Basics of Quality Management in CT

Site: EUPATI Open Classroom
Course: Documentation & Management
Book: Basics of Quality Management in CT
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Date: Wednesday, 29 June 2022, 2:37 PM

1. Why Quality Management?

You have already learned enough about clinical trials to know that it generally takes a lot of resources to set one up. No matter whether it is a large international trial conducted at several centres, or just a small trial with few patients at a single centre, clinical trials are always expensive. They cost a lot of money, e.g. for medicine, laboratory tests, databases, extra personnel, etc. But they are also expensive in terms of the time that they take:

  • The researchers involved often need to spend a lot of time on both scientific and administrative tasks.
  • The sponsor spends time monitoring the trial.
Another important point is that a clinical trial uses the time and energy of the patients who are willing to participate without even knowing if the experiment will lead to a useful treatment.

It is easy to understand how important it is to prevent anything unforeseen happening that would put the safety participants and the result of the trial at risk.

What could actually go wrong when conducting a clinical trial?

1.1. What Could Actually Go Wrong When Conducting a Clinical Trial?

  • Wrong medication given to patient.
  • Measurements taken at the wrong time.
  • Participant did not show up for appointment.
  • Participant included in the trial even though they were not eligible.
  • Adverse reaction not reported.
  • No back-up of data entered into the computer.
  • Wrong statistical analysis is being used to calculate the result of the trial.
When thinking about this question one realises that many things could go wrong in the course of a clinical trial. These were some examples, but many more can be found.

It also becomes evident that most of the mistakes that can occur during a clinical trial can be avoided simply by proper planning and regular control of the trial procedures. This is what is understood as ‘quality management’.

Quality management is described in the Guideline for Good Clinical Practice (ICH-GCP guideline). It is the responsibility of the ‘sponsor’ i.e. the person, institution, organisation or company that takes responsibility for initiation, management and/or financing of the clinical trial. If the trial is large, the sponsor may not be able to oversee all activities and might even lack the necessary qualifications for ensuring the proper quality of all steps of the trial. In such circumstances, the sponsor is obliged to hire qualified people to help ensure that the trial is planned, conducted and analysed correctly.

Quality management activities can be divided into two sub-groups – those done before starting the trial (quality assurance or QA) and those done after the trial has been initiated (quality control or QC). Examples of these activities are described below.

Quality assurance (QA) can be described as the activities done in order to avoid any mistakes happening, whereas quality control (QC) might be described as the activities done in order to identify and to correct mistakes that have occurred. Both are regarded as equally important and it should always be carefully considered how to incorporate both QA and QC activities in each individual trial. They are necessary to ensure the validity of the trial.

The following parts of this lesson describe the QA and QC activities as defined in the GCP-guideline.

2. Standard Operating Procedures (SOPs)

Standard operating procedures (SOPs) are defined in the GCP-guideline as: ‘Detailed, written instructions to achieve uniformity of the performance of a specific function’. It is not a requirement to have SOPs when performing clinical trials, since one may also have detailed, written instructions in the trial protocol. However, most organisations and hospital departments working with many trials usually have SOPs that describe the critical procedures of a trial. Often the SOPs are more general and can be used for many trials. For example:
  • An SOP can describe the procedures used when informing patients about a new trial.
  • If measurement of blood pressure is the most important parameter in a certain trial, a specific SOP can be developed describing exactly how this must be done and by whom, as there are multiple methods available to measure blood pressure.
SOPs are characterised as being ‘controlled documents’. This is to ensure that old and new versions of the instructions are not mixed, and that one always has access to all pages and attachments of the SOP in force. It is also important to be able to document the version af an instruction that has been followed in a clinical trial in case of an inspection from the health authority years after the trial has been completed.

SOPs are always assigned a version number and it is stated from what date they should be used. Whenever a new version is made, all old versions must be replaced. It is however important that old versions are archived. The purpose of this is to ensure transparency if procedures are changed during the course of a clinical trial. There must be a named person who has the task of managing SOP replacements and archiving. In fact, one must also have a separate SOP that describes the procedures for writing, approving, distributing, replacing and archiving SOPs. This is normally the first SOP written!

It is the responsibility of the sponsor of the trial to establish a system of SOPs, if necessary. If an SOP system has been established, all personnel involved in a trial should be trained in the relevant SOPs. This training must of course be completed before undertaking any trial related duties and must be documented as well.

3. Audits

Even though SOPs are an important part of quality management activities, they cannot stand alone. Imagine you are writing an SOP and you have misunderstood the procedure! You might be very skilled in producing good descriptions of the work to be performed, but if you have misunderstood the process, your instructions might lead to a situation where the procedure is repeatedly performed incorrectly.

So how can we avoid this situation? One possibility is to invite independent experts to supervise the organisation and operational procedures of the clinical trial. This will provide an impartial view on how the trials are or should be performed. This supervision is called ‘audit’ and the independent experts are called ‘auditors’. It is the responsibility of the sponsor to ensure that audits are performed on a regular basis.

According to the GCP-guideline an ‘independent’ auditor means that the sponsor and the auditor should not be working within the same organisational unit. A sponsor may hire an external auditor, but many pharmaceutical companies often employ their own auditors. In this case, the auditors work in a completely separate department.

In practice an audit may be performed in two different ways:
  • The auditor uses one trial as an example and evaluates all the procedures that have been used in that trial.
  • The auditor looks at one specific procedure. For example, they might look at the procedure for ‘reporting of adverse reactions’ and then evaluate a number of trials where this has been performed.
Auditors normally work systematically with both types of audits. A thorough audit of a trial normally takes several days as the auditors have to examine all activities and documents of the trial. The audit will evaluate trial conduct and compliance with what has been described in:
  • The relevant SOPs.
  • The protocol of the trial.
  • GCP-guideline.
  • Applicable regulatory requirements.
Definition of an audit in the GCP-guideline

‘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, analysed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s).’

An audit may be initiated for two reasons: either as a part of a routine supervision or in response to a special concern that has been raised about a certain trial. The latter type of audit is called ‘for cause audit’ and may be a useful tool for a trial sponsor if they have a concern about malpractice in a trial.

The most important part of the audit is often what takes place afterwards. Each deviation from the intended trial conduct is described. These are called ‘findings’ and are always graded in two to three categories expressing how serious they are. These findings are described in an audit report. If a deviation can compromise the trial result or the patients’ safety or rights, the sponsor must describe concretely how the situation will be handled. It is equally important that the sponsor implements so called ‘corrective actions’ to ensure that the deviation will not happen again. When the audit is completed the auditor will issue an audit certificate which confirms that the audit has taken place.

4. Monitoring

Unlike audits, monitoring is part of the routine control of the trial process and is always carried out for all trials. It is a QC activity and as such is not intended to oversee systems but simply to control that a trial is being performed according to how it has been planned, described and approved.

Definition of monitoring in the GCP-guideline

‘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).’

Monitoring is carried out by a monitor, who must be trained in the trial protocol and GCP-guideline. They must not be taking part in conducting the study. According to the GCP-guideline monitoring should normally be performed before, during and after the trial. This is normally practised as follows.

4.1. Monitoring Before The Trial: Initiation Visit (One Visit At Each Centre)

Monitoring before the trial: Initiation visit (one visit at each centre)


  • To check and document that everything is ready for trial initiation at a centre before the first patient is enrolled.
Examples of activities

  • Is the trial approved by relevant authorities?
  • Are all personnel adequately trained?
  • Is the trial medicine on site and properly labelled and stored? • Is relevant rescuing equipment in place in order to guarantee patient safety?
  • Have necessary agreements with other departments been made?
  • Are the forms for data recording ready to use?

4.2. Monitoring During The Trial: Monitoring Visits (often many visits at each centre)

Monitoring during the trial: Monitoring visits (often many visits at each centre)


  • To check and document that the trial is being conducted as planned.
Examples of activities

  • Have all patients signed the Informed Consent Form?
  • Have all patients been registered on an ID-list and allocated a unique trial number?
  • If a blinded trial, has the blinding of trial medicine been compromised?
  • Have all patients received the correct trial medicine?
  • Have all data been correctly entered into the trial database?
  • Have possible adverse reactions been registered and reported according to the procedures?
  • Have any problems registered at previous monitoring visits been resolved?

4.3. Monitoring After The Trial: Close-Out Visit (one visit at each centre)

Monitoring after the trial: Close-out visit (one visit at each centre)


  • To verify and document that the trial has been closed properly at each centre.
Examples of activities

  • Have necessary reports been submitted to the authorities?
  • Is all trial medicine accounted for?
  • Have all questions regarding the data registration been solved?
  • Have all lists and reports been signed as necessary?
  • Have possible adverse reactions in participants been resolved or minimised?
  • Has trial participation been appropriatelly noted in the personal medical records of participating patients?
  • Are there any procedures in place for archiving of trial data?
One of the duties of a monitor is to write a monitoring report after each visit. This report describes what has been checked, and what follow-up needs to be done and by whom. The report is always sent to the sponsor of the trial who has the overall responsibility of the trial. A copy of the report will be sent to the investigator who is responsible for trial conduct at the centre.

An important part of monitoring a trial is to check whether all trial data have been registered correctly in the trial database. This is done by comparing the data entries in the database with the documents where the trial data was originally recorded (the source data).

5. Inspections

Inspections are another check of all trial related activities, but they are conducted by the regulatory authority(ties) and are as such not part of the quality management which is planned by the sponsor. However, if an inspection is performed, it will ensure and typically increase the quality of a trial by flagging short-comings and requiring corrective actions.

Definition of inspections in the GCP-guideline

‘The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial. They may be located at the site of the trial, at the sponsor's and/or contract research organisations (CROs) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).’

As with audits, inspections may also be performed on a ‘for-cause’ basis if, for instance, the clinical trial is part of the documentation for a new medicine. They may also be performed simply by chance as a part of a routine control. Following an inspection of a trial the sponsor will receive an inspection report stating all the details that have been examined and the ‘findings’ that have been made by the inspectors.

The findings will be graded into ‘minor’, ‘major’ and ‘critical’. ‘Critical’ findings are those that actually have put participant safety, participant rights or the trial result at a considerable risk. The inspection report will outline what requirements the inspectors have made for the trial. In the worst case, an inspector may suspend or even terminate a trial.