Clinical Investigations in the UK
MHRA Guidance update
Medical equipment, in vitro diagnostics, and clinical trials are regulated by the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Clinical investigations of medical devices – guidance for manufacturers from the MHRA, covers everything from the choice to conduct a clinical trial to the approval process. This document will help you understand UK clinical investigation legislation if you plan to conduct one.
In this article, we give you an overview of the guidance and highlight some of its most key aspects.
What is the guidance for Northern Ireland?
Going through the guidance, it’s clear that clinical investigations in Northern Ireland are unique.
The MHRA guidance document states:
“The Northern Ireland Protocol requires Northern Ireland to continue to align with EU rules for devices after 1 January 2021… This means that clinical investigations being conducted in Northern Ireland must meet the requirements of the EU MDR and be submitted to MHRA in accordance with these regulations.”
Therefore, three scenarios exist:
1. You have a study site(s) in Northern Ireland.
Your submission to the MHRA must be EU MDR compliant.
2. You have a study site(s) in Northern Ireland and Great Britain (England, Wales, and Scotland).
You must still meet the requirements of EU MDR. By doing so, the MHRA will consider you to be UK MDR 2002 compliant.
3. You do not have study sites in Northern Ireland.
Your clinical investigation must meet UK MDR 2002 requirements.
If you intend to have study sites in Northern Ireland, then focus must be given to the instruction boxes that explain Northern Ireland-specific regulations.
For example: 
It’s also worth noting the different markings that are discussed in the guidance.
- UKCA (UK Conformity Assessed) marking. For products placed on the market in Great Britain (England, Wales, and Scotland).
- UKNI marking. For products placed on the market in Northern Ireland.
- CE marking. For products placed on the market in the European Union.
Great Britain plans to indefinitely recognise the CE mark for UK-marketed goods. The guidance uses UKCA/CE and UKNI/CE because of that, and CE-marked devices can be sold in the UK.
What are the general considerations for Clinical investigation in the UK?
If your device is not already UKCA/CE or UKNI/CE marked then notifying MHRA of your proposed investigation is crucial.
Non-UKCA/CE or UKNI/CE marked devices must have Clinical Investigations designed to:
- Establish that the performance claimed by the manufacturer can be adequately demonstrated.
- Demonstrate that the device is judged to be safe to use on patients taking into account any risks associated with the use of the device when weighed against the expected benefits.
If the purpose of your clinical investigation is anything other than demonstrating performance and safety (e.g. user handling or preference studies) then the investigation should not be carried out on a non-UKCA/CE or UKNI/CE marked device.
You must prove your device’s performance and safety to become UKCA/CE marked. You must demonstrate that the device meets Annex I of EU MDR’s general safety and performance requirements before conducting more studies.
The MHRA guidance also states that the principles of clinical investigations of medical devices are set out in the standard BS EN ISO 14155:2020 Clinical investigation of medical devices for human subjects – Good clinical practice. This is not a designated standard; however, they expect manufacturers to adhere to this ISO standard as it is deemed to be best practice.
When is a clinical investigation required?
In making a decision as to whether a clinical investigation is required, manufacturers need to work through a series of decisions in order to reach a conclusion.
These include asking questions like:
- Is this a UKCA Marked device (MD/IVD)?
- Are you doing studies within the Intended Purpose listed in the conformity certificate or is it a new Intended Purpose or Indication?
- Is clinical data required to demonstrate compliance? If so, does the clinical data already exist on the device in question (published or unpublished) or by analogy with published data generated in respect of an equivalent device?
- Is this a new or novel device with no pre-existing market history in the world?
A clinical investigation of a non-UKCA/CE and UKNI/CE marked medical devices should at least be considered in the following circumstances:
- Implantable or Class III medical devices.
- Introduction of a completely new concept of device into clinical practice where components, features and/or methods of action, are previously unknown.
- An existing device is modified in such a way that it contains a novel feature particularly if such a feature has an important physiological effect; or where the modification might significantly affect the clinical performance and/or safety of the device.
- The device incorporates materials previously untested in humans, coming into contact with the human body or where existing materials are applied to a new location in the human body or where the materials are to be used for a significantly longer time than previously, in which case compatibility and biological safety will need to be considered.
- The device, whether UKCA/CE or UKNI/CE marked or non-UKCA/CE or UKNI/CE marked, is proposed for a new purpose or function.
- In vitro and/or animal testing of the device cannot mimic the clinical situation.
- There is a new manufacturer, especially of a high-risk device.
What does MHRA consider as ‘special circumstances’?
The guidance also outlines several things that are considered to be special circumstances for clinical investigations. These should be paid close attention to, as one or more could apply to your device:
- Change in intended use/performance claims of a device.
- Comparative studies.
- Prototype devices.
- Clinical investigations also submitted to the FDA or other regulatory authorities.
- In-house manufactured medical devices.
- Off-label use.
- Research tools.
- Humanitarian use of non-UKCA/CE and UKNI/CE marked devices.
The guidance goes into detail for each of the above, which will enable manufacturers to determine whether they are applicable.
What should be considered for Clinical Investigations?
There are a number of planning considerations to take into account for clinical investigations. These include:
- Healthcare treatment pathway for the intervention and map out various stakeholders.
- Overall health economics of the intervention.
- Patient sample size to prove the Clinical benefit and investigate the potential adverse effects.
- Safety and Performance Endpoints. Primary and secondary endpoints.
- Number of clinical investigation prototype devices needed for clinical investigation. Retrieval strategy post investigation.
- Clinical investigation duration.
- Type of Investigation.
- Suitability of research sites and investigators.
- Labelling and Information brochure.
- Research ethics committee opinions.
- Approvals.
Manufacturers must read them all in detail, however post market clinical follow-up is crucial. Both UK MDR 2002 and EU MDR require manufacturers to regularly update their clinical evaluation using post market surveillance data.
If you don’t believe a PMCF is required in your case, you must justify and document your decision not to use a PMCF. However, many circumstances listed in the guidance require a PMCF:
- Innovation, where the design of the device, the material, the principles of operation, the technology or the medical indication is new.
- Severity of the disease.
- Sensitive target population.
- Risky anatomical location.
- Well-known risks associated with a similar marketed device.
- Well-known risks identified from the literature.
- Identification of an acceptable risk during pre-market clinical evaluation, which should be monitored in a longer term and/or through a larger population.
- Identification of emerging risks in similar products.
Obvious discrepancy between the pre-market follow-up windows and the expected life of the product.
CLIN-r+ recommendations
Start your journey by having suitable processes and templates formulated to ensure all required information is formulated and adequate.
Manufacturers should consider partnering with an experienced consultancy when assessing standards, risk, clinical data and considering what clinical studies are best suited for your devices marking needs. Consultancies also come with resources such as clinical study designers, statisticians, CRA’s and experienced medical writers that help expand your companies’ capabilities cost-effectively.
Should you have any questions or need professional assistance, CLIN-r+ has a wealth of experience in clinical investigations and post market services to call upon. Get in touch
Regulating Medical Devices in the UK
UKCA postponed for 1 year
