Clinical trials: Non-investigational medicinal products
Source: gov.uk (2025-10-01)

Guidance on using non-investigational medicinal products in a clinical trial.

This guidance accompanies the Medicines for Human Use (Clinical Trials) Regulations 2004 (“the Clinical Trials Regulations”), as amended by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 (https://www.legislation.gov.uk/uksi/2025/538).

These amendments come into force on 28 April 2026.

Until this date, this guidance is in draft and should only be used to support sponsors in preparing for the implementation of the new regulations. Please see Clinical trials for medicines: apply for authorisation in the UK (https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-authorisation-in-the-uk) and Clinical trials for medicines: manage your authorisation, report safety issues (https://www.gov.uk/guidance/clinical-trials-for-medicines-manage-your-authorisation-report-safety-issues) for the guidance that should be followed prior to 28 April 2026.

Legal status of this guidance

The following guidance accompanies the Medicines for Human Use (Clinical Trials) Regulations 2004 (https://www.legislation.gov.uk/uksi/2004/1031/contents) (“the Clinical Trials Regulations”), as amended by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 (https://www.legislation.gov.uk/uksi/2025/538). These amendments come into force on 28 April 2026. For assistance in determining whether a clinical trial is within the scope of these Regulations, see the Is it a clinical trial of a medicinal product? (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/949145/Algorithm_Clean__1_.pdf) algorithm.

Part 2 of Schedule 1 to the Clinical Trials Regulations requires that the investigator and sponsor (https://www.hra.nhs.uk/planning-and-improving-research/research-planning/roles-and-responsibilities/) (and any individual or organisation that the sponsor delegates trial-related activities to) have regard to all relevant guidance with respect to commencing and conducting a clinical trial. Investigators and sponsors must, therefore, ensure that they are fully aware of the information within this guidance and act accordingly to achieve and maintain regulatory compliance.

Definitions

Non-investigational medicinal products

Per regulation 2 of the Clinical Trials Regulations, a non-investigational medicinal product (NIMP) is a medicinal product used or to be used in a clinical trial, as described in the protocol, but not as an investigational medicinal product (IMP). For the purpose of the above definition:
- a medicinal product is defined per regulation 2 of the Human Medicines Regulations 2012 (https://www.legislation.gov.uk/uksi/2012/1916/contents)
- an investigational medicinal product is defined per regulation 2 of the Clinical Trials Regulations
Non-medicinal products

Non-medicinal products are products that are used or to be used in a clinical trial in the same way as an NIMP but that do not meet the definition of a medicinal product (e.g. use of pollen or house dust in a skin prick test).

This guidance also applies to these non-medicinal products, unless otherwise specified.

Using non-investigational medicinal products in a clinical trial

Authorisation

In most cases, NIMPs used in a clinical trial should hold a marketing authorisation. Where an authorised NIMP does not exist or where the sponsor cannot be reasonably expected to use it, the sponsor may use an unauthorised NIMP, ensuring that clear justification for this is given in the trial protocol.

Acceptable justifications for using an unauthorised NIMP include where there are issues with the availability of the authorised product (not including issues relating to the price) and where the NIMP does not have a marketing authorisation but is prepared in accordance with a magistral or official formula.

Examples of non-investigational medicinal products

Rescue medications

Rescue medications (or escape medications) are NIMPs identified in the protocol as medicinal products that may be administered to patients:
- when the IMP does not have satisfactory efficacy
- when the effect of the IMP is too great and is likely to cause an adverse reaction in the patient
- to manage an emergency situation
Examples of this type of NIMP include:
- where the IMP is ineffective: a repeated-dose, randomised, double-blind, placebo-controlled, three-parallel group study performed to evaluate the analgesic efficacy and safety of intravenous acetaminophen as compared with its prodrug (propacetamol) and placebo in patients suffering mild to moderate pain after an orthopaedic surgical operation, in which participants were allowed “rescue” participant-controlled intravenous morphine for pain
- to minimise expected adverse reactions: a phase III clinical trial trying to assess the efficacy of a new anti-neoplasic IMP where all participants receive a corticosteroid and antihistamine treatment in order to minimise the appearance of expected adverse reactions
- to manage an anticipated emergency situation: a clinical trial where a new biotechnology product is to be given for the first time to humans, so the protocol requires the availability of appropriate medicinal products needed for the treatment of anaphylactic shock
Challenge agents

Challenge agents are NIMPs (or sometimes non-medicinal products) given to trial participants to produce a physiological response that is necessary before the pharmacological action of the IMP can be assessed. This would include, for example, the product used in a skin prick test used to identify allergic responses to specific allergens (as the NIMP is being administered to modify a physiological function by exerting an immunological action).

Examples of this type of NIMP include:
- skin prick tests used to identify subjects with allergic responses to specific allergens. Dilute solutions are manufactured from extracts of allergens and a drop of each solution is placed on the person’s skin, which is then pricked with a needle. If the person is allergic to one or more substances, he/she has a wheal and flare reaction. This test may be used as part of the inclusion criteria for a clinical trial of a new medicine to control or prevent symptoms from allergic reactions
- open-label sensitivity test of blood pressure response to oral tyramine following treatment with an IMP (new monoamine oxidase inhibitor) in healthy volunteers
- a drug-drug interaction (DDI) study of the effect of an IMP on midazolam pharmacokinetics in healthy participants. Midazolam, a short-acting benzodiazepine central nervous system depressant, is a sensitive substrate of CYP3A and is routinely used in DDI studies as a probe of hepatic and intestinal CYP3A activity (where it would be classified as an NIMP)
NIMPs used to assess endpoints

NIMPs can be given to a trial participant as a tool to assess a relevant clinical trial endpoint. In these cases, the product is not being tested or used as a reference in the clinical trial.

Examples of this type of NIMP include:
- PET radiopharmaceuticals administered to a clinical trial population to measure the function of a certain organ before and after the subject has been given an IMP whose effects in this organ are the primary endpoint of the clinical trial
- PET radiopharmaceuticals administered as part of a lung scintigraphy study to evaluate the effects of an IMP on ventilation and perfusion in asthma patients
- acetylcholine is administered directly in coronary arteries to evaluate coronary endothelium dysfunction. The test is performed at baseline – before the first administration of an IMP, and at the end of the study, after the treatment period
Background treatment

This type of NIMP is administered to each of the clinical trial participants, regardless of randomisation group, either to treat the indication which is the object of the study or as part of the standard of care treatment for a condition which is not the indication under investigation but is relevant for the clinical trial design.

The IMP for the clinical trial is given in addition to the background treatment. The protocol may require that the IMP plus the background treatment is compared to an active comparator, or to placebo plus background treatment.

Where the current standard of care treatment is given as a background treatment, either:
- participants may already be taking the standard care medicine(s) when entered into the study, and this treatment would be one of the inclusion criteria
- newly diagnosed subjects may be assigned to the standard care medicines at the same time as they are assigned to the IMP
The nature of the background medicine(s) will be specified in the protocol e.g. as the standard treatment given according to local clinical practice, by the name of active substances or medicinal products prescribed depending on patient needs and according to the doctor’s judgement.

The standard care medicine(s) for a specific indication (recognised standard of care), or a component of the standard care for a particular medical indication, is based on national and international consensus.

Please note that:
- the current standard of care treatment (or parts of it) is considered to be an IMP, not a background treatment, if it is part of the trial hypothesis (e.g. where the primary or secondary trial objectives include the investigation of interactions with the test product for complimentary effects or possible adverse interactions, or the standard of care treatment is being used as a reference to compare the effect of the test product)
- concomitant medications are not considered NIMPs, as these are unrelated to the clinical trial and not relevant for its design.
Examples of this type of NIMP include:
- development of a new medicinal product for Human Immunodeficiency Virus (HIV) patients who need prophylaxis against cytomegalovirus (CMV) is likely to include patients on standard of care medicine(s) for their primary disease (e.g. antiretroviral medicinal products)
- in oncology, patients often receive combination treatments. These may all be approved for the treatment of the disease to be investigated but may not be completely defined in the protocol. For example, the development of a new indication for a medicine used in women with breast cancer recently compared that medicine versus observation in patients who had received, regardless of trial, at least four cycles of neoadjuvant or adjuvant chemotherapy and were allowed concurrent hormonal adjuvant therapy. In this case that medicine would be considered an IMP and the neoadjuvant or adjuvant chemotherapy and hormonal therapy products would be NIMPs
- a novel oncology IMP is to be given on top of standard of care as ‘add on’ therapy. There is no proposed mechanistic interaction with standard of care, no evaluation of the standard of care products (in endpoints or as planned in the statistical analyses) and no randomisation related to the standard of care. The trial design includes all subjects receiving standard of care and then being randomised to receiving the novel IMP, or nothing. The standard of care is acceptable as background therapy, with the novel IMP being evaluated for additional benefit as an add-on therapy
In contrast, an example of when the current standard of care treatment is not considered to be background therapy is:
- a novel oncology IMP is to be given on top of standard of care (chemotherapy) as combination therapy. There is no proposed mechanistic interaction with standard of care, but participants are randomised to standard of care plus IMP or standard of care alone. The primary objective is to compare outcomes of the combination (IMP + chemotherapy) versus chemotherapy alone. In this case, the standard of care is considered to be an IMP (in addition to the novel IMP)
Documentation for non-investigational medicinal products

Per Schedule 3 of the Clinical Trials Regulations, an application for clinical trial approval must include a dossier that contains details of the quality of any NIMP. For further guidance, please refer to the guidance on Documents required for an application for clinical trial approval (https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-approval-in-the-uk#documents-required-for-an-application-for-clinical-trial-approval). Please note that although this guidance refers to IMPs, it also applies to NIMPs. A list of NIMPs proposed for use in the trial should also be included in the cover letter.

For NIMPs that are both authorised and unmodified (i.e. packaged and labelled according to their authorisation), a simplified dossier is accepted, per the guidance on Cross-referencing and simplified investigational medicinal product dossiers (https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-approval-in-the-uk#cross-referencing-and-simplified-investigational-medicinal-product-dossiers).

Non-medicinal products do not necessarily require their own dossier but must, as a minimum, be listed in the cover letter and included in an IMP dossier with information about their properties, labelling, manufacture, stability and safety controls, as appropriate to the product.

Manufacture of a non-investigational medicinal product

Per regulation 45A of the Clinical Trials Regulations, all NIMPs (regardless of authorisation status) must be manufactured or assembled in accordance with the principles and guidelines for Good Manufacturing Practice that apply under the Medicines for Clinical Trials Regulations or the Human Medicines Regulations 2012. Evidence of this (e.g. a manufacturer’s authorisation for the site of manufacture) should be included in the application for clinical trial approval.

The manufacture of non-medicinal products must be shown to comply with the safety standards applicable to that product. It may also be necessary to demonstrate compliance with relevant safety standards applicable to medicines suitable for use in humans.

Labelling of a non-investigational medicinal product

Per regulation 46A of the Clinical Trials Regulations, NIMPs used in a clinical trial are subject to the same labelling requirements as IMPs (which are described in regulation 46 of the Clinical Trials Regulations.

The exception to this is that there are different labelling requirements where an authorised IMP is to be exclusively administered in a hospital or health centre taking part in the clinical trial, but this is not the case for authorised NIMPs.

As the majority of NIMPs are expected to be authorised medicinal products, used unmodified, they should in most cases be labelled in accordance with the existing UK requirements for prescribed medicines dispensed by pharmacies set out in Part 13 of the Human Medicines Regulations 2012 (https://www.legislation.gov.uk/uksi/2012/1916/contents/made).

Detailed guidance on labelling requirements for non-investigational medicinal products used in a clinical trial can be found in Labelling for products used in clinical trials (https://www.gov.uk/guidance/clinical-trials-for-medicines-labelling).

Safety reporting in relation to non-investigational medicinal products

See the Guidance on the collection, verification and reporting of safety events in clinical trials of an investigational medicinal product (https://www.gov.uk/guidance/clinical-trials-for-medicines-collection-verification-reporting-of-safety-events) for:
- guidance on reporting a serious adverse event that is suspected to be related to a NIMP
- guidance on inclusion of serious adverse events or reactions suspected to be related to a NIMP in Development Safety Update Reports