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So you think you know GCP ...

The document provides information about an upcoming presentation on Good Clinical Practice (GCP). It includes: 1) Details about the presenter including his background and experience in clinical research. 2) The learning objectives of the presentation which are to define GCP, differentiate GCP requirements from recommendations, and identify circumstances where industry best practices go beyond FDA requirements. 3) An introduction stating the presentation was developed to correct common myths and errors heard about GCP throughout the presenter's career.

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“So You Think You Know GCP ...” Northern California Chapter ACRP March 21, 2013 1
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
Disclosure • Paul has no 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 presenter throughout his clinical research career 4
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
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) FDA Guidance Documents State Law GCP International Standards SampleLaw Local Title (Institutional Sponsor Sample Text and IRB Policies) SOPs Industry Best Practices 9
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
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
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
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
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
• 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
• 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
• 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
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
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 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
Informed Consent Questions 23
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
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
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
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
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
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
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
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
Financial Disclosure Question 32
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
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
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
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
IRB Question 37
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
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
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
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
Monitoring Question 42
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
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
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
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
Source Documentation Question 47
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
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
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
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
Investigator Responsibilities Question 52
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
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
Study Records Storage Question 55
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
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
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
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
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
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
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
In Conclusion I’m not sure but it doesn’t matter. It’s a requirement of my sponsor company. 63
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
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
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
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
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
• 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.

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So you think you know GCP ...

  • 1.
    “So You ThinkYou 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 surethis 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 heardof 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 GoodClinical 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 CompletionGuidelines • 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 DocumentationPractices 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 ofthe parts of GCP can take some time and may seem daunting to those new to the clinical research industry 19
  • 20.
    Time to TestYour GCP Knowledge 20
  • 21.
    • The followingslides 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 Voteby 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.