Clinical Trial Protocol

Transcription

1 Clinical Trial Protocol Compliance at Investigator Sites GCP Seminar, Dublin, 27 th January 2010 Ms. Sinead Curran GCP/Pharmacovigilance Inspector 26/01/2010 Slide 1

2 Presentation Topics Legal framework: Key Reference Documents and Requirements Expectations Common Deficiencies: i i Examples Expectations Minimize Potential for Deviations: Risk Factors Preventative Measures 26/01/2010 Slide 2

3 Legal Framework Protocol and Investigator Responsibilities: National Legislation S.I No. 190 of 2004 S.I No. 374 of 2006 ICH Topic E6, Guideline for Good Clinical Practice Chapter 2, Principle 2.6 Chapter 4, Section /01/2010 Slide 3

4 Legal Framework Protocol and Investigator Responsibilities: Key Requirements Authorisation Compliance with Protocol Management of Deviations 26/01/2010 Slide 4

5 Authorisation Requirement: Favourable opinion of Recognised Ethics Committee Authorisation from the IMB Investigator and Sponsor written agreement Expectation: Documented evidence Approval letters Protocol Signature Pages Timely implementation of amendments 26/01/2010 Slide 5

6 Compliance with Protocol Instructions Requirement: Regulation 25, S.I No. 190 of 2004, A person shall not conduct a clinical trial otherwise than in accordance with the clinical trial protocol relating to that trial Expectation: Strict adherence to protocol instructions Maintain anticipated positive benefit/risk 26/01/2010 Slide 6

7 Compliance with Protocol Instructions Exception: Eliminate immediate hazard Urgent Safety Measures IMB and Ethics Committee notification Within 3 days Protocol Instruction: Stated as optional in protocol Investigator discretion can be applied 26/01/2010 Slide 7

8 Management of Deviations Requirement: Document and explain any deviation from the approved protocol Expectation: Low level of deviations Documented and explained within Trial Master File Reported to Sponsor Active Management: Establish root cause Corrective and Preventative Actions 26/01/2010 Slide 8

9 Interaction with GCP Investigator Responsibilities GCP 4.3 Medical Care GCP 4.6 Inv. Product GCP 4.8 Informed Consent GCP 4.2 Resource & Facilities GCP 4.9 Records and Reports GCP 4.1 Inv. & Delegation of Duties Protocol Compliance GCP 4.5 GCP 4.11 Safety Reporting 26/01/2010 Slide 9

10 KEY MESSAGE Protocol NOT a guideline and instructions are mandatory Exceptions: Immediate hazard Instruction I t ti is stated t as optional Active management of deviations 26/01/2010 Slide 10

11 Presentation Topics Legal framework: Key Reference Documents and Requirements Expectations Common Deficiencies: Examples Expectations Minimize Potential for Deviations: Risk Factors Preventative Measures 26/01/2010 Slide 11

12 Common Deficiencies Non compliance with Protocol Instructions Instructions most commonly not complied with: 1. Assessment of Subject Eligibility 2. Test/Procedure methodology 3. Test/Procedure Assessment/Evaluation 26/01/2010 Slide 12

13 Common Deficiencies What are the expectations Review examples of deficiencies 26/01/2010 Slide 13

14 Common Deficiencies Assessment of Subject Eligibility 26/01/2010 Slide 14

15 Screening All tests/procedures Research Nurse/Investigator/ performed Other HCP s Assessment of Eligibility All criteria assessed Investigator Decision Subject Eligible = Yes or No Investigator Only Eligible Subjects Randomised 26/01/2010 Slide 15

16 KEY MESSAGE! Investigator to decide if Subject is eligible! Decision documented 26/01/2010 Slide 16

17 Randomisation of Ineligible Subjects Example: Subject A, was randomised to the clinical trial, although all eligibility criteria were not met, as follows.. Investigator enrolled subject, although not eligible Maintain anticipated positive benefit/risk balance Eligibility assessment not adequate All Inclusion/exclusion l i criteria i should be thoroughly hl assessed Protocol Waiver System: Investigator sought approval from Sponsor Sponsor granted waiver No legal basis, Should not exist! 26/01/2010 Slide 17

18 Inadequate Assessment of Eligibility Criteria Example: The eligibility of Subject A was not verified by an Investigator Investigator: Initial suitability assessment Continued Involvement: Research Nurse only Management of Screening tests/procedures Possible discussions with Investigator not documented Investigator assessed all criteria Eligibility decision: Who Investigator made decision? Subject randomised 26/01/2010 Slide 18

19 Poor Documentation Practices Example: The decision that Subject A was considered eligible, was not documented by the Investigator t Investigator: Evidence Eid of finvolvement All screening results assessed All criteria assessed Signed and Dated No Clear Investigator Statement: YES or NO All inclusion criteria met Any exclusion criteria met Patient Eligible 26/01/2010 Slide 19

20 Common Deficiency Compliance with Test/Procedure Methodology 26/01/2010 Slide 20

21 Expectations What? When? How? Where? Why? Tests/Procedures are performed Timely manner According to protocol methodology Using adequate and qualified facilities and staff Instructions in the protocol are mandatory Maintain Anticipated positive benefit/risk balance 26/01/2010 Slide 21

22 Generalised Non Compliance Example, Tests/Procedures: - Missed tests/procedures - Performed, but not according to protocol instructions - Not performed in required timelines Low level l of deviations System for management of deviations Corrective and Preventative Actions taken High level of deviations: Significant deficiency Indicative of a poor system at site 26/01/2010 Slide 22

23 Systematic Non Compliance with Required Test/Procedure Example: Test A, required by the protocol, was not performed, throughout the duration of the trial.. Laboratory analysis Lab analyte required, but not on routine panel Facilities are not available Consistently not requested when lab test are ordered Be aware of changes from routine practice! 26/01/2010 Slide 23

24 Systematic Non Compliance with Required Standard Example: Standard X, required by the protocol, was not implemented at site Tumor Imaging, Oncology trials: RECIST standard: change from routine practice Methodology/Assessment: Not implemented Not fully implemented 26/01/2010 Slide 24

25 Common Deficiency Assessments/Evaluations 26/01/2010 Slide 25

26 Expectations Test/Procedure performed Result Documented Assessment/Evaluation performed Assessment/Evaluation and any decision documented 26/01/2010 Slide 26

27 Expectations Investigator Involvement Clinical Trial Specific General expectations (minimum): Oversight: Treatment interruption and reduction necessary Withdrawal of patient Examples: Out of Range results: Clinical significance Adverse Events: clinical management and causality evaluation Review of Efficacy measures, as necessary for clinical management 26/01/2010 Slide 27

28 Out of Range Results Not Assessed Example: The clinical significance of Out of Range results, reported for Test A, were not assessed by an Investigator AllOut of frange results require assessment tfor clinical significance and determine if: Adverse Event Dose limiting Toxicity Withdrawal criteria Timely assessments e s required ed 26/01/2010 Slide 28

29 Assessment Not Compliant Example: Action taken in relation to the dose limiting toxicity (DLT), experienced by Subject A, was not in compliance with the protocol Investigator not aware DLT occurred Good communication necessary! Investigator not aware of protocol specific DLTs Be aware of changes from routine practice! 26/01/2010 Slide 29

30 Poor Documentation Practices Example: It was not possible to verify if an assessment of Adverse Events and Concomitant Medication was performed at Visit X for Subject Y All assessments should be documented Common outcomes not documented: No Adverse Events reported No changes in concomitant medication Lab reports reviewed, signed and dated, but clinical significance of abnormal results not documented d 26/01/2010 Slide 30

31 Presentation Topics Legal framework: Key Reference Documents and Requirements Expectations Common Deficiencies: Examples Expectations Minimize Potential for Deviations: Risk factors Preventative Measures 26/01/2010 Slide 31

32 Minimizing Potential for Deviations Smaller sites: Due Diligence Larger sites: Formalised systems Identify Factors Implement measures Maintain Awareness 26/01/2010 Slide 32

33 Risk Factor: Changes from Routine Practice Preventative Measures: Identify during feasibility Targeted training Measures equivalent to Red Flags 26/01/2010 Slide 33

34 Risk Factor: Lack of Awareness Preventative Measures: Target training: How to Meet Requirements Defined roles: Investigator/Research Nurse Communication between site staff 26/01/2010 Slide 34

35 Risk Factor: Poor Documentation Practices Documentation of: Result Assessment Medical decision 26/01/2010 Slide 35

36 Risk Factor: Poor Management of Deviations Preventative Measures: Active management: Smaller sites: due diligence Larger sites: formalised systems may be necessary Elements: Establish root cause Implement preventative and corrective actions were necessary Agreement with Sponsor about communication of deviations identified via monitoring 26/01/2010 Slide 36

37 Risk Factor: High Site Activity level Preventative measures: Formalised systems may be necessary Standard Procedures Procedures to manage anticipated changes: Changes from routine practice Substantial amendments Changes in staff (registrar rotation) 26/01/2010 Slide 37

38 Key Message Systems and Procedures Risk Factors 26/01/2010 Slide 38

39 Summary Key Requirements Expectations Common Deficiencies Root Causes Considerations for Preventative Measures 26/01/2010 Slide 39

40 Thank you 26/01/2010 Slide 40