MHRA produced FAQs for Investigational Medicinal Product (IMP)

[SIZE=4][B]1. Where can I find further information on this subject?[/B][/SIZE]

The following FAQs are presented below:
2. What is an investigational medicinal product (IMP)?
3. Who is permitted to manufacture an IMP?
4. What is meant by the terms Qualified Person (QP) release and Qualified Person certification?
5. What documentation needs to be maintained relating to IMP manufacture and shipment?
6. Do records of accountability need to be maintained?
7. Do staff preparing the product need to be trained in the protocol?
8. Do staff administering the product need to be trained in the protocol?
9. What records should be maintained if the product is a refrigerated product or requires frozen storage?
10. When does the Regulation 37 (Exemption for hospitals and health centres) apply?
11. When does Paragraph 26 (Annex 13 IMP Labelling Requirements) apply?
12. Is it necessary for a pharmacy to obtain QP certification documents when receiving clinical trial stock?
13. Where can I find guidance on the manufacturing requirements for non-investigational products (NIMPs)?
14. Do pharmacies always have to be involved in the receipt and storage of investigational medicinal product (IMPs)?
15. Is there any legislation which states how and where the code breaks for clinical trials should be stored?

Further frequently asked questions about IMPs can be found on the GMP area of the MHRA website: [URL="http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/FAQ/index.htm"]click here[/URL].

[SIZE=4][B]2. What is an investigational medicinal product (IMP)?[/B][/SIZE]

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:
[LIST][*]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. [/LIST]

[SIZE=4][B]3. Who is permitted to manufacture IMP?[/B][/SIZE]

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:
[URL="http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/ManufacturersandWholesaleDealerslicences/index.htm"]Manufacturer?s and wholesale dealer?s licences[/URL]

[SIZE=4][B]4. What is meant by the terms Qualified Person (QP) release and Qualified Person certification?[/B] [/SIZE]

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.

[SIZE=4][B]5. What documentation needs to be maintained relating to IMP manufacture and shipment? [/B][/SIZE]

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:
[LIST][*]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.[/LIST]
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.

[SIZE=4][B]6. Do records of accountability need to be maintained? [/B][/SIZE]

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.

[SIZE=4][B]7. Do staff preparing the product need to be trained in the protocol?[/B][/SIZE]

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.

[SIZE=4][B]8. Do staff administering the product need to be trained in the protocol? [/B][/SIZE]

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.

[SIZE=4][B]9. What records should be maintained if the product is a refrigerated product or requires frozen storage? [/B][/SIZE]

Records should be maintained to demonstrate that the product was stored within the required temperature range during transit and has continued to be stored within the required temperature range prior to use.

Records should be maintained of the checks made on the storage temperature including calibration records of temperature monitors used.

It is expected that there is traceability in the calibration records to National Standards (for example a ‘reference thermometer’ may be annually certified traceable to National Standards).

[SIZE=4][B]10. When does the Regulation 37 (Exemption for hospitals and health centres) apply?[/B][/SIZE]

Regulation 36 requires IMPs to be manufactured, assembled or imported in accordance with a manufacturing authorisation (MIAIMP).

Under the Regulation 37 exemption, hospitals and health centres are allowed to perform assembly activities for IMPs, without the need to hold a MIAIMP licence.

Assembly is defined as:
a. Enclosing the IMP in a container which is labelled, before the IMP is supplied or used in a clinical trial
b. where the IMP is already contained in the container in which it is to be supplied or used in a clinical trial, labelling the container, before it is supplied or used in a clinical trial, in that container.

However, exemption is only applicable for hospitals or health centres performing the assembly and by hospitals or health centres actively involved as a clinical site for that trial (this exemption does not apply to commercial Phase I units).

[SIZE=4][B]11. When does Paragraph 26 (Annex 13 IMP Labelling Requirements) apply?[/B][/SIZE]

All IMP for use within a clinical trial must be labelled in accordance with paragraph 26 of annex 13. This applies to not only the investigational product but also to any comparators and placebos used.

In some cases, however, abridged labelling is permitted. Paragraph 26 lists the information which should appear on labels, but does allow some flexibility if the absence can be justified. This is often referred to as abridged labelling and is agreed on a trial-specific basis. The cases where this form of labelling is permitted are as follows:
[LIST=1][*]For marketed product used within its marketing authorisation, the product can be labelled according to dispensed medicine requirements if this was approved as part of the CTA. However, sponsors may wish their products be labelled following the guidance in Paragraph 32 of Annex 13[*]if the IMP being used is a drug product in a vial which needs to be reconstituted aseptically for the purposes of administration, then the vial would need Annex 13 labelling.[/LIST]
For further information please see [URL="http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm"]Annex 13[/URL] (external link)

[SIZE=4][B]12. Is it necessary for a pharmacy to obtain QP certification documents when receiving clinical trial stock?[/B][/SIZE]

There is often confusion between IMP release and QP certification ? those managing IMP should be clear on the distinction between these two processes, as the answer differs.

QP certification is the process whereby the QP certifies that the prepared IMP is both manufactured to EU GMP standards and that the product has been assembled as requested and approved in the CTA.

Release is defined as approval to ship IMP to a site when all the required approvals (as defined in Article 9 of 2001/20/EC) are in place and release should only happen after QP certification has been achieved for that batch.

It is normally expected that the pharmacy has the documentation of QP certification for each batch of IMP.

If the NHS trust is sponsoring the trial, the responsibility for technical release may be contracted out to a contract manufacturing organisation as defined in a technical agreement. In such cases, the trust pharmacy only needs confirmation by the sponsor or sponsor?s representative that QP certification has taken place and the product is ready for use.

If the pharmacy is acting on behalf of a host organisation, they must have assurance from the sponsor that QP certification has been performed. Such assurance may be a copy of the QP certification document or a letter or email confirmation from the sponsor.

[SIZE=4][B]13. Where can I find guidance on the manufacturing requirements for non-investigational products (NIMPs)? [/B][/SIZE]

Non-investigational products (NIMPs) are products which are not the object of the investigation, but supplied to a subject in a trial and used as per protocol eg support or rescue/escape medication or preventative, diagnostic or therapeutic treatment to ensure adequate medical care for subjects.

Sponsors must ensure NIMPs are of suitable quality for human use. Guidance on NIMPs is included in Volume 10 Clinical Trials Notice to applicants. Supply of NIMPs with an MA in the Member State or other EU Member State is recommended. However, if they are not licensed in the UK they may be considered to be ?Specials? and appropriate approvals / licenses obtained.

Additional guidance relating to NIMPs is available as follows:
[URL="http://ec.europa.eu/health/documents/eudralex/vol-10/"]In Chapter III of Volume 10[/URL] (external link)
[URL="http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/IsaclinicaltrialauthorisationCTArequired/index.htm"]On the MHRA website[/URL]

[SIZE=4][B]14. Do pharmacies always have to be involved in the receipt and storage of investigational medicinal product (IMPs)?[/B][/SIZE]

There is no legal requirement for pharmacy involvement. However, lack of pharmacy involvement has often been associated with negative inspection findings in that often poor record keeping and accountability have been identified.

The Institute of Clinical Research and the Royal Pharmaceutical Society of Great Britain has produced guidance on this topic, which states that, ‘When a clinical trial is taking place in a hospital all IMPs should be stored and issued by the hospital pharmacy and managed to the same standards as licensed medicines. IMPs must not be stored in offices, clinics or ward areas unless by prior agreement with pharmacy’.

The guidance can be found [URL="http://www.icr-global.org/community/special-interest-groups/pharmacy-special-interest-group/pharmacy-publications/?locale=en"]here [/URL](external link)

[SIZE=4][B]15. Is there any legislation which states how and where the code breaks for clinical trials should be stored?[/B][/SIZE]

The guidance from the Pharmaceutical Society states that ’The pharmacy should, where possible, hold the code breaks’

The storage location of any code breaks is not specified in the legislation.

What is of concern is the security of the blinding (ie that the blind cannot be broken without it being detected or code breaks removed/accessed by unauthorised personnel), ensuring that the ability to unblind is in place prior to or at the same time that IMP is made available to the investigator and that there is the ability to promptly unblind for a particular subject in an emergency. ICH GCP requires (section 5.13.4, 8.2.17) a documented procedure to be in place to describe how this is to be done. If the investigator only holds the envelopes (or IVRS access codes), what would happen should the investigator be unavailable? Is there an alternative way of breaking the blind? The pharmacy may have a role to play in the process, for example, would the pharmacy be contacted if the investigator/sponsor was unavailable? And is there a documented procedure for this to enable locum staff to follow this procedure? It is the robustness of the process that is important, how it is achieved is the responsibility of the sponsor/organisation.