Clinical trial authorisations: Additional information for applicants

From 1 November 2007, letters from the MHRA relating to clinical trial submissions will not be signed. The wording and format of letters from the MHRA relating to clinical trial submissions will also be modified from this date. This is in line with MHRA policy.

This section provides additional information applicants of clinical trial authorisations. It includes three sections: Application information; Assessment information; and Information on manufacturing authorisations and inspection.

1. Application information

What is the definition of a foodstuff and of a medicine?
A medicinal product is any substance or combination of substances which is presented as having properties for treating or preventing disease or which may be used in human beings with a view to restoring, correcting or modifying physiological functions (Directive 2001/83/EC, Art. 1 (2)).

Food supplements are defined as foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect (Directive 2002/46/EC, Art. 2a).

‘Dietary foods for special medical purposes' means a category of foods for particular nutritional uses specially processed or formulated and intended for the dietary management of patients and to be used under medical supervision. They are intended for the exclusive or partial feeding of patients with a limited, impaired or disturbed capacity to take, digest, absorb, metabolise or excrete ordinary foodstuffs or certain nutrients contained therein or metabolites, or with other medically-determined nutrient requirements, whose dietary management cannot be achieved only by modification of the normal diet, by other foods for particular nutritional uses, or by a combination of the two.(Directive 1999/21/EC, Art 1b)

Talc preparations for pleurodesis
The MHRA is of the opinion that talc preparations for pleurodesis are medicinal products. We therefore consider  that these are not medical devices and intend to treat these products as medicines with effect from 1 January 2008. Where trials are currently being conducted using talc preparations for pleurodesis, the sponsor needs to consider whether a clinical trial authorisation will be required from 1 January 2008.

Further information on talc preparations for pleurodesis is available below:
› MHRA statement on talc preparations for pleurodesis


What is the role of the sponsor’s legal representative?
If the main sponsor of a clinical trial with a medicinal product is not based in the European Economic Area (EEA), for example, an American or Japanese company, it is a statutory requirement to appoint a legal representative based in the EEA for the purposes of the trial.
The legal representative:

• may be an individual person or a representative of a corporate entity
• does not have to be a legally qualified person
• should be willing to act as the agent of the sponsor in the event of any legal proceedings instituted in the EEA (for example, for service of legal documents)
• should be established and contactable at an address in the EEA
• does not assume any of the legal liabilities of the sponsor(s) for the trial by virtue of the role of legal representative and does not therefore require insurance or indemnity to meet such liabilities, but may in some cases enter into specific contractual arrangements to undertake some or all of the statutory duties of the sponsor in relation to the trial, in which case the legal representative would also be regarded as a co-sponsor and would then require insurance or indemnity cover.

What are the labelling requirements for investigational medicinal products (IMPs)?
Information on the labelling requirements for investigational medicinal products to be used in a clinical trial can be found in Annex 13 of Volume 4 of The Rules Governing Medicinal Products in the EU: Good Manufacturing Practices. Regulation 46 of The Medicines for Human Use (Clinical Trial) Regulations 2004 allows for a particular situation where specific trial labelling is not required. This applies to trials of marketed products being used in certain situations.

A sample of the labelling is required as part of the clinical trial authorisation (CTA) application. This sample should include the text of the labelling to be used and be provided in a format representative in terms of size of the label to be used. Samples of the actual labels to be used may be provided but are not required. Where actual samples are not included, it will be assumed that the labelling is black type on a white background unless otherwise specified.

Where labelling is not included as part of the CTA application or where the labelling to be used does not contain all the items required by Annex 13, this should be justified.

Clinical trials for medical devices
Studies involving non-CE marked medical devices carried out in the UK may be regulated as clinical investigations under the Medical Devices Regulations 2002. For further information on clinical trials of medical devices,  please see our 'Clinical trials for medical devices' section:
› Clinical trials for medical devices

Common errors seen at validation
The most frequent causes of an application being considered invalid are:

1. Failure to supply an XML file of the completed clinical trial application form

Why we need the XML file
The XML file of the completed Clinical Trial Application Form information is required to enable us to enter the details of the trial into the EudraCT database, as we are obliged to do by the Clinical Trials Directive 2001/20/EC.

2. Failure to complete sections C1 of the Clinical Trial Application Form or section D1 of the Notification of Amendment Form

Why we need Sections C1 of the Clinical Trial Application Form or section D1 of the Notification of Amendment Form completed
Section C1 of the Clinical Trial Application Form and D1 of the Notification of Amendment form provide information on the person authorised by the sponsor to correspond with the MHRA on behalf of the sponsor. We need this information in order to be able to communicate with you.

3. Failure to supply a letter of authorisation from the sponsor

Why we need the letter of authorisation
If the sponsor is not making the application, a letter of authorisation for the person or organisation named as applicant (Section C1 of the Clinical Trial Application Form and D1 of the Notification of Amendment form) to act on behalf of the sponsor is required. The letter of authorisation from the sponsor is required in all cases where the person or organisation named as applicant is not the sponsor because of the statutory responsibilities of the sponsor in the legislation.

4. Failure to provide PDF documents for the protocol, investigator’s brochure, IMPD and SPC (where appropriate) that have undergone optical character recognition (OCR)

Why we need OCR PDF documents
PDF documents of the protocol, investigator’s brochure, IMPD and SPC (where appropriate) should be created directly from Word or undergo Adobe Acrobat optical character recognition (OCR) at the time of creation. PDF document scanned images should not be provided as it is not possible to cut-and-paste data in this format. The OCR layer also supports text searching within the document and across the entire MHRA document store.

For further information on OCR files and how to make them, please see Special Mail 5: Frequently Asked Questions (882Kb)

5. Password protection on disks

Why we do not want password protection of documents or disks
We ask that you do not password protect documents or disks as we may not have the software to access your data even if you supply the password.

We need this information in order to be able to process and assess your application.

2. Assessment information

Pharmaceutical guidance

Analytical validation
Sections 2.2.1.S.4.3 and 2.2.1.P.5.3 of the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials require that a tabulated summary of the results of the validation of analytical methods used in the control of the drug substance and drug product is included in the IMP dossier. There is no requirement for the inclusion of a full validation report. This should not be provided.

Batch analysis data
Sections 2.2.1.S.4.4 and 2.2.1.P.5.4 of the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials require the provision of representative batch analysis data.  Batch analysis data for each company listed in the IMP dossier as a proposed site of manufacture for drug substance and for drug product should be provided.  In this context, a company is regarded as a legal entity.

In the same way, a substantial amendment supported by batch analysis data will have to be submitted and approved prior to the inclusion of manufacturing sites which represent a new company (legal entity).  For biological/biotechnological products, batch analysis data will be required for each site of manufacture.

Retest period
Section 2.2.1.S.7 of the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials requires the provision of stability data summarised in a tabular format.  To ensure that the drug substance complies with its specification at the time of manufacture of the drug product, a retest period based on the available stability data should be included in the IMP dossier.  Extrapolation may be used in the setting of the retest period.  Where the drug substance continues to meet its approved specification and where the proposed retest period is matched by acceptable real time stability data, no substantial amendment will be required to extend the retest period.

These provisions also apply to setting the shelf life for a biological/ biotechnological drug substance.

Shelf life
Section 2.2.1.P.8 of the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials requires that a shelf life based on available stability data be set.  Extrapolation may be used.  Where an acceptable shelf life extension plan is included in the IMP dossier, no substantial amendment will be required to extend the shelf life of the drug product. 

For products coming within the scope of the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials, an acceptable shelf life extension plan should comprise the following elements:

• Specification against which the product is tested
• Criteria used to extrapolate data
• Analysis of trends 
• Proposed extension based on available real time data  and acceptable accelerated data – this should not exceed four times the available real time data to a maximum of 12 months or 12 months plus the available real time data ie

3 months real time data	12 months shelf life
6 months real time data	18 months shelf life
12 months real time data	24 months shelf life
24 months real time data	36 months shelf life

The same principles can be applied to biological/biotechnological products where an acceptable shelf life extension plan should comprise the following elements:

• Specification against which the product is tested
• Proposed extension based on available real time data
  

Labelling
The Commission Guidelines on “detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial” requires the submission of trial labelling as part of the application for a clinical trial authorisation.  Following the introduction of electronic submissions, the inclusion of labelling will be required for an application to be considered valid.  Where a sponsor wishes to claim an exemption from the need for trial specific labelling under the provisions of Regulation 46 of SI 2004 No 1031, a statement to this effect has to be included in the application.  This file should be named following the requirements for naming the file containing the labelling sample [4.12 Label]. 

Where labelling is revised after the clinical trial authorisation is approved, this may constitute a substantial amendment. However, there is no requirement for the prior submission and approval of a substantial amendment where the change is to alter the particulars of items in the approved labelling eg a new expiry date or a change in sponsor name or where the change is repositioning of the components of an approved label.

IMP dossier design
Where an IMP comprises multiple strengths of the product, only one IMP dossier is required. This should cover all strengths of the product. The provision of one dossier per product strength is not required.

Medical guidance
› Clarification of contraceptive wording in clinical trials (32Kb)
› Regulatory requirements for QT interval assessment (118Kb)

3. Information on Good Clinical Practice (GCP) Good Manufacturing and Distribution Practice (GMP and GDP) and Good Laboratory Practice (GLP)

Good Clinical Practice (GCP)
EU Directive 2001/20/EC, article 1, clause 2 states “Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects”. Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible and accurate.

For information on regulations, guidance and inspection relating to Good Clinical Practice, please see the following section:
› Good Clinical Practice

Good Manufacturing and Distribution Practice (GMP and GDP)
Good Manufacturing Practice (GMP) is that part of quality assurance which ensures that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation (MA) or product specification. GMP is concerned with both production and quality control. Good Distribution Practice (GDP) is that part of quality assurance which ensures that products are consistently stored, transported and handled under suitable condition as required by the marketing authorisation (MA) or product specification

For further information on regulations, guidance and inspection relating to GMP and GDP, please see the following section:
› Good Manufacturing and Distribution Practice

Good Laboratory Practice (GLP)
Directives 99/11/EEC and 99/12/EEC and the Good Laboratory Practice Regulations 1999/3106 as amended by SI 994, 2004 require that non-clinical safety studies be conducted according to the principles of Good Laboratory Practice.

For further information on regulations, guidance and inspection relating to Good Laboratory Practice, please see the following section:
› Good Laboratory Practice