Good Clinical Practice (GCP) Inspections

Remote Inspections / Distant Assessments

The HPRA has initiated a process to conduct inspections remotely via distant assessment. The requirement to conduct a distant assessment will be determined on a case-by-case basis. Notifications will be sent in advance of the distant assessment in the same way as for an on-site inspection. The distant assessment process will, in general, follow a similar format to that for an on-site inspection and will commence with an opening meeting and conclude with a closing meeting via videoconference or alternative remote communication platform.

The communication platform used will be particularly important to facilitate the smooth running of the distant assessment. The sites hosting the distant assessment will be requested to propose a suitable communications platform and this will be agreed with the Inspector in advance of the distant assessment. The process will require electronic copies of documents and other information to be provided to the Inspector for review. Consideration should be given to the use of platforms which provide for live sharing of documents and videos, in addition to the use of cameras to allow for a virtual review of physical facilities, equipment and manufacturing operations, where applicable.

To avoid delays during distant assessment, companies will be requested to make certain documentation available prior to the commencement of the distant assessment. Documentation requirements will be specified in the pre-distant assessment notification. In certain circumstances, a distant assessment on its own may not be sufficient to enable a decision to be made regarding the level of compliance with GxP requirements and, as such, an on-site inspection may be performed at the earliest possible time. It is envisaged that this would generally focus on areas of the site that could not be inspected remotely and/or areas requiring further follow-up resulting from the distant assessment.

Why the HPRA conducts GCP inspections of clinical trials

Good Clinical Practice (GCP) is a set of internationally recognised ethical and scientific quality requirements that must be observed for designing, conducting, recording and reporting on clinical trials that involve the participation of human subjects. 
Compliance with GCP provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are accurate and credible.  The regulations require that all clinical trials covered by the provisions of the regulations, including bioavailability and bioequivalence studies, be designed, conducted and reported in accordance with the principles of GCP.

Clinical trials involving medicines are inspected by the HPRA who are responsible for conducting inspections to determine whether clinical trials are in compliance with the clinical trial permission, the trial protocol and the applicable legislation and guidance. GCP inspectors use a risk based approach to select sites for inspection. Part of the planning involves a request to a sample of sponsors for information about the status of their trials. Inspections can take place on a routine or on a for cause basis.

A request to inspect a trial may also be received from the Competent Authority of another EU member state or the Committee for Human Medicinal Products (CHMP).

The HPRA inspects according to agreed European procedures.

On inspection, HPRA verifies compliance with the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004, and amendments. Adherence to relevant guidance with respect to commencing and conducting a clinical trial (regulation 17 of S.I No. 374/2006) is also examined, in particular ICH GCP E6 and the guidelines of Eudralex Volume 10.

Types of GCP Inspections

Any site involved in a clinical trial may be subject to inspection, such as the investigator sites, any laboratory used for clinical trial analyses and the sponsor’s premises. Contract research organisations/facilities, acting under arrangements with a sponsor or investigator to perform some or all of the functions of the sponsor or investigator, may also be subject to GCP inspection.

Inspections may be conducted on a routine basis, or may arise as a result of a specific trigger.

Inspections may be conducted on ongoing or completed studies and may be announced or unannounced; however, they are generally announced.

The legal framework does not distinguish between academic versus commercial trials, be they run through a clinical research facility or other. Therefore, HPRA applies the same standards to all GCP related inspections.

Notification of inspection

In general, the sponsor of a clinical trial will be notified 4-6 weeks prior to the proposed inspection date and asked to confirm availability. The notification will identify the study to be inspected, if applicable, and the proposed sites, including any investigator sites.

In relation to for cause or triggered inspections, the HPRA may provide a shorter notice period.

The following information may be requested from the inspectee prior to the inspection:

• Participant status per trial site (number randomised, drop-out rate, and number of serious adverse events reported per site).

• Copies of company standard operating procedures e.g. (monitoring procedure, informed consent procedure, serious adverse event reporting procedure, drug supply management procedure).

• Trial-specific documents such as a copy of the current protocol and informed consent form, source data verification guidelines, product handling instructions, laboratory manual, randomisation code breaking procedure, monitoring plans and reports.

• CV of principal investigator

• Arrangements for direct access to any computerised systems upon which trial data or essential documents are stored

• Any other documentation deemed necessary by the inspectors

An inspection plan, outlining the units to be inspected and the schedule of meetings to be held with the investigator and/or sponsor personnel, will be provided to the inspectee prior to the inspection.

In accordance with the regulations, the trial master file comprising the essential documents which enable both the conduct of the trial and the quality of the data produced to be evaluated must be available by direct access and shall provide the basis for the GCP inspection.

Inspection Fees

Information on inspection fees are available in the Guide to Fees for Human Products. 

Inspection Conduct

Routine Inspections

Routine inspections are inspections carried out as part of HPRAs congoing monitoring of GCP compliance. HPRA inspectors will perform the inspection. The duration of the inspection and the number of inspectors present on an inspection will vary depending on the complexity of the clinical trial and activities conducted at the site. Typically, they are scheduled for 3-5 days.

Inspections usually consist of an opening meeting, document review, interview sessions, tour of facilities and a closing meeting.

The scope and activities examined during some of the more common types of GCP inspections undertaken by the HPRA are outlined below:

Investigator site inspections may include:

• Legal and administrative aspects

  • Communication with the Ethics Committee

  • Communication with the Regulatory Authority

  • Other communications

• Organisational aspects

  • Implementation of the trial at the investigator site

  • Facilities and equipment

  • Management of biological samples

  • Organisation of the documentation

  • Monitoring and auditing

  • Use of computerised systems 

• Informed consent of trial participants

• Review of the trial participant data

• Adverse event reporting

• Management of the investigational medicinal product(s)

• Other, as required

Sponsor inspections can take two different approaches and may include:

• System inspection

• Specific clinical trial inspection

  System Inspection

• Organisation and personnel

• Facilities and equipment

• Sponsor/CRO Operating Procedures

• Implementation and termination of the clinical trial

• Monitoring

• Investigational Medicinal Product

• Sample management

• Safety and adverse events reporting

• Data handling and clinical trial report

• Documentation archiving

• Sponsor audit and quality assurance system

• Delegation of duties

  Specific clinical trial inspection

• Implementation and termination of the clinical trial

• Monitoring

• Investigational Medicinal Product

• Safety and adverse events reporting

• Case Report Form data verification

• Data handling and clinical trial report (CTR)

• Clinical trial documentation and archiving

• Audit

For cause/triggered inspections

This is an inspection requested because there is a concern due to either the actual issues observed or the potential impact of deviations from GCP on the conduct of the study as a whole or at a particular site. The scope and activities examined during such inspections are decided upon a case by case basis, relative to the nature of the concern. 

Issuance of a report

During the closing meeting, on the last day of inspection, the inspectee(s) will be provided with a verbal overview of the preliminary deficiencies noted during inspection.  A written report outlining deficiencies observed during inspection is then issued to the sponsor within 15 days from the last day of inspection. In general, written reports are issued in paper format, and an electronic copy is sent to a nominated contact via Eudralink.

Classification of deficiencies

Deficiencies are classified into three categories; critical, major and minor. A summary for the criteria for judging deficiencies as critical, major or other are detailed below.

•  Critical deficiency:

Conditions, practices or processes that adversely affect the rights, safety or well-being of the subjects and/or the quality and integrity of data.

•  Major deficiency:

Conditions, practices or processes that might adversely affect the rights, safety or well-being of the subjects and/or the quality and integrity of data. Major observations are serious deficiencies and are direct violations of GCP principles.

•  Minor deficiency:

Conditions, practices or processes that would not be expected to adversely affect the rights, safety or well-being of the subjects and/or the quality and integrity of data.

•  Comments:

The observations might lead to suggestions on how to improve quality or reduce the potential for a deviation to occur in the future.

•  Clarifications:

 Issues arising from the inspection, which do not fit the definitions of above classifications but require clarification from the sponsor company or trial site. These may become graded findings depending on the nature of the clarification.

Company response to report and close out

The company must provide a response to the deficiencies outlined in the inspection report within 35 days after the last day of inspection, and should include a proposal for corrective and preventative action and a timeline for completion of those actions. The responses are reviewed by the inspection team to determine whether or not they are acceptable. Once an acceptable response has been received from the company, the inspection will be closed.