The Medicines and Healthcare Products Regulatory Agency (MHRA), the UK authority responsible for medical device regulation, has issued guidance on clinical investigations of medical devices in order to assist manufacturers in complying with any and all applicable requirements.
Clinical Investigation in the UK
According to the existing legal framework, the manufacturer of a medical device must confirm compliance of a device with all applicable requirements to be allowed to mark the device with a CE mark. In order to receive the confirmation, the manufacturer could provide clinical data including either:
- A clinical evaluation of reliable information sources (e.g. scientific literature) describing a similar device that is already present on the market and complies with all applicable requirements (in the USA the term “predicate” could be used in such cases),
- A clinical investigation results evaluation, if they had been duly performed by the manufacturer, clinical evaluation of the data, and information obtained from both aforementioned sources.
Scientific literature constitutes a reliable source of information that could be used to assess potential compliance of a device with applicable requirements. This is only if the manufacturer is able to prove the equivalence with another device similar to the device subject to review in the terms of design, composition, safety and performance.
In certain cases, clinical investigation could be necessary in order to assess safety and performance issues. For example, it is required to conduct a clinical investigation for implantable and Class III medical devices to prove that the device performs as intended by the manufacturers, and to identify potential side effects and/or risks associated with the use of the device. For this purpose, the manufacturer must conduct a clinical investigation in a way that ensures the achievement of the aforementioned purpose. The agency emphasizes that if it is necessary to use additional accessories to perform a clinical investigation, the investigation should also cover these accessories unless they already bear a CE mark.
If clinical investigations are planned in the UK, the manufacturer should notify the MHRA in advance by filing 60 days prior notice. Such notice could be filed either by the manufacturer itself or by its authorized representative based in the EU. The notice should be deemed formally accepted if the MHRA would not provide any objections due to concerns regarding public health within 60 days.
Requirements for Clinical Investigation Design and Reports
Describing the requirements applicable to clinical requirements the guidance refers to the Medical Devices Regulations 2002, Active Implantable Medical Devices Directive, and also to the Medical Devices Regulation 2017/745 (MDR). According to the requirements listed in the aforementioned regulations, a clinical investigation should:
- Be based on a properly developed plan containing clear and measurable aims and objectives,
- Utilize procedures required for the particular type of device,
- Imitate the conditions similar to ones used in similar devices,
- Utilize the number and scope of devices reasonably necessary to achieve the defined objectives of the investigation,
- Cover the features and characteristics of the device that should be examined in order to access safety and performance issues,
- Keep records on all adverse events, and also to notify the authority on the severe ones,
- Be performed under the responsibility of a particular healthcare professional,
- Result in creating a final written report containing the evaluation of clinical investigation data together with the conclusions, signed by a responsible person.
To define whether a clinical investigation should be held in each particular case, a manufacturer must evaluate several aspects, including, among others, the following:
- The essential requirements related to compliance,
- The scope of data that is necessary to prove compliance,
- The scope of testing to be performed in order to collect the data necessary to prove compliance,
- The importance and necessity of clinical data, and also the possibility to use existing data related to a similar device already present on the market.
If the medical device is not marked with a CE mark, a clinical investigation would be required if it is an implantable device or belongs to Class III in accordance with the risk-based classification. This would also be required if the device is entirely new and employs novel components or approaches, the manufacturer is a new one and/or the device is high-risk, or the existing device has been modified substantially making it impossible to refer to the appropriate clinical data to confirm compliance. Similarly, if the composition of the device contains novel materials or the device is intended for another purpose, it requires investigation, as well as in cases when IVD or animal testing of the device does not allow to collect the information necessary.
Specific Cases Related to Clinical Investigation
The manufacturer must also collect additional clinical data if they are making changes to the intended purpose of the device. In such a case, the manufacturer shall also notify the authority and conduct in a proper way a clinical investigation with the appropriate objectives and aims. At the same time, in case of comparative studies aimed at comparison of two CE-marked devices it is not required to notify the MHRA while it could be necessary in cases when at least one of the devices subject to examination is not CE-marked.
In some cases, the manufacturer is allowed to use prototype devices in a clinical investigation and then make changes to the design or composition of the device before issuing its final version. In such cases, the authority is entitled to request the manufacturer to make a new submission in order to verify that the new version of the device complies with all applicable safety and performance requirements.
In the situations when the manufacturer is going to use clinical investigation reports to provide them to more than one regulating authority (including also non-EU authorities), it is necessary to pay attention to differences in requirements for the clinical investigation reports employed by each authority. For example, sometimes the requirements employed in non-EU countries could be wider than those provided by the MDR. In such cases, the manufacturer shall inform the MHRA on all additional information provided to foreign authorities.
Despite the fact that the MDR does not cover devices produced by a healthcare establishment to be used solely to be used for internal purposes, the appropriate requirements on the clinical investigation could be applied if the manufacturer and the healthcare establishment are not the same legal entity.
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