QUALITY ASSURANCE, QUALITY
CONTROL AND GCP
Tina Liden Mascher & Catherine Mai-Trang Pham
PARTS OF THE TRAINING/PRESENTATION
QA/Quality Assurance (RCO managers)
GCP - In summary (RCO managers)
GCP – In practice (registerhållare/registry Manager, QA)
CONTENTS
Why QA?
Good and bad examples
Background: GCP and definitions
QA/QC
QA system and parts
Overall responsibilities
Sponsor responsibilities
CRA Monitoring and SDV (source data verification)
Risk-based monitoring
Computerized systems in clinical research (FDA)
WHY? REGULATORY REQUIREMENT IN GCP
Regulatory requirement:
for organizations to manage and monitor their quality
control and quality assurance systems and their
control documents (SOPs and other quality
documents), so as to provide high-quality products
and services that fully satisfy customer needs and
expectations
for organizations who perform clinical trial studies,
so as to protect the safety and integrity of patients
WHY? THE NATIONAL QUALITY REGISTRIES - EVIDENCE-BASED APPROACH
WHY? PUBLICATIONS FROM REGISTRIES (DATA SHOULD BE VALID
AND CHECKED)
WHY? REGULATORY REQUIREMENT EXTRAPOLATED TO REGISTER
CENTERS
For Quality Registers: to manage and monitor the organization’s
quality control and quality assurance systems and their control
documents (SOPs and other quality documents) so as to provide
high-quality systems and services (system and database development
and maintenance, data extraction, etc) that fully satisfy register
owners’/researchers’ needs and expectations
For Studies using data from Quality Registers: to manage and
monitor the organization’s quality control and quality assurance
systems and their control documents (SOPs and other quality
documents) so as to provide high-quality data and processes
(informed consent, data standards, traceability, data transfer, etc.)
that fully satisfy academic and commercial sponsors’/regulatory
needs and expectations
GOOD EXAMPLE - QUALITY CONTROL
THE BEST POSSIBLE CARE FOR THE PATIENT
Working procedures: Cataract Registry
THE BEST POSSIBLE CARE FOR THE PATIENT
Research and Development: Rheumatoid Arthritis Registry
THE BEST POSSIBLE CARE FOR THE PATIENT
Quality Improvements:
Swedheart Registry
THE BEST POSSIBLE CARE FOR THE PATIENT
New drugs/devices, e.g. Hip arthroplasty registry
Publication:
BAD EXAMPLES: FDA (WARNING LETTERS)
Deficiencies relating to “Quality Systems” are by far the most
commonly observed during inspections (MHRA inspection
deficiencies report year 2013)
“Failure to maintain adequate and accurate case histories that
record all observations and other data pertinent to the investigation
on each individual administered the investigational drug or
employed as a control in the investigation” is cited in 6 out of the
10 warning letters issued by US-FDA to clinical investigators in 2010
(FDA warning letters)
At one investigator site, source documents were not available
because the computer “crashed”. So in the absence of
availability, adequacy of the records could not be evaluated. The
investigator was warned for “failure to retain records required to be
maintained for the required timeframe per regulations” (FDA warning
letters)
QUALITY MANAGEMENT
QA System: defined as the organizational structure,
responsibilities, processes, procedures and resources for
implementing quality management
Quality Management: QA+QC
QA: focused on providing confidence that quality
requirements are fulfilled
QC: focused on fulfilling quality requirements
Quality Management must be commensurate with the
Company business objectives and business model. Top
management commitment and active involvement are critical
in order to ensure at all times the adequacy, suitability,
effectiveness and efficiency of the quality systems.
QUALITY MANAGEMENT - TWO LEVELS
Organizational level: Quality system based on ISO 9001,
ISO 13485 etc, to define:
Organizational structure (management, tasks,
responsibilities)
Resources, trainings
SOPs: Authorities submission, study planning, investigator
assessment, etc
Internal audits
Host external audits/inspections
Contact person for internal members and for external
parties on regulatory issues
QUALITY MANAGEMENT- TWO LEVELS
Study/Project level: ICH GCP requires study
processes/traceability/documentation at different stages:
Such questions should be answered via process and
documentation:
Study design: Is the trial design appropriate? Can the trial
answer the proposed research question or will the data be
equivocal, e.g. adequate statistical power? … etc.
Study performance: Is the trial performed according to
approved protocol? Do patients give informed consent freely?
QUALITY FOUR STEPS APPROACH
Say what you do
Do what you say
Prove it
Improve it
QA FUNCTION
QA Function: To manage Quality System (processes and
documentation) + Quality Management (QA+QC)
QA Function: for regulatory requirements as a minimum,
and for add-in value to an organization
QA FUNCTION - DAILY SUPPORT
Increasing the value of the registry
- Inspection
- Audits
- Long-term development and survival
By daily collaboration = no surprises, internal/external
Results can be seen in high score auditing and quality
control
BACKGROUND
Good Clinical Practice (GCP) is a set of internationally recognized
ethical and scientific quality requirements for designing, conducting,
recording, and reporting Clinical Trials.
Compliance with GCP provides assurance that the rights, safety and
well-being of subjects are protected, while maintaining data quality
throughout the study.
The objective of this ICH GCP Guideline is to provide a unified standard for
the EU, Japan, and the United States to facilitate the mutual acceptance of
clinical data by the regulatory authorities in these jurisdictions.
GUIDELINES
The principles of GCP are defined in:
ICH Guideline for Good Clinical Practice E6 (Guidance
for Industry E6 Good Clinical Practice: Consolidated
Guidance)
adopted within Europe in July 1996
adopted within Japan in March 1997
adopted within the US in May 1997
GCP - BACKGROUND
ICH Harmonized Tripartite guidelines for GCP3
WHO guidelines for GCP for trials on pharmaceutical
products
Code of Federal Regulations Good Clinical Practice
Guidelines, Parts 50, 54, 56, 312 and 314
GCP
Good Clinical Practice [GCP] guidelines provide an
international ethical and scientific quality standard
for the design, conduct, performance, monitoring,
auditing, recording, analysis and reporting of clinical
trials that provides assurance that the data and reported
results are credible and accurate, and that
the rights, integrity, and confidentiality of the trial subjects
are protected
GCP - THE DESIGN
A protocol is a document that describes the objective(s),
design, methodology, statistical considerations and
organization of a study.
According to the principles of GCP, a clinical study
should be scientifically sound, and described in a clear,
detailed protocol.
The principles of GCP also state that a study should be
conducted in compliance with the protocol that has
received the Independent Ethics Committee’s (IEC)
approval/favorable opinion
GCP - CONDUCT, PERFORMANCE
Evidence-based medicine is fundamental in the treatment
of disease. GCP requires studies to be conducted to
ensure the safety of the clinical trial subjects as well as
the integrity of the data, which will be used to support
changes in evidence-based care and the regulatory
approval of new medicines.
Compliance GCP requires that trials be conducted in
compliance with the approved protocol, including
eligibility criteria, adverse event monitoring, treatment
and modifications
GCP - MONITORING
The ICH GCP document defines monitoring as “the act of
overseeing the progress of the clinical trial and ensuring that it
is conducted, recorded, and reported in accordance with the
protocol, standard operating procedures, GCP, and applicable
regulatory requirements.”
Risk Based Monitoring Approach
Additional protection for human subjects is the use of a Data
Monitoring Committee (DMC) or Data Safety Committee
(DSC) to evaluate accumulating data in a clinical trial
GCP - AUDITING
Auditing is defined in the ICH CGP document as “the
systematic and independent examination of trial-related
activities and documents.”
The audit is usually conducted at the conclusion of the trial.
The sponsor may hire field auditors who document findings in
a written report to the sponsor.
Authorities inspectors also conduct independent study audits.
Traditionally, the purpose of authorities inspections has been
to verify data submitted in support of a marketing application.
However, the authorities and the sponsor may conduct “for
cause” or directed audits at any stage of the study, if there is
reason to suspect a problem with trial conduct or data integrity.
GCP - RECORDING
“If it is not written down, it did not happen”
It is the investigator who produces the source data
collected in Case Report Forms (CRFs). In creating the
source information, investigators must ensure that they
document not only routine patient care information but
also protocol-specific information.
If there are discrepancies between the data and the
source document, an explanation must be included.
GCP - ANALYSIS AND REPORTING
Analysis: E9 ICH Statistical Principles for Clinical Trials
Reporting: E3 ICH Structure and Content of Clinical
Study Report
GCP - ESSENTIAL DOCUMENTS
Essential documents : “documents that individually and collectively permit evaluation of the conduct of a
trial and the quality of the data produced. These documents serve to demonstrate the compliance of the
investigator, sponsor and monitor with the standards of GCP and with all applicable regulatory
requirements.” Essential documents for clinical trials include:
Investigator's brochure with updates
Protocol with amendments
Date-documented authorities/EPN approvals
CVs of study investigators
Normal/reference laboratory ranges
Investigational agent documentation and accountability
Quality plan
Monitoring reports
Signed informed consents
Source documents
Complete CRFs with documentation of corrections
Serious Adverse Event notifications
Safety reports and annual reports to authorities/ EPN
OVERALL RESPONSIBILITIES DURING CLINICAL RESEARCH
Regulatory authorities
Ethics
Sponsor
Investigator
GCP - SPONSOR RESPONSIBILITIES
Selecting qualified investigators
Providing investigators with the information they need to
conduct an investigation properly
Ensuring proper monitoring of the investigation
Ensuring that review and approval are obtained from Ethical
Committee (EPN)
Ensuring that the investigation is conducted in accordance
with the approved study plan
Maintaining an effective regulatory documentation
Ensuring that authorities, all participating investigators, and
EPN are promptly informed of significant new adverse events
GCP - INVESTIGATOR RESPONSIBILITIES
Ensuring that an investigation is conducted according to
the signed investigator statement, the approved study
protocol, and applicable regulations, e.g. radiation, etc
Protecting the rights, safety, and welfare of subjects
Controlling drugs/devices under investigation
Obtaining informed consent from each human subject
Promptly reporting significant new adverse events
REGISTERS: WHY AND FOR WHAT?
Why
Safety and follow-up
Method development
Clinical research
Health economics
Patient outcome
Risk factors, prevalence, incidence
What
Development of guidelines
International and local comparisons in healthcare
Industry follow-up of new drugs/devices
Epidemiological studies
Real world studies(medical effect and cost)
Feasibility studies
Randomized studies (phase II, III, IV)
DIFFERENT TYPES OF STUDIES - DIFFERENT REGULATIONS
Study Type
Regulations/Laws
FIM/Phase I
Clinical Trials –
MPA approvals
GCP ICH 6
Phase II/Phase III
Clinical Trials –
MPA approvals
GCP ICH E6
Low Interventional Clinical Trials –
MPA approvals
GCP ICH E6
Non-Interventional Studies –
Non MPA approvals
- Helsingforsdeklarationen (DoH)
- Etikprövningslagen, PUL och övrig nationell, tillämplig
lagstiftning
- LIF Policy 2010:1; Rules for non-interventional studies and
financial support for healthcare quality registries LIF Policy Ickeinterventionsstudier
och LIFs Etiska Regelverk (LER) (rev Juni 2014) LIF
Läkemedelsbranschens Etiska Regelverk
-
DIFFERENT TYPES OF STUDIES - DIFFERENT RISKS FOR PATIENTSDIFFERENT LEVELS/FOCUSES OF GCP
Study Type
Risks to Patients
GCP level
FIM/Phase I
Clinical Trials –
MPA approvals
High
Organization level: Quality system
Study level: full study protocol,
”extensive ”monitoring, etc
Phase II/Phase III
Clinical Trials –
MPA approvals
Medium to High
Organization level: Quality system
Study level: full study protocol,
”extensive ”monitoring, etc
Low Interventional Clinical Trials –
MPA approvals
Low
Organization level: SOPs
Study level: full study protocol,
lower requirement for monitoring,
etc
Non-Interventional
Studies –
Non MPA approvals
Low
Study level: Abbreviated protocol,
reports or publication
GCP AND REGULATORY COMPLIANCE DEFICIENCIES
The most common deficiencies noted during Regulatory Authority inspections pertain
to:
•Inadequate medical records: should include information on disease/indication, legibility,
concomitant diseases, patient included in study ID XXXX, written consent obtained, concomitant
medication
•Protocol non-adherence: inform CRA about all deviations, of problems following the protocol
•Inadequate drug accountability: reconstitution, doses administrated, vials used per patient and
dose and also concomitant medication
•Improper consenting procedures: by Investigator, including copy of signed consent given to
patient, signed and personally dated by the subject and by the person who conducted the informed consent
discussion
•Inadequate reporting of adverse events: Related or non-related, significant or non-significant
events should be reported
FDA WARNING LETTERS 2012
Number 1
Failure to ensure that the investigation was conducted according to the
investigational plan, the signed agreement, applicable FDA regulations, and
conditions of approval imposed by the IRB or FDA:
(a) Failure to perform study visits at location specified in protocol
(b) Failure to ensure that assessments were conducted by an individual
qualified by credentials to do so
(c) Failure to enroll subjects who met eligibility criteria
(d) Failure to perform protocol required testing
(e) Failure to perform protocol required testing within stipulated timeframes
(f) Failure to comply with state regulations regarding the reporting of
newly-identified HIV positive laboratory results to the Centers for
Disease Control and Prevention (CDC)
DEFINITIONS: QA, QC
Quality control : steps taken during the generation of a product or service, to ensure
product/service quality,
to ensure that the trial meets protocol and procedural requirements and is
reproducible.
Quality assurance refers to a systematic process to determine whether the quality
control system is working and effective. A company QA system is the interpretation
of the laws and regulations.
Quality assurance in clinical trials is implemented
- by the sponsor : through independent auditing of quality control activities
- by regulatory authorities : through inspection of quality control systems and
activities
QA ROLE
• Purpose: Company interpretation of legal requirements
• Goal:
External - recognition
Internal – quality through standardization
Roles are functions, SECURE the business
Anyone should be able to take over a
role/function and apply the same standards
BASIS OF QA SYSTEM
External:
• ICH
• EC legislation and guidelines
Internal:
• Organogram
• Job descriptions
• Work descriptions
QA/SOP SYSTEM-HIRARCHY
Policies
QA handbook
SOPs
Working instructions
Templates
WORK INSTRUCTIONS/SOP
The organization’s interpretation of the guidelines and
regulations
Describes the most important, critical procedures
Who is doing what, how and when
QA AS A SUPPORT
Ensure that procedures are followed and support inspections
• GCP
• GCLP
• GMP
• Working instructions/SOPs
Continuous improvement comes from learning from each other and
from previous experiences ...
The result is increased efficacy
QC - QUALITY CONTROL
Checks performed by Operations themselves
For example by a CRA performing monitoring
INFORMED CONSENT
Freely given informed consent should be obtained from every subject prior to clinical trial
participation.
Before informed consent may be obtained, the investigator or designee should provide the
subject enough time and opportunity to inquire about details and to decide whether or not to
participate in the trial.
Prior to a subject’s participation in the trial, the informed consent form (ICF) should be signed
and personally dated by the subject and by the person who conducted the informed
consent discussion. A copy of the ICF should be provided to the subject.
Before any trial procedure such as examinations/ evaluations and tests, it should be reconfirmed
that the (ICF) has been obtained.
ICF signature procedure must always be documented in the patients’ medical records.
RESPONSIBILITIES OF INVESTIGATORS (1)
The investigator should be qualified by education, training and experience to assume responsibility
for the proper conduct of the trial, and should provide evidence of such qualifications
through an up-to-date CV including GCP training/experience.
The investigator should be aware of, and should comply with, GCP and the applicable
regulatory requirements.
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6_R1/Step4/E6_R1__Guideline.pdf
Declaration of Helsinki: http://www.wma.net/en/30publications/10policies/b3/
To conduct studies in full accordance with the current protocol. Trial provided materials such
as check lists and flowcharts are useful tools to help with trial planning.
To document and report any protocol deviations to the Company/Sponsor.
RESPONSIBILITIES OF INVESTIGATORS (2)
To report all AEs to Company. If a patient suffers an AE during an assessment, the assessor
shall report this to the Principal Investigator and ensure that it is documented and
reported.
Report any SAEs within 24 hours of becoming aware of the event to Company and
IEC/Ethics committee and Health Authorities as applicable .
To read and understand the Investigator’s Brochure (including potential risks and side effects
of the IMP).
To ensure that all study personnel are informed about their obligations and study duties.
To maintain properly completed and accurate study records and to make those records
available for monitoring, audits and inspection.
Permit trial-related monitoring, audits, IEC review, and regulatory inspection(s), providing
direct access to source data/ documents.
RESPONSIBILITIES OF INVESTIGATORS (3)
The investigator should maintain a list of appropriately qualified persons to whom the
investigator has delegated trial-related duties.
The Principal Investigator is responsible for ensuring that all trial staff is adequately trained
in trial processes and procedures, as well as the standardized working instructions used.
Duties can be delegated, not responsibility.
CRA should be always informed about all changes in study staff, study facilities and duties
assignation as soon as they happen.
For all equipment used by the site and departments, devices must be identified, calibrated
and have documentation of controls.
RESPONSIBILITIES OF INVESTIGATORS (4)
All product accountability.
Storage of the investigational product and ensuring that all equipment (infusion
pumps, freezers, refrigerator) used in the trial is adequately calibrated and
controlled.
The investigator or designee should maintain records of:
• the product’s delivery to the trial site
• the inventory at the site
• study medication administered to each subject
• destruction of unused product
• destruction of used study medication (vials)
DATA COLLECTION (1)
Clinical Trial data must be recorded, handled and stored to enable accurate reporting,
interpretation and verification.
All trial data must be recorded in the paper/electronic Case Report Forms (CRFs) in a timely
manner, preferably as soon as they are generated.
The investigator should ensure the accuracy, completeness, legibility, and timeliness of
the data reported to the sponsor in the CRFs and in all required reports (as per Section
4.9.1 of ICH E6)
Data reported on the CRF, that are derived from source documents, should be consistent
with the source documents or the discrepancies should be explained (As per
Section 4.9.2 of ICH E6
Source documents can be hospital records, lab reports, ECGs, MRIs, patient diaries,
pharmacy records, etc.
An explanation for the omission of any required data must be recorded on the appropriate
page.
Any data, CRF and information sheet collected should be signed and dated.
Only the Principal Investigator or authorised Sub-investigator can sign the CRFs for
assurance of the correctness and completeness of each page.
DATA COLLECTION, CONT. (2)
Any change or correction to a CRF should be dated, initialled and explained (if necessary)
and previous/original entries should not be obscured. This will allow for the maintenance
of an audit trail.
Draw a single line through the incorrect entry, not erasing, blacking out or using
correction fluid;
Write the correct information next to the original entry;
Initial and date.
Subject confidentiality should be protected to the possible extent. Although all trial
documents should be appropriately identified by subject number and/or date of birth (if
applicable), reports sent to Company should make use of anonymised data.
e.g. in some EU countries, MRI, CT scans and other source documents should not
include direct and identifiable patient data such as name, full DOB (year allowed) and
patient initials.
DATA COLLECTION, CONT. (3)
The investigator must arrange for the retention and storage of:
-Patient identification codes (hospital/unit code, trial identification code and trial number)
-Other source documents - patient files, clinic case notes and appropriate hospital records
-Radiology or study specific data
Radiology and Audiometric Data should be delivered to the Investigative Site for retention in
the Subject Notes and/or Investigator Site File.
If the Principal Investigator relocates or retires, Company must be notified (in writing).
Trial documents and data including Site files should be retained for >15 years and, before
destruction, Company must be informed by the Investigator.
COMPANY/INDUSTRY
Ensure that preset Sponsor requirements and authority regulations are
fulfilled by internal and external teams
Plan: audit plans, organograms, flow charts, roles and job descriptions
Do:
Inspection preparation and hosting
Support operations: Advice and problem solving
(Draft) Review and approve documents
Training
Audits
Correct: findings
Improve: SOPs and process
Systematic approach with QA as a development team support.
SPONSOR RESPONSIBILITIES DURING CLINICAL RESEARCH
5.18 Monitoring
5.18.1 Purpose The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are protected.
(b) The reported trial data are accurate, complete, and verifiable from source documents.
(c) The conduct of the trial is in compliance with the currently approved
protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
5.18.2 Selection and Qualifications of Monitors
(a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the scientific and/or clinical
knowledge needed to monitor the trial adequately. A monitor’s qualifications should be
documented.
(c) Monitors should be thoroughly familiar with the investigational product(s), the protocol,
written informed consent form and any other written information to be provided to subjects,
the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
5.18.3 Extent and Nature of Monitoring The sponsor should ensure that the trials are
adequately monitored. The sponsor should determine the appropriate extent and nature of
monitoring.
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SPONSOR RESPONSIBILITIES, CONT. 2
5.18.4 Monitor’s Responsibilities. The monitor(s) in accordance with the sponsor’s requirements should
ensure that the trial is conducted and documented properly by carrying out the following activities when
relevant and necessary to the trial and the trial site:
(a) Acting as the main line of communication between the sponsor and the investigator.
(b) Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and remain
adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are
adequate in order to safely and properly conduct the trial and remain adequate throughout the trial
period.
(c) Verifying, for the investigational product(s):
(i) That storage times and conditions are acceptable, and that supplies are sufficient
throughout the trial.
(ii) That the investigational product(s) are supplied only to subjects who are eligible
to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on properly using, handling,
storing, and returning the investigational product(s).
(iv) That the receipt, use, and return of the investigational product(s) at the trial sites
are controlled.
(v) That the disposition of unused investigational product(s) at the trial sites complies
with applicable regulatory requirement(s).
(d) Verifying that the investigator follows the protocol and approved amendment(s).
(e) Verifying that written informed consent was obtained.
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SPONSOR RESPONSIBILITIES, CONT. 3
(f) Ensuring that the investigator receives the current Investigator’s Brochure, all documents, and all trial
supplies needed to conduct the trial.
(g) Ensuring that the investigator and the investigator’s trial staff are adequately informed.
(h) Verifying that the investigator and the investigator’s trial staff have not delegated functions to
unauthorized individuals.
(i) Verifying that the investigator only enrolls eligible subjects.
(j) Reporting the subject recruitment rate.
(k) Verifying that source documents and other trial records are accurate and complete.
(l) Verifying that the investigator provides all the required reports, notifications, applications on time.
(m) Checking the accuracy and completeness of the CRF entries:
(i) The data required by the protocol are reported accurately on CRFs and consistent
(ii) Any dose and/or therapy modifications are well documented for each of subjects.
(iii) Adverse events, concomitant medications and intercurrent illnesses are reported.
(iv) Visits that the subjects fail to make, tests that are not conducted, and examinations
that are not performed are clearly reported as such on the CRFs.
(v) All withdrawals and dropouts of enrolled subjects from the trial are reported.
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SPONSOR RESPONSIBILITIES, CONT. 4
(n) Informing the investigator of CRF entry error, omission, or illegibility.
(o) Determining whether all adverse events (AEs) are appropriately reported
within the time periods required by GCP
(p) Determining whether the investigator is maintaining the essential
documents
(q) Communicating deviations from the protocol, SOPs, GCP, and the
applicable regulatory requirements to the investigator and taking appropriate
action designed to prevent recurrence of the detected deviations.
SPONSOR RESPONSIBILITIES, CONT. 5
5.18.5 Monitoring Procedures: The monitor(s) should follow the sponsor’s established written SOPs as well as
those procedures that are specified by the sponsor for monitoring a specific trial.
5.18.6 Monitoring Report
5.19 Audit
5.19.1 Purpose: The purpose of a sponsor’s audit, which is independent of and separate from routine monitoring
or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP,
and the applicable regulatory requirements if or when sponsors perform audits, as part of implementing quality
assurance
5.19.2 Selection and Qualification of Auditors
(a) The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.
(b) Auditors should be qualified by training and experience.
5.19.3 Auditing Procedures
(a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the
sponsor’s written procedures on what to audit, how to audit, the frequency of audits, and the form and content
of audit reports
5.20 Noncompliance
5.21 Premature Termination or Suspension of a Trial
If a trial is prematurely terminated or suspended, the sponsor should promptly inform the
investigators/institutions, and the regulatory authority(ies)
5.22 Clinical Trial/Study Reports
5.23 Multicenter Trials REG7IRB approvals protocol, responsibilities, communication between Inv.
60
SOURCE DATA VERIFICATION - DEFINITION
GCP requires Source Data Verification [SDV] to be
undertaken for all studies.
SDV: All information in original records and certified copies
of original records of clinical findings, observations, necessary
for the reconstruction and evaluation of the trial.
can be said to be the first place where information is
recorded/captured
The source documents are one of the “Essential documents”
and serve to demonstrate quality of the data, as well as
sponsor, investigator and monitor compliance with GCP and
regulatory requirements
SOURCE DOCUMENTS
Original documents
Data
Hospital records
Clinical and office charts
Laboratory notes
Memoranda
Subjects’ diaries (medical records?)
“Checklists”
Pharmacy dispensing records
Recordings
Data from automated instruments, copies or transcriptions
Certified as being accurate after verification
Copies, microfiches, photographic negatives, microfilm, magnetic media, X-rays, subject files
Records kept at the pharmacy
Record at laboratories and at medico-technical departments involved in the clinical
trial
WHY?
HOW?
Why: To ensure that data is complete, accurate, valid, reliable and
verifiable.
SDV is also required
to provide confidence in any data reported, for example in
published manuscripts
How:
Source Data Verification [SDV] is an evaluation of the conformity
of the data presented in case report forms [CRFs] with source data.
Data reported is compared with the original records.
Every item of data that appears in a CRF should be documented
somewhere else to allow verification.
SOURCE DATA VS DATA MONITORING
Data monitoring = ensuring that the data have been
correctly entered and that all corrections have been dated
and initialed, while checking for error and inconsistencies.
SDV= data checked against source documents
CONFIDENTIALITY
Maintain confidentiality of subjects’ identities.
Maintain confidentiality of sponsors’ proprietary
information.
Patient’s informed consent should be obtained and
documented prior to the study.
FILING AND ARCHIVING
Source data are retained at the study site.
Trial documents as specified in the essential documents in
study files
Archived for a minimum of 15 years
It is the responsibility of the sponsor to inform the
investigator/institution as to when these documents are
no longer needed
KEY DATA
1) Primary efficacy data
2) Inclusion/exclusion criteria
3) Medical and medication history
4) Physical examination/vital signs
5) Visit dates
6) Adverse Events
7) Concomitant medication
8) Confirmation that the patient has entered a clinical study
9) (Date of) informed consent
METHODS OF SDV
Back to back method: the investigator holds all the
source documents and answers questions
Direct method: the monitor has direct access to source
documents
Signed Approval for review of source documents should
be obtained to allow monitoring (Sweden: applies to each
monitor).
****FDA must be able to make a copy of any records or reports made by the investigational team as part of the trial . FDA
regulations state that the investigator is not required to divulge subject names unless a more detailed study of the records for a
particular individual is required.
STUDY PERFORMANCE AND EXTENT OF SDV
According to SOP
According to monitoring plans (SDV plans)
Performed before data are retrieved from the site
Performed in early stages of the clinical trial so
that any problems elicited can be resolved
100% SDV for all patients, or 100% SDV of key data and
a sample of the rest
See also key areas on previous slide
PRECAUTIONS
High numbers of write-overs
Poorly completed
Serious adverse events
Lack of/no adverse events when they should be expected
Rapid recruitment
Withdrawals
SDV RECORDED
1. Which source documents were examined
2. Which CRFs were checked and why they were selected
3. The critical data items checked on each CRF
4. The non-critical data items checked on each CRF
5. The frequency of errors
6. The nature of errors
7. Whether any ameliorative action was undertaken at the site
IMPORTANT! If, when and why changes were made,
these changes should be signed off
RESULT OF SDV
The results of SDV should be critically evaluated to
determine:
Data accuracy
Standard appropriate
Reasons for inconsistencies
Actions to be taken?
Implications for not performing SDV: Data false?
Rejection of data?
EFFECTIVE SDV
Discuss and agree upon SDV with the site/institution,
encounter real life settings
Assure SDV availability at contracting, prior to start of study
visit
SOPS, plans for SDV should be developed
Consider the help of an onsite nurse/medical person first time
Document which data have been verified
Focus on key data
Educate people on process and objectives
Undertake SDV in peace and quiet, without interruption
RISK-BASED MONITORING
Includes identification, assessment, communication and ongoing
review of trial risks and priorities, and control through mitigation of
significant and serious risks.
Factors that may affect collection and performance
Risk management plan: Risk assessment. Risk control, risk review and
reporting
Identify critical data and processes (endpoints, SAE, consent,
inclusion/exclusion)
Monitoring plan should focus on risks (and systemic errors)
Central and remote monitoring
Well designed forms and completion instructions
COMPUTERIZED SYSTEMS USED IN CLINICAL INVESTIGATIONS
(FDA)
Applies to records in eletronic forms that are used to create, modify,
maintain, archive, retrieve and transmit clinical data.
Part 11: requires validation, audit trails, record retention, and record
copying.
The guideline is intended to assist in ensuring reliability, quality and
integrity of electronic records.
Study protocol should define when electronic records are used
SOPs
Source document: when data is entered directly into a remote
computerized system, a copy of the data should be maintained at
another location. Copies with data entry should be preserved (as PDF,
XML or other)
COMPUTERIZED SYSTEMS USED IN CLINICAL INVESTIGATIONS
(FDA) CONT.
Internal Security:
Limited access to authorized individual and individual
account and password. Automatic log off could be
considered.
Audit trails keep track of all changes (who, when, what was
changed)
Date (time-stamped: year, month, day, hour)
External Security:
Procedures/controls in place to prevent altering, querying or
reporting of data via external software instead of the
protective system software. Data restricted to authorized staff.
List of authorized staff.
COMPUTERIZED SYSTEMS USED IN CLINICAL INVESTIGATIONS
(FDA) CONT.
Other system features
Direct entry of data, and consistent usage of terminology.
Avoid data field to be automatically populated.
Retrieving data: How source data were obtained and
managed, electronic records used.
System documentation: for each study, identify
software/hardware used.
System controls: Sufficient backups and recovery procedures.
Records should be stored offsite.
Change controls: changes to system should be documented
Training of staff: should be documented
LIST OF SOPS FOR COMPUTERIZED SYSTEMS
User/regulatory requirements for system
System set up/installation (including description and specific use of
software)
System operating manual
Validation and functionality testing
Data collection and handling (data archiving, audit trails, risk assessment)
System maintenance (system decommissioning)
System security measures
Change control
Data backups, recovery and contingency plans
Alternative recording methods (system unavailability)
Computer used training
Roles and responsibilities
Evaluate/assess key vendors
SOME REFERENCES…
1. Khosla R. GCP guidelines: differences between the ICH
and WHO guidelines. Good Clin Pract J 1998;3:24-30.
2. Verma D.D. , Sharma G., Arora H. ; GCP guidelines : FDA
Vs WHO. Good Clin Pract J 1999;6:18-22.
3. ICH Harmonized Tripartite Guidelines for Good Clinical
Practice [E6: good clinical practice:consolidated guideline],
1997.
4. WHO guidelines for Good Clinical Practice for Trials on
Pharmaceutical Products, 1994.
5. Code of Federal Regulations (CFR) Good Clinical Practice
Guidelines Parts 50, 54, 56, 312 & 314, April 1999.
6. Bruckheimer M. FDA’s Inspections of Clinical Investigators.
Drug Inf J 1993;27:213-6.
7. US Department of Health and Human Services, US Food
and Drug Administration, 21 CFR Part 11, Electronic
Records; Electronic Signatures: Final Rule, 1997.
8. Guidance for Industry . Computerized systems used in Clinical investigations, FDA May 2007
9.Guidance for Industry: Oversight of Clinical Investigations - A Risk-Based Approach to Monitoring” FDA. (August 2013),
10. The European Medicines Agency (EMA) issued the “Reflection Paper on Risk Based Quality Management in Clinical Trials”
(November 2013)
TACK!
Tina Liden Mascher & Catherine Mai-Trang Pham
+46 8-452 71 75 +46 76-526 90 71 +46 18 611 95 62 +46 72 241 12 8
kristina.lidenmascher@skl.se
www.kvalitetsregister.se
Nationella Kvalitets Register