Medicinal product importation into the United Kingdom

Investigational Medicinal Products (IMPs) are for administration to patients in clinical trials in accordance with Article 3(3) of the Pharmaceutical Code. It is noted that the MHRA guidance recognises IMPs as a category of unlicenced medicine, so there is some overlap in the legislative guidance provided on various MHRA websites.

The requirements and procedures for clinical trials in the UK are set out in the Medicines for Human Use (Clinical Trials) Regulations 2004. These regulations include requirements for the supply of IMPs. 

Detailed guidance on the import of IMPs are described in Eudralex Volume 4 and Volume 10 including guidance for the issuance of the Qualified Person Declaration for the importation of IMPs manufactured in third countries outside the European Economic Area (EEA). 

For UK clinical trials using IMPs imported into GB from countries on an ‘approved country for import’ list (initially, all EU and EEA countries), a UK Manufacturer Licence for Investigational Medicinal Products (MIA(IMP)) holder is required, requiring an appropriate assurance system and QP oversight, but without the need for recertification. The QP named on the UK MIA(IMP) that is responsible for this verification process may be resident in the UK or a listed country (N.B. Any manufacturing activity or importation from a non-listed country must be certified by a QP who resides in the UK).

From 1 January 2022 a UK MIA(IMP) holder will be required to verify that these IMPs have been certified by a Qualified Person (QP) in a listed country (the ‘oversight process’).

A Pharmaceutical Quality System (PQS) solely for the purposes of the oversight of import of IMPs from approved countries should be in place.

There is no requirement to re-certify batches already QP certified in a listed country, or for the QP named on the UK MIA(IMP) to maintain a register of certified batches. Records of all shipments to trial sites in GB using the oversight process should be visible within the PQS and be traceable. 

IMPs coming directly to GB from third countries that are not on the approved country for import list will continue to require import and QP certification in the UK by the MIA(IMP) holder as per the existing requirements i.e., the ‘oversight process’ will not apply. 

IMPs can be supplied in EU based on Article 83 of the EMA Regulation, known as the ‘compassionate use’ exemption, which was not implemented in the UK.

The UK has introduced a scheme allowing for the early access of medicines, EAMS, which is similar but not identical.

Compassionate use is a treatment option that allows the use of an unauthorised medicine. Under strict conditions, products in development can be made available to groups of patients who have a disease with no satisfactory authorised therapies and who cannot enter clinical trials (Article 83 Regulation (EC) 726/2004 as consolidated, the ‘EMA Regulation’). Strict conditions must be met and compassionate use programmes are coordinated and implemented by Member States, which set their own rules and procedures.

Early Access to Medicines Scheme (EAMS) in UK 

In the UK, the Early Access to Medicines Scheme (EAMS) was introduced in April 2014. 

The aim of the scheme was to bridge the long gap between positive clinical trials and marketing authorisation. 

EAMS is a voluntary and non-statutory scheme that runs in parallel with the existing UK and EU licensing procedures i.e., it does not replace the normal licensing procedures for medicines. 

Under the scheme, the MHRA provides a scientific opinion on the benefit/risk balance of the medicine, based on the data available when the EAMS submission is made. The opinion lasts for a year and can be renewed. 

EAMS is aimed at products that have completed Phase III trials but may be applied to those that have completed Phase II trials in exceptional circumstances. 

The scientific opinion will be provided after a 2-step evaluation process: 

1. the promising innovative medicine (PIM) designation 
2. the early access to medicines scientific opinion 

Since launch in April 2014 to July 2021, 104 PIM designations have been granted of a total of 138 applications. 

The medicine must be provided to the NHS free of charge during the EAMS period. This is the period between the award of an EAMS positive scientific opinion from MHRA and the grant of MA. On EAMS approval, physicians can request the medicine from the company. However with strict rules on promotion of unlicensed medicinal products continuing to apply, companies are not permitted to draw the attention of prescribers to products that have received such opinions. 

Currently, the uptake of this pathway is dominated by big pharma, who have the deepest pockets to supply the medicines free of charge until NICE recommendation is received.

Article 5(1) of the Pharmaceutical Code allows EU Member States to introduce national regimes that exempt certain medicinal products for individual patient use from the prior MA requirement. 

HMR 2012, Regulation 167 (SI 2012/1916) implements this Article of the Code in the UK and provides an exemption from an MA under the following conditions: 

• in response to an unsolicited order 
• manufactured and assembled in accordance with the specification of a person who is a doctor, dentist, nurse independent prescriber, pharmacist independent prescriber or supplementary prescriber registered in UK 
• for use by a patient for whose treatment that person is directly responsible to fulfil the special needs of that patient; and meets the conditions specified in regulation 167(2)-(8) 
• product is manufactured and supplied under specific conditions (see below) 

NOTE: This exemption does not apply to other unlicensed products or substances e.g.,: 

• unlicensed herbal or homeopathic products 
• intermediates for further processing 
• IMPs 
• repackaging licensed products 
• products for compassionate use (Article 83 of Regulation (EC) 726/2004) as discussed above
• temporarily authorised medicinal products (Article 5(2) of Directive 2001/83/EC) 

Unlicensed/unauthorised medicines can be imported/used in the UK for the ‘special needs’ of an individual doctor’s patient. This is known as ‘named patient’ supply. Medicines supplied on this basis are known as ‘specials’. The specials regime is further implemented by MHRA Guidance Note 14 ‘The supply of unlicensed medicinal products (“specials”)’. 

Unlicensed medicines can only be prescribed by physicians if they are satisfied that there are no suitable licensed alternatives. Pharmacists can then dispense such medicines, while nurses and midwives can administer them to patients

Importing a special product

This requires either a manufacturer ‘specials’ licence if you’re importing an unlicensed medicine (ULM) from a country, other than an approved country for import (EU and EEA), or if you are in Northern Ireland from outside the EEA (this is the same licence as required to manufacture and assemble specials), or a wholesaler licence if you’re importing a medicine from a country on an approved country for import list (EU and EEA).

Given the exit of the UK from the EU, the MHRA guidance has clarified the situation with regards importing or manufacturing in the UK an ULM, for export to the EU/EEA or between GB and NI, from 1st January 2021, with certain conditions to be met (please refer to the full insight paper).

Special clinical need – the ‘special needs’ test

An unlicensed medicinal product may only be supplied to meet the special needs of an individual patient. An unlicensed medicinal product should not be supplied where an equivalent licensed medicinal product can meet the special needs of the patient. The responsibility for deciding an individual patient’s “special needs” resides with the doctor, dentist, nurse, pharmacist responsible for the patient’s care. It relates to the special clinical therapeutic needs of the individual patient. It does not include reasons of cost, convenience, or operational needs. 

Examples of such ‘special needs’ include an intolerance or allergy to a particular ingredient of the product (active ingredient or excipient of the formulation), or an inability to ingest solid oral dosage forms.

In detailed MHRA guidance (Guidance Note 14), it states that the MHRA expects documentary evidence of this special need should be obtained by manufacturers, importers or distributors and that this evidence should be made available on request to the MHRA.

A UK licensed product that can meet the clinical need, even off-label should be used instead of an unlicensed product. 

There is guidance regarding the strict hierarchy for the use of ULMs in the UK:

Licensed (UK or EU) product > “off-label” use (UK or EU product) > imported ‘special’ licensed in COO > manufactured ‘special’ completely unlicensed > extemporaneously dispensed > imported and unlicensed in COO

Special need from product shortages

Also, where a licensed medicinal product becomes unavailable (for example, because of a manufacturing interruption), which means it is not obtainable from normal distribution channels in a ‘reasonable time’ (not defined), it may be necessary for an unlicensed equivalent to be supplied. This is to be seen as a temporary expedient and not justification for long term supply. Supply in these circumstances should cease as soon as practicable, following re-instatement of the licensed product. 

The MHRA expects documented evidence of the shortage (e.g. correspondence from the relevant MAH, notices in The Pharmaceutical Journal or confirmation from the MHRA or the Department of Health’s commercial medicines unit). 

Special needs may also arise where a licensed product is discontinued for commercial reasons alone and there are no concerns as to patient safety. 

GMP requirements

The manufacturer or assembler of specials must hold a MS Licence. The manufacturing/assembly site and its operations will be inspected for compliance with GMP and the conditions of the licence. However, a QP is not required to be named on a MS Licence for release of a finished unlicensed product. 

Additionally, as part of the notification of intent to import, evidence of GMP status of the exporting manufacturer will be required.

Regulatory requirements

The importer of a special into the UK must hold either/both a WDA(H) or an MS licence, depending on the country the product is being imported from. Certain obligations apply, set out in Schedule 4 of the HMR 2012, including the import must be in response to an unsolicited order, no more than the quantity notified should be imported, records must be kept, no advertising or other promotion is permitted etc.

Detailed guidance relating to the distribution, advertising, obligations on persons who sell or supply and exporting ULMs to other EU/EEA Member States is provided in MHRA Guidance Note 14 ‘The supply of unlicensed medicinal products (“specials”)’. 

A completed notification of intent form (MS Excel format) is required to be sent to MHRA at imports@mhra.gov.uk

The notification needs to be made 28 days before you intend to import it. From experience this timeline can be much shorter. The notification must provide specific information, as laid out in the MHRA form, noting the defining of the special clinical need. Additional supporting documentation includes evidence of GMP status of the exporting manufacturer, a letter of declaration from the ULM MAH and evidence of its registration in the exporting country.

Import can be made if MHRA does not object within 28 days of their acknowledgement letter. But in cases of a clinical emergency (usually for life-threatening illnesses or where imminent serious injury is likely) MHRA can waive the need for the 28-day notice period and usually process the notification within one working day. Commercial or other non-clinical reasons are not acceptable reasons for urgency.