MHRA produced FAQs for Investigational Medicinal Product (IMP)

[MHRA Super Moderator]

2. What is an investigational medicinal product (IMP)?

An investigational medicinal product is any medicinal product which is being tested within a trial or any product, including placebo, used as a reference in a clinical trial. This includes products with a marketing authorisation where the product is:

• used in a different form from the marketing authorisation
• used for an indication not included in the summary of product characteristics for that product or
• used to gain further information about the product as authorised in the clinical trial authorisation.

[MHRA Super Moderator]

3. Who is permitted to manufacture IMP?

Part 6 of SI 2004/1031 (as amended) deals with the need for a manufacturers? authorisation for investigational medicinal products (MIAIMP) if IMPs are to be manufactured, assembled or imported. Any UK site wishing to manufacture an IMP would need to apply for an MIAIMP. For sites in other EU countries wishing to manufacture IMP, they must obtain a relevant licence from the appropriate Competent Authority.

Further information on the application process can be found using the following link to the MHRA website:
Manufacturer?s and wholesale dealer?s licences

[MHRA Super Moderator]

4. What is meant by the terms Qualified Person (QP) release and Qualified Person certification?

The terms QP release and QP certification, are often (incorrectly) used interchangeably. However the responsibilities for release and certification are defined in clinical trials legislation. EUGMP Annex 13, Paragraph 44 requires IMPs remain under the control of the sponsor until after completion of a two-step procedure: Certification by the QP; and release following fulfillment of the requirements of Article 9 (commencement of a clinical trial) of 2001/20/EC.

The QP has a legal responsibility as laid out in Article 13 of 2001/20/EC to ensure that the IMP has been manufactured in accordance with EU GMP and meets the conditions of the clinical trial authorisation and the product specification file (PSF). In certifying a batch against the PSF, investigational medicinal product dossier or the clinical trial authorisation (CTA) the QP is providing certification, which has been known previously as the technical green light.

Release of IMPs for use in a clinical trial should not occur until after the QP has certified the batch(s). Under Article 9 of 2001/20/EC, the sponsor may not start a clinical trial until the clinical trial authorisation has been granted for the trial and all conditions of the authorisation have been met; and an Ethics Committee positive opinion has been granted and each trial site has been approved. The process for ensuring that the appropriate approvals are in place has been known previously as the regulatory green light.

In practice, although the QP certification and regulatory approval processes may be run in parallel, the sponsor is responsible for ensuring both steps are completed prior to the release of IMPs for use in a clinical trial. The QP certification must be provided by a QP named on the MIAIMP licence specified in the clinical trials authorisation as responsible for the manufacturing and importation of the IMP. The regulatory green light release may be delegated by the sponsor to the QP, regulatory affairs or trial manager. However the sponsor retains legal responsibility.

[MHRA Super Moderator]

5. What documentation needs to be maintained relating to IMP manufacture and shipment?

SI 2004/1031 (as amended) defines the principles of GCP (Schedule 1 Part 2.9) without defining what records to maintain. One of the objectives of GCP is to enable trial data to be accurately reconstructed and reported. IMP records must be maintained to demonstrate adherence to the trial protocol and credibility and integrity of the data. Such records may include but are not limited to the following:

• Original prescription
• randomisation code and code break
• drug accountability or dispensing records (including any marketed authorised products used as IMPs, comparator or adjuvant therapy) and destruction records
• production worksheet or batch sheet
• evidence that QP certification has been performed
• storage temperature records including calibration records of temperature monitors
• transit temperature records
• re-labelling records
• validation documents for electronic prescribing systems including validation document for prescribing module or protocol set-up within the electronic prescribing system.

The list is not exhaustive, but the concept is clear: Any factors that could affect the integrity of the data relating to the IMP should be recorded, monitored and maintained. The principle applies irrespective of the storage medium.

[MHRA Super Moderator]

6. Do records of accountability need to be maintained?

For those trials where the pharmacy provides the IMP on prescription from the investigator, there must be a full record of accountability maintained at the investigator site with summary evidence also held at the sponsor site. This means that all records of goods in, all records of goods dispensed and all records of goods returned or destroyed, including records for any marketed authorised products used as IMPs, comparators or adjuvant therapy must be kept. The records should be clear and it should be easy to rapidly determine the stock remaining at a site in case of an emergency such as an IMP recall.

For pragmatic trials, where IMP is provided on prescription from a local or community pharmacy, the sponsor should develop a system to document batch numbers dispensed to each patient wherever this is possible. This is required to ensure that subject receives the correct medication and compliance with the treatment regimen which ultimately can affect data integrity.

[MHRA Super Moderator]

7. Do staff preparing the product need to be trained in the protocol?

Yes, Part 2, 2 of SI 2004/1031 (as amended) requires that each individual involved in conducting a trial shall be qualified by education, training and experience to perform his tasks. Staff preparing product therefore need to be trained in the trial-specific requirements of the protocol applicable to the preparation of product, to ensure adherence to the trial protocol and preserve the credibility and integrity of the data.

[MHRA Super Moderator]

8. Do staff administering the product need to be trained in the protocol?

Yes, and there must be documented evidence of this training. It is important that the person administering the product has knowledge of the protocol which the subject receiving that product is participating in. There will be some aspects within protocols that are not particularly relevant for those administering the product but it is expected that the staff member administering the product has appropriate knowledge of the study.