A CTA application that references DM (either in part or in whole of the manufacturing process) is enabled by award of a DM designation which confirms that in the view of the MHRA, the legal test for DM is justified in the context of an Investigational Medicinal Product (IMP) proposed for use in a clinical trial. The application process for DM designation is detailed separately in The Designation Step.

The CTA application should include evidence of DM designation. It should be confirmed in the CTA application that the information that was provided in support of the DM designation remains unchanged. Where a significant change has been made to the supporting information, a new DM designation should be sought.

Where a clinical trial includes the use of a DM IMP alongside other IMPs, a conventional centralised manufacturing approach must be applied to any IMPs without DM designation. In most cases, it is expected that a conventional centralised manufacturing approach would apply to placebo IMPs.

A Control Site is required for a DM IMP and must be proposed in the CTA application. This site must be certified to control the required mode of DM before submission of the CTA application, and a suitably scoped MIA(IMP) for the Control Site is required in the CTA application dossier. The DM master file template (MS Word Document, 70 KB) should also be submitted.

The general principles of product development, manufacture, and control apply to a DM IMP as they would to a conventional centralised manufactured IMP. General IMPD requirements continue to apply and are detailed in Requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials and Requirements for quality documentation concerning biological investigational medicinal products in clinical trials. Batch analysis data from a representative number of DM locations should be included in section P.5.4 for assurance of compliance with the quality attributes of IMP batches manufactured at all DM locations. Process validation and/or extended characterisation information commensurate with the phase of development may also be required to demonstrate comparability between batches and/or manufacturing locations for more complex or potentially variable products.

In cases where principles of RTRT are proposed for assurance of the quality of selected aspects of a DM IMP, section P.2 of the IMPD should include information demonstrating enhanced product and process knowledge that supports this approach. Results of representative process validation for multiple batches made at a representative scale covering at least the critical manufacturing steps should be provided in section P.3.5. The RTRT strategy should be based on a firm understanding of the manufacturing process and of the relationship between process parameters, in-process controls and final IMP attributes. Further information about the principles of RTRT are described in the Guideline on Real Time Release Testing (formerly guideline on parametric release) and also from a GMP perspective in Eudralex Vol 4 Annex 17 on ‘RTRT and Parametric Release’.

See information about labelling.

Additional considerations for blinded trials involving DM IMPs

Clinical trials are often blinded. Blinding is the process that keeps one or more parties involved in a trial (for example, the sponsor, the investigator team and/or the participant) unaware of what treatment arm participants have been randomised to. It is vital that the blind is maintained throughout the trial to ensure that no bias is introduced when making safety and efficacy assessments. Maintaining the integrity of the blind is a key consideration for all those involved with the trial, as compromising the blinding may have a significant impact on the interpretation of the results. The sponsor is responsible for ensuring that measures are taken to protect the integrity of the blind and these should be detailed in the protocol. Formal assessment of blinding controls during trial set up and periodic review of these controls following use should be implemented.

In relation to point of care manufacture, these controls should include ensuring that the manufacturing and administration of the IMP does not inadvertently reveal the treatment assignment, for example:

Process required to manufacture the dose unit
Time taken to manufacture or prepare the dose
Difference in appearance or other characteristics, such as temperature or equipment required, between active and placebo products
Process required for administration of the dose
Record keeping, especially those associated with manufacture and release of the IMP

Decentralised manufacture: Clinical Trial Authorisation (CTA) and Good Clinical Practice (GCP)