The Medicines for Human Use (Clinical Trials) Regulations 2004

Each individual involved in conducting a trial shall be qualified by education, training and experience to perform his tasks.

3

Clinical trials shall be scientifically sound and guided by ethical principles in all their aspects.

4

The necessary procedures to secure the quality of every aspect of the trial shall be complied with.

5

The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the proposed clinical trial.

6

Clinical trials shall be conducted in accordance with the principles of the Declaration of Helsinki.

7

The protocol shall provide for the definition of inclusion and exclusion of subjects participating in a clinical trial, monitoring and publication policy.

8

The investigator and sponsor shall consider all relevant guidance with respect to commencing and conducting a clinical trial.

9

All clinical information shall be recorded, handled and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of records of the trial subjects remains protected.

10

Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A trial should be initiated and continued only if the anticipated benefits justify the risks.

11

The medical care given to, and medical decisions made on behalf of, subjects shall always be the responsibility of an appropriately qualified doctor or, when appropriate, of a qualified dentist.

12

A trial shall be initiated only if an ethics committee and the licensing authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored.

13

The rights of each subject to physical and mental integrity, to privacy and to the protection of the data concerning him in accordance with the Data Protection Act 1998 are safeguarded.

14

Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor which may arise in relation to the clinical trial.

3A

Where the application relates to the inactivation of viral or non-conventional agents, a statement of the manufacturing process to which the authorisation is to relate.

2

In regulation 8(1) (interpretation)—

• (a) the definition “assemble” is substituted by the definition of that expression in regulation 2(1) of these Regulations; and

• (b) there is inserted in the appropriate position in alphabetical order a definition “container” in the same terms as the definition of that expression in regulation 2(1) of these Regulations; and

• (c) the definition “qualified person” is substituted by the definition of that expression in regulation 2(1) of these Regulations.

List of countries for the purpose of the definition of “marketing authorization”

2A

• (1) The licensing authority must publish a list of countries for the purpose of the definition of “marketing authorization”.

• (2) In order to determine whether a country should be included in the list referred to in paragraph (1), the licensing authority may, in particular, take into account the regulatory equivalence of that country to the United Kingdom in assessing the safety, quality and efficacy of medicinal products.

• (3) The licensing authority must—

• (a) review the countries it has included in the list referred to in paragraph (1) to determine if it is still satisfied that the country should remain on that list, and if it is not so satisfied, remove that country from the list; and

• (b) undertake such a review at least every three years beginning with the date on which that country is included in that list.

Sponsor of a clinical trial

Sponsor’s responsibility for the investigator’s brochure

Responsibility for functions under the Directive

Clinical trials conducted in countries other than the United Kingdom

Publication of information

27B

• (1) Subject to paragraph (3), the licensing authority may make accessible to the public information contained in the items listed in paragraph (2) insofar as it relates to a clinical trial carried out, or being carried out, under these Regulations.

• (2) The items listed in this paragraph are—

• (a) the request for authorisation made under regulation 17;

• (b) any amended request for authorisation made under regulation 18, 19 or 20;

• (c) any amendment to the protocol made under regulation 23, 24 or 25;

• (d) the favourable opinion of the ethics committee given in accordance with regulation 15 or the favourable opinion given by an appeal panel in accordance with paragraph 4 of Schedule 4;

• (e) the notification of the end of the clinical trial made under regulation 27.

• (3) Prior to making information available to the public under paragraph (1), the licensing authority must, after consulting such persons as the licensing authority considers appropriate, publish a list of the information which may be made accessible to the public under paragraph (1).

Clinical trials conducted in countries other than the United Kingdom

Approved country for import

43A

• (1) The licensing authority must publish a list of countries which it is satisfied have a regulatory framework applicable to investigational medicinal products exported to Great Britain that is equivalent to the regulatory framework in Great Britain, in that the respective control and enforcement activities in those countries ensure an equivalent level of protection of public health.

• (2) In order to determine whether a country should be included in the list referred to in paragraph (1), the licensing authority may, in particular, take into account—

• (a) the country's system for ensuring that each batch of an investigational medicinal product has been manufactured and checked in accordance with the requirements of its legislation and any authorisation in respect of the clinical trial in which the product is to be used;

• (b) the country's rules for good manufacturing practice;

• (c) the regularity of inspections to verify compliance with good manufacturing practice;

• (d) the effectiveness of enforcement of good manufacturing practice;

• (e) the regularity and rapidity of information provided by that country relating to non-compliant manufacturers of investigational medicinal products;

• (f) any on-site review of that country's regulatory system undertaken by the licensing authority;

• (g) any on-site inspection of a manufacturing site in that country observed by the licensing authority; and

• (h) any other relevant documentation available to the licensing authority.

• (3) The licensing authority must—

• (a) review the countries it has included in the list referred to in paragraph (1) to determine if it is still satisfied that the country should remain on that list, and if it is not so satisfied, remove that country from the list; and

• (b) undertake such a review at least every three years beginning with the date on which that country is included in that list.

Variation of manufacturing authorisation

Suspension and revocation of manufacturing authorisation

Functions in relation to good clinical practice

57

• (1) Regulations may, in respect of Great Britain—

• (a) amend the conditions and principles of good clinical practice to take account of technical and scientific progress;

• (b) specify requirements for documentation relating to a clinical trial which constitute the master file on the trial at the time the file is archived;

• (c) amend or revoke the requirements of regulation 31A relating to the content of the trial master file; and

• (d) require guidance published under regulation 58 to be taken into account when interpreting any enactment or other requirement to which the guidance relates.

• (2) Any power to make regulations under paragraph (1)—

• (a) is exercisable by the Secretary of State by statutory instrument;

• (b) includes power to make—

• (i) different provision for different purposes or different areas;

• (ii) consequential, supplementary, incidental, transitional, transitory or saving provisions, including consequential amendments to these Regulations.

• (3) Regulations under paragraph (1) are subject to annulment in pursuance of a resolution of either House of Parliament.

Detailed guidance

58

The licensing authority may publish guidance on—

• (a) the application format and documentation to be submitted in an application for an ethics committee opinion, in particular regarding the information that is given to subjects, and on the appropriate safeguards for the protection of personal data;

• (b) the format and contents of a request for authorisation of a clinical trial, as well as the documentation to be submitted to support that request, on the quality and manufacture of the investigational medicinal product, any toxicological and pharmacological tests, the protocol and clinical information on the investigational medicinal product including the investigator's brochure;

• (c) the presentation and content of any proposed substantial amendment to the clinical trial authorisation insofar as it relates to the protocol;

• (d) the declaration of the end of the clinical trial;

• (e) the collection, verification and presentation of adverse event or adverse reaction reports, together with decoding procedures for unexpected serious adverse reactions;

• (f) the content of essential documents forming part of the trial master file;

• (g) the elements to be taken into account when evaluating investigational medicinal products for the purpose of regulation 43(2).

SCHEDULE 13 — Transitional provisions relating to EU Exit

List of countries for the purpose of the definition of “marketing authorization” on IP completion day (regulation 2A)

1

• (1) For the purpose of regulation 2A, during the transitional period, the licensing authority must include each EEA State in the list referred to in paragraph (1) of that regulation.

• (2) Notwithstanding regulation 2A(3), the licensing authority must not, before the end of the transitional period, remove an EEA State from the list referred to in regulation 2A(1).

• (3) In this paragraph, “transitional period” is the period of two years beginning with IP completion day.

List of countries where a sponsor of a clinical trial, or their legal representative, may be established on IP completion day (regulation 3(11A))

2

• (1) For the purpose of regulation 3, the licensing authority must include each EEA State in the list referred to in paragraph (11A) of that regulation.

• (2) Notwithstanding regulation 3(11C), the licensing authority must not, before the end of the transitional period, remove an EEA State from the list referred to in regulation 3(11A).

• (3) In this paragraph, “transitional period” is the period of two years beginning with IP completion day.

Import of investigational medicinal products into Great Britain from EEA States during the transitional period

3

• (1) The condition in regulation 13(2)(b) and the restriction in regulation 36(1) do not apply to an investigational medicinal product that is imported into Great Britain from an EEA State before the end of the transitional period, provided that the production batch of investigational medicinal products of which the product is a part has been checked and certified by a qualified person pursuant to Article 13(3) and (4) of the Directive.

• (2) In this paragraph, “transitional period” is the period of one year beginning with IP completion day.

Approved country for import list on IP completion day (regulation 43A)

4

• (1) For the purpose of regulation 43A, during the transitional period, the licensing authority must include each EEA State in the list referred to in paragraph (1) of that regulation.

• (2) Notwithstanding regulation 43A(3), the licensing authority must not, before the end of the transitional period, remove an EEA State from the list referred to in regulation 43A(1).

• (3) In this paragraph, “transitional period” is the period of two years beginning with IP completion day.

14A

The holder of the authorisation shall only manufacture or assemble EAMS medicinal products if and to the extent that such products are required for the Early Access to Medicines Scheme.

9A

The holder of the authorisation shall only import EAMS medicinal products if and to the extent that such products are required for the Early Access to Medicines Scheme.

Manufacture of MM investigational medicinal products

36A

• (1) No person shall manufacture or assemble an MM investigational medicinal product unless—

• (a) the activity and product type is specified in a manufacturing authorisation (MM); and

• (b) there is an MM (IMP) master file relating to the product and the product is manufactured and assembled in accordance with that master file.

• (2) Paragraph (1) does not apply to the manufacture or assembly of an MM investigational medicinal product to the extent that the manufacture or assembly is in accordance with the terms and conditions of a UK marketing authorisation or a marketing authorisation issued by the competent authority of an EEA State in accordance with Directive 2001/83/EC relating to that product.

Manufacture of POC investigational medicinal products

36B

• (1) No person shall manufacture or assemble a POC investigational medicinal product unless—

• (a) the activity and product type is specified in a manufacturing authorisation (POC); and

• (b) there is a POC (IMP) master file relating to the product and the product is manufactured and assembled in accordance with that master file.

• (2) Paragraph (1) does not apply to the manufacture or assembly of a POC investigational medicinal product to the extent that the manufacture or assembly is in accordance with the terms and conditions of a UK marketing authorisation or a marketing authorisation issued by the competent authority of an EEA State in accordance with Directive 2001/83/EC relating to that product.

Exemption for hospitals and health centres

Application for manufacturing authorisation

Consideration of application for manufacturing authorisation

Grant or refusal of manufacturing authorisation

Application and effect of manufacturing authorisation

Obligations of manufacturing authorisation holder

Qualified persons

Approved country for import

Variation of manufacturing authorisation

Variation of MM (IMP) master file

44A

Subject to regulation 45(5), the holder of a manufacturing authorisation (MM) may amend the information in the MM (IMP) master file provided in accordance with paragraph 10(a), (c) and (h) to (k) of Schedule 6 and paragraph 14E(a) of Schedule 7 without applying to the licensing authority for a variation under regulation 44.

Variation of POC (IMP) master file

44B

Subject to regulation 45(6), the holder of a manufacturing authorisation (POC) may amend the information in the POC (IMP) master file provided in accordance with paragraph 11(a), (b) and (g) to (i) of Schedule 6 and paragraph 14M(a) of Schedule 7 without applying to the licensing authority for a variation under regulation 44.

Suspension and revocation of manufacturing authorisation

10

Where the application relates to an MM investigational medicinal product, the application for each product must be accompanied by a dossier which includes, as a minimum, the following:

• (a) a description and means of identification of each modular unit at which manufacture or assembly of the MM investigational medicinal product is to take place;

• (b) the location of each unit at which manufacturing or assembly of the MM investigational medicinal product is to take place;

• (c) the location of each site at which operations related to the manufacture or assembly of the MM investigational medicinal product are to take place;

• (d) a description of the process by which the proposed holder of the authorisation will approve new modular units;

• (e) a description of the processes by which the proposed holder of the authorisation will initiate, suspend and cease manufacturing or assembly of the product at a modular unit;

• (f) a description of the manufacturing, assembly and product release processes to take place at each modular unit;

• (g) a description of the arrangements for supervision and control by the proposed holder of the authorisation of the manufacture or assembly operations at each modular unit;

• (h) a description of the arrangements for reporting of suspected adverse reactions from modular units to the MM (IMP) control site;

• (i) the name and contact details of the person at the MM (IMP) control site who is to be contacted in respect of manufacturing or assembly operations under the authorisation;

• (j) the name and contact details of the person to be contacted in respect of manufacturing or assembly operations at each modular unit;

• (k) the name and contact details of the person at the MM (IMP) control site who is to be contacted in respect of quality operations under the authorisation;

• (l) the name and contact details of the person to be contacted in respect of quality operations at each modular unit; and

• (m) a description of the processes by which the proposed holder of the authorisation will review and amend the MM (IMP) master file for the product.

11

Where the application relates to a POC investigational medicinal product, the application for each product must be accompanied by a dossier which includes, as a minimum, the following:

• (a) the location of each site at which manufacturing or assembly of the POC investigational medicinal product is to take place;

• (b) the location of each site at which operations related to the manufacture or assembly of the POC investigational medicinal product are to take place;

• (c) a description of the process by which the proposed holder of the authorisation will approve new POC (IMP) sites;

• (d) a description of the processes by which the proposed holder of the authorisation will suspend and cease manufacturing or assembly of the POC investigational medicinal product at a POC (IMP) site;

• (e) a description of the manufacturing, assembly and product release processes to take place at each POC (IMP) site;

• (f) a description of the arrangements for supervision and control by the proposed holder of the authorisation of the manufacture or assembly operations at each POC (IMP) site;

• (g) a description of the arrangements for reporting of suspected adverse reactions from POC (IMP) sites to the POC (IMP) control site;

• (h) the name and contact details of the person at the POC (IMP) control site who is to be contacted in respect of manufacturing or assembly operations under the authorisation;

• (i) the name and contact details of the person to be contacted in respect of manufacturing or assembly operations at each POC (IMP) site;

• (j) the name and contact details of the person at the POC (IMP) control site who is to be contacted in respect of quality operations under the authorisation;

• (k) the name and contact details of the person to be contacted in respect of quality operations at each POC (IMP) site; and

• (l) a description of the processes by which the proposed holder of the authorisation will review and amend the POC (IMP) master file for the product.

2A

The holder of a manufacturing authorisation (MM) shall not use premises other than the MM (IMP) control site and the modular units specified in the MM (IMP) master file for the purposes specified in paragraph 2(a).

2B

The holder of a manufacturing authorisation (POC) shall not use premises other than the POC (IMP) control site and the sites specified in the POC (IMP) master file for the purposes specified in paragraph 2(a).

6A

The holder of the authorisation shall inform the licensing authority before making a material alteration to the premises or plant used at the MM (IMP) control site or to any modular unit specified in the MM (IMP) master file, or to the operations for which they are used.

6B

The holder of the authorisation shall inform the licensing authority before making a material alteration to the premises or plant used at the POC (IMP) control site, or to the operations for which they are used.

PART 2A — Manufacturing authorisation (MM)

14B

The provisions of paragraphs 14C to 14I are incorporated as additional standard provisions of a manufacturing authorisation (MM).

14C

The holder of the authorisation shall maintain and make available on request of the licensing authority an MM (IMP) master file for each MM investigational medicinal product to which the authorisation relates.

14D

Each master file may relate to one MM investigational medicinal product only.

14E

An MM (IMP) master file shall contain, as a minimum, the following information:

• (a) the information specified in paragraph 10 of Schedule 6; and

• (b) the location of any modular units at which manufacturing or assembly of the MM investigational medicinal product has commenced, has been suspended or has ceased, and the date on which manufacturing or assembly commenced, the dates on which it is suspended, or the date from which it has ceased.

14F

The holder of the authorisation shall ensure that the information in the MM (IMP) master file is kept up to date at all times.

14G

The holder of the authorisation shall submit to the licensing authority at annual intervals an update of any changes to the MM (IMP) master file made in the previous 12 month period, the first update being required to be submitted no later than the date that is 12 months from the date on which the manufacturing authorisation (MM) was granted.

14H

The holder of the authorisation shall conduct regular reviews of the arrangements for supervision and control of the manufacture or assembly operations at each modular unit and ensure that, where appropriate, remedial action is taken as soon as reasonably practicable.

14I

The holder of a manufacturing authorisation (MM) shall ensure that—

• (a) the requirements of paragraphs 1 to 14 and 14C to 14H are complied with in relation to manufacturing carried out at the modular units specified in the MM (IMP) master file;

• (b) only the MM investigational medicinal products specified in the MM (IMP) master file are manufactured or assembled at those modular units; and

• (c) an MM investigational medicinal product specified in the MM (IMP) master file is only manufactured on premises specified in the MM (IMP) master file.

PART 2B — Manufacturing authorisation (POC)

14J

The provisions of paragraphs 14K to 14Q are incorporated as additional standard provisions of a manufacturing authorisation (POC).

14K

The holder of the authorisation shall maintain and make available on request of the licensing authority a POC (IMP) master file for each POC investigational medicinal product to which the authorisation relates.

14L

Each master file may relate to one POC investigational medicinal product only.

14M

A POC (IMP) master file shall contain, as a minimum, the following information:

• (a) the information specified in paragraph 11 of Schedule 6; and

• (b) the location of any POC (IMP) sites at which manufacturing or assembly of the POC investigational medicinal product has commenced, has been suspended or has ceased, and the date on which manufacturing or assembly commenced, the dates on which it is suspended, or the date from which it has ceased.

14N

The holder of the authorisation shall ensure that the information in the POC (IMP) master file is kept up to date at all times.

14O

The holder of the authorisation shall submit to the licensing authority at annual intervals an update of any changes to the POC (IMP) master file made in the previous 12 month period, the first update being required to be submitted no later than the date that is 12 months from the date on which the manufacturing authorisation (POC) was granted.

14P

The holder of the authorisation shall conduct regular reviews of the arrangements for supervision and control of the manufacture or assembly operations at each POC (IMP) site and ensure that, where appropriate, remedial action is taken as soon as reasonably practicable.

14Q

The holder of a manufacturing authorisation (POC) shall ensure that—

• (a) the requirements of paragraphs 1 to 14 and 14K to 14P are complied with in relation to manufacturing carried out at the POC (IMP) sites specified in the POC (IMP) master file;

• (b) only the POC investigational medicinal products specified in the authorisation are manufactured or assembled at those sites; and

• (c) a POC investigational medicinal product specified in the authorisation is only manufactured at a POC (IMP) site specified in the POC (IMP) master file.