Site Selection, Training, and Surveillance
IMMPACT XVIII
Richard Malamut, MD
ICH GCP - The Most Important Requirement for a Clinical Study
The 1996 International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
(ICH) guidance on good clinical practice (ICH E6)
The rights, safety, and wellbeing of the trial subjects are
the most important
considerations and should
prevail over interests of
science and society.
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Clinical Study Time Points and Activities
Study start – up
Study conducted
Protocol Sign Off
First Patient In
Study Design
Clinical Study
Report
Last Patient Last Visit
Last Patient In
First Patient
Screened
Study closure
Data Base Lock
Patient Recruitment
Statistical Analysis Plan
Site Management (e.g. Study Visits)
Vendor Selection
KOM
Informed Consent
Medical Monitoring
Inv. Meetings
Countries and Sites Selection
Site Activation
Regulatory Submissions
Clinical DB Creation
Data Collection & Cleaning
Site Audits
Drug Supply
Study Timelines Management
Study Budget Management
Study Documentation- TMF
Vendor Oversight
Inspection Readiness
Data Analysis and report
SITE SELECTION
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Country Selection and Feasibility
 The process is led by the operational manager while
involving various functions such as Commercial (country
selection only based upon marketing plan), Clinical,
regulatory and clinical supply
 Sponsor/CRO previous experience play a key role
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Quality of data from prior studies
Compliance with study requirements in prior studies
Success in recruiting high-quality patients in prior studies
Disease indication prevalence
 Marketing authorization may depend upon the
participation of that country in a global study
 The country list is impacted by protocol requirements
(disease prevalence, placebo allowance, comparator not
approved, standard-of-care, study procedures, etc.)
Site selection and Feasibility
 Sponsor/CRO previous experience with the site play a key role
 Quality of data from prior studies
 Expert in the disease area
 Speed and facility of study start-up activities (e.g. IRB
approval, contract finalization)
 Compliance with study requirements in prior studies
 Success in recruiting high-quality patients in prior studies
 Less common or more complex disease indications may require
specialist sites with access to those patients (e.g.,
erythromelalgia) or with special skills in carrying out protocol
requirements (e.g., NCS/QST)
Site selection and Feasibility
 The proposed sites review the study protocol details under CDA
and are asked to provide their willingness and capabilities to
perform the study (man power, facility, recruitment potential,
experience in clinical trials, participation in competitive studies)
and any potential concerns they envision
 Sites found to be suitable for the study based on the above will
be visited (Pre Site Selection Visit= PSSV) to confirm sites
qualification to conduct the study properly
 If the Investigator has been previously inspected by the FDA or
other government agency, confirm that any issues were
addressed and resolved in a timely manner
Site selection and Feasibility
 Compare site list with the following data lists and eliminate
those listed from consideration for a Teva-sponsored study
How can we do better—future research questions?
 Site selection
 Academic sites vs research sites (high quality vs high
recruitment?)
 The lure of “fast-recruiting” countries—is quality
maintained?
 If clinical study experience matters, how do we identify
and encourage our future high-quality sites?
 What is the impact of recruitment speed and quantity
upon study results?
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TRAINING
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Study Team Training
Provide appropriate training to the study team (which includes Vendors,
Sponsor functions, and study site personnel)
Investigators’ Meeting
 GCP requirement ( Phase II-IV)
 The purpose of the Investigators’ Meeting is to train the team on the
study protocol and processes
 Includes eligibility criteria, study procedures, Informed Consent
process, safety reporting, Source Documentation, Investigator
responsibilities, Site File
 Now may be a virtual IM via webex with multiple e-trainings occurring
both before and after the IM
Conduct periodic team meetings after IM (internal ,with vendors, and as
needed with study site personnel)
The Role of the Principal Investigator (PI)
 Ensuring that a clinical investigation is conducted
according to the signed investigator statement for clinical
investigations of drugs, the investigational plan, and
applicable regulations
 Protecting the rights, safety, and welfare of subjects under
the investigator’s care
 Controlling drugs, biological products, and devices under
investigation
 Personally conducts or supervises the investigation
 May delegate tasks to appropriate members but is
responsible for providing adequate supervision
 The investigator is accountable for regulatory violations
resulting from failure to adequately supervise the conduct
of the clinical study
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Site Initiation Visit (SIV)
 SIV must occur prior to the first patient enrolment at site
 Ensure all regulatory documents are available and filed
 Ensure understanding of the study protocol, investigator
informed consent, Investigator Brochure, Investigational
Medicinal Product, etc.
 Prepare, train and set up site to conduct the study
(equipment, internet connection, study drug storage
capabilities, lab kits, etc.)
 Resolve any outstanding issues regarding site
readiness (training, equipment needs, recruitment
projection and obstacles, missing documents etc.)
Informed Consent Training
Informed Consent Process
Informed consent is a process by which a subject voluntarily confirms his
or her willingness to participate in the study
The informed consent process is documented in an informed consent
form (ICF).
During the informed consent process, the subject is informed of all
aspects of the study (study procedures, their purposes, risks and
anticipated benefits) in a face-to-face discussion with the investigator
The subject (or a legally acceptable representative) must sign and date
the ICF before any study-related procedures are performed
Many sponsors are now attempting to standardized the informed
consent process to avoid introduction of potential bias by the PI or
coordinator which may impact study results
How can we do better—future research questions?
 Training
 What is the relative involvement of PIs and coordinators
in study conduct?
 Is there any measurable difference in study conduct
between F2F and virtual IM
 Is attendance at an investigator meeting sufficient to
demonstrate study conduct proficiency and familiarity
with the specific protocol?
 Should there be a mandatory national or international
certification in clinical study conduct?
 Should we standardize the informed consent process
across all sites and all studies?
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STUDY SURVEILLANCE
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Interim Monitoring Visits
 GCP requirement though sponsors have flexibility as to
process
 Conducted by the monitor (CRA) who is the primary
point of contact between the site and the sponsor
 Interim monitoring visits are conducted throughout
the study- frequency is determined according to
patients visit schedule, site recruitment and
performance
 Preparation for internal QA and inspection audits with
review of identified deficiencies
Interim Monitoring Visits
 The purpose of the monitoring visit is to verify that
 Reported trial data is accurate, complete and verifiable from
the source
 The conduct of the trial is in compliance with the
protocol/amendments, GCP and regulatory requirements
 Proper study drug accountability, storage condition according
to the protocol and temperature conditions
 Safety events are reported within the required timelines and
via the appropriate channels
 Protocol violations are identified and reported as per local
requirements
 Re-training is provided upon need
 Assist the sites in query resolution
Source Documents
Patient medical file= Source Document
The medical file contains the patient’s medical history, all study
visits summary, laboratory results (signed by the Inv.), ECG
strips
e-Source becoming more prevalent
Source Data Verification (SDV)
 Comparing the data from the medical files (source) to the
CRF and make sure all relevant information is accurately
captured
 Crucial process to ensure proper patient diagnosis and
potential exclusions due to unknown medical history
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Study site monitor responsibility to conduct the SDV either
during site visit or remotely
Teva currently follow 100% SDV policy—is this standard
across sponsors? Should it be?
Vendor Oversight
Ongoing Training
Monitoring
Periodic Team
Meetings:
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Vendors’
Management
Share information
and updates
Discuss Study
Related Issues,
Global or country
specific
Financial
Management
Sponsor’s
Oversight
Audits
Visits
Vendor Oversight
Global Outsourcing Requires Greater Sponsor Scrutiny
 While the idea to forge strategic partnerships to gain greater
efficiencies is a growing trend, Sponsors need to be aware of the risks
and take a more proactive role to ensure quality and compliance
 FDA warning letters (Sanofi-Aventis Oct 2007, J&J Aug 2009, ICON Nov
2009, Pfizer 2010 ) have made it very clear that Sponsors need to
systematically evaluate and monitor their vendor’s activities
throughout the course of outsourced clinical trials
 Teva implemented oversight activities within the regional vendor
oversight model which applies to all Teva-sponsored studies from
phase I to IV.
 The extent of oversight activities is outlined in the study-specific
Vendor Management Plan (VMP)
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Vendor Oversight
Sponsor oversight activities include:
 Country and site selection and approval
 Review and approval of country and site-specific Informed
Consent Forms (ICFs)
 Conduct of oversight visits
 Review of monitoring visit reports
 Review of protocol violations and deviations
 Monitoring the follow-up of Quality Assurance (QA) audit and
inspection findings
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Study Documentation- Trial Master File (TMF)
Study Documentation- Trial Master File (TMF)
those essential documents that individually and collectively
permit the evaluation of the conduct of a trial and the quality of the data
produced
These documents serve to demonstrate the compliance of the investigator/site,
CRO and the Sponsor with the standards of GCP and with all applicable
regulatory requirements
Documents that pre-define
how the study will be conducted
 Protocols and amendments,
regulatory approvals, study plans
 ICFs
 Study Plans
Data collected during the study
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Patient / Subject data
Safety-related data
Meeting minutes
Summaries and analysis of the
results
Evidence of qualification to be part of the study and compliance with regulations and
procedures
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Sponsor personnel
Vendors (CROs and Laboratories)
Physicians / Investigators and their personnel
Investigational product
Database Lock
 Ensure all outstanding issues are resolved (queries answered,
lab samples accounted for and analyzed, serious adverse events
reconciled, etc.)
 Ensure all final study documents are uploaded to the TMF and
required trackers are complete
 Ensure posting of the updated study operational information
and the study results in the appropriate registries
MEDICAL SURVEILLANCE
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Clinical Study Monitoring
Safety monitoring
Efficacy monitoring
Clinical - Operational input
Manage DMC and SC
• Medical Monitoring during a study is a key study success factor
focusing on 2 of the most important aspects of a trial:
• Maintaining safety of participants
• Assuring that high quality Safety and Efficacy Data is
collected to support the regulatory application of the product
• Requires a collaborative effort from the entire study team
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The Clinical Study Monitoring Team
 Medical Monitor (MM)
 Outsourced role (in most cases)
 Responsible for ongoing medical monitoring of the trial
 Direct contact with sites (queries, mails, phone)
 Clinical Study Physician (CSP)
 In-house role
 Responsible and accountable for medical decisions and safety
including
-Issues escalated by MM
-Oversight of MM activities
-Trend analysis and benchmark comparison
-DMC preparation and presentation
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Medical Monitoring Plan
 Created jointly by CSP and Medical Monitor
 Describes the scope of medical monitoring during the trial
e.g:
 Eligibility questions from sites
 SAE reports
 Medical queries
 Handling of alerts: Lab, ECG, disallowed medications
 Protocol violations
 Review of periodic reports
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Clinical Study Medical Monitoringl | Confidential
Safety Medical Monitoring
 Individual Patient Safety
 Track, review and query
safety events
- SAEs
- AEs of interest
- Lab and ECG panic alerts
- Pregnancy
- Other study specific
measures
- Continued Eligibility
questions
 Population Trend Safety
Analysis
 SAEs
 Abnormal Labs
 Discontinuations
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Periodic Reports (PR)
 Ongoing disallowed medications
 Potentially Clinically Significant labs (e.g., liver function
tests)
 New AEs of interest
 Cumulative number of events of interest
 How many cases of disallowed medications taken?
 How many AEs of interest thus far
 Protocol violation trends
 Early Termination reasons
 Suspicious medical history ( violation of
inclusion/exclusion criteria?)
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Clinical Study Medical Monitoringl | Confidential
Medical Center Review
 The Institutional Review Board (IRB) or Ethics Committee
(EC) is composed of various individuals that are
knowledgeable in the process of clinical research and the
regulations that surround it. This group of non-scientific and
scientific experts comes together to review all documentation
on a proposed study to determine if it is safe and ethical
 In some countries several sites may be associated under one
central ethical committee
 During the review process questions, further clarifications and
additional information both from the national level as well as
the medical center level are addressed promptly
Data Monitoring Committee & Clin Steering Committee
 The DMC is composed of independent physicians
with expertise in the relevant therapeutic field and
other relevant experts, such as a statistician in order
to monitor the overall safety of the study patients.
 The DMC will receive safety data periodically. They
will have the right to recommend discontinuation of
the study for safety reasons
 The CSC is compose of a group of experts
contributing to the planning of the study protocol,
involved in discussions around patients’ eligibility
 Not all studies include a DMC or CSC
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How can we do better—future research questions?
 Surveillance
 Should source document verification be a mandatory
requirement?
 How do we ensure proficiency of medical monitors?
 DMC’s primarily evaluate patient safety. Is there a role
for an independent committee that monitors study
conduct?
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