Download SNM SESSION III CLINICAL TRIALS PARTICIPATION

Session III: (Breakout A) - Nuts and Bolts of Clinical
Trials Participation for
Investigators and Sub-Investigators
Clinical Research Documentation and Review
Tuesday, February 2, 2010
Lindsey J. Klane
Objectives
 GCP And Training Requirements (GCP, GMP And GLP)
 Role And Responsibilities
 Sponsor
 Monitor
 IRB/ERB
 Clinical Research Site Staff
 Documentation
 Site Binder
 Subject Binder
 Central Image Binder
 Reporting And Training
Good Clinical Practice is…
… an international ethical and scientific quality
standard for designing, conducting, recording, and
reporting trials that involve the participation of
human subjects. Compliance with this standard
provides public assurance that the rights, safety and
well being of trial subjects are protected….
The guidance was developed with consideration of the
current good clinical practices of the European
Union, Japan, and the United States, as well as those
of Australia, Canada, the Nordic countries and the
World Health Organization (WHO).
April 2006 CFR & ICH Guidelines
Good Clinical Practice (continued) &
Additional Regulations
 All Research Staff Must Receive Documented Training
•
•
•
•
Investigator Meetings
Online Training
CRO Monitor On-Site
Refresher Training (annual)
 Good Manufacturing Practices
•
Manufacturing radiopharmaceuticals
 Good Lab Practices
•
Handling/analyzing study specific lab samples
Sponsor Responsibilities
 Prepare the IB (Investigational
Brochure)
 Manage proper monitoring &
quality assurance procedures
 Design medically & scientifically
sound clinical protocols
 Handle and manage adverse
events
 Obtain regulatory approvals
 Process clinical data
(Outsource)
 Select clinical investigators
(CRO)
 Supply the investigators with all
the necessary technical & safety
data to treat patients
 Define the compensation to the
investigator & subjects (if
applicable)
 Prepare and report safety
findings
 Prepare clinical study reports
 Establish & maintain company
SOPs
Monitor Responsibilities

Trained

Follow sponsor (CRO) SOPs

Conduct pre-study assessments

Support & Train the investigator site staff

Ensure compliance with the protocol through monitoring & quality
assurance measures (Source Document Verification) Manage
clinical data & CRFs

Confirm proper handling of Investigational Product (IP) & drug
supply

Identify & ensure follow up of adverse events

Ensure local regulatory compliance
Institutional Review Board
Responsibilities
 Establish and maintain IRB SOPs
 Review protocol within reasonable
time; document in writing its
views, identify trial/documents
reviewed and dates of review
 Consider qualifications of the PI
proposed for the study
 Conduct continuing review of
ongoing trials at least once per
year
 Review of Informed Consent form
(often request additions or
deletions of text)
 No coercion for subjects to
participate
 Review amount of payment (PI
and subject
 Where prior consent of a
subject/legally acceptable
representative is not possible
(e.g., emergency situations),
determine that the protocol/other
documents address ethical
concerns & meet regulatory
requirements
 Ensure that method of subject’s
compensation is included in ICF;
payment must be pro-rated
 Ensure additional safeguards are
included in the study to protect
the rights/welfare of vulnerable
subjects
(children, prisoners, pregnant
women, handicapped,
economically/educationally
disadvantaged persons)
Ref: ICH 3.1.9; FDA 21 CFR 56.111
Principal Investigator Responsibilities
 Establish and maintain Standard Operating Procedures (SOPs)
 Qualified to conduct the clinical trial
 Read the protocol … then read it again
 Understand properties, effects & safety of the investigational
product and/or modality
 Training
•
•
•
•
•
Good Clinical Practice
Protocol
Procedures
SOPs
Ensure all Site Staff Receives Training
 Facilities, staff and time for the clinical trial
Principal Investigator Responsibilities
 Review all study documentation: amendments, ICFs, handouts,
etc. by an IRB/IEC
 Present subjects with enough information (not just the Informed
Consent procedure/document)
 Ensure subject confidentiality
 Employ unbiased selection of subjects
 Document deviations/violations
 Provide adequate & safe medical care & FU of subjects
Principal Investigator Responsibilities
 Collect and record all data accurately & appropriately document
all corrections
 Notify the sponsor & IRB of SAEs, violations/deviations, annual
summary
 Be available for monitoring visits
 Manage accountability of drug supplies
 Accept source document verification & other quality assurance
procedures
 Maintain study records as required by the health authorities and
the sponsor (regulatory files/source documents)
 Retain study related documents
Source Documentation
 Original documents, data, and records (hospital records,
clinical and office charts, laboratory notes, memoranda,
subjects’ diaries or evaluation checklists, pharmacy
dispensing records, recorded data from automated
instruments, copies or transcriptions certified after
verification, x-rays, subject files, Informed Consent Form,
Appointment Book, consultants’ letters…..
Definition: (ICH 1.52)
 For all data entered onto the CRF identical source
documentation must exist where the data was first recorded.
 No photocopies or “shadow charts”.
 Source document file containing original documentation is
acceptable.
 All source documentation should be initialed/signed and dated
by the PI or a delegated member of the study team
The site must have the following
materials prior to initiation:
 Site Regulatory Binder
 Central Laboratory Supplies and Manual (If applicable)
 IVRS and IWRS Manual with worksheets, Site number, access code
envelope, IVRS PIN number/ password and/or IWRS UserName/Password
(If applicable)
 Imaging Binder (to include Image Operations Manual, Image Acquisition
Guidelines, transmittal forms)
 Subject Binders
 Screen Failure Binder
 Case Report Forms (CRFs) (this may be electronic)
 Protocol
 Investigator’s Brochure
 IRB/EC approval of protocol, Informed Consent and Investigator’s Brochure
 Investigational Medicinal Product (interchangeable with Investigational
Product)
Site Regulatory Binder Example
Each site is responsible for maintaining the Site Regulatory
Binder in accordance with local regulations.
 Protocol
 Protocol Amendments
 Informed Consent
•
•
Templates of all approved versions
Note to File indicating location of the original signed and dated
ICF for each subject
 Protocol/Amendment Signature Page(s)
 Investigator Drug Brochure (all versions received by the site)
 Sample Drug Label(s)
 IND Safety Reports (may be maintained in a separate binder)
 Form FDA 1572
Site Regulatory Binder Example
(continued)
 Curriculum Vitae (CV) of all study personnel listed on the Form FDA 1572
will be filed. In addition, CV of all study personnel listed on the Site
Signature of Duties and Delegation Log will be filed. CVs of all study
personnel should be updated every two years during the study or initialed
and dated as current every two years.
 Licensure all study personnel listed on the Form FDA 1572 will be filed in.
Wherever requested by the local legal requirements, documentation stating
investigator’s medical license number will be filed instead of the licensure.
 Institutional Review Board (IRB)/Ethics Committee (EC) Approvals
•
•
•
•
•
•
•
•
•
•
IRB/EC membership list or multiple assurance number (where
applicable)
IRB/EC approval of protocol and amendments
IRB/EC approval of informed consent form (all versions)
IRB/EC approval of CRF (where required)
IRB/EC approval of subject recruitment and retention procedures and
materials
IRB/EC approval renewals/updates
IRB/EC correspondence
IRB/EC notification of study termination
IRB/EC approval of patient privacy authorization form (where
applicable)
IRB/EC acknowledgement of IND Safety Reports (where applicable)
Site Regulatory Binder Example
(continued)
 Subject Identification Code List (or Note To File indicating location of log)
 Laboratory Information (reference ranges, certification, signed and dated
CV of director, medical license for director). These documents should be
updated every two years.
 Monitoring Visit Sign-In Logs, including Qualification Visit Sign-In Log and
Initiation Visit Sign-In Log
 Any other written information given to the subject (i.e. patient brochures,
etc)
 Financial Documents to document the agreement between the sponsor and
the investigator
•
•
•
Fully executed contract or Note to File indicating location of fully
executed contract
Copy of site’s W-9 (where applicable)
Financial Disclosure Forms for all site staff listed on the Form FDA 1572
 IRE (Immediately Reportable Event) Forms
•
•
The original template form should be filed here. Subject specific forms
should be filed in the appropriate Subject Binder
All versions of the IRE Forms issued for the duration of the study should
be filed here.
Site Regulatory Binder Example
(continued)
 Drug Shipping/Return Records/Accountability Log/Study Medication
Inventory Log/ Storage conditions/Procedures for handling investigational
product
 Signed Agreements
•
•
•
•
Confidentiality Disclosure Agreement
Insurance Statement (varies by region)
SDV agreement (for EU only)
Data protection form (for EU only)
 Training Certifications/ Documentation
•
This documentation includes at least one documented Investigator GCP
training. Examples of GCP training documentation include the
Investigator Meeting attendance certificate for this study, Initiation
Visit sign-in sheet for this study, as well as documentation of other
types of GCP training meetings, sessions or presentations that may
have been attended by the investigator (e.g. as documented in the form
of a certificate, memo, or referenced within the investigator’s CV).
Site Regulatory Binder Example
(continued)
 Newsletters
 Blank sample copy of the CRF and CRF completion instructions (all
versions)
 Study Correspondence
•
All study-related correspondence, including telephone
contacts, relevant emails, faxes, and Sponsor and CRO Memos
 Site Signature and Delegation of Duties Log
 Copies of air waybills (if applicable or requested)
Central Imaging Laboratory Binder Example
The Central Imaging Binder will contain study specific documents for sites to
acquire study compliant imaging and properly transfer images to central
lab.
 Site Operations Manual with operational procedures and workflow
definitions
 Image Acquisition Guidelines define in detail the specific modalities,
sequences, and parameters to be used when acquiring required clinical trial
imaging.
 Image Transmittal Form required to document patient demographics and
critical image acquisition information
 Image Shipment Tracker
 Query & Reporting Procedures
 Preprinted air bills and packaging material to transfer images
Subject Binder Example
The Subject Binder will contain study specific documents for subjects in
accordance with local regulations. Where applicable, the following
documents should be filed in this binder:
 Signed, dated Informed Consent Form (s) and any signed patient privacy
documentation (if required)
 All IVRS and IWRS worksheets (initialed and dated if used) and FAX back
confirmation forms
 Disease History and Disease Outcomes documentation if taken on a
supplementary sheet (unless included in the subject’s source document)
 A copy of the results (if not filed in the CRF), signed, dated and assessed by
the investigator (or medically qualified designee), for each study visit for
which it is a required procedure, Lab Reports and any fax data clarification
forms received, signed and dated by the Investigator.
Subject Binder Example (continued)
 Laboratory reports faxed from Lab or CRO, signed, dated and assessed by
the investigator (or medically qualified designee), for each study visit for
which laboratory analyses are required and laboratory requisition forms.
 Investigational product Label Pages (if not filed in the CRF)
 Drug dispensation/ return information
 Immediately Reportable Event (IRE) Forms signed by the Investigator and
completed for individual subjects, as required, and documentation of
appropriate reporting procedures
 All patient related communication between the site and the Imaging facility
(inclusive of Imaging-related data case acceptance and case faxes, data
queries/resolution and Imaging Transmittal Forms).
Reporting
 Case Report Forms: Electronic vs. Paper
•
•
•
•
•
•
•
Demographic
Inclusion
Medication
SAE / AE
Imaging
ECG
Ongoing Visit Schedule
 Screening, Screen Fails, Randomization.. Subject Status
 Monitoring Visits
 Trends
 Queries
Site Training
 Investigator Meetings
 Regulatory Training
 Operational Overview
 Review criteria training
 Documentation Review
 Reporting
 Web-Ex Training Sessions
 Operational Overview
 Analysis criteria specific training for site (imaging staff
that could not attend IM)
 Individual training for sites that are not performing to
standard (trends & part of escalation plan)
 Refresher or for new staff
Lessons Learned
 DOCUMENT EVERYTHING!
 Frequent Reporting
•
It will get the best of you if you don’t
 Investigators Be Available
 Communication!
•
Investigator – Study Coordinator – Radiology – Imaging Core lab –
CRO MONITOR
• All need to work together harmoniously to be successful