Site Selection, Training, and SurveillanceIMMPACT XVIIIRichard Malamut, MD

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ICH GCP - The Most Important Requirement for a Clinical Study

The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

The 1996 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance on good clinical practice (ICH E6)

Clinical DB Creation

Clinical Study Time Points and ActivitiesStudy closureStudy start – up Study conducted

Protocol Sign Off

First Patient Screened

Data Base Lock

Clinical Study ReportLast Patient Last Visit

Last Patient In

First Patient In

Study Design

Statistical Analysis Plan

Vendor Selection

Countries and Sites Selection

Informed Consent

Regulatory Submissions

Drug Supply

Patient Recruitment

Site Management (e.g. Study Visits)

Medical Monitoring

Data Collection & Cleaning

Data Analysis and report

Site Activation

Inv. Meetings

Study Timelines Management

Study Budget Management

KOM

Study Documentation- TMF

Vendor Oversight

Site Audits

Inspection Readiness

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 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 envisionSites 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 properlyIf 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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Provide appropriate training to the study team (which includes Vendors, Sponsor functions, and study site personnel)

Investigators’ MeetingGCP 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 FileNow 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)

Study Team Training

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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

The Role of the Principal Investigator (PI)

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.)

Site Initiation Visit (SIV)

Informed Consent Training

How can we do better—future research questions?

TrainingWhat is the relative involvement of PIs and coordinators in study conduct?Is there any measurable difference in study conduct between F2F and virtual IMIs 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 DocumentThe 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

Study site monitor responsibility to conduct the SDV either during site visit or remotelyTeva currently follow 100% SDV policy—is this standard across sponsors? Should it be?

Vendor Oversight

Vendors’ Management

Ongoing Training

Sponsor’s Oversight

Financial Management

Monitoring

AuditsVisits

Periodic Team Meetings:•Share information and updates•Discuss Study Related Issues, Global or country specific

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 complianceFDA 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

Vendor Oversight

Sponsor oversight activities include:

Country and site selection and approvalReview and approval of country and site-specific Informed Consent Forms (ICFs) Conduct of oversight visitsReview of monitoring visit reportsReview of protocol violations and deviationsMonitoring the follow-up of Quality Assurance (QA) audit and inspection findings

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Study Documentation- Trial Master File (TMF)

those essential documents that individually and collectivelypermit 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 plansICFsStudy Plans

Evidence of qualification to be part of the study and compliance with regulations and procedures•Sponsor personnel•Vendors (CROs and Laboratories)•Physicians / Investigators and their personnel•Investigational product

Data collected during the study•Patient / Subject data•Safety-related data•Meeting minutes

Summaries and analysis of the results

Study Documentation- Trial Master File (TMF)

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

• 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

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

The Clinical Study Monitoring Team

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Clinical Study Medical Monitoringl | Confidential

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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

Medical Monitoring Plan

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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

Safety Medical Monitoring

Clinical Study Medical Monitoringl | Confidential

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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?)

Periodic Reports (PR)

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

Medical Center Review

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?

SurveillanceShould 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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