UNIT III
Definitions of GCP
1.24 Good Clinical Practice (GCP)
A standard for the
design, conduct, performance, monitoring, auditing, recording, analyses, 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 trial subjects are protected.
Auditing
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.
(b) The sponsor's
audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions
to regulatory authorities, the number of
subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any
identified problem(s).
(c) The observations
and findings of the auditor(s) should be documented.
(d) To preserve the
independence and value of the audit function, the regulatory authority(ies) should not routinely
request the audit reports. Regulatory
authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP
non-compliance exists, or in the course
of legal proceedings.
(e) When required by
applicable law or regulation, the sponsor should provide
an audit certificate.
Monitoring
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. The determination of the extent and nature of
monitoring should be based on considerations
such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general
there is a need for on-site monitoring,
before, during, and after the trial; however in exceptional circumstances the sponsor may determine that
central monitoring in conjunction with
procedures such as investigators’ training and meetings, and extensive written guidance can assure
appropriate conduct of the trial in accordance
with GCP. Statistically controlled sampling may be an acceptable
method for selecting
the data to be verified.
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 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 and documented
adequately.
(v) That the
disposition of unused investigational product(s) at the trial sites complies with applicable regulatory
requirement(s) and is in accordance with
the sponsor.
(d) Verifying that the
investigator follows the approved protocol and all approved amendment(s), if any.
(e) Verifying that
written informed consent was obtained before each subject's participation in the trial.
(f) Ensuring that the
investigator receives the current Investigator's Brochure, all documents, and all trial
supplies needed to conduct the trial properly
and to comply with the applicable regulatory requirement(s).
(g) Ensuring that the
investigator and the investigator's trial staff are adequately informed about the trial.
(h) Verifying that the
investigator and the investigator's trial staff are performing the specified trial functions, in
accordance with the protocol and any
other written agreement between the sponsor and the investigator/institution, and have not
delegated these functions to unauthorized
individuals.
(i) Verifying that the
investigator is enroling only eligible subjects.
(j) Reporting the
subject recruitment rate.
(k) Verifying that
source documents and other trial records are accurate, complete, kept up-to-date and maintained.
(l) Verifying that the
investigator provides all the required reports, notifications, applications, and submissions,
and that these documents are accurate,
complete, timely, legible, dated, and identify the trial.
(m) Checking the
accuracy and completeness of the CRF entries, source documents and other trial-related records against
each other. The monitor specifically
should verify that:
(i) The data required
by the protocol are reported accurately on the CRFs and are consistent with the source
documents.
(ii) Any dose and/or
therapy modifications are well documented for each of the trial subjects.
(iii) Adverse events,
concomitant medications and intercurrent illnesses are reported in accordance with the protocol
on the CRFs.
(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 and explained on the CRFs.
(n) Informing the
investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate
corrections, additions, or deletions are
made, dated, explained (if necessary), and initialled by the investigator or by a member of the investigator's
trial staff who is authorized to initial
CRF changes for the investigator. This authorization should be documented.
(o) Determining
whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the
protocol, the IRB/IEC, the sponsor, and
the applicable regulatory requirement(s).
(p) Determining
whether the investigator is maintaining the essential documents (see 8. Essential Documents for the
Conduct of a Clinical Trial).
(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.
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
(a) The monitor should
submit a written report to the sponsor after each trialsite visit or
trial-related communication.
(b) Reports should
include the date, site, name of the monitor, and name of the investigator or other individual(s)
contacted.
(c) Reports should
include a summary of what the monitor reviewed and the monitor's statements concerning the
significant findings/facts, deviations and deficiencies, conclusions, actions taken
or to be taken and/or actions recommended
to secure compliance.
(d) The review and
follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated
representative.
GCP auditing requirements from a regulatory
perspective
5.19 Audit
If or when sponsors
perform audits, as part of implementing quality assurance, they should consider:
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.
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) The sponsor should
ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s
qualifications should be documented.
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.
(b) The sponsor's
audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to
regulatory authorities, the number of
subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any
identified problem(s).
(c) The observations
and findings of the auditor(s) should be documented.
(d) To preserve the
independence and value of the audit function, the regulatory authority(ies) should not routinely
request the audit reports. Regulatory
authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP
non-compliance exists, or in the course
of legal proceedings.
(e) When required by
applicable law or regulation, the sponsor should provide an audit certificate
GCP compliance and audit certificates
1.15 Compliance (in
relation to trials)
Adherence to all the
trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory
requirements.
4.5 Compliance with
Protocol
4.5.1 The
investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if
required, by the regulatory authority(ies)
and which was given approval/favourable opinion by the IRB/IEC. The
investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm
agreement.
4.5.2 The investigator
should not implement any deviation from, or changes of the protocol without agreement by the sponsor and
prior review and documented approval/favourable
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s)
to trial subjects, or when the change(s)
involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone
number(s)).
4.5.3 The
investigator, or person designated by the investigator, should document and explain any deviation from the approved
protocol.
4.5.4 The investigator
may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial
subjects without prior IRB/IEC approval/favourable
opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate,
the proposed protocol amendment(s)
should be submitted:
(a) to the IRB/IEC for
review and approval/favourable opinion,
(b) to the sponsor for
agreement and, if required,
(c) to the regulatory
authority(ies).
1.7 Audit Certificate
A declaration of
confirmation by the auditor that an audit has taken place.
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.
(b) The sponsor's
audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions
to regulatory authorities, the number of
subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any
identified problem(s).
(c) The observations
and findings of the auditor(s) should be documented.
(d) To preserve the
independence and value of the audit function, the regulatory authority(ies) should not routinely
request the audit reports. Regulatory
authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP
non-compliance exists, or in the course
of legal proceedings.
(e) When required by applicable law or
regulation, the sponsor should provide an
audit certificate.
GCP auditor training
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) The sponsor should
ensure that the auditors are qualified by training and experience to conduct audits properly. An
auditor’s qualifications should be documented.
GCP audit team structure
Pharmacovigilance also known as Drug Safety, is the
pharmacological science relating to the collection, detection, assessment,
monitoring, and prevention of adverse effects with pharmaceutical products. As
such, pharmacovigilance heavily focuses on adverse drug reactions, or ADRs,
which are defined as any response to a drug which is noxious and unintended,
including lack of efficacy, which occurs at doses normally used for the
prophylaxis, diagnosis or therapy of disease, or for the modification of
physiological function. Medication errors such as overdose, and misuse and
abuse of a drug, are also of interest because they may result in an ADR.
Information received from patients and healthcare
providers, as well as other sources such as the medical literature, plays a
critical role in providing the data necessary for pharmacovigilance to take
place. In fact, in order to market or to test a pharmaceutical product in most
countries, adverse event data received by the license holder (usually a
pharmaceutical company) must be submitted to the local drug regulatory
authority.
Ultimately, pharmacovigilance is concerned with
identifying the hazards associated with pharmaceutical products and with
minimising the risk of any harm that may come to patients.
Pharmacovigilance
Programme of India (PvPI)
The Central
Drugs Standard Control Organization (CDSCO), Directorate General of Health
Services under the aegis of Ministry of Health & Family Welfare, Government
of India in collaboration with Indian Pharmacopeia commission, Ghaziabad is
initiating a nation-wide Pharmacovigilance programme for protecting the health
of the patients by assuring drug safety. The programme shall be coordinated by
the Indian Pharmacopeia commission, Ghaziabad as a National Coordinating Centre
(NCC). The centre will operate under the supervision of a Steering Committee.
Goal
and Objectives
Goal
To ensure that the benefits of use of medicine
outweighs the risks and thus safeguard the health of the Indian population.
Objectives
To monitor
Adverse Drug Reactions (ADRs) in Indian population
To create awareness amongst health care
professionals about the importance of
ADR reporting in India
To monitor benefit-risk profile of medicines
Generate independent, evidence based recommendations
on the safety of medicines
Support the CDSCO for formulating safety related
regulatory decisions for medicines
Communicate
findings with all key stakeholders
Create a
national centre of excellence at par with global drug safety monitoring
standards
Programme governance and reporting structures
The
Pharmacovigilance Programme of India will be administered and monitored by the
following two committees.
I. Steering Committee
II. Strategic Advisory
Committee
Technical support will be provided by the following
committees:
I. Signal Review Panel
II. Core Training Panel
III. Quality Review Panel
SOPs
1.55 Standard
Operating Procedures (SOPs)
Detailed, written
instructions to achieve uniformity of the performance of a specific function.
A systematic and
independent examination of trial related activities and documents to determine whether the evaluated trial
related activities were conducted, and the
data were recorded, analyzed and accurately reported according to the
protocol, sponsor's standard operating procedures
(SOPs), Good Clinical Practice (GCP), and
the applicable regulatory requirement(s).
The act of overseeing
the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in
accordance with the protocol, Standard Operating
Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
A written report from
the monitor to the sponsor after each site visit and/or other trial-related communication according to the
sponsor’s SOPs.
The sponsor is
responsible for implementing and maintaining quality assurance and quality control systems with
written SOPs to ensure that trials are
conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the
applicable regulatory requirement(s).
When using electronic
trial data handling and/or remote electronic trial data systems, the sponsor should:
(a) Ensure and
document that the electronic data processing system(s) conforms to the sponsor’s established requirements
for completeness, accuracy, reliability,
and consistent intended performance (i.e. validation).
(b) Maintains SOPs for
using these systems 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)
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
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.
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.
Noncompliance with the
protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an
investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the
sponsor to secure compliance.
GCP audit planning
Planning of Audits
Before conducting an audit, the auditor (including
the auditing department manager) should establish a written audit plan (such as
an annual plan, a monthly plan, and a plan specific to each trial or audit)
based on the results of the risk assessment according to the written auditing
procedures.
5.1 Establishing the Goals of Audits
One or more objectives are generally established for
a trial audit based on the importance of the trial with regard to submissions
to regulatory authorities, the type and complexity of the trial, the level of
risk to the trial, and any problem(s) identified previous. The most important
part of audit planning is to specify the goal(s) of the audit. By establishing
the goal(s) of an audit, the subjects and methods of the audit will be
determined and the consistent conduct of the audit will be ensured. One or more
objectives may be chosen from the following examples:
• Evaluation of the compliance of any organization
involved in a clinical trial (pre-qualification).
• Evaluation of the compliance with regulatory
requirements and human subject protection.
• Confirmation of the appropriate conduct of a
trial, the credibility of data obtained, and the condition of record keeping at
a participating medical institution(s) through direct access.
• Confirmation of the conduct of monitoring.
• Confirmation of the credibility of a clinical
trial/study report.
• Early detection and collection and prevention of
any existing problems or potential problems with a system and/or process.
• Early detection and collection and prevention of
any existing problems or potential problems occurring at an institution
entrusted with trial-related duties.
5.2 Designing and Updating the Audit Plan
Planning is essential to systematically-
effectively, and efficiently conduct an audit with consideration of resource
management in the auditing department. Audit plans, such as an annual plan, a
monthly plan, and a plan specific to each trial or audit, should be established
based on consideration of the goal(s), contents (e.g.subjects and methods), and
timing of an audit, the progress of the targeted trial, and other relevant
factors. The audit plan should be updated in accordance with progress of the
trial or auditing activity. Prior to conducting an audit, the auditors and the
auditee will discuss and adapt the audit plan, as necessary.
5.3 Determining the Subject[s], Timing, and
Method[s] of an Audit
The subject(s) (e.g., a medical institution. CRO,
system, clinical trial/study report, computerized system validation, and
database), timing (e.g., before the start of the trial, during the trial, after
the completion of the trial, or periodically), and the method(s) (e.g.,
sampling, interview, or tour) of an audit should be determined based on the
goal(s) established for the audit.
5.4 Information in the Audit Plan
An audit plan should provide the following
information, although the contents may vary depending on the type of the plan
(e.g., annual plan, monthly plan, or plan for a specific trial or audit).
• The goal(s) of the audit.
• The subject(s) of the audit.
• The scope of the audit.
• The timing of the audit.
• The name(s), title and address of the auditor
(s)(and the auditing department manager).
• The reference documents required.
• The person(s) to whom the audit report will be
submitted.
• Timelines for the audit(s) and report(s) (if
possible)
GCP audit conduct Reporting
6. Conduct of an Audit
Auditing is performed by the auditor in accordance
with a written audit plan and procedures, and involves the examination and
evaluation of information obtained through investigation of the audit trail
(e.g. essential documents and SOPs) and a trial site(s) (e.g. facilities and
equipment), as well as interviews with the auditee, etc. It is important to
specify reference documents that auditees comply with before performing an
audit so as to ensure fair conduct of audit. The auditor evaluates conformity
and compliance with these reference documents. The auditor should inform the
sponsor about the conduct of an audit in advance.
6.1 Explaining The Auditing Procedures
To efficiently collect accurate information through
auditing, the auditor should give the auditee a prior explanation about the
conduct of an audit (e.g. the goal(s) and method(s) of the audit).
When providing an explanation for the auditee, the
auditor should confirm the subject(s) (i.e. materials and facilities that will
be audited), the schedule, and the contact person(s) for the audit so that both
the parties obtain the necessary and full understanding about the audit.
6.2 Conducting an Audit and Collecting Information
There are two types of sponsor’s audit, i.e.,
auditing of internal trial-related department(s) and auditing of external
establishment(s) involved in the trial concerned, e.g., a medical institution,
laboratory, and/or CRO. To ensure the smooth conduct of an audit of an external
institution. such as a participating medical institution, laboratory, or CRO,
it is important to properly perform a preliminary internal audit.
When conducting an audit, the auditor should collect
audit observations by reviewing the documents subject to the audit and
interviewing the auditee etc. Based on audit observations collected, the
auditor should confirm and document whether or not the audit observations are
compliant to GCP, all applicable regulatory requirement(s), SOPs, the study
protocol, and any other relevant documents and procedures.
Utilization of an audit checklist and a sampling
method is useful for the standardization and efficient conduct of auditing
activities.
6.3 Confirmation and Evaluation of Audit
Observations
The auditor should discuss audit observations with
the auditee so that the absence of errors can be confirmed. The auditor should
then review the confirmed audit observations and further information can be
collected if required.
The auditor should examine (within the auditing
department) whether the audit observations involve any violations of GCP or
applicable regulatory requirements, deviations from the relevant protocol and
sponsor’s SOPs. or problems with respect to the reliability of clinical data
and then should determine the observations to be reported as audit findings.
The auditor should also examine whether any of the obtained audit observations
could have an influence
on other trials, medical institutions, clinical
trial/study systems, etc. When audit findings are reported, they may be graded
according to the level of importance.
GCP audit conduct Reporting
INTRODUCTION
Only GCP Inspection Reports relating to inspections
requested by the EMEA are detailed in this procedure. The duties of the involved parties (Reporting
Inspector, Lead Inspector etc.) are provided in the “Procedure for co-ordinating GCP Inspections requested by
the EMEA” INS/GCP/1, the legal basis of which is to be found in article 57(i) of Regulation (EC) No.
726/2004. When a GCP inspection has been performed, the GCP Inspection Reports should be part of the
documentation used for the assessment of the application.
This document allows for incorporation of modules
pertaining to a particular type or focus of the
inspection. The module presented provides procedure for reports of
inspections at the investigator site.
Inspections are co-ordinated by the EMEA Inspection
Sector and in general conducted by the EU/EEA national inspectors. The request for an
inspection is made by CHMP in a document stating the grounds for the inspection, the scope and suggested sites
as well as any other information relevant to the inspectors.
PREPARING INSPECTION REPORTS
For each site inspected an Inspection Report (IR) is
prepared. In some circumstances it may
be appropriate to generate 1 report for two or more sites, even though
these represent separate inspections
(e.g. where a particular process at a sponsor/MAH is inspected at two or more sites globally, but it makes more sense
to combine the findings as they address elements of the same process). If this
is to apply it will be indicated in the CHMP adopted Inspection Request, that a
single report is requested combining the
results for a group of specified sites. These remain separate site inspections nonetheless.
For multiple site inspections on a given
application, the individual Inspection Reports are integrated into one report, the Integrated Inspection Report
(IIR), addressing the major and critical findings recorded and providing an
evaluation of the quality and usefulness of the data inspected.
The Definition of Terms in the procedure INS/GCP/1
provides definitions for the IR and IIR. Section 3.4 of procedure INS/GCP/1 should also be referred
to concerning provision of relevant inspection findings in advance of the circulation of the inspection
reports. See sections 2.2.4 and 2.2.5 of
the procedure for co-ordinating GCP inspections requested by the EMEA (INS/GCP/1)
regarding signatures and availability of inspectors to sign reports. Where only
one site is inspected an IR can fulfil the requirement for IIR provided the
objectives and content of both are
addressed.
The target dates for the availability of the
inspection reports are agreed and stated in the Inspection Request adopted by CHMP.
Responsibilities
of the Lead Inspector
2.1.1 The Inspection Report (IR)
The Lead Inspector(s) appointed by the
Inspectorate(s) concerned prepares an Inspection Report for each site inspected. This Inspection Report (IR) is
prepared according to a common standard and in cooperation with all participating inspectors, and will be
ready within [15]* days of the end of the inspection. Where multiple sites are
inspected in sequence the IR may be prepared [15]* days from the last day of
inspection, at the last site inspected
The IR should be sent to the inspectee and/or the
sponsor responsible with a request for comments on major factual errors, points of disagreement or
remedial actions to be provided, to the Lead Inspector, within [15] days of
receipt of the report. If a response is not received within the stipulated time
frame, the absence of a reply should be recorded in the IR. On receipt of
comments, these should be included in the final version of the IR as an
appendix. The inspectors will consider the responses of the inspectee and will
indicate, as an additional appendix, whether or not these are acceptable and
what impact, if any, they have on the original inspection findings. A copy of
the assessment of the comments will be sent to the the inspectee and/or the sponsor.
The final version of the IR should be prepared and
sent by the Lead Inspector to the Reporting Inspectorate within [40] days after
the completion of the inspection.
Language
of IR
The Inspection Report will be written in English, unless required by local regulations to be in local language. In the latter case the Inspection Report will be translated / modified to English under the responsibility of the Lead Inspector prior to signature by all involved inspectors. The timelines for the finalisation of the IR will be extended as needed.
2.1.3 Content and format of IR
The IR should reflect the inspection procedures as described in “Procedure for conducting GCP inspections requested by the EMEA (INS/GCP/3)”. There should be an evaluation of the compliance with EU and local regulations, the principles and guidelines of Good Clinical Practice and applicable ethical and scientific standards. The validity and reliability of the data submitted should be evaluated in accordance with the scope of the inspection and issues identified in the request for the inspection. Also any other major or critical findings may be addressed. The IR should be printed on the paper with the Lead Inspectorate/Reporting Inspectorate (as applicable) national authority headed paper or on plain A4 paper. A common format has been developed for the IR. Appendix 1a gives an example of the table of contents for an IR of an investigator site and Appendix 1b for a sponsor site, other examples (e.g. for clinical laboratories) are given in the procedure on the inspection of that type of site. The table of contents will be amended in accordance with the scope of the individual inspection.
Items inspected will be extensively described in the
IR (for structure and content see appendices 1a and 1b) and the findings classified
as minor, major and critical deviations (see appendix 3 for definitions). Each finding
should refer to the requirement for which it is non-compliant. An evaluation of
the significance of the deviations should be presented. An overall conclusion
should be presented on whether the conduct, recording and reporting of the trial
is acceptable/non-acceptable according to the principles of GCP. A
recommendation should be given on whether the quality of the reported data
allows use their for the assessment by the CHMP.
2.2 Responsibilities of the Reporting Inspector
The Reporting Inspector is nominated by the
Reporting Inspectorate. It is the duty of the Reporting Inspector to monitor
the timely production of the IRs. The Reporting Inspector is also responsible
for the integration of the IRs into the IIR and the communication with the EMEA
Inspection Sector.
Any questions related to the reports are handled by
the Reporting Inspector, who is responsible for the necessary communication
with the Lead Inspectors, EMEA, CHMP Members, (Co)-Rapporteur and the assessors.
2.2.1 The Integrated Inspection Report (IIR)
The Reporting Inspector compiles an Integrated
Inspection Report (IIR) in English based on the IRs. The format of the IIR will
be as outlined in Appendix 2. The IIR will summarise the major and critical findings
and contain an evaluation of the quality of the data submitted and compliance
with the principles of GCP based on the findings at all inspected sites. Any
finding that is process related and not site specific will also be highlighted
in the IIR. The IIR will also contain a conclusion on whether the quality of
the data inspected as a whole or in parts may be used for the evaluation by the
assessors regarding acceptance/nonacceptance of the trial data. The IIR
conclusions should recommend any follow-up to be requested from the applicant
or a further inspection if considered necessary.
The IIR will be approved and signed by all the Lead
Inspectors who have contributed with IRs. This should be done within [50] days
after the completion of the inspection. The Reporting Inspectorate sends the
signed IIR to the EMEA Inspection Sector. This refers to a electronic copy by
secured email and a paper copy with the original signature page by post.
GCP audit findings Follow – up to GCP audit
reports
GCP INSPECTION FINDINGS CLASSIFICATION
Critical:
a) Where
evidence exists that significant and unjustified departure(s) from applicable legislative requirements has
occurred with evidence that
i) the safety or well-being of trial subjects either
have been or have significant potential
to be jeopardised, and/or
ii) the clinical trial data are unreliable and/or
iii) there are a number of Major non-compliances
(defined in (c) and (d)) across areas of
responsibility, indicating a systematic quality
assurance failure, and/or
b) Where inappropriate, insufficient or untimely
corrective action has taken place regarding
previously reported Major non-compliances (defined in (c) and (d))
Major:
c) A non-critical finding where evidence exists that
a significant and unjustified departure
from applicable legislative requirements has occurred that may not have developed into a critical issue, but may
have the potential to do so unless
addressed, and/or
d) Where evidence exists that a number of departures
from applicable legislative requirements
and/or established GCP guidelines have occurred within a single area of responsibility, indicating a
systematic quality assurance failure.
Other:
e) Where evidence exists that a departure from
applicable legislative requirements
and/or established GCP guidelines and/or procedural requirement and/or good clinical practice has
occurred, but it is neither Critical nor
Major.