Quality Assurance (QA)

Quality Control (QC) is defined as ICH-GCP as “Operational techniques and activities undertaken within the quality assurance systems to verify that the requirements for quality of trial related activities have been fulfilled”.

QC is a real time assessment of how systems are functioning, and can help build quality into processes, rather than relying solely on an end-product assessment.

Examples of QC include:

• Checks performed during monitoring on quality and accuracy of data transcribed from source data into case report forms (Source Data Vertification)
• Checks on data entry for SAE information entered into safety databases
• Accuracy of scanned documents (i.e. into the electronic trial master files or electronic subjects notes)

Any QC activities performed by an member of the team must be documented, and where possible , performed by a second individual who is independent of trial activities.

Quality Assurance (QA) is defined in ICH-GCP as “all those planned and systematic actions that are established to ensure the trial is performed and the data generated, documented and reported in compliance with GCP and the applicable regulatory requirements.

It is recommended that the frequency and approach to QA activities (for example auditing) are proportionate to the nature and scope of clinical trial activities performed by the organisation. Scheduled activities and unscheduled audits may be required in the event of a serious non-compliance or other triggers.

QA activities should be carried out by someone who is independent of the activity being audited and report into independent lines of management.

Examples of types of audits include:

• System audits – looking at functionality of complete systems
• Process audits – looking at performance of specific processes within the system
• Investigator site audits – trial-specific assessment of trial activities in the clinical setting
• Documentation audits – review of trial-specific or system documentation

It is important that all QC and QA activities are documented and move through an agreed reporting pathway to ensure any learning needs, improvement of processes and areas or risk are identified, ensuring continuous quality improvement.

Finding from audits can be classified into the 3 groups: Critical, Major and other.

For any questions or queries regarding audits please contact researchsafety@uhs.nhs.uk

A vital part of the Quality Assurance Team’s remit is to ensure that UHS is inspection-ready at all times. Then, when an inspection is announced, the QA team manage the process from beginning to end.

Who can inspect UHS with regards to research?

Several agencies are able to inspect the Trust in relation to the research activities happening at the Trust.

1. The Medicines and Healthcare Products Regulatory Agency (MHRA)
2. The Human Tissue Authority (HTA)
3. The Health and Safety Executive (HSE)
4. Care Quality Commission (CQC)
5. US Food and Drug Administration (FDA)
6. European Medicines Agency (EMA)

Audits and monitoring activities carried out by any other organisations are not classed as inspections unless they are by an equivalent competent authority from another country.

Why are we inspected?

Clinical research is very tightly regulated with a variety of regulations, guidance and other legislation that has to be abided by. This tight regulation has two main purposes, to keep participants safe and to ensure high quality data are collected. The regulations are designed to ensure that medicines and devices being tested are safe and effective to ensure any side effects are able to be managed and any risks mitigated. Inspections are performed in order to assure the regulatory authorities that the applicable regulations and guidance are adhered to and to ensure issues and problems are addressed appropriately.

Types of inspection

There are three main types of inspection:

1. Mandatory Regulatory inspections compulsory since 2004.
2. Triggered inspections as a result of serious breach, whistle blowing or concerns raised by other government departments or the Health Research Authority.
3. Site/study specific inspections where a site or vendor has been involved in a specific study inspected under one of the other types of inspection.

Inspection outcomes

Inspection findings are generally categorised into 3 levels of concern with different requirements by the regulatory authorities with regards to responses and actions.

1. Critical – Indicates a significant and unjustified departure from regulations that jeopardizes the rights, safety, or well-being of trial subjects, or compromises the reliability of clinical trial data. It may also indicate a systematic failure of quality assurance.

This is the most serious level of finding and are referred to the GCP Inspection Action Group (IAG). This is a cross-agency group that oversees all critical findings and decides on the actions to be taken in addition to the review of the CAPA for the critical finding.

2. Major - A non-critical finding that, while not immediately critical, has the potential to become critical if not addressed. It could involve deficiencies that could adversely affect patient safety or public health, or a violation of regulations.
3. Other - A deficiency that is not expected to adversely affect patient safety or public health.

There are a number of possible non-routine post-inspection actions that the IAG may consider, depending on the critical finding and the impact on public safety and data integrity. These include:

• Quarterly reporting
• Early re-inspection
• Referral to relevant stakeholders (for example, other regulators/agencies, health research authority (hra), general medical council (gmc), care quality commission (cqc))
• Suspension of cta(s)
• An infringement notice
• Prosecution

Timelines of MHRA Statutory Inspection

Once Notification is received from the MHRA that we have been chosen for an inspection, the team have 30 days in which to complete a dossier of information and submit it.

Once submitted the inspectors will be assigned and will offer dates for the inspection. There is usually more than 6 weeks notice and the dates can be negotiated for availability of key staff.

6 weeks prior to the final inspection dates, an inspection plan is sent to the Trust which lists the studies chosen for in depth review.

2 weeks prior to the inspection dates a request for further documentation is sent to the Trust and this is uploaded to the MHRA Teams Channel.

The inspectors are usually on site for between 3 and 5 days.

Once completed the MHRA inspectors will send the inspection report within 25 working days from the end of the inspection.

The Trust then has 25 working days to respond to the inspection report with a comprehensive CAPA.

Once accepted the Inspection Statement is issued.

Important links

• Template MHRA Inspection Dossier
• GCP Inspections: Expectations and the dos and don’ts for hosting
• CQC Inspection frameworks for independent acute hospitals
• HTA Inspection guidance

An Advanced Therapy Medicinal Product (ATMP) is a medicine for human use that is based on genes, tissues, or cells. These products offer groundbreaking opportunities for the treatment of diseases and injuries.

ATMPs can be classified into three main types:

• Gene Therapy Medicinal Product (GTMP)
• Somatic Cell Therapy Medicinal Product (sCTMP), which may be:
• Autologous (starting material is from the intended recipient)
• Allogeneic (starting material originates from a donor)
• Xenogeneic (starting material is of non-human origin)
• Tissue Engineered Product (TEP), which may also be:
• Autologous (starting material is from the intended recipient)
• Allogeneic (starting material originates from a donor)
• Xenogeneic (starting material is of non-human origin)
• Combination Product that includes one or more medical devices or active implantable medical devices, along with a cell or tissue component.

Advanced Therapy Medicinal Products (ATMPs) are regulated in a manner consistent with conventional medicinal products. Accordingly, they must fulfil the definition of a medicinal product as stipulated in Directive 2001/83/EC and are therefore subject to the same regulatory requirements.

Within the Trust, overall responsibility for the governance and use of ATMPs resides with the Chief Pharmacist. This responsibility is, in practice, exercised with the support of appropriately delegated authorities, in accordance with established governance frameworks.

The status of ATMPs for use in the Trust may vary, for example:

• Licensed ATMP used in line with its Marketing Authorisation
• Licensed ATMP used off-label (not in line with its Marketing Authorisation)
• Unlicensed ATMP, such as:
• Compassionate access use of clinical trial stock outside of a clinical trial protocol
• One-off Special, as per MHRA Guidance Note 14
• ATMP used as an Investigational Medicinal Product (AT(I)MP) within a clinical trial
• Licensed ATMP or AT(I)MP that, following manufacture, has been deemed Out of Specification (OOS). (Refer to the UHS Out-of-Specification ATMP Policy—not covered in this document.)

The Human Tissue Authority (HTA) is the Competent Authority responsible for regulating the procurement processes of cells or tissues that serve as starting materials for advanced therapies within the UK. This includes procurement, storage, testing, and—where applicable—distribution and import/export, all of which are directly relevant to this policy, alongside the requirements of the Medicines and Healthcare products Regulatory Agency (MHRA).

Regulations stipulate that the organisation responsible for contained use (e.g. the NHS Trust conducting the trial) must obtain advice on the risk assessment from a Genetic Modification Safety Committee (GMSC), or from a competent individual with expertise in contained use risk assessments. Most uses of Genetically Modified Organism (GMO) Advanced Therapy (Investigational) Medicinal Products [AT(I)MPs] on University Hospital Southampton (UHS) premises are expected to fall under Class 1 contained use activities, involving either hospital patients or healthy volunteers. All GMO AT(I)MPs must undergo formal review to determine the appropriate classification, as some may meet the criteria for Class 2.

The Health and Safety Executive (HSE) was notified when UHS first administered a GMO AT(I)MP. For subsequent Class 1 activities, no further HSE notification is required under the Contained Use Regulations. However, any activity involving a Class 2 GMO AT(I)MP necessitates additional notification, as such activities are subject to higher levels of regulatory oversight.

All AT(I)MPs used at UHS must be approved by the AT(I)MP Oversight Committee. Each product must undergo a comprehensive technical, regulatory, and clinical assessment prior to use within the Trust.

Please contact the QA team for a sample of the Technical & Regulatory Assessment Form.

For early-phase studies (Phase 1 / first-in-human studies) conducted in the Clinical Research Facility, the protocol will also undergo review by the Early Phase Safety Committee (EPSC).

Please contact the QA team for a sample copy of the EPSC Risk Stratification Matrix and Contingency Plans Form.

GMO AT(I)MP must also receive approval from the Biological Risk Management Committee (BRMC) prior to the issuance of the UHS Confirmation of Capacity and Capability Statement.

Please contact the QA team for a sample copy of the BRMC Form.

The AT(I)MP Oversight Committee meets every 2 months and reports directly to the UHS Drugs and Therapeutics Committee (DTC) and the Research and Development Quality Oversight Committee.

Please contact the QA team for the AT(I)MP Oversight Committee Terms of Reference and the AT(I)MP Policy.

Important contact details:

• ATIMP Queries: atmpqueries@uhs.nhs.uk
• Pharmacy Advanced Therapies Unit (PATU): pharmadvancedtherapies@uhs.nhs.uk

All research study data must be kept so that data may be accessed after closure of the study. This may be necessary, for example, in the event of unexpected side effects after a study drug has been approved, if allegations of fraud are made or if the data is to be used in a follow-up study.

All essential documents relating to clinical research studies should be archived for a period of time in accordance with the regulations. The provider UHS uses for archiving is Oasis information secured who are based in Winchester. To see how long the study should be stored for, please refer to the study IRAS application and or Protocol. The SOP can be found in Florence under R&D/Gen/Admin/011.

If you have any queries on archiving or destruction of archiving, please get in touch with the team at researchsafety@uhs.nhs.uk.

SOPs are detailed written instructions to achieve uniformity of the performance of specific functions and set out the way practice and procedures must (i.e. mandatory) or should (i.e. advisory) be performed.

In research, SOPs form part of the systems required to assure the quality of every aspect of a trial.

At UHS, SOPs are managed through Florence. To gain access to an SOP, please email florenceadmin@uhs.nhs.uk with the reason why you need access to the SOP.

If you need to write an SOP, please contact researchsafety@uhs.nhs.uk, who will provide you a latest version of the template. Whenever an SOP is written, this should be sent to the QA team to review, to ensure it meets regulatory requirements and UHS SOP template standards. Once this has been reviewed by the QA team and sent back to the individual, it will be uploaded by the QA Officers, who will request a QC review to make sure that the author, expert authorisation and the QA team are happy for this document to be distributed to users.

The process for lab reference ranges has changed, due to UHS moving to a new national system where we are unable to pull generic reference ranges from the system.

The ranges in this system are tailored ranges to the individual patients, and only the ranges for the requested tests are visible. This is an issue that is being looked at by the developers of the software. We have collated a list of reference ranges that have been requested previously, but please bear in mind this will not be up to date.

If you have any questions or queries around this, then please do not hesitate to get in contact with the research safety team via researchsafety@uhs.nhs.uk.

As a part of GCP principles, anyone working on a research study must be duly trained for their delegated responsibilities. A key element is Good Clinical Practice (GCP).

Each member of staff should have a research CV. If you need a template for a research CV, then please follow the HRA template.

There are additional training courses that the NIHR provide, such as Valid Inform Consent and GCP Consolidated, which can be access via https://learn.nihr.ac.uk.

It is expected that all staff complete statutory and mandatory training as required for their role.

At UHS we have multiple clinical systems. Two of the main systems used within research at UHS are EDGE and Florence.

Edge is used as a communication, study and recruitment tracking tool. Florence is a validated and accredited electronic trial master file and electronic investigator site file system.

For any questions regarding Edge, please contact Edge2admin@uhs.nhs.uk. For any Florence questions, please email florencadmin@uhs.nhs.uk.

Following the TGN1412 incident in March 2006, the prominence and scrutiny of Phase I clinical studies have increased substantially. In response, the MHRA established a voluntary ‘Phase I Accreditation Scheme’¹ aimed at research facilities conducting Phase I clinical trials.

To obtain accreditation, organisations are required to surpass the fundamental regulatory standards of Good Clinical Practice (GCP) by implementing enhanced procedures designed to uphold the highest standards in safeguarding trial participants and managing any medical emergencies.

In 2021, the UKCRF Network introduced the Phase I and Experimental Medicine Governance Standards Framework. This framework integrates the supplementary requirements of the accreditation scheme and delineates enhanced governance processes, including comprehensive risk assessments, thereby enabling Clinical Research Facilities (CRFs) to adhere to a uniformly agreed minimum standard for conducting the highest-risk studies.

The NIHR Southampton Clinical Research Facility has elected to adopt the standards articulated within the UKCRF Network Phase I and Experimental Medicine Governance Standards Framework (hereafter referred to as the Framework).

The Early Phase Safety Committee (EPSC) has been established to support the scientific review and clinical risk assessment of all Phase I and First-in-Human (FIH) studies conducted within the NIHR Southampton Clinical Research Facility. Where deemed necessary by the CRF Directors, the EPSC may also support the review and risk assessment of other early-phase studies.

Please see the Terms of Reference for the Early Phase Safety Committee and a sample of the Early Phase Safety Committee Risk Stratification Matrix and Contingency Plans Form.

Secretariat for EPSC is provided by the NIHR Southampton Clinical Research Facility Senior Quality Assurance Lead, contactable via the email address kim.lee@uhs.nhs.uk.

The risk register is a record of the recognised risks and issues identified by each department. The risks are scored according to the impact of the risk occurring and the likelihood that the risk will occur. There is guidance on how to score these aspects of a risk available from the Trust and is located on staffnet.

The risk register consists on two levels. The local level and the Trust wide level. Local risks are identified locally and logged with the QA team and are divided into different parts of the R&D infrastructure. The Trust risk register is where those risks which cannot be addressed locally are highlighted. The Trust risk register is reviewed at a high level and only those significant risks are put on to the register.

Local risks are discussed at the R&D Quality Oversight Committee and a decision made as to whether these are further highlighted onto the central Trust Risk register for action.

In accordance with the UK Policy Framework for Health and Social Care Research and the Medicines for Human Use (Clinical Trial) Regulations, organisations hosting and sponsoring research must have systems in place that allow them to give “the safety of participants and of research and other staff priority at all times, and [ensure that] health and safety regulations [are] strictly observed – including the provision of information, containment, shielding and monitoring as required.”

Researchers must ensure that all patient safety related incidents are always reported according to the Trust’s Incident Reporting and Management Policy. Serious Adverse incidents report forms, relating to a research project, will be provided to the R&D office for information.

The UHS R&D Department has the responsibility to record and report SAEs/SUSARs in accordance with the Trust’s Research Related Adverse Event Reporting Policy, and to ensure that any onward reporting requirements are met for studies sponsored by UHS.

Definitions:

AI	Adverse Incident
AE	Adverse Event
AR	Adverse Reaction
ADE	Adverse Device Effect
CTIMP	Clinical Trial of an Investigational Medicinal Product
DSUR	Development Safety Update Report (annual safety report format)
GCP	Good Clinical Practice
IMP	Investigational Medicinal Product
MDI	Medical Device Investigation (acronyms not commonly used)
MHRA	Medicines and Healthcare products Regulatory Agency
SAE	Serious Adverse Event
SADE	Serious Adverse Device Effect
SAR	Serious Adverse Reaction
SSAR	Suspected Serious Adverse Reaction
SUSAR	Suspected Unexpected Serious Adverse Reaction
USADE	Unanticipated Serious Adverse Device Effect

An Investigational Medicinal Product is a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial including a medicinal product which has a marketing authorisation but is, for the purposes of the trial, being used or assembled (formulated or packaged) in a way different from the approved form or being used for an unapproved indication or when used to gain further information about an approved use.

A Medical Device means any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of:

1. Diagnosis, prevention, monitoring, treatment or alleviation of disease,
2. Diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,
3. Investigation, replacement or modification of the anatomy or of a physiological process,
4. Control of conception,

and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting and reporting trials that involve the participation of Human subjects. Otherwise known as ICH-GCP, guideline E6 on Good Clinical Practice was produced by the International Conference on Harmonisation.

An Adverse Incident (AI) is any incident/accident, near miss or untoward event which had or may have had, the potential to cause harm, dissatisfaction or injury to persons, loss or damage to property. In clinical terms, an adverse event is any occurrence, which did or could have resulted in unintended or unexpected harm to one or more participants(s). This definition includes hazards, accident, ill health, dangerous occurrences and near misses.

An Adverse Event (AE) is any untoward medical occurrence in a subject to whom a medicinal product/medical device/intervention has been administered, including occurrences which are not necessarily caused by or related to that product.

An adverse event can therefore be any unfavourable and unintended sign (including abnormal lab results, traffic accident, pregnancy), symptom or disease temporally associated with the use of the medicinal product/medical device/intervention, whether or not considered to be related to the medicinal product/medical device/intervention.

An Adverse Reaction (AR) is any untoward and unintended response in a subject to an investigational medicinal product/medical device/intervention which is related to any dose administered to that subject.

Any adverse event judged by either the reporting investigator or the Sponsor as having reasonable causal relationship to a medicinal product/medical device/intervention qualifies as an adverse reaction; there is evidence or argument to suggest a causal relationship. All adverse reactions are adverse events.

An Adverse Device Effect/incident (ADE) is any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which might lead to or might have led to endangering the health of a patient or the device user.

The EU Medical Device Directive 93/42 and UK’s Medical Device Regulations 2002:618 (as amended) currently do not provide a common terminology and definition, both 'effect' and 'incident' are used. The ISO 14155-2:2003 Clinical investigation of medical devices for human subjects - Part 2: Clinical investigation plans uses the term 'effect'. Unless the study Sponsor requests otherwise, for UHS recording and reporting purposes the term 'effect' should be used.

An Unexpected Adverse Reaction is an adverse reaction where the nature and severity of which is not consistent with the information about the medicinal product or intervention in question set out:

• in the case of a product with a marketing authorisation, in the Summary of Product Characteristics (smpc) for that product,
• in the case of any other investigational medicinal product, in the Investigator's Brochure (IB)

When the outcome of the adverse reaction is not consistent with the applicable product information this adverse reaction should be considered as unexpected. All unexpected adverse reactions are adverse events.

An adverse event, adverse reaction, unexpected adverse reaction, adverse device effect is defined as serious if it:

1. results in death
2. is life-threatening
3. requires hospitalisation or prolongation of existing hospitalisation
4. results in persistent or significant disability or incapacity
5. consists of a congenital anomaly or birth defect

Life threatening in the definition of an SAE/SAR/SADE refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe. Medical judgement should be exercised in deciding whether an SAE/SAR/SADE is serious in other situations. Important SAE/SAR/SADEs that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise the subject or may require intervention to prevent one or the other outcomes listed in the definition above, should also be considered serious.

A Suspected Serious Adverse Reaction (SSAR), is any serious adverse reaction that is suspected (possibly or probably) to be related to the investigational medicinal product/medical device/intervention.

A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an SSAR which is also “unexpected”, meaning that its nature and severity are not consistent with the information about the medicinal product in question set out:

1. In the case of a product with a marketing authorisation, in the summary of product characteristics for that product
2. In the case of any other investigational medicinal product, in the investigator’s brochure relating to the trial in question.

A non-IMP SUSAR is an SAE that occurs in a non-IMP trial and is:

1. 'Related' – that is, possibly, probably or definitely resulted from administration of any of the research procedures, and
2. 'Unexpected' – that is, the type of event is not listed in the protocol as an expected occurrence.

An Unanticipated Serious Adverse Device Effect (USADE) is an untoward medical occurrence that happens in a subject or other person; which is related to the investigational device, device procedure, or comparator; which is serious and was unanticipated.

UHS sponsored studies: Please complete the SAE reporting form and send via email to researchsafety@uhs.nhs.uk, within 24 hours of becoming aware of the event. These will then be reviewed and assessed by the team, who will acknowledge receipt.

If the initial report is the not the final report, all follow up reports should be provided as soon as new information becomes available and should be sent via email to researchsafety@uhs.nhs.uk.

To obtain a copy of the latest reporting form, please contact researchsafety@uhs.nhs.uk.

Hosted Studies at UHS: Please complete your SAE form supplied to you by the sponsor for your study and send this to your sponsor in accordance with their reporting policy, please also ensure that the SAE is added to EDGE under the appropriate study and participant. A copy of the form should then also be emailed to researchsafety@uhs.nhs.uk.