the sponsor of any unblinding (for blinded trials) 18

  18. Regulations and Guidance ICH 4.8 45 CFR 46 These require the same basic elements of consent. 45 CFR 46 must be followed for research involving human subjects that is conducted, supported, or otherwise subject to regulation by any federal department or agency. 19

  19. Adhere to GCP and the ethical principles that have their origin in the Declaration of Helsinki Update consent document when new information becomes available Avoid: Coercion or undue influence Language that causes the participant to waive any legal rights 20

  20. Fully inform participant of all pertinent aspects of the trial Use lay and non-technical language Should be understandable to the subject 8th grade reading level Translated to native language as applicable (IRB must approve translations) Provide enough time for participant to review the consent document and ask questions 21

  21. The consent document must be signed and dated Obtain consent prior to start of any study-related activities. Initial phone screening can precede consenting. If a participant or representative is unable to read, a witness should be present during the consenting process Provide the participant with a copy of the signed and dated consent form 22

  22. The informed consent discussion and the consent document should include all essential and additional elements Essential elements include: Statement that the study involves research Statement that participation is voluntary Information about purpose, duration, and procedures 23

  23. Essential elements (continued): Number of subjects involved in the study Description of risks, benefits, and alternatives Information about compensation/care for injury Statement regarding confidentiality of records Description of possible unforeseen risks 24

  24. Essential elements (continued): Circumstances for termination without subject consent Consequences of withdrawing from the study Additional costs that may result from participation Statement that new research findings will be shared Contact information for questions/concerns 25

  25. Additional elements from Title 45 CFR 46: Subpart B: Additional protections for pregnant women, human fetuses, and neonates Subpart C: Additional protections for prisoners Subpart D: Additional protections for children 26

  26. Explain the study to the extent it can be understood by participants who can only be enrolled with the consent of a legally acceptable representative (LAR) Follow guidelines for nontherapeutic trials (trials in which there is no anticipated direct clinical benefit to the participant) If participant and LAR can t provide consent, follow measures described in the protocol 27

  27. ICH 4.9 (Records and Reports) ICH 4.10 (Progress Reports) 28

  28. Data must be ALCOA (Accurate, Legible, Contemporaneous, Original, and Attributable) and complete How and where the data is recorded is key! If it is not documented, it does not exist Data on CRFs should match the source documents (raw data) 29

  29. All changes to a CRF must be dated and signed such that the original data is not obscured Retain essential documents for at least 2 years after the last approval of a marketing application Provide monitors, auditors, IRB/IEC, or regulatory authorities with direct access to trial records 30

  30. Record UP/SAE events thoroughly Meets criteria PI to determine causality Follow-up information Make records available to monitors, auditors and inspectors Record retention Institutional requirements ICH GCP 2 years after last approval of marketing application in an ICH region Follow protocol, NIH, and local institutional requirements Longest requirement should be followed 31

  31. Essential Documents Permit evaluation of the conduct of the study and the validity of the data ICH GCP E6 section 8.0 provides a table of essential documents, the purpose of the document, and the location broken down according to the stage of the study Approved documents maintained at centralized location with copies (protocol, MOP) at satellite locations Reviewed for completeness and accuracy 32

  32. Essential Documents (Examples) Investigator of Record (IoR) or 1572 CVs for PI and Sub-Investigators Licenses, as appropriate Training records for all study personnel Protocol / amendment signature page IRB membership list or roster IRB approvals of protocol, consents, ads, handouts Communication with IRB, sponsor, CRO, if applicable 33

  33. Submit a written report at least annually and in accordance with the IRB s request Submit a written report if there are changes that might significantly change the conduct of the trial and/or increase risk to subjects 34

  34. ICH 4.11 (Safety Reporting) ICH 4.12 (Premature Termination or Suspension of a Trial) 35

  35. Immediately report all SAEs to the sponsor; follow-up with a written report EXCEPTION: SAEs identified in protocol as not requiring immediate reporting Identify study participants using codes rather than personal identifiers Comply with applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC 36

  36. Report AEs and/or lab abnormalities critical to safety evaluations to the sponsor per protocol Provide the sponsor and IRB with additional requested information Autopsy report in the event of a death EKG or other supporting documentation 37

  37. Condition Notify Study terminated/suspended All participants PI terminates study Institution, sponsor, IRB* Sponsor terminates study Institution, IRB* IRB terminates study Institution, sponsor* * Notify in writing 38

  38. At study completion, the investigator should provide: Documentation Provided to Notification of study completion Institution* Summary of the trial s outcome IRB/IEC Any required report(s) Regulatory Authority(ies) *Where applicable 39

  39. Insufficient evidence of Investigator involvement/oversight No documented delegation of responsibility/scope of work Failure to adhere to protocol requirements Inadequate source documents Changes made to original records without audit trail of when, why, by whom Failure to report UPs/SAEs appropriately Participants not signing most current version of consent form Inadequate product accountability records 40

  40. Non-compliance runs the gamut from simple mistakes to fraud. Even simple mistakes can be costly! Consent Specimen handling and processing (labeling, etc.) Consequences can range from: Loss of data (Subject, Site, or Study data considered invalid) Professional/reputational risk for PI and institution 41

  41. Understanding is key to protecting subject safety and integrity of data Monitoring and quality management help ensure compliance Ultimately, it is the PI s responsibility 42

  42. Q&A Resources NIDCR Forms 43

  43. 44

  44. Electronic Code of Federal Regulations http://www.ecfr.gov/cgi-bin/text-idx?c=ecfr&tpl=%2Findex.tpl Office for Human Research Protections (OHRP) http://www.hhs.gov/ohrp/ ICH E6 Guideline http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelin es/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf 45

  45. Objective Objective Resource Resource Protection of human subjects 45 CFR 46 Staff qualifications/training ICH E6, Sec 4.1, Sec 4.2 Research resources ICH E6, Sec 4.2 Protocol adherence ICH E6, Sec 4.5 ICH E6, Sec 4.4.1, Sec 4.9, Sec 8 Record keeping FAQs (OHRP Investigator Responsibilities) http://answers.hhs.gov/ohrp/cat egories/1567 46

  46. NIDCR Investigator of Record Agreement Delegation of Responsibilities Log Training Log Site Screening and Enrollment Log Subject Code List Adverse Event Forms Monitoring Visit Log These forms and other tools are available through NIDCR s Toolkit for Clinical Researchers: http://nidcr.nih.gov/research/toolkit 47

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