“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 jmatzat@cra-training.com • Paul Below, CCRA paul@gcp-training.net • 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