The Medicines for Human Use (Clinical Trials) Regulations 2004

the sponsor may, within 28 days, or such extended period as the licensing authority may in any particular case allow, of the notice being given, give notice in writing to the licensing authority of his wish to make written or oral representations to the appropriate committee ....

• (2) Schedule 5 shall have effect to regulate the procedure for reference to the appropriate committee ... following receipt of a notice in accordance with paragraph (1).

Conclusion of clinical trial

27

• (1) Subject to paragraph (2), within 90 days of the conclusion of a clinical trial the sponsor shall notify the licensing authority and the relevant ethics committee in writing that the trial has ended.

• (2) If a trial is terminated—

• (a) before the date for the conclusion of the trial specified in the protocol for that trial, or

• (b) before the event specified in the protocol as the event which indicates the end of the trial has occurred,

the sponsor shall notify the licensing authority and the relevant ethics committee in writing of the termination of the trial within 15 days of the date of termination.

• (3) A notification made in accordance with paragraphs (1) or (2) shall contain the particulars specified in Part 4 of Schedule 3.

PART 4 — GOOD CLINICAL PRACTICE AND THE CONDUCT OF CLINICAL TRIALS

Good clinical practice and protection of clinical trial subjects

28

• (1) No person shall—

• (a) conduct a clinical trial; or

• (b) perform the functions of the sponsor of a clinical trial (whether that person is the sponsor or is acting under arrangements made with that sponsor),

otherwise than in accordance with the conditions and principles of good clinical practice.

• (2) Subject to paragraph (5), the sponsor of a clinical trial shall put and keep in place arrangements for the purpose of ensuring that with regard to that trial the conditions and principles of good clinical practice are satisfied or adhered to.

• (3) Subject to paragraphs (4) and (5), the sponsor of a clinical trial shall ensure that—

• (a) the investigational medicinal products used in the trial, and

• (b) any devices used for the administration of such products,

are made available to the subjects of the trial free of charge.

• (4) The restriction in paragraph (3) shall not apply in relation to any charge payable by a subject under regulations made under—

• (a) the National Health Service Act 1977 ;

• (b) the National Health Service (Scotland) Act 1978 ; or

• (c) the Health and Personal Social Services (Northern Ireland) Order 1972 ,

in respect of any medicinal products or devices provided in pursuance of those Acts or that Order.

• (5) If—

• (a) a clinical trial is conducted at more than one trial site; and

• (b) the request for authorisation to conduct that trial specifies that in relation to one or more trial sites the duties of the sponsor under paragraphs (2) and (3) are to be performed by a person other than the sponsor,

those duties shall, in relation to that site or those sites, be performed by the person so specified.

Conduct of trial in accordance with clinical trial authorisation etc.

29

Subject to regulation 30, no person shall conduct a clinical trial otherwise than in accordance with—

• (a) the protocol relating to that trial, as may be amended from time to time in accordance with regulations 22 to 25;

• (b) the terms of—

• (i) the request for authorisation to conduct that trial,

• (ii) the application for an ethics committee opinion in relation to that trial, and

• (iii) any particulars or documents, other than the protocol, accompanying that request or that application,

as may be amended from time to time in accordance with regulations 22 to 25; and

• (c) any conditions imposed by the licensing authority under regulation 18(2) or (6), 19(8), 20(5), 24(5) or Schedule 5.

Urgent safety measures

30

• (1) The sponsor and investigator may take appropriate urgent safety measures in order to protect the subjects of a clinical trial against any immediate hazard to their health or safety.

• (2) If measures are taken pursuant to paragraph (1), the sponsor shall—

• (a) where paragraph (3) applies, as soon as possible; and

• (b) in any other case, immediately, and in any event no later than 3 days from the date the measures are taken,

give written notice to the licensing authority and the relevant ethics committee of the measures taken and the circumstances giving rise to those measures.

• (3) This paragraph applies for any period during which a disease—

• (a) is pandemic; and

• (b) is a serious risk to human health or potentially a serious risk to human health.

Suspension or termination of clinical trial

31

• (1) If, in relation to a clinical trial—

• (a) the licensing authority have objective grounds for considering that—

• (i) any condition, restriction or limitation which applies to the conduct of the trial and is set out in the request for authorisation or the particulars or documents accompanying that request, or

• (ii) any condition imposed by the licensing authority under regulation 18(2) or (6), 19(8), 20(5), 24(5) or Schedule 5,

is no longer satisfied (either generally or at a particular trial site); or

• (b) the licensing authority have information raising doubts about the safety or scientific validity of the trial, or the conduct of the trial at a particular trial site,

the licensing authority may, by a notice served in accordance with paragraph (2), require that the trial, or the conduct of the trial at a particular trial site, be suspended or terminated.

• (2) A notice in accordance with paragraph (1) shall be served—

• (a) in a case where the suspension or termination applies to the trial generally, on—

• (i) the sponsor, or

• (ii) the investigator at each trial site;

• (b) in a case where the suspension or termination applies to the conduct of a trial at a particular trial site, on—

• (i) the sponsor, or

• (ii) the investigator at that trial site.

• (3) The notice shall specify—

• (a) whether the notice applies to the trial generally or to one or more of the trial sites;

• (b) whether the notice requires suspension or termination of the trial;

• (c) if the notice requires suspension of the trial—

• (i) whether the suspension applies until further notice from the licensing authority or for such period as may be specified in the notice, and

• (ii) any conditions which are to be satisfied before the trial or, as the case may be, the conduct of the trial at a particular site, may be recommenced; and

• (d) whether suspension or termination is to take effect immediately on receipt of the notice or on such date as may be specified in the notice.

• (4) If the licensing authority issues a notice under paragraph (1), they shall forthwith inform—

• (a) where the notice has not been served on the sponsor, the sponsor;

• (b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

• (c) the relevant ethics committee;

• (d) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

• (e) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

• (5) Subject to paragraph (6), at least one week before issuing a notice under paragraph (1) the licensing authority shall, by a notice in writing to the sponsor or the investigator—

• (a) inform him that the authority is minded to issue a notice suspending or terminating the trial, or the conduct of a trial at a particular site, and of the reasons why they are so minded; and

• (b) advise him that they may, within one week of the date of the notice, furnish the authority with written representations as to whether the trial, or the conduct of the trial at a particular site, should be so suspended or terminated.

• (6) Paragraph (5) shall not apply where it appears to the licensing authority that there is an imminent risk to the health or safety of any of the subjects of the clinical trial.

• (7) A person on whom a notice has been served in accordance with paragraphs (1) and (2) may, within 28 days, or such extended period as the licensing authority may in any particular case allow, of the notice being given, give notice of his wish to make written or oral representations to the appropriate committee....

• (8) Schedule 5 shall have effect to regulate the procedure for reference to the appropriate committee ... following receipt of a notice in accordance with paragraph (7).

• (9) Where the notice of suspension or termination is referred to an appropriate committee ...it shall remain in force unless revoked in accordance with Schedule 5.

PART 5 — PHARMACOVIGILANCE

Notification of adverse events

32

• (1) An investigator shall report any serious adverse event which occurs in a subject at a trial site at which he is responsible for the conduct of a clinical trial immediately to the sponsor.

• (2) An immediate report under paragraph (1) may be made orally or in writing.

• (3) Following the immediate report of a serious adverse event, the investigator shall make a detailed written report on the event.

• (4) Paragraphs (1) to (3) do not apply to serious adverse events specified in the protocol or the investigator’s brochure as not requiring immediate reporting.

• (5) Adverse events, other than those to which paragraphs (1) to (3) apply, that are identified in the protocol as critical to evaluations of the safety of the trial shall be reported to the sponsor in accordance with the reporting requirements, including the time periods for such reporting, specified in that protocol.

• (6) The reports made under paragraphs (1), (3) and (5) shall identify each subject referred to in the report by a number assigned to that subject in accordance with the protocol for the trial.

• (7) The number assigned to a subject in accordance with the protocol must be different from the number of any other subject in that trial, including any subject at a trial site outside the United Kingdom.

• (8) Where the event reported under paragraph (1) or (5) consists of, or results in, the death of a subject, the investigator shall supply—

• (a) the sponsor; and

• (b) in any case where the death has been reported to the relevant ethics committee, that committee,

with any additional information requested by the sponsor or, as the case may be, the committee.

• (9) The sponsor shall keep detailed records of all adverse events relating to a clinical trial which are reported to him by the investigators for that trial.

• (10) The licensing authority may, by sending a notice in writing to the sponsor, require him to send the records referred to in paragraph (9), or copies of such records, to the authority.

Notification of suspected unexpected serious adverse reactions

33

• (1) A sponsor shall ensure that all relevant information about a suspected unexpected serious adverse reaction which occurs during the course of a clinical trial in the United Kingdom and is fatal or life-threatening is—

• (a) recorded; and

• (b) reported as soon as possible to—

• (i) the licensing authority,

• (ii) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

• (iii) the relevant ethics committee,

and in any event not later that 7 days after the sponsor was first aware of the reaction.

• (2) A sponsor shall ensure that within 8 days of a report in accordance with paragraph (1)(b), any additional relevant information is sent to the persons or bodies listed in that paragraph.

• (3) A sponsor shall ensure that a suspected unexpected serious adverse reaction which occurs during the course of a clinical trial in the United Kingdom, other than those referred to in paragraph (1), is reported as soon as possible to—

• (a) the licensing authority;

• (b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

• (c) the relevant ethics committee,

and in any event not later that 15 days after the sponsor is first aware of the reaction.

• (4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

• (5) A sponsor shall ensure that, in relation to each clinical trial in the United Kingdom for which he is the sponsor, the investigators responsible for the conduct of a trial are informed of any suspected unexpected serious adverse reaction which occurs in relation to an investigational medicinal product used in that trial, whether that reaction occurs during the course of that trial or another trial for which the sponsor is responsible.

• (6) The licensing authority shall—

• (a) keep a record of all suspected unexpected serious adverse reactions relating to an investigational medicinal product which are brought to its attention, whether pursuant to paragraphs (1) or (3) or otherwise; and

• (b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Clinical trials conducted in third countries

34

If a clinical trial is being conducted at a trial site in another country in addition to sites in the United Kingdom, the sponsor of that trial shall ensure that all suspected unexpected serious adverse reactions occurring at that site are reported as soon as possible to the licensing authority, and in any event—

• (a) in the case of a reaction that is fatal or life-threatening, within 7 days beginning with the day after the sponsor was first aware of the reaction; or

• (b) in any other case, within 15 days beginning with the day after the sponsor is first aware of the reaction.

Annual list of suspected serious adverse reactions and safety report

35

• (1) As soon as practicable after the end of the reporting year, a sponsor shall, in relation to each investigational medicinal product tested in clinical trials in the United Kingdom for which he is the sponsor furnish the licensing authority and the relevant ethics committees with—

• (a) a list of all the suspected serious adverse reactions which have occurred during that year in relation to—

• (i) those trials, whether at trial sites in the United Kingdom or elsewhere, or

• (ii) any other trials relating to that product which are conducted outside the United Kingdom and for which he is the sponsor,

including those reactions relating to any investigational medicinal product used as a placebo or as a reference in those trials; and

• (b) a report on the safety of the subjects of those trials.

• (2) In paragraph (1), “reporting year”, in relation to an investigational medicinal product, means the year ending on the anniversary of—

• (a) in the case of a product which has a marketing authorization, the earliest date on which any such authorization relating to that product was granted or issued; or

• (b) in any other case, the earliest date on which any clinical trial—

• (i) relating to that product, and

• (ii) for which the person responsible for making the report was the sponsor,

was authorised in an any country.

• (3) For the purposes of paragraph (2)(b), the date on which a clinical trial was authorised in a country is—

• (a) the date on which the trial was authorised by a regulatory body responsible for authorising clinical trials in that country; or

• (b) where the clinical trial was conducted in a country without a formal authorisation process, a date designated by the sponsor that is linked to the commencement of the first clinical trial.

PART 6 — MANUFACTURE AND IMPORTATION OF INVESTIGATIONAL MEDICINAL PRODUCTS

Requirement for authorisation to manufacture or import investigational medicinal products

36

• (1) Subject to paragraph (2) and regulation 37, no person shall manufacture, assemble or import any investigational medicinal product except in accordance with an authorisation of the appropriate type granted by the licensing authority for the purposes of this regulation (“a manufacturing authorisation”).

• (1A) For the purposes of paragraph (1), the appropriate type of authorisation is an authorisation that relates to whichever, or whichever combination, of the following that is appropriate—

• (a) manufacture or assembly of investigational medicinal products, except for MM investigational medicinal products and POC investigational medicinal products;

• (b) import of investigational medicinal products, except for MM investigational medicinal products and POC investigational medicinal products;

• (c) manufacture or assembly of MM investigational medicinal products;

• (d) manufacture or assembly of POC investigational medicinal products.

• (2) The restriction in paragraph (1) shall not apply to the manufacture or assembly of a medicinal product to the extent that such manufacture or assembly is in accordance with the terms and conditions of a marketing authorization or marketing authorisation issued by the competent authority of an EEA State in accordance with Directive 2001/83/EC relating to that product.

• (3) Regulation 36A sets out additional requirements in relation to the manufacture and assembly of MM investigational medicinal products.

• (4) Regulation 36B sets out additional requirements in relation to the manufacture and assembly of POC investigational medicinal products.

Exemption for hospitals and health centres

37

• (1) The restriction imposed by regulation 36(1) shall not apply to the assembly of an investigational medicinal product where the conditions specified in paragraph (2) are satisfied.

• (2) The conditions referred to in paragraph (1) are that—

• (a) the assembly is carried out in—

• (i) in a hospital or health centre, and

• (ii) by a doctor, a pharmacist or a person acting under the supervision of a pharmacist; and

• (b) the investigational medicinal products are assembled exclusively for use in—

• (i) that hospital or health centre, or

• (ii) any other hospital or health centre which is a trial site for the clinical trial in which the product is to be used.

Application for manufacturing authorisation

38

• (1) An application for the grant of a manufacturing authorisation shall be—

• (a) made to the licensing authority;

• (b) in writing; and

• (c) signed by or on behalf of the applicant.

• (2) Every application for the grant of a manufacturing authorisation shall specify which, if any, of the standard provisions referred to in regulation 40(4) it is desired shall be excluded or modified in relation to the grant of the authorisation.

• (3) Subject to paragraph (3A), every application for the grant of a manufacturing authorisation shall be accompanied by—

• (a) the particulars specified in Schedule 6 to these regulations; and

• (b) any fee which may be payable in connection with that application under the Medicines (Products for Human Use) (Fees) Regulations 2016.

• (3A) No fee need accompany an application for the grant of a manufacturing authorisation where arrangements have been made with the licensing authority for the payment of the fee referred to in paragraph (3)(b) other than at the time of the application.

• (4) The application and any accompanying material shall be supplied to the licensing authority in the English language.

Consideration of application for manufacturing authorisation

39

• (1) Subject to paragraph (3) and regulation 40, the licensing authority shall consider a valid application for a manufacturing authorisation and grant, or refuse to grant, an authorisation within a period not exceeding 90 days from the date the application is received.

• (2) Following receipt of an application, the licensing authority may give a notice in writing to the applicant requesting him to provide further information relating to—

• (a) the particulars referred to in regulation 38(3); or

• (b) the qualified person referred to in regulation 43.

• (3) Where the licensing authority give a notice pursuant to paragraph (2), the period specified in paragraph (1) shall be suspended from the date the notice is given and shall recommence only on receipt of the information requested.

• (4) If the application for a manufacturing authorisation relates (wholly or partially) to the importation of investigational medicinal products, the licensing authority may, if they think fit, require the production by the applicant of an undertaking, given by the manufacturer of any such products, to permit—

• (a) the premises where they are or are to be manufactured; and

• (b) the operations carried on or to be carried on in the course of manufacturing them,

to be inspected by or on behalf of the licensing authority.

• (4A) If the application for a manufacturing authorisation relates (wholly or partially) to an MM investigational medicinal product, the licensing authority shall take into consideration the arrangements for—

• (a) supervising and controlling operations at a modular unit specified in the application; and

• (b) ensuring that manufacture or assembly is under appropriate control so that the MM investigational medicinal product consistently meets the requirements in the MM (IMP) master file when manufactured at that modular unit.

• (4B) If the application for a manufacturing authorisation relates (wholly or partially) to a POC investigational medicinal product, the licensing authority shall take into consideration the arrangements for—

• (a) supervising and controlling operations at any POC (IMP) site specified in the application; and

• (b) ensuring that manufacture or assembly is under appropriate control so that the POC investigational medicinal product consistently meets the requirements in the POC (IMP) master file when manufactured at that site.

• (5) In this regulation, “valid application” means an application which complies with the provisions of regulation 38.

Grant or refusal of manufacturing authorisation

40

• (1) The licensing authority shall grant a manufacturing authorisation only if—

• (a) the applicant—

• (i) has complied with the requirements of regulation 38,

• (ii) has at his disposal—

• (aa) the services of staff, and

• (bb) suitable and sufficient premises, technical equipment and control facilities,

complying with the requirements of Commission Directive 2003/94/EC, as regards the manufacture or import, and control, of the products to which the authorisation relates and the storage of such products,

• (iii) has at his disposal the services of at least one qualified person, and

• (iv) if a notice has been given under regulation 39(2), has provided the information requested by the licensing authority; and

• (b) they have established that the particulars supplied pursuant to regulation 38(3) are accurate.

• (2) Subject to paragraph (1), the licensing authority may grant a manufacturing authorisation in respect of any or all of—

• (a) the descriptions of investigational medicinal products;

• (b) the manufacturing, assembling or importation operations; or

• (c) the premises,

specified in the application made pursuant to regulation 38.

• (3) The licensing authority may grant a manufacturing authorisation containing—

• (a) any provisions to be incorporated in the authorisation in accordance with paragraph (4); or

• (b) such other provisions as the licensing authority consider appropriate.

• (4) The provisions specified—

• (a) in the case of a manufacturing authorisation relating to the manufacture or assembly of investigational medicinal products, in Part 2 of Schedule 7; and

• (b) in the case of a manufacturing authorisation relating to the importation of investigational medicinal products, in Part 3 of Schedule 7,

may be incorporated by the licensing authority in any manufacturing authorisation, with or without modifications and either generally or in relation to investigational medicinal products of any particular class.

• (5) The provisions of Schedule 8 shall have effect where the licensing authority propose—

• (a) to refuse to grant a manufacturing authorisation; or

• (b) to grant a manufacturing authorisation otherwise than in accordance with the application.

• (6) Where the licensing authority—

• (a) refuse to grant a manufacturing authorisation; or

• (b) grant a manufacturing authorisation otherwise than in accordance with the application,

and the applicant requests the authority to state their reasons, the licensing authority shall give the applicant a notice in writing stating the reasons for their decision.

Application and effect of manufacturing authorisation

41

A manufacturing authorisation shall apply only in relation to—

• (a) the descriptions of investigational medicinal products;

• (b) the manufacturing, assembling or importation operations; ...

• (bb) in the case of an authorisation relating to the inactivation of viral or non-conventional agents, the manufacturing process; and

• (c) except in the case of an MM investigational medicinal product or a POC investigational medicinal product, the premises,

specified in the application made pursuant to regulation 38 and in respect of which the authorisation is granted.

Obligations of manufacturing authorisation holder

42

The holder of a manufacturing authorisation shall—

• (a) comply with the principles and guidelines of good manufacturing practice;

• (b) comply with the provisions referred to in regulation 40(3);

• (c) allow the licensing authority access to his premises at any reasonable time; and

• (d) put and keep in place arrangements which enable the qualified person to carry out his duties, including placing at his disposal all the necessary facilities.

Qualified persons

43

• (1) Subject to paragraphs (4) and (5), the holder of a manufacturing authorisation must have at his disposal the services of at least one qualified person—

• (a) where the manufacturing authorisation relates wholly to the import of an investigational medicinal product into Great Britain from an approved country for import, who must operate and be ordinarily resident in either the United Kingdom or an approved country for import, or

• (b) in any other case, who must operate and be ordinarily resident in the United Kingdom, except, in relation to a EAMS medicinal product, to the extent that conditions attached to the scientific opinion in respect of that product in accordance with regulation 167C(2)(c) of the 2012 Regulations provide otherwise, and

who is responsible for carrying out the duties referred to in paragraph (1A) or 2.

• (1A) The qualified person is responsible for ensuring that, in relation to an EAMS medicinal product, if conditions attached to the scientific opinion in respect of that product in accordance with regulation 167C(2)(c) of the 2012 Regulations require the qualified person to carry out any duties in respect of that product, that qualified person carries out those duties.

• (2) Subject to paragraphs (2A) and (2C), the qualified person is responsible for ensuring that—

• (a) in the case of an investigational medicinal product manufactured in Northern Ireland, each production batch has been manufactured and checked in compliance with—

• (i) the requirements of these Regulations;

• (ii) the principles and guidelines of good manufacturing practice;

• (iii) the product specification, as defined in Part 1 of Schedule 7; and

• (iv) the request, particulars and documents submitted to the licensing authority under regulation 17 in respect of the clinical trial in which the product is to be used;

• (b) in the case of an investigational medicinal product manufactured in Great Britain, each production batch has been manufactured and checked in compliance with—

• (i) the requirements of these Regulations;

• (ii) the principles and guidelines of good manufacturing practice, as modified by Schedule 2A to the 2012 Regulations or any regulations made under the power in regulation B17(1) of those Regulations;

• (iii) the product specification, as defined in Part 1 of Schedule 7; and

• (iv) the request, particulars and documents submitted to the licensing authority under regulation 17 in respect of the clinical trial in which the product is to be used;

• (c) in the case of an investigational medicinal product imported into Northern Ireland from a country other than an EEA State, each production batch has been manufactured and checked in compliance with—

• (i) standards of good manufacturing practice at least equivalent to the principles and guidelines of good manufacturing practice;

• (ii) the product specification, as defined in Part 1 of Schedule 7; and

• (iii) the request, particulars and documents submitted to the licensing authority under regulation 17 in respect of the clinical trial in which the product is to be used;

• (d) in the case of an investigational medicinal product imported into Great Britain other than from Northern Ireland, each production batch has been manufactured and checked in compliance with—

• (i) standards of good manufacturing practice at least equivalent to the principles and guidelines of good manufacturing practice, as modified by Schedule 2A to the 2012 Regulations or any regulations made under the power in regulation B17(1) of those Regulations;

• (ii) the product specification, as defined in Part 1 of Schedule 7; and

• (iii) the request, particulars and documents submitted to the licensing authority under regulation 17 in respect of the clinical trial in which the product is to be used.

• (2A) The qualified person is not responsible for carrying out the controls in paragraph (2) where—

• (a) the product is imported into Great Britain from a country that is included on the list referred to in regulation 43A (“approved country for import”); and

• (b) the qualified person ensures that there is appropriate evidence to confirm that each production batch has been certified as provided for in Article 13 of the Directive, or such equivalent certification procedure as applies in the approved country for import.

• (2B) The licensing authority must publish guidance on the evidence that it considers to be appropriate for the purposes of paragraph (2A)(b).

• (2C) The qualified person is not responsible for carrying out the controls in paragraph (2) where—

• (a) an investigational medicinal product—

• (i) which has a marketing authorization other than a UKMA(GB), is imported into Northern Ireland as a comparator product; or

• (ii) which has a marketing authorization, or has been approved for marketing in another country, is imported into Great Britain as a comparator product; and

• (b) documentation cannot be obtained certifying that each production batch has been manufactured and checked in accordance with standards of good manufacturing practice at least equivalent to those laid down in Commission Directive 2003/94/EC.

• (2D) Where paragraph (2) does not apply by virtue of paragraph (2C), the qualified person is responsible for ensuring that each production batch has undergone all relevant analyses, tests or checks necessary to confirm its quality in accordance with the request, particulars and documents submitted to the licensing authority under regulation 17.

• (2E) The qualified person is responsible for ensuring, in relation to an investigational medicinal product, that documentary evidence is produced that each batch of the product satisfies the provisions of paragraph (2), (2A) or (2D) (as the case may be).

• (2F) The documentary evidence referred to in paragraph (2E) must be—

• (a) kept up to date as operations are carried out; and

• (b) available for inspection by the licensing authority for a period of at least five years beginning with the date on which the documentary evidence is produced.

• (3) A qualified person shall perform his functions under these Regulations in accordance with the Code of Practice for Qualified Persons in the Pharmaceutical Industry, published jointly by the Institute of Biology, the Royal Pharmaceutical Society of Great Britain and the Royal Society of Chemistry in March 2004 .

• (4) If the holder of the authorisation satisfies the requirements as to qualifications and experience specified in paragraph (a) or (b) of the definition of “qualified person” in regulation 2(1), he may act as the qualified person in accordance with paragraph (1A) or (2) for the purposes of that authorisation.

• (5) For the purposes of this paragraph, but without prejudice to paragraph (6) below, the holder of the authorisation may regard a person as satisfying the provisions of the said Article 49 or 50, as respects formal qualifications if—

• (a) in relation to the obligation in paragraph (1)(a), he is already named as a qualified person in respect of an authorisation issued in an approved country for import; or

• (b) he produces evidence that—

• (i) he is a member of—

• (aa) the Institute of Biology,

• (bb) the Pharmaceutical Society,

• (cc) the Royal Society of Chemistry, or

• (dd) such other body as may appear to the licensing authority to be an appropriate body for the purpose of this paragraph; and

• (ii) he is regarded by the body of which he is a member as so satisfying those provisions.

• (6) Where, after giving the holder of the authorisation and the person acting as a qualified person the opportunity of making representations to them (orally or in writing), the licensing authority are of the opinion that—

• (a) the person so acting does not satisfy—

• (i) the provisions of the said Articles 49 and 50 of Directive 2001/83/EC as respects qualifications and experience, or

• (ii) the requirements as to qualifications and experience specified in paragraph (b) of the definition of “qualified person” in regulation 2(1); or

• (b) he is failing to carry out the duties referred to in paragraph (2) adequately or at all,

and have notified the holder of the authorisation accordingly in writing, the holder of the authorisation shall not permit that person to act as a qualified person.

Variation of manufacturing authorisation

44

• (1) The licensing authority may vary a manufacturing authorisation, whether on the application of the holder of the authorisation or otherwise.

• (2) Subject to the following provisions of this regulation, if the holder of a manufacturing authorisation makes a valid application to vary the manufacturing authorisation the licensing authority shall consider the application and—

• (a) in a case where the effect of the variation would be to change—

• (i) the types of investigational medicinal products,

• (ii) the manufacturing, assembling or importation operations,

• (iia) the manufacturing process,

• (iii) the premises,

• (iv) the technical equipment and control facilities, or

• (v) the staff, including the qualified person,

in respect of which the authorisation has been granted, may vary or refuse to vary the authorisation within a period not exceeding 30 days from the date the application is received;

• (b) in any other case, may vary or refuse to vary the authorisation within such period as the licensing authority consider appropriate.

• (3) If the application falls within paragraph (2)(a), but it appears to the licensing authority to be necessary to conduct an inspection of any premises to which the variation relates, the authority may vary or refuse to vary the authorisation within a period not exceeding 90 days from the date the application is received.

• (4) Following receipt of a valid application to vary a manufacturing authorisation, the licensing authority may give a notice in writing to the applicant requesting him to provide further information relating to the contents of the application or any particulars relevant to the application.

• (5) Where the licensing authority give a notice pursuant to paragraph (4), and a period specified in paragraph (2)(a) or paragraph (3) applies, that period shall be suspended from the date the notice is given and shall recommence only on receipt of the information requested.

• (6) The provisions of Schedule 8 shall have effect where the licensing authority propose to vary a manufacturing authorisation otherwise than on the application of the holder of the authorisation.

• (7) Where the licensing authority—

• (a) vary a manufacturing authorisation, otherwise than in accordance with a valid application by the holder of the authorisation; or

• (b) after consideration of such an application, refuse to vary a manufacturing authorisation,

the licensing authority shall notify the holder of that authorisation in writing, stating the reasons for their decision.

• (8) In this regulation—

• “any relevant fee” means, in relation to an application to vary a manufacturing authorisation, any fee which may be payable in connection with that application under the Medicines (Products for Human Use) (Fees) Regulations 2016; and

• “valid application” means an application—made to the licensing authority,in writing and signed by or on behalf of the applicants,specifying the variation requested by the applicant,accompanied by—such particulars as are necessary to enable the licensing authority to consider the application, andunless arrangements have been made with the licensing authority for the payment of any relevant fee other than at the time of the application, any such fee, andwhere the application, and any accompanying material, is in the English language.

• (9) In the case of an application of a type specified in paragraph (11), the information to be provided under sub-paragraph (d) in the definition of “valid application” in paragraph (8) shall include the information specified in paragraph 10 of Schedule 6.

• (10) In the case of an application of a type specified in paragraph (12), the information to be provided under sub-paragraph (d) in the definition of “valid application” in paragraph (8) shall include the information specified in paragraph 11 of Schedule 6.

• (11) The following types of application are specified for the purpose of paragraph (9)—

• (a) an application to vary the licence so that it relates to the manufacture or assembly of MM investigational medicinal products;

• (b) an application to vary a manufacturing authorisation (MM) to add a new MM investigational medicinal product.

• (12) The following types of application are specified for the purpose of paragraph (10)—

• (a) an application to vary the licence so that it relates to the manufacture or assembly of POC investigational medicinal products;

• (b) an application to vary a manufacturing authorisation (POC) to add a new POC investigational medicinal product.

• (13) In dealing with an application of a type specified in paragraph (11), the licensing authority shall take into consideration the arrangements made or to be made for—

• (a) supervising and controlling operations at a modular unit; and

• (b) ensuring that manufacturing or assembly is under appropriate control so that the MM investigational medicinal product consistently satisfies the requirements in the MM (IMP) master file when manufactured at a modular unit.

• (14) In dealing with an application of a type specified in paragraph (12), the licensing authority shall take into consideration the arrangements made or to be made for—

• (a) supervision and controlling operations at a POC (IMP) site specified in the application; and

• (b) ensuring that manufacturing or assembly is under appropriate control so that the POC investigational medicinal product consistently satisfies the requirements in the POC (IMP) master file when manufactured at that POC (IMP) site.

Suspension and revocation of manufacturing authorisation

45

• (1) The licensing authority may by a notice in writing to the holder of a manufacturing authorisation, forthwith or from a date specified in the notice, suspend the authorisation for such period as the authority may determine, or revoke the authorisation, on one or more of the following grounds—

• (a) the holder is not carrying out, or has indicated by a notice in writing that he is no longer to carry out, the manufacturing, assembly or importation operations to which the authorisation relates;

• (b) the particulars accompanying the application in accordance with regulation 38(3), were false or incomplete in a material particular;

• (c) a material change of circumstances has occurred in relation to any of those matters or particulars;

• (d) the holder of the authorisation has failed to any material extent to comply with his obligations under regulation 42 or 43(1);

• (e) the holder has manufactured, assembled or, as the case may be, imported investigational medicinal products otherwise than in accordance with the terms of the authorisation;

• (f) the holder has manufactured or assembled investigational medicinal products otherwise than in accordance with—

• (i) in the case of products manufactured before a request for authorisation to conduct the clinical trial involving those products has been made in accordance with regulation 17 or, in the case of an investigational medicinal product manufactured or assembled in Northern Ireland, any equivalent provisions in any EEA State, the specification for the product provided by the person who is to act as the sponsor of the proposed clinical trial,

• (ii) in the case of products manufactured for the purpose of export, the specification for the product provided by the person to whose order the products are manufactured, or

• (iii) in any other case, the specification for the product contained in the investigational medicinal product dossier for that product;

• (g) the qualified person has failed to carry out the duties referred to in regulation 43(2), adequately or at all; and

• (h) the holder of the authorisation does not have the staff, premises, equipment or facilities necessary for carrying out properly—

• (i) the manufacture or assembly operations to which the authorisation relates, or

• (ii) the importation operations to which the authorisation relates,

including any handling, storage or distribution activities relating to those operations.

• (2) The suspension or revocation of an authorisation under this regulation may be—

• (a) total; ...

• (b) limited to investigational medicinal products—

• (i) of one or more descriptions, or

• (ii) manufactured, assembled or stored on any particular premises or in a particular part of any premises;

• (c) in the case of a manufacturing authorisation (MM), limited to modular units specified in an MM (IMP) master file associated with the authorisation; or

• (d) in the case of a manufacturing authorisation (POC), limited to POC (IMP) sites specified in a POC (IMP) master file associated with the authorisation.

• (3) The provisions of Schedule 8 shall have effect where the licensing authority propose to suspend or revoke a manufacturing authorisation in accordance with this regulation.

• (4) Where the licensing authority suspend or revoke a manufacturing authorisation in accordance with this regulation, they shall notify the holder of that authorisation in writing, stating the reasons for their decision to suspend or revoke the authorisation.

• (5) If the licensing authority suspends or revokes a manufacturing authorisation (MM) in accordance with paragraph (2)(c) so that manufacturing or assembly is suspended, or no longer authorised, at a modular unit, the holder of the authorisation may not approve that unit for the purpose of manufacturing or assembly of the MM investigational medicinal product other than by way of an application under regulation 44.

• (6) If the licensing authority suspends or revokes a manufacturing authorisation (POC) in accordance with paragraph (2)(d) so that manufacturing or assembly is suspended, or no longer authorised, at a POC (IMP) site, the holder of the authorisation may not approve that site for the purpose of manufacturing or assembly of the POC investigational medicinal product other than by way of an application under regulation 44.

PART 7 — LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS

Labelling

46

• (1) An investigational medicinal product shall be labelled in accordance with Article 15 of Commission Directive 2003/94/EC .

• (2) Paragraph (1) shall not apply where the investigational medicinal product is—

• (a) for use in a clinical trial with the characteristics specified in the second paragraph of Article 14 of the Directive;

• (b) dispensed to a subject in accordance with a prescription given by a health care professional; and

• (c) labelled in accordance with the requirements of Part 13 of the 2012 Regulations that apply in relation to medicinal products sold or supplied in accordance with a prescription given by a person who is an appropriate practitioner within the meaning of regulation 214(3) to (6) of those Regulations.

• (3) Paragraph (1) does not apply to a POC investigational medicinal product that is to be administered in its entirety immediately after manufacture.

PART 8 — ENFORCEMENT AND RELATED PROVISIONS

Application of enforcement provisions of the 2012 Regulations

47

• (1) Regulations 2, 8(1), 322, 323(1), 324(1), 325 to 330, 332 to 339, 343 and Schedule 31 of the 2012 Regulations (“those provisions”) shall apply for the purposes of these Regulations as they apply for the purposes of the 2012 Regulations, but with the modifications specified in Schedule 9, and any reference in those provisions to the 2012 Regulations includes a reference to these Regulations.

• (2) In those provisions as applying by virtue of paragraph (1), a reference to any part of those provisions or a part of any of them is a reference to the provision or part as so applying.

• (3) In those provisions as applying by virtue of paragraph (1), any reference to, or relating to, a requirement, a power, a function, a right, a duty, an entitlement, or a protection shall be read as a reference to, or relating to, that requirement, power, function, right, duty, entitlement, or protection as applied by this regulation.

Infringement notices

48

• (1) If an enforcement authority have objective grounds for considering that any person has contravened any provision to which this regulation applies, they may serve upon that person a notice in writing (in these Regulations referred to as an “infringement notice”)—

• (a) informing him of the authority’s grounds for considering that the person has contravened one or more of those provisions;

• (b) specifying the relevant provision of these Regulations;

• (c) specifying the measures which the person must take in order to ensure that the contravention does not continue or, as the case may be, does not recur;

• (d) requiring the person to take those measures, within such period as may be specified in the notice;

• (e) warning the person that unless the requirements of sub-paragraph (d) are met, further action may be taken in respect of the contravention.

• (2) An infringement notice may include directions as to the measures to be taken by the person on whom the notice is served to ensure that the contravention does not continue or, as the case may be, does not recur, including the different ways of securing compliance.

• (3) If an enforcement authority serves an infringement notice in accordance with paragraph (1), they shall forthwith inform—

• (a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

• (b) the relevant ethics committee; and

• (c) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

• (4) This regulation applies to regulations 3A, 12(1), 22(b), 27, 28(1) to (3), 29, 29A, 30(2), 31A, 32 to 35, 36A and 36B.

• (5) In this regulation, “enforcement authority” means any Minister or body on whom a duty or power to enforce any provisions of these Regulations is imposed or conferred by or under regulation 323(1) or 324(1) of the 2012 Regulations as applied by regulation 47.

Offences

49

• (1) Any person who contravenes any of the following provisions—

• (a) regulation 3A;

• (aa) regulation 12(1) and (2);

• (b) regulation 13(1);

• (c) regulation 27;

• (d) regulation 28(1) to (3);

• (e) regulation 29;

• (ee) regulation 29A;

• (f) regulation 30(2);

• (ff) regulation 31A(1) to (3) and (5) to (10);

• (g) regulation 32(1), (3), and (5) to (9)

• (h) regulation 33(1) to (5)

• (i) regulation 34

• (j) regulation 35(1);

• (k) regulation 36(1);

• (ka) regulation 36A;

• (kb) regulation 36B;

• (l) regulation 42; and

• (m) regulation 43(1) and (6),

shall be guilty of an offence.

• (2) Any person who has in his possession a medicinal product for the purpose of selling or supplying it in contravention of regulation 13(1) shall be guilty of an offence.

• (3) Any person who fails to comply with a notice of suspension or termination served on him under regulation 31, unless that notice has been withdrawn or revoked by the licensing authority, shall be guilty of an offence.

• (4) Where an investigational medicinal product is manufactured, assembled or imported in contravention of regulation 36(1), any person who sells or supplies the product for the purposes of a clinical trial knowing or having reasonable cause to suspect that it was so manufactured, assembled or imported shall be guilty of offence.

• (5) Where an investigational medicinal product is imported in contravention of regulation 36(1), any person who, otherwise than for the purpose of performing or exercising a duty or power imposed or conferred by or under these Regulations, the 2012 Regulations or any other enactment, is in possession of the product knowing or having reasonable cause to suspect that it was so imported shall be guilty of offence.

• (6) Any sponsor who sells or supplies, or procures the sale or supply, of an investigational medicinal product—

• (a) to a subject for the purposes of a clinical trial; or

• (b) to a person for the purpose of administering the product to such a subject,

the labelling of which does not comply with regulation 46, shall be guilty of an offence.

• (7) Any person who sells or supplies an investigational medicinal product—

• (a) to a subject for the purposes of a clinical trial; or

• (b) to a person for the purpose of administering the product to such a subject,

the labelling of which does not comply with regulation 46, knowing, or having reasonable cause to believe, that the labelling does not so comply, shall be guilty of an offence.

False or misleading information

50

• (1) Any person who in the course of—

• (a) making an application for an ethics committee opinion;

• (b) making a request for authorisation to conduct a clinical trial; or

• (c) making an application for the grant or variation of a manufacturing authorisation,

provides to the licensing authority or an ethics committee any relevant information which is false or misleading in a material particular shall be guilty of an offence.

• (2) Any person who—

• (a) is conducting a clinical trial authorised in accordance with these Regulations;

• (b) is a sponsor of such a clinical trial;

• (c) while acting under arrangements made with a sponsor of such a clinical trial, performs the functions of that sponsor; or

• (d) holds a manufacturing authorisation,

and who, for the purposes of these Regulations, provides to the licensing authority or an ethics committee any relevant information which is false or misleading in a material particular shall be guilty of an offence.

• (3) Any person who, for the purpose of being engaged as a qualified person in accordance with regulation 43, provides to the licensing authority or to the holder of a manufacturing authorisation any information which is false or misleading in a material particular shall be guilty of an offence.

• (4) In this regulation, “relevant information” means any information which is relevant to an evaluation of—

• (a) the safety, quality or efficacy of an investigational medicinal product;

• (b) the safety or scientific validity of a clinical trial; or

• (c) whether, with regard to a clinical trial, the conditions and principles of good clinical practice are being satisfied or adhered to.

Defence of due diligence

51

• (1) A person does not commit an offence under these Regulations if he took all reasonable precautions and exercised all due diligence to avoid the commission of that offence.

• (2) Where evidence is adduced which is sufficient to raise an issue with respect to that defence, the court or jury shall assume that the defence is satisfied unless the prosecution proves beyond reasonable doubt that it is not.

Penalties

52

A person guilty of an offence under these Regulations shall be liable—

• (a) on summary conviction to a fine not exceeding the statutory maximum or to imprisonment for a term not exceeding three months or to both;

• (b) on conviction on indictment to a fine or to imprisonment for a term not exceeding two years or to both.

PART 9 — MISCELLANEOUS PROVISIONS

Construction of references to specified publications

53

• (1) Where any authorisation granted under these Regulations refers to a specified publication, but not to any particular edition of that publication, then, for the purpose of determining whether anything done, at a time when the authorisation is in force, is done in accordance with the authorisation, the reference shall, unless the authorisation otherwise expressly provides, be construed as a reference to the current edition of that publication as in force at that time.

• (2) In this regulation any reference to the current edition of a specified publication as in force at a particular time is a reference to the edition of that publication in force, under whatever title, at that time together with any amendments, additions and deletions made to it up to that time.

• (3) In this regulation, “specified publication” has the meaning given by regulation 321(1) of the 2012 Regulations.

Consequential and other amendments to enactments

54

The provisions of the enactments specified in Schedule 10 are amended as there specified.

Revocations

55

The enactments specified in column (1) of Schedule 11 are revoked to the extent specified in column (3) of that Schedule.

Transitional provisions

56

The transitional provisions set out in Schedules 12 and 13 shall have effect.

SCHEDULE 1 — CONDITIONS AND PRINCIPLES OF GOOD CLINICAL PRACTICE AND FOR THE PROTECTION OF CLINICAL TRIAL SUBJECTS

PART 1 — APPLICATION AND INTERPRETATION

1

• (1) The conditions and principles specified in Part 2 apply to all clinical trials.

• (2) If any subject of a clinical trial is—

• (a) an adult able to give informed consent, or

• (b) an adult who has given informed consent to taking part in the clinical trial prior to the onset of incapacity,

the conditions and principles specified in Part 3 apply in relation to that subject.

• (3) Subject to sub-paragraphs (6) and (7), if any subject of a clinical trial is a minor, the conditions and principles specified in Part 4 apply in relation to that subject.

• (4) Subject to sub-paragraphs (6) and (7), if any subject—

• (a) is an adult unable by virtue of physical or mental incapacity to give informed consent, and

• (b) did not, prior to the onset of incapacity, give or refuse to give informed consent to taking part in the clinical trial,

the conditions and principles specified in Part 5 apply in relation to that subject.

• (5) If any person—

• (a) is an adult unable by virtue of physical or mental incapacity to give informed consent, and

• (b) has, prior to the onset of incapacity, refused to give informed consent to taking part in the clinical trial,

that person cannot be included as a subject in the clinical trial.

• (6) Sub-paragraph (7) applies if treatment is being, or is about to be, provided for a subject who is a minor or an incapacitated adult as a matter of urgency and, having regard to the nature of the clinical trial and of the particular circumstances of the case—

• (a) it is also necessary to take action for the purposes of the clinical trial as a matter of urgency; but

• (b) it is not reasonably practicable to meet the conditions set out in paragraphs 1 to 5 of Part 4 in the case of a minor or paragraphs 1 to 5 of Part 5 in the case of an incapacitated adult.

• (7) Where this sub-paragraph applies, paragraphs 1 to 5 of Part 4 in the case of a minor or paragraphs 1 to 5 of Part 5 in the case of an incapacitated adult shall not apply in relation to the subject if the action specified in sub-paragraph (6) is carried out in accordance with a procedure approved by an ethics committee or by an appeal panel appointed under Schedule 4 at the time it gave its favourable opinion.

2

In this Schedule—

• “Declaration of Helsinki” means the Declaration of Helsinki adopted by the World Medical Assembly in June 1964, as amended by the General Assembly of the Association in October 1975, October 1983, September 1989 and October 1996;

• “guardian” shall be construed in accordance with section 51(8) of the Adults with Incapacity (Scotland) Act 2000 ;

• “legal representative” means, in relation to a minor or to an adult unable by virtue of physical or mental incapacity to give informed consent, and who is, or is being considered as, a subject for a clinical trial—in relation to adults and minors in England, Wales and Northern Ireland, and minors in Scotland—a person, other than a person connected with the conduct of the trial, who—by virtue of their relationship with that adult or that minor, is suitable to act as their legal representative for the purposes of that trial, andis available and willing to so act for those purposes, orif there is no such person, a person, other than a person connected with the conduct of the clinical trial, who is—the doctor primarily responsible for the medical treatment provided to that adult or that minor, ora person nominated by the relevant health care provider; andin relation to adults in Scotland—any guardian or welfare attorney who has power to consent to the adult’s participation in research, orif there is no such guardian or welfare attorney, the adult’s nearest relative, orif it is not reasonably practicable to contact a guardian or welfare attorney or the adult’s nearest relative before the decision to enter the adult as a subject of the clinical trial is made, a person, other than a person connected with the conduct of the clinical trial, who is—the doctor primarily responsible for the medical treatment provided to that adult, ora person nominated by the relevant health care provider;

• “nearest relative” has the meaning given by section 87(1) of the Adults with Incapacity (Scotland) Act 2000;

• “parental responsibility”—in relation to England and Wales, has the same meaning as in the Children Act 1989 ,in relation to Scotland, has the same meaning as in the Children (Scotland) Act 1995 , andin relation to Northern Ireland, has the same meaning as in the Children (Northern Ireland) Order 1995 ;

• “person connected with the conduct of the trial” means—the sponsor of the trial,a person employed or engaged by, or acting under arrangements made with, the sponsor and who undertakes activities in connection with the management of the trial,an investigator for the trial,a health care professional who is a member of an investigator’s team for the purposes of the trial, ora person who provides health care under the direction or control of a person referred to in paragraphs (c) and (d) above, whether in the course of the trial or otherwise;

• “relevant health care provider” means—in relation to a person receiving services in pursuance of the National Health Service Act 1977 , the National Health Service (Scotland) Act 1978 , or the Health and Personal Social Services (Northern Ireland) Order 1972 —in a case where a health service body is providing those services, that body, orin any other case, the health service body which entered the arrangements under which those services are provided, orin relation to any other person receiving health care, the person primarily responsible for providing that health care; and

• “welfare attorney” shall be construed in accordance with section 51(8) of the Adults with Incapacity (Scotland) Act 2000.

3

• (1) For the purposes of this Schedule, a person gives informed consent to take part, or that a subject is to take part, in a clinical trial only if his decision—

• (a) is given freely after that person is informed of the nature, significance, implications and risks of the trial; and

• (b) either—

• (i) is evidenced in writing, dated and signed, or otherwise marked, by that person so as to indicate his consent, or

• (ii) if the person is unable to sign or to mark a document so as to indicate his consent, is given orally in the presence of at least one witness and recorded in writing.

• (2) For the purposes of this Schedule, references to informed consent—

• (a) shall be construed in accordance with paragraph (1); and

• (b) include references to informed consent given or refused by an adult unable by virtue of physical or mental incapacity to give informed consent, prior to the onset of that incapacity.

PART 2 — CONDITIONS AND PRINCIPLES WHICH APPLY TO ALL CLINICAL TRIALS

Principles based on International Conference on Harmonisation GCP Guideline

1

Clinical trials shall be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with good clinical practice and the requirements of these Regulations.

2

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.

3

The rights, safety, and well-being of the trial subjects are the most important considerations and shall prevail over interests of science and society .

4

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

5

Clinical trials shall be scientifically sound, and described in a clear, detailed protocol.

6

A trial shall be conducted in compliance with the protocol that has a favourable opinion from an ethics committee.

7

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.

8

Each individual involved in conducting a trial shall be qualified by education, training, and experience to perform his or her respective task(s).

9

Subject to the other provisions of this Schedule relating to consent, freely given informed consent shall be obtained from every subject prior to clinical trial participation.

10

All clinical trial information shall be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.

11

The confidentiality of records that could identify subjects shall be protected, respecting the privacy and confidentiality rules in accordance with the requirements of the Data Protection Act 1998 and the law relating to confidentiality.

12

Investigational medicinal products used in the trial shall be—

• (a) manufactured or imported, and handled and stored, in accordance with the principles and guidelines of good manufacturing practice, and

• (b) used in accordance with the approved protocol.

13

Systems with procedures that assure the quality of every aspect of the trial shall be implemented.

Conditions based on Article 3 of the Directive

14

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.

15

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.

16

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.

PART 3 — CONDITIONS WHICH APPLY IN RELATION TO AN ADULT ABLE TO CONSENT OR WHO HAS GIVEN CONSENT PRIOR TO THE ONSET OF INCAPACITY

1

The subject has had an interview with the investigator, or another member of the investigating team, in which he has been given the opportunity to understand the objectives, risks and inconveniences of the trial and the conditions under which it is to be conducted.

2

The subject has been informed of his right to withdraw from the trial at any time.

3

The subject has given his informed consent to taking part in the trial.

4

The subject may, without being subject to any resulting detriment, withdraw from the clinical trial at any time by revoking his informed consent.

5

The subject has been provided with a contact point where he may obtain further information about the trial.

PART 4 — CONDITIONS AND PRINCIPLES WHICH APPLY IN RELATION TO A MINOR

Conditions

1

A person with parental responsibility for the minor or, if by reason of the emergency nature of the treatment provided as part of the trial no such person can be contacted prior to the proposed inclusion of the subject in the trial, a legal representative for the minor has had an interview with the investigator, or another member of the investigating team, in which he has been given the opportunity to understand the objectives, risks and inconveniences of the trial and the conditions under which it is to be conducted.

2

That person or legal representative has been provided with a contact point where he may obtain further information about the trial.

3

That person or legal representative has been informed of the right to withdraw the minor from the trial at any time.

4

That person or legal representative has given his informed consent to the minor taking part in the trial.

5

That person with parental responsibility or the legal representative may, without the minor being subject to any resulting detriment, withdraw the minor from the trial at any time by revoking his informed consent.

6

The minor has received information according to his capacity of understanding, from staff with experience with minors, regarding the trial, its risks and its benefits.

7

The explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in the previous paragraph to refuse participation in, or to be withdrawn from, the clinical trial at any time is considered by the investigator.

8

No incentives or financial inducements are given—

• (a) to the minor; or

• (b) to a person with parental responsibility for that minor or, as the case may be, the minor’s legal representative,

except provision for compensation in the event of injury or loss.

9

The clinical trial relates directly to a clinical condition from which the minor suffers or is of such a nature that it can only be carried out on minors.

10

Some direct benefit for the group of patients involved in the clinical trial is to be obtained from that trial.

11

The clinical trial is necessary to validate data obtained—

• (a) in other clinical trials involving persons able to give informed consent, or

• (b) by other research methods.

12

The corresponding scientific guidelines of the European Medicines Agency are followed.

Principles

13

Informed consent given by a person with parental responsibility or a legal representative to a minor taking part in a clinical trial shall represent the minor’s presumed will.

14

The clinical trial has been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and the minor’s stage of development.

15

The risk threshold and the degree of distress have to be specially defined and constantly monitored.

16

The interests of the patient always prevail over those of science and society.

PART 5 — CONDITIONS AND PRINCIPLES WHICH APPLY IN RELATION TO AN INCAPACITATED ADULT

Conditions

1

The subject’s legal representative has had an interview with the investigator, or another member of the investigating team, in which he has been given the opportunity to understand the objectives, risks and inconveniences of the trial and the conditions under which it is to be conducted.

2

The legal representative has been provided with a contact point where he may obtain further information about the trial.

3

The legal representative has been informed of the right to withdraw the subject from the trial at any time.

4

The legal representative has given his informed consent to the subject taking part in the trial.

5

The legal representative may, without the subject being subject to any resulting detriment, withdraw the subject from the trial at any time by revoking his informed consent.

6

The subject has received information according to his capacity of understanding regarding the trial, its risks and its benefits.

7

The explicit wish of a subject who is capable of forming an opinion and assessing the information referred to in the previous paragraph to refuse participation in, or to be withdrawn from, the clinical trial at any time is considered by the investigator.

8

No incentives or financial inducements are given to the subject or their legal representative, except provision for compensation in the event of injury or loss.

9

There are grounds for expecting that administering the medicinal product to be tested in the trial will produce a benefit to the subject outweighing the risks or produce no risk at all.

10

The clinical trial is essential to validate data obtained—

• (a) in other clinical trials involving persons able to give informed consent, or

• (b) by other research methods.

11

The clinical trial relates directly to a life-threatening or debilitating clinical condition from which the subject suffers.

Principles

12

Informed consent given by a legal representative to an incapacitated adult in a clinical trial shall represent that adult’s presumed will.

13