Tips for Inspection Readiness - Asia-Pac Site...
52
Tips for Inspection Readiness Vicki Day Quality & Compliance Manager Janssen Miriam Dwyer Chief Executive Officer Gallipoli Medical Research Foundation 1
Transcript of Tips for Inspection Readiness - Asia-Pac Site...
Tips for Inspection Readiness
Vicki Day Quality & Compliance Manager
Janssen
Miriam Dwyer Chief Executive Officer
Gallipoli Medical Research Foundation
1
2
Faculty Disclosure In compliance with ANCC Guidelines, I hereby declare:
I do not have financial or other relationships with the manufacturer(s)
of any commercial service(s) discussed in this educational activity.
Vicki Day Quality & Compliance Manager
Janssen &
Miriam Dwyer Chief Executive Officer
Gallipoli Medical Research Foundation
3
We’re Going to be Audited/Inspected !!!!
Coverage – Session map
• Review Types & Tips – Visits, Audits & Inspections
• Review Preparation & Conduct • Common Findings & Solutions • Case study – presented by Miriam
4
• Monitor Visit • Sponsor Audit • Regulatory Inspection • What’s the difference?
5
Review Types & Tips for Inspection Readiness
What’s the difference?
Not a lot really; except for their focus.
6
Visit
Inspection Audit
Robust Process & Practice
Inspection Ready Audit Ready
Patient Safety &
Integrity of Data
Monitor Visit • Why: Oversee the progress of the trial. • Focus: To ensure that the trial is conducted, recorded
and reported in accordance with the protocol. • Key Points:
– SDV/Generate Queries – Review Trial Centre File – Visit Pharmacy and review IP – Visit Laboratory – Meet with the Principal Investigator – Reviews/conducts training documents – Visits site on a regular basis
8
Sponsor Audit • Why: High Risk – Enrolment, Deviations. • Focus: A systematic and independent examination
of the trial to determine whether it was properly conducted, recorded, analysed and reported.
• Key Points: – Review how you work – Process and conduct of study visit – Looking for trends and trying to identify issues
that may or may not have occurred 9
Regulatory Inspections • Why: Verify the Quality and Integrity of Data. • Focus: To determine if the Safety, Rights and
Welfare of Subjects were protected. • Key Points:
– Verify compliance with Protocol, SOPs and applicable Laws/Regulations (i.e. GCP, local law).
10
What’s the difference, apart from focus?
• Preparation should be the same for all. • Standard Processes and Practice means
you are Inspection Ready at all times.
11
Review Types & Tips Review Preparation & Conduct
- Preparation - Conduct
Common Findings & Solutions
12
Session Map – Where are we?
Preparation A well organised clinical trial site,
with processes/SOPs in place, and adequate resources and support
= An Inspection Ready site
13
Preparation Checklist • Organise processes before the trial starts
– SOPs • Qualifications/Training/Delegation • Approvals • Essential Documents/Source Documentation • Protocol Compliance/Safety Reporting • Calibrated Equipment • Regular Team Meetings/Communication
14
Conduct • Agenda • Meeting with relevant staff • Trial documents/records
– Trial Centre File – Source Documents – eCRFs
• Compliance with the protocol/procedures • Investigational product • Close out meeting to discuss findings
15
Review Types & Tips Review Preparation & Conduct
- Preparation - Conduct
Common Findings & Solutions
16
Session Map – Where are we?
Common Findings & Solutions
• Definition • Findings • Root Cause • Solution
17
Common Findings • Informed Consent • Investigator Oversight • Training • Essential Documents • Investigational Product • Protocol Compliance • Source Documentation
18
Informed Consent • A process by which a subject voluntarily confirms his or her
willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate.
• Informed consent is documented by means of a written, signed and dated informed consent form. (ICH Guidelines E6 (R 1, 1.28)
19
Informed Consent • Consent signed after first study procedure
– Protocol not checked for timing of required procedures – Review Protocol for required procedures and timing – Plan visits
• Consent process not documented in source notes – PI filled in subjects names and/or dated some ICFs – Person obtaining consent not aware of the process – Training for Site staff on ICF process
• Incorrect version of the consent used – Superceded versions remain in the Study Files – Up to date Study Files
20
Informed Consent • Re-consenting subjects not done in a timely manner • Incorrect version of the consent used
– Team member unaware of updated approved consents – Communication to team for updated consents
• Investigators not delegated/listed on Site Signature log obtained consent from trial subjects – Training and delegation log not maintained throughout the study – Accurate delegation
21
Investigator Oversight • The investigator should be qualified by education, training
ad experience • Familiar with the protocol and use of the IP • Comply with GCP and applicable regulatory requirements • Allow monitoring/auditing/inspections • Maintain a list of appropriately qualified persons to whom
they have delegated significant trial-related duties. ICH Guidelines E6 (Section 4) for complete list
22
Inspection Findings
23 FDA Warning Letter - Clinical Site May 2015
Inspection Findings
24 FDA Warning Letter - Clinical Site May 2015
Investigator Oversight • PI has not seen any patients
– All tasks were delegated to a SI – PI did not document interactions with team members – Meeting minutes and discussion to be recorded
• Assessment of Adverse Events and Concomitant Medications not done by PI/SI – Process at site did not allow for review at visit – Ensure time and resources to conduct study visits
25
Investigator Oversight • Study team not trained
– Training completion not tracked – Regular review of training status for team members – Planning and Delegation of Tasks
• Protocol Compliance/Patient Eligibility – Full review of eligibility not documented – Training of Site Staff
26
Training • All people working on the trial at the site should be qualified by
education and training before working on the trial
27
Training • Inadequate documentation
– Certificates not filed – Filing up to date and
organised • People working on the study were
not qualified – Over delegation of tasks by PI – Resourcing at site – Planning at start of trial
28
• Training completed late – Staff unaware of new information – Lack of time – Track Training of team members – Regular Team Meetings – Training Folder/Process
Essential Documents • Documents which individually and collectively
permit evaluation of the conduct of a study and the quality of the data produced (ICH Guidelines E6 (R1 1.23)
29
Essential Documents • Missing Essential documents and Incomplete Sections
– Working Folder stored documents – Contracts, CVs etc. filed centrally – If a document filed elsewhere provide at NTF
• Ethics Packages not filed – Filing divisions for submission and approvals incomplete – Filing up to date and organised – File all Ethics correspondence to document questions and
answers
30
Investigational Product • A pharmaceutical form of an active ingredient or
placebo tested or used as a reference in a clinical trial (ICH Guidelines E6 (R1 1.33)
31
Inspection Findings
32 FDA Warning Letter - Clinical Site May 2015
Investigational Product
• Drug accountability – Inaccurate records – Maintain accurate accountability records
• Compliance Checks not completed – Subject not questioned at visit – Compliance = Safety and Integrity of Data
33
Investigational Product
• IP transferred within the site – Normal process for hospital – Chain of Custody Document
• IP storage issues – Uncalibrated equipment, temperature excursions – Review Equipment and Sponsor requirements at planning
stage
34
Source Documents • All information in original records and certified
copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.
• Source data are contained in source documents (original records and certified data) (ICH E6 (R1 1.51)
35
Source Documentation Findings • Inadequate source data • Study Results not filed
– Unorganised and incomplete files
– Identify Source Data Requirements
– Filing up to date and organised
• Updates not initialled and dated • Unable to verify who made entry • Missing information
– Staff not aware how to make corrections
– Delegation Log not current – Train staff on Good
Documentation Practices
36
Common Solutions
• Planning • Training • Filing & Documentation • Communication
37
Robust Process & Practice
Inspection Ready Audit Ready
Patient Safety &
Integrity of Data
39
Case Study at GMRF • GMRF notified on an EMEA audit for a metastatic
melanoma study 2 weeks before Christmas!
• 15 patients screened, 10 patients enrolled – study still active
• Original Study Coordinator no longer with the organisation and the study had been running for over 3 years!!!
• Our compliance officer wanted to vomit!
40
Plan for success • Pulled out our SOP on audits!
– Including our trusty audit checklist which is a practical guide to a robust internal audit
• Share the load – Allocated patient file reviews to each member of the team – Allocated the Investigator Site File to another member of
the team
41
Life goes on!
• We needed to maintain “business as usual” so sharing the internal review helped lighten the individual coordinator’s load
42
Happy Holidays
• Over the coming 6 weeks we prepared for the audit.
• The CRO came to help on 2 occasions • Despite 3 years of monitoring and site file
reviews we found plenty of issues that required clarification or resolution
43
The audit
• 2 auditors arrived at 9am on Monday morning – they only wanted to work from 9am to 6pm – which we
needed to accommodate!
• 5 days of auditing – Including visits to pharmacy, pathology and radiology
44
The scope of the inspection was to verify compliance with GCP and applicable regulations • Directive 2001/20/EC of the European Parliament and of the Council of
4 April 2001 • Directive 2001/83/EC as amended by Directive 2003/63/EC of 25 June
2003 • Directive 2005/28/EC of the European Commission of 8 April 2005 • CPMP/ICH/135/95 ‘Note for Guidance on Good Clinical Practice’, July
1996 • World Medical Association Declaration of Helsinki, in the version 2013 • GMP, Annex 13 Manufacture of investigational medicinal products
45
The Team • We delegated staff to speak on various topics
according to their expertise and responsibilities on the study – Principal Investigator – Ethics Coordinator – Business manager – Lead Coordinator – Data Manager
46
We survived the week!
47
Findings of Note • The inspective revealed 2 critical deviations, 7
major and 12 minor • Critical (both Sponsor Responsibilities)
– The sponsor has not ensured adequate stock of IMP and as a consequence trial subjects have for a period of time been without study drug
– Expired IMP was assigned to trial subject by the IWRS. In addition, the sponsor has performed site-to site transfers.
48
Findings • Major (both Sponsor and Investigator):
– eCRF cannot be signed off by PI for interim data (eCRF design problem)
– No back up ePros provided and paper versions could not be accommodated in the database
– PI did not have un-blinding code (needed to go through the Sponsor)
– Radiology Department was not monitored – Some AEs of special interest were not reported within 24hours – No contractual agreements in place with 3rd party providers
49
What a relief!
• “the inspectors found no deviations of concern to the current marketing authorisation application and consider the data to be reliable”
50
Lessons to take on board • Internal audits help prepare for the real thing
– A focus on GCP compliance and institutional SOPs are key to success
• The need for an overarching MOU with the 3rd party service providers to clearly document their responsibilities as they apply to clinical trials (especially as they relate to confidentiality, reporting and record retention)
51
It’s definitely a team effort
• Audit readiness is a must at all times, but ahead of a regulatory audit its all hands on deck to put your best foot forward.
• A good audit report is something the to be
very proud of!
52
