PART 1 INTRODUCTORY PROVISIONS

Citation and commencement

1. These Regulations may be cited as the Medicines for Human Use (Clinical Trials) Regulations 2004 and shall come into force on 1st May 2004.

Interpretation

2.—(1) In these Regulations—

[^F1 “ the 2012 Regulations ” means the Human Medicines Regulations 2012 ; ^F1]

^M3 “ the Act ” means the Medicines Act 1968 ;

“ adult ” means a person who has attained the age of 16 years;

“ adverse event ” means any untoward medical occurrence in a [^F2 participant ^F2] to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product;

“ adverse reaction ” means any untoward and unintended response in a [^F3 participant ^F3] to an investigational medicinal product which is related to any dose administered to that [^F3 participant ^F3] ;

^F4...

[^F5 “ appropriate committee ” for the purposes of any provision of these Regulations under which a function falls to be performed means whichever the licensing authority considers to be appropriate of—

“ assemble ”, in relation to an investigational medicinal product, means—

and “assembly” has a corresponding meaning;

[^F6 “ the Authority ” is to be construed in accordance with regulation 5(3); ^F6]

“business”, except in [^F7 regulation 9 ^F7] , includes a professional practice and includes any activity carried on by a body of persons, whether corporate or unincorporate;

[^F8 “ chief investigator ” means—

“ clinical trial ” means any investigation in human [^F9 participants ^F9] , other than a non-interventional trial, intended—

with the object of ascertaining the safety or efficacy of those products;

[^F10 “ Commission Delegated Regulation 2017/1569 ”, other than in Parts 2 and 3 of Schedule 7, means, in the case of an investigational medicinal product manufactured or assembled in, or imported into, Northern Ireland, Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017 supplementing Regulation (EU) No 536/2014 of the European Parliament and of the Council by specifying principles of and the guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections, as that Regulation has effect in EU law; ^F10]

[^F11 “ Commission Directive 2003/94/EC ” , other than in Parts 2 and 3 of Schedule 7, means—

[^F13 “ the Commission on Human Medicines ” means the Commission on Human Medicines within the meaning of regulation 9 of the 2012 Regulations; ^F13]

“ conditions and principles of good clinical practice ” means the conditions and principles specified in Schedule 1;

“ conducting a clinical trial ” includes—

“ container ”, in relation to an investigational medicinal product, means the bottle, jar, box, packet or other receptacle which contains or is to contain it, not being a capsule, cachet or other article in which the product is or is to be administered, and where any such receptacle is or is to be contained in another such receptacle, includes the former but does not include the latter receptacle;

[^F15 “ country ” means a country or territory; ^F15]

^M4,F16 “ dentist ” means a person registered in the dentists register under the Dentists Act 1984 ...;

^F17...

[^F18 “Directive 2001/83/EC ” means _dfnDirective 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use; ^F18]

^M5 “ doctor ” means a registered medical practitioner ;

[^F19 “ EAMS medicinal product ” means a medicinal product that—

[^F19 “ EAMS scientific opinion ” is to be construed in accordance with regulation 167C(2)(b) of the 2012 Regulations; ^F19]

[^F19 “ Early Access to Medicines Scheme ” means the scheme of that name established and operated under regulation 167C(1) of the 2012 Regulations; ^F19]

[^F20 “EEA State” means a Member State, Norway, Iceland or Liechtenstein; ^F20]

^F21...

[^F22 “ electronic signature ” means data in electronic form which is attached to or logically associated with other data in electronic form and which is used by the signatory to sign; ^F22]

“ European Economic Area ” means the European Economic Area created by the EEA Agreement;

[^F23 “the European Medicines Agency” means the European Medicines Agency established by Regulation (EC) No. 726/2004 of the European Parliament and of the Council laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency; ^F23]

“ ethics committee ” means—

[^F29 “ the EU Regulation ” means Regulation 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC , as that Regulation has effect in EU law; ^F29]

“ export ” means export to [^F30 another country from the United Kingdom ^F30] , whether by land, sea or air;

^F31...

^F32...

^F33...

^M7 “ Health Board ” means a Health Board established under the National Health Service (Scotland) Act 1978 ;

“ health care ” means services for or in connection with the prevention, diagnosis or treatment of illness;

“ health care professional ” means—

“ health centre ” means a health centre maintained under [^F44 section 2 or 3 of the National Health Service Act 2006 , section 2 or 3 of the National Health Service (Wales) Act 2006 ^F44] , section 36 of the National Health Service (Scotland) Act 1978 or Article 5 of the Health and Personal Social Services (Northern Ireland) Order 1972 ;

“ health service body ” means—

“ hospital ” includes a clinic, nursing home or similar institution;

[^F54 “import”, except in regulation 13 and Schedule 13, means import, or attempt to import—

“ informed consent ” shall be construed in accordance with paragraph 3 of Part 1 of Schedule 1;

“ insurance or indemnity ” includes provision for meeting losses or liabilities—

“ investigational medicinal product ” means a pharmaceutical form of an active substance or placebo being tested, or to be tested, or used, or to be used, as a reference in a clinical trial, and includes a medicinal product which has a marketing authorization but is, for the purposes of the trial—

“ investigational medicinal product dossier ” means, in relation to an investigational medicinal product, the dossier relating to that product which accompanies a request for [^F56 approval ^F56] to conduct a trial in which that product is or is to be used, in accordance with [^F57 paragraph 5(b) ^F57] of Schedule 3;

[^F58 “ investigator ” means, in relation to a clinical trial, the health care professional who is responsible for the conduct of that trial at that trial location or, if more than one, the trial locations; and who is, if the trial is conducted by a team of health care professionals at that location or locations, the leader responsible for that team; ^F58]

“ investigator’s brochure ” means a document containing a summary of the clinical and non-clinical data relating to an investigational medicinal product which are relevant to the study of the product in human [^F59 participants ^F59] ;

“ labelling ”, in relation to an investigational medicinal product, means affixing to or otherwise displaying on it a notice describing or otherwise relating to the contents, and “label” has a corresponding meaning;

^F60 “legal representative”, other than in regulation 3 and ... Schedule 3, has the meaning given by Part 1 of Schedule 1;

“ licensing authority ” shall be construed in accordance with [^F61 regulation 6 of the 2012 Regulations ^F61] ;

“ manufacture ”, in relation to an investigational medicinal product, includes any process carried out in the course of making the product, but does not include dissolving or dispersing the product in, or diluting it or mixing it with, some other substance used as a vehicle for the purposes of administering it;

[^F62 “ manufacturer’s licence (MM) ” has the meaning given in regulation 8(1) of the 2012 Regulations; ^F62]

[^F62 “ manufacturer’s licence (POC) ” has the meaning given in regulation 8(1) of the 2012 Regulations; ^F62]

“ manufacturing authorisation ” has the meaning given by regulation 36(1);

[^F62 “ manufacturing authorisation (MM) ” means a manufacturing authorisation that authorises the manufacture or assembly of MM investigational medicinal products; ^F62]

[^F62 “ manufacturing authorisation (POC) ” means a manufacturing authorisation that authorises the manufacture or assembly of POC investigational medicinal products; ^F62]

[^F63 “ marketing authorization ” means—

[^F64 “ medicinal product ” means a medicinal product within the meaning of regulation 2(1) of the 2012 Regulations. ^F64]

“ minor ” means a person under the age of 16 years;

[^F62 “ MM ” means modular manufacture; ^F62]

[^F62 “ MM (IMP) control site ” means the premises at which the holder of a manufacturing authorisation (MM) supervises and controls the manufacture or assembly of MM investigational medicinal products; ^F62]

[^F62 “ MM (IMP) master file ” means a detailed description of the arrangements for manufacture or assembly of an MM investigational medicinal product; ^F62]

[^F62 “ MM investigational medicinal product ” means an investigational medicinal product that, for reasons relating to deployment, the licensing authority determines it necessary or expedient to be manufactured or assembled in a modular unit; ^F62]

[^F62 “ modular unit ” means a relocatable manufacturing unit; ^F62]

“ non-interventional trial ” means a study of one or more medicinal products which have a marketing authorization, where the following conditions are met—

[^F65 “ non-investigational medicinal product ” means a medicinal product used or to be used in a clinical trial, as described in the protocol, but not as an investigational medicinal product;

“ notifiable trial ” has the meaning given in regulation 11A;

“ participant ” means, in relation to a clinical trial, an individual, whether a patient or not, who participates in a clinical trial—

^F66...

“ pharmaceutical form of an active substance ” includes any substance or article to which these Regulations have effect by virtue of an order under section 104 or 105 of the Act (which relate to the application of Act to certain articles and substances which are not medicinal products);

“ Pharmaceutical Society ” in relation to Great Britain means the Royal Pharmaceutical Society of Great Britain, and in relation to Northern Ireland means the Pharmaceutical Society of Northern Ireland;

“ pharmacist ” means—

“ Phase I trial ” means a clinical trial to study the pharmacology of an investigational medicinal product when administered to humans, where the sponsor and investigator have no knowledge of any evidence that the product has effects likely to be beneficial to the [^F69 participants ^F69] of the trial;

[^F62 “ POC ” means point of care; ^F62]

[^F62 “ POC (IMP) control site ” means the premises at which the holder of a manufacturing authorisation (POC) supervises and controls the manufacture or assembly of POC investigational medicinal products; ^F62]

[^F62 “ POC (IMP) master file ” means a detailed description of the arrangements for the manufacture or assembly of a POC investigational medicinal product; ^F62]

[^F62 “ POC (IMP) site ” means a site at which the manufacture or assembly of a POC investigational medicinal product takes place; ^F62]

[^F62 “ POC investigational medicinal product ” means an investigational medicinal product that, for reasons relating to method of manufacture, shelf life, constituents or method or route of administration, can only be manufactured at or near the place where the product is to be used or administered; ^F62]

“ the principles and guidelines of good manufacturing practice ” means the principles and guidelines of good manufacturing practice set out in Commission Directive 2003/94/EC [^F70 in respect of Great Britain or Commission Delegated Regulation 2017/1569 in respect of Northern Ireland ^F70] ;

“ protocol ” means a document that describes the objectives, design, methodology, statistical considerations and organisation of a clinical trial;

“ qualified person ” means—

[^F72 “ radiopharmaceutical ” has the same meaning as in regulation 8(1) of the 2012 Regulations; ^F72]

“ relevant ethics committee ”, in relation to a clinical trial, means—

“serious adverse event”, “serious adverse reaction” or “ unexpected serious adverse reaction ” means any adverse event, adverse reaction or unexpected adverse reaction, respectively, that—

[^F78 “ signatory ” means a natural person who creates an electronic signature; ^F78]

“ sponsor ” shall be construed in accordance with regulation 3;

^F79...

^F80...

^F81...

[^F82 “ trial location ” means a hospital, health centre, surgery or other establishment, or facility or premises at or from which a clinical trial, or any part of such a trial, is conducted; ^F82]

[^F83 “ UK marketing authorization ” —

“ unexpected adverse reaction ” means an adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out—

(2) Any reference in these Regulations to the holder of a manufacturing authorisation shall be construed as a reference to the holder of such an authorisation which is for the time being in force.

(3) Any reference in these Regulations to an application, request or other document that is signed includes a reference to an application, request of other document that is signed with an electronic signature.

[^F85List 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.^F85]

Sponsor of a clinical trial

3. —(1) In these Regulations, subject to the following paragraphs, “ sponsor ” means, in relation to a clinical trial, the person who takes responsibility for the initiation, management and financing (or arranging the financing) of that trial.

(2) If two or more persons take responsibility for the matters specified in paragraph (1) in relation to a clinical trial, those persons may—

(a)take joint responsibility for carrying out the functions of the sponsor of that trial under these Regulations; or

(b)allocate responsibility for carrying out the functions of the sponsor of that trial in accordance with paragraphs (4) to (10).

(3) If two or more persons take joint responsibility in accordance with paragraph (2)(a)—

(a)any reference to the sponsor in these Regulations shall, in relation to that trial, be construed as a reference to those persons; and

(b)paragraphs (4) to (10) shall not apply.

(4) One of the persons referred to in paragraph (2) shall be responsible for carrying out the functions of a sponsor under Part 3 (authorisation for clinical trials and ethics committee opinion) and shall make the [^F86request for approval^F86] to conduct the trial in accordance with [^F87regulation 16^F87] .

(5) The [^F88request for approval^F88] referred to in [^F89regulation 16^F89] shall specify—

(a)who, in accordance with paragraph (4), is responsible for carrying out the functions of the sponsor under Part 3;

(b)who is to be responsible for carrying out the functions of the sponsor under Part 4 (good clinical practice and the conduct of clinical trials); and

(c)who is to be responsible for carrying out the functions of the sponsor under Part 5 (pharmacovigilance).

(6) After the clinical trial has been [^F90approved^F90] in accordance with regulation 18 [^F91or 18A^F91] , a different person may be specified as responsible for carrying out the functions of the sponsor under Part 3, 4 or 5 by making a [^F92modification of an important detail as defined in Part 3^F92] to the terms of a clinical trial[^F93 approval^F93] in accordance with [^F94regulation 22^F94] .

(7) Where a person is responsible for carrying out the functions of the sponsor under Part 3 by virtue of paragraph (5), or is specified in accordance with paragraph (6) as responsible for those functions, any reference to the sponsor in—

(a)^F95that Part ...,

(b)^F96... Schedule 3,

(c)^F97Schedule 5 ..., and

(d)Schedule 12,

shall, in relation to the trial, be construed as a reference to that person.

(8) Where a person is specified in accordance with paragraph (5) or (6) as responsible for carrying out the functions of the sponsor under Part 4, any reference to the sponsor in—

(a)that Part, except regulation 28(1), or

(b)Schedule 5, in so far as it relates to notices under regulation 31(1),

shall, in relation to the trial, be construed as a reference to that person.

(9) Where a person is specified in accordance with paragraph (5) or (6) as responsible for carrying out the functions of the sponsor under Part 5, any reference to the sponsor in that Part shall, in relation to the trial, be construed as a reference to that person.

(10) Any reference to the sponsor in—

(a)[^F98 regulation 28(1)^F98] ,

(b)Parts 2 and 6 to 9, and

(c)^F99Schedules 1 and 7 ...,

shall, in relation to the trial, include a reference to a person specified in accordance with paragraph (5) or (6).

(11) A person who is a sponsor of a clinical trial in accordance with this regulation must—

(a)be established in [^F100the United Kingdom or a country that is included in the list referred to in paragraph (11A)^F100] , or

(b)have a legal representative who is so established.

[^F101 (12) A person who is a sponsor of a clinical trial in accordance with this regulation may delegate any or all of his functions under these Regulations to any person but any such arrangement shall not affect the responsibility of the sponsor.^F101]

[^F102 (11A) The licensing authority must publish a list of countries where a sponsor of a clinical trial, or their legal representative, may be established for the purpose of paragraph (11).

(11B) In order to determine whether a country should be included in the list referred to in paragraph (11A), the licensing authority may, in particular, take into account—

(a)the mechanisms that the country has in place to assist the licensing authority in contacting, or obtaining information in respect of, a sponsor or legal representative that is established there; and

(b)the country's ability to assist the licensing authority in any action it may need to take in respect of a sponsor or legal representative that is established there.

(11C) The licensing authority must—

(a)review the countries it has included in the list referred to in paragraph (11A) 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 on the date on which that country is included in that list.^F102]

[^F103Sponsor’s responsibility for the investigator’s brochure

3A. The sponsor of a clinical trial shall—

(a)ensure that the investigator’s brochure for that trial, and any update of that brochure, presents the information it contains in a concise, simple, objective, balanced and non-promotional form that enables a clinician or potential investigator to understand it and make an unbiased risk-benefit assessment of the appropriateness of the proposed clinical trial; and

(b)validate and update the investigator’s brochure at least once a year.^F103]

[^F104Investigator in a clinical trial

3B. The investigator, in relation to a clinical trial, shall be a health care professional who is appropriately trained to undertake that role in a clinical trial.^F104]

Responsibility for functions under the Directive

^F1054. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

PART 2 ETHICS COMMITTEES

United Kingdom Ethics Committees Authority

5.—(1) The body responsible for establishing, recognising and monitoring ethics committees in the United Kingdom in accordance with these Regulations is the United Kingdom Ethics Committees Authority, which is a body consisting of—

(a)[^F106 the Health Research Authority^F106] ;

(b)the [^F107Welsh Ministers^F107] ;

(c)the Scottish Ministers; and

(d)the [^F108Department of Health in Northern Ireland^F108] .

(2) The functions of the Authority—

(a)may, by agreement between them, be performed by any one of [^F109the Health Research Authority^F109] , the [^F110Welsh Ministers^F110] , the Scottish Ministers and the [^F111Department of Health in Northern Ireland^F111] acting alone, or any two or more of them acting jointly; and

(b)may be performed by any one of [^F109the Health Research Authority^F109] , the [^F110Welsh Ministers^F110] , the Scottish Ministers and the [^F111Department of Health in Northern Ireland^F111] acting alone solely in relation to a part of the United Kingdom with respect to which [^F112the Health Research Authority^F112] , the Assembly, the Ministers or the Department, as the case may be, have responsibilities.

(3) In accordance with the preceding provisions of this regulation, in these Regulations “ the United Kingdom Ethics Committees Authority ” (“ the Authority ”) means any one or more of [^F113 the Health Research Authority ^F113] , the [^F114 Welsh Ministers ^F114] , the Scottish Ministers and the [^F115 Department of Health in Northern Ireland ^F115] , and, in the case of anything falling to be done by the Authority, means any one or more of them acting as mentioned in paragraph (2).

^F116(4) The Authority may appoint such persons as they think necessary for the proper discharge by them of their functions, and those persons shall be appointed on such terms and conditions ... as the Authority think fit.

(5) Arrangements may be made between the Authority and any relevant authority for—

(a)^F117any functions of the Authority to be exercised by, or by members of staff of, the relevant authority; ...

^F117(b). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(6) Any arrangements under paragraph (5) for the exercise of any functions of the Authority shall not affect the responsibility of the Authority.

(7) In this regulation, “ relevant authority ” means any government department, local or public authority or holder of public office.

Establishment [^F118and abolition^F118] of ethics committees

6.—(1) The Authority may establish [^F119an ethics committee^F119] to act—

^F120(a). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(b)in relation to such descriptions or classes of clinical trials,

as the Authority consider appropriate.

[^F121 (1A) The Authority must ensure that the arrangements for the membership and operation of that committee—

(a)enable that committee to perform the functions of an ethics committee; and

(b)comply with regulation 9.^F121]

[^F122 (2) The Authority may—

(a)specify any conditions or limitations that apply to an ethics committee, including whether that committee may act for the entire United Kingdom or only for a particular area of the United Kingdom;

(b)where they consider it necessary or appropriate to do so—

(i)vary the description or class of clinical trial in relation to which that committee may act as an ethics committee, or

(ii)vary or revoke any conditions or limitations imposed under paragraph (2)(a); and

(c)abolish any such committee if the Authority is satisfied that—

(i)the arrangements for the membership and operation of that committee are no longer such that the committee is able to adequately perform its functions under these Regulations,

(ii)the committee is failing to perform its functions under these Regulations adequately or at all, or

(iii)it is otherwise necessary or appropriate to do so.^F122]

[^F123 (3) Where the Authority abolishes an ethics committee or an ethics committee ceases operation—

(a)the Authority may nominate another committee to be responsible for the work of that committee;

(b)the committee nominated in accordance with sub-paragraph (a) must—

(i)consider any applications made to the old committee in accordance with regulation 15, if the old committee had not given an opinion before the date of abolition or ceasing of operation, and

(ii)be the relevant ethics committee for any clinical trial in relation to which the old committee had given a favourable opinion in accordance with regulation 18 or 18B.^F123]

Recognition of ethics committees

^F1247. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Revocation of recognition

^F1258. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

[^F126Operation of ethics committees

9.—(1) This regulation does not apply in relation to an Ethics Committee constituted by regulations made by the Scottish Ministers under section 51(6) of the Adults with Incapacity (Scotland) Act 2000.

(2) An ethics committee established under regulation 6 must—

(a)be constituted of 5 or more members, appointed by the Authority, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial; and

(b)include one member appointed by the Authority to be a Chairperson.

(3) An ethics committee may—

(a)establish sub-committees consisting of members of the committee; and

(b)make arrangements for the exercise, on behalf of the committee, of any of its functions by such a sub-committee,

in accordance with the standing orders and standard operating procedures adopted under paragraph (4).

(4) An ethics committee—

(a)must, subject to the approval of the Authority, make standing orders, and adopt standard operating procedures for the regulation of its proceedings and business; and

(b)may, subject to the approval of the Authority, vary or revoke such orders or procedures.

(5) The meetings and proceedings of an ethics committee and its sub-committees must be conducted in accordance with the standing orders made, and the standard operating procedures adopted, under paragraph (4).

(6) All applications for an ethics committee opinion must be considered by a full meeting of an ethics committee.

(7) In this regulation—

“ a full meeting of an ethics committee ” means a meeting at which—

“ lay member ” means an individual who does not have a formal qualification related to, or professional experience in, the field of clinical research or healthcare. ^F126]

Other functions of the Authority

10.—(1) The Authority shall monitor the extent to which ethics committees adequately perform their functions under these Regulations.

(2) The Authority may provide advice and assistance to ethics committees with respect to the performance of their functions.

PART 3 AUTHORISATION FOR CLINICAL TRIALS AND ETHICS COMMITTEE OPINION

[^F127Interpretation of Part 3

11. In this Part—

“ advanced therapy medicinal product ” has the meaning given by regulation 2A of the 2012 Regulations ;

“ authorities ” means the licensing authority and the ethics committee in collaboration with each other;

“ modification of an important detail ” means a modification to a clinical trial approval which—

“ modification to a clinical trial approval ” means a modification to—

“ relevant committee ” means—

“ Route A substantial modification ” means a modification to a clinical trial approval which is likely to have a substantial impact on the safety or rights of the participants or on the reliability or robustness of the data generated in the trial;

“ Route B substantial modification ” has the meaning given in regulation 11B;

“ specialist group or committee ” means a group or committee whose functions include the provision of advice on ethical or scientific issues in relation to—

“ substantial modification ” means—

“ valid modification request ” means a modification request which complies with the provisions of regulation 22;

“ valid request for approval ” means a request for approval which complies with the provisions of regulation 16. ^F127]

[^F128Definition of notifiable trial

11A. —(1) In these Regulations, “ notifiable trial ” means a trial—

(a)where there are no significant safety concerns with any of the investigational medicinal products, as far as the sponsor is aware having made reasonable enquiries;

(b)which meets either Condition A, Condition B or Condition C; and

(c)which does not involve either—

(i)participants who are—

(aa)under the age of 18 years,

(bb)pregnant, or

(cc)breastfeeding, or

(ii)an investigational medicinal product that is—

(aa)an advanced therapy medicinal product, or

(bb)used for the first time in humans.

(2) Condition A is that the investigational medicinal product or, if there is more than one, each of the investigational medicinal products, is authorised for use in the United Kingdom and either—

(a)the product is used in accordance with that authorisation; or

(b)the use of the product in the trial is supported by established clinical practice.

(3) Condition B is that a trial relating to the investigational medicinal product or, if there is more than one, each of the investigational medicinal products, has been approved in the United Kingdom within the preceding 2 years of the date of request for approval whereby—

(a)the product was investigated at—

(i)the same or higher dose,

(ii)the same or higher frequency, and

(iii)the same or longer duration;

(b)the same manufacturing process was utilised for the product; and

(c)the approved trial—

(i)utilised the same route of administration for the product, and

(ii)investigated the product for the same indication.

(4) Condition C is that the trial has undergone assessment, and been approved, by the appropriate authority responsible for the licensing of clinical trials in one or more of the following—

(a)the European Union;

(b)an EEA State;

(c)the United States of America.

Definition of Route B substantial modification

11B. —(1) In these Regulations, “ Route B substantial modification ” means a modification to the approval of a clinical trial (“the relevant clinical trial”)—

(a)where there are no new significant safety concerns with any of the investigational medicinal products, as far as the sponsor is aware having made reasonable enquiries; and

(b)which meets either Condition A, Condition B or Condition C.

(2) Condition A is that—

(a)the relevant clinical trial does not involve an investigational medicinal product that is used for the first time in humans;

(b)the modification has been reviewed and approved by the appropriate authority responsible for the licensing of clinical trials in one or more of the following—

(i)the European Union;

(ii)an EEA State;

(iii)the United States of America; and

(c)the particulars and documents that have been reviewed in connection with the approval of the modification by the authority referred to in sub-paragraph (b)—

(i)are the same as those that accompany the modification request, and

(ii)do not include any particulars that are specific to the United Kingdom.

(3) Condition B is that the modification is limited to one or more of the following changes to the protocol for the relevant clinical trial—

(a)a change to the primary objective of the relevant clinical trial;

(b)an inclusion of new measurements for the primary endpoint;

(c)a change to the design of the relevant clinical trial, which has a significant impact on the statistical consideration;

(d)a change in the criteria by reference to which the relevant clinical trial ends;

(e)where the relevant clinical trial involves an investigational medicinal product that has been authorised for use in the United Kingdom, and which is used in accordance with the terms of that authorisation in the trial, a change to the number of planned interactions with the participants to assess their ongoing safety as a participant in the trial, which is not in response to a new safety concern;

(f)a change to the list of concomitant medication that a participant in the relevant clinical trial is or is not allowed to use;

(g)in relation to a clinical trial which is conducted in more than one country in accordance with a global protocol, a change to that protocol to include all requirements specific to the United Kingdom that were approved by the authorities in a separate protocol or addendum to the global protocol that is specific to the United Kingdom, where this change does not result in a change to the safety reporting requirements as set out in Part 5.

(4) Condition C is that the modification is limited to one or more of the following changes to the investigator’s brochure or the summary of product characteristics for the relevant clinical trial—

(a)an inclusion of new toxicological or pharmacological data related to the investigational medicinal product, where there are no changes to the protocol of the relevant clinical trial as a result of safety concerns with the data;

(b)a change to the reference safety information which involves an increase in the frequency of adverse reactions, where there are no new expected adverse reactions;

(c)a change to the investigator’s brochure which is not a change to—

(i)the assessment of the risks and benefits of the relevant clinical trial as approved by the authorities, or

(ii)the safety profile of any of the investigational medicinal products used in the relevant clinical trial;

(d)an update to the section of the summary of product characteristics which deals with undesirable effects of the investigational medicinal product.

(5) In this regulation—

“ concomitant medication ”, in relation to a clinical trial, means any medicinal product that is not used for the purposes of the trial;

“ primary endpoint ” means the variable or measure capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial, for example, the period between the first receipt of treatment or a placebo by a participant and the occurrence of a pre-defined event;

“ reference safety information ” means information in the product information relating to expected serious adverse reactions associated with an investigational medicinal product, which is used to determine the adverse reactions that are to be treated as suspected unexpected serious adverse reactions in relation to that investigational medicinal product. ^F128]

Requirement for authorisation and ethics committee opinion

12.—(1) No person shall—

(a)start a clinical trial or cause a clinical trial to be started; or

(b)conduct a clinical trial,

unless the conditions specified in paragraph (3) are satisfied.

(2) No person shall—

(a)recruit an individual to be a [^F129participant^F129] in a trial;

(b)issue an advertisement for the purpose of recruiting individuals to be [^F130participants^F130] in a trial,

unless the condition specified in paragraph (3)(a) has been satisfied.

[^F131 (3) The conditions referred to in paragraphs (1) and (2) are—

(a)an ethics committee has given a favourable opinion in relation to the clinical trial; and

(b)the clinical trial has been authorised by the licensing authority,

in accordance with these Regulations.^F131]

^F132(4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Supply of investigational medicinal products for the purpose of clinical trials

13.—(1) Subject to paragraphs (3) and (4), no person shall, in the course of a business carried on by him, sell or supply any investigational medicinal product to—

(a)an investigator,

(b)a health care professional who is a member of an investigator’s team,

(c)a person who provides or is to provide health care under the direction or control of a person referred to in sub-paragraphs (a) and (b), or

(d)a [^F133participant^F133] ,

for the purpose of administering that product in a clinical trial, unless the conditions specified in paragraph (2) are satisfied.

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

(a)the licensing authority has authorised the clinical trial for the purposes of which the product is sold or supplied;

[^F134 (b) in the case of—

(i)an investigational medicinal product manufactured or assembled in the United Kingdom [^F135 except for an MM investigational medicinal product or a POC investigational medicinal product^F135] , the product has been manufactured or assembled—

(aa)in accordance with the terms of a manufacturing authorisation, or

(bb)in the case of assembly only, under the exemption in regulation 37;

[^F136 (ia)an MM investigational medicinal product manufactured or assembled in the United Kingdom, the product has been manufactured or assembled in accordance with the terms of a manufacturing authorisation (MM) or assembled under the exemption in regulation 37;

(ib)a POC investigational medicinal product manufactured or assembled in the United Kingdom, the product has been manufactured or assembled in accordance with the terms of a manufacturing authorisation (POC) or assembled under the exemption in regulation 37;^F136]

(ii)an investigational medicinal product imported into Northern Ireland from an EEA State—

(aa)the product has been manufactured, assembled or imported into an EEA State in accordance with the terms of an authorisation referred to in [^F137 Article 62 of the EU Regulation^F137] granted by a competent authority of an EEA State, and

(bb)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 [^F138 Article 62 of the EU Regulation^F138] ;

(iii)an investigational medicinal product imported into Northern Ireland from a country other than an EEA State, the product has been imported into Northern Ireland in accordance with the terms of a manufacturing authorisation;

(iv)an investigational medicinal product imported into Great Britain other than from Northern Ireland, the product has been imported in accordance with the terms of a manufacturing authorisation.^F134]

[^F139 (2A) The condition specified in paragraph (2)(b) does not apply to an investigational medicinal product that has been manufactured or assembled in accordance with the terms 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.^F139]

^F140(3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

[^F141 (4) The restriction in paragraph (1) shall not apply to—

(a)the sale or supply of a medicinal product in Great Britain in accordance with the terms of a UKMA(GB) or UKMA(UK), and

(b)the sale or supply of a medicinal product in Northern Ireland in accordance with—

(i)the terms of a UKMA(NI) or UKMA(UK), or

(ii)an EU marketing authorisation (as defined in the 2012 Regulations).^F141]

[^F142Request for authorisation to conduct a clinical trial

14.—(1) The sponsor must make a request for authorisation to conduct a clinical trial to the licensing authority in accordance with the procedure set out in regulation 16.

(2) Where the trial is a notifiable trial, the sponsor must indicate that it is a notifiable trial in accordance with regulation 16(2)(b).

Application for ethics committee opinion

15.—(1) The sponsor must make an application for an ethics committee opinion in relation to a clinical trial in accordance with the procedure set out in regulation 16.

(2) The application must be made to one ethics committee only, regardless of the number of trial locations at which the trial is to be conducted.

(3) Subject to paragraph (4), the application must be made to an ethics committee established or recognised—

(a)for the entire United Kingdom; and

(b)in relation to a description or class of clinical trial into which the proposed trial falls.

(4) If—

(a)a clinical trial is conducted at one or more trial locations in Scotland;

(b)the trial involves adults unable by virtue of physical or mental incapacity to give informed consent; and

(c)the chief investigator is professionally based at a hospital, health centre, surgery or other establishment or facility in Scotland,

the application for an ethics committee opinion in relation to that trial must be made to an Ethics Committee constituted by regulations made by the Scottish Ministers under section 51(6) of the Adults with Incapacity (Scotland) Act 2000.

(5) For the purposes of paragraph (4), a chief investigator is professionally based at the hospital, health centre, surgery or other establishment or facility at or from which the chief investigator’s professional practice is primarily conducted.

Request for approval and combined procedure

16. —(1) Subject to paragraph (5), the request for authorisation under regulation 14 and the application for an ethics committee opinion under regulation 15 must be made by way of a single application dossier (a “request for approval”).

(2) The request for approval must—

(a)be submitted to an online portal made available for this purpose;

(b)where the trial is a notifiable trial, include a statement confirming that the trial is a notifiable trial;

(c)be accompanied by—

(i)the particulars and documents specified in Part A1 of Schedule 3, and

(ii)subject to paragraph (3), any fee which may be payable in connection with that application under the Medicines (Products for Human Use) (Fees) Regulations 2016.

(3) Paragraph (2)(c)(ii) does not apply where arrangements have been made with the licensing authority or the ethics committee for payment of the fee referred to in that paragraph other than at the time of the request.

(4) The request for approval and accompanying material must be supplied in English.

(5) In exceptional circumstances (for example, in an urgent situation where it would be beneficial to progress one request or application while preparing the other), and if agreed in advance by the licensing authority or the ethics committee, a request for authorisation under regulation 14 and an application for an ethics committee opinion under regulation 15 may be made separately.

(6) Where an agreement has been reached under paragraph (5), the licensing authority or the ethics committee (as the case may be) must confirm—

(a)which of the particulars and documents specified in Part A1 of Schedule 3 must accompany—

(i)the request for authorisation, and

(ii)the application for an ethics committee opinion; and

(b)the arrangements for the payment of the fee specified in paragraph (2)(c)(ii).

(7) Where an agreement has been reached under paragraph (5), the submission of both the request for authorisation and the application of an ethics committee constitutes a “request for approval”.

(8) The authorities must confirm whether the request for approval is valid within the period of 7 days beginning with the date of the submission of the request and notify the sponsor accordingly.

Assessment of request for approval

17.—(1) Where the licensing authority and an ethics committee receive a valid request for approval—

(a)the licensing authority must assess the request for authorisation in relation to the clinical trial to which the request for approval relates;

(b)the ethics committee must assess the application for an ethics committee opinion in relation to the clinical trial to which the request for approval relates.

(2) The licensing authority—

(a)must consider the safety of the clinical trial and the safeguarding of clinical trial participants; and

(b)may have regard to whether the sponsor has failed to comply with regulation 25(1) or 25(2)(a) in relation to another clinical trial, and not rectified that failure.

(3) The ethics committee must consider—

(a)whether the anticipated benefits to participants and other individuals or groups affected by the medical condition under investigation outweigh the anticipated risks and inconveniences, taking account of—

(i)the risks to the health of any of the participants posed by the medical condition for which the product is being investigated, and

(ii)the nature of the intervention compared to normal clinical care; and

(b)the measures used to—

(i)seek and obtain informed consent for participation in the trial, and

(ii)protect and promote the interests of participants and the general public (including by promoting transparency in research).

(4) Where the request for approval contains a statement under regulation 16(2)(b) confirming that the trial is a notifiable trial, the licensing authority may, if it considers appropriate and without undertaking further assessment, rely on that statement to provide an authorisation of the clinical trial to which the request for approval relates.

(5) The ethics committee may consider, and give an opinion on, any other issue relating to the clinical trial, if—

(a)the committee has been asked by the sponsor to consider the issue;

(b)it is, in the committee’s opinion, relevant to the other matters considered by the committee in accordance with paragraph (3).

(6) The ethics committee may, before giving its opinion, obtain expert advice on any field which relates to the clinical trial.

(7) If the licensing authority or the ethics committee considers it appropriate to do so, they may consult either or both of the following—

(a)a relevant committee;

(b)a specialist group or committee.

(8) The authorities must not approve a clinical trial involving products for gene therapy if the use of those products in that trial would result in modifications to any participant’s germ line genetic identity.

Approval procedure for clinical trials

18.—(1) Having carried out the assessments required by regulation 17—

(a)the licensing authority must provide its decision in relation to the request for authorisation to conduct the clinical trial in accordance with this regulation; and

(b)the ethics committee must give an opinion in relation to the clinical trial in accordance with this regulation.

(2) The authorities must notify the sponsor of the decision in paragraph (1)(a) and the opinion in paragraph (1)(b).

(3) A notice under paragraph (2) must—

(a)be in writing; and

(b)state that the authorities—

(i)approve the request for approval,

(ii)approve the request for approval, subject to conditions specified in the notice, or

(iii)do not approve the request for approval, setting out the grounds for this decision.

(4) Subject to paragraphs (7) and (8) and regulation 18C, the authorities must take all reasonable steps to ensure that the notice is given within the period of 30 days beginning with the date on which the authorities notified the sponsor that the request for approval was valid in accordance with regulation 16(8).

(5) If a notice is given in accordance with paragraph (3)(b)(ii)—

(a)the notice must specify whether the conditions relate to either or both of the following—

(i)the licensing authority’s decision on the clinical trial authorisation;

(ii)the ethics committee opinion;

(b)the clinical trial is to be treated as approved only if the conditions specified in the notice are satisfied.

(6) If a notice is given in accordance with paragraph (3)(b)(iii), regulations 18A and 18B apply.

(7) The time period referred to in paragraph (4) is extended by 90 days where the licensing authority or the ethics committee consults either or both of the following—

(a)a relevant committee;

(b)a specialist group or committee.

(8) If the clinical trial involves a medicinal product for xenogenic cell therapy, the time periods set out in paragraphs (4) and (7) do not apply and the authorities may give written notice under this regulation at any time after the date on which the authorities notified the sponsor that the request for approval was valid in accordance with regulation 16(8).

(9) Where an ethics committee gives an opinion in accordance with this regulation, it must publish the conclusion of that opinion, whether favourable or unfavourable.

(10) Where a request for authorisation under regulation 14 and an application for an ethics committee opinion under regulation 15 are made separately in accordance with regulation 16(5)—

(a)the time periods mentioned in this regulation, regulation 18A and 18B applies separately to the request for authorisation and the application for an ethics committee opinion;

(b)the clinical trial is to be treated as approved upon receiving both the authorisation from the licensing authority and a favourable opinion from the ethics committee.

Request for further information regarding a request for approval

18A.—(1) A notice given in accordance with regulation 18(3)(b)(iii) must—

(a)request further information required to reconsider the approval of the request; and

(b)specify whether the request for further information relates to either or both of the following—

(i)the licensing authority’s decision on the clinical trial authorisation;

(ii)the ethics committee opinion.

(2) If the sponsor is given a notice which contains a request for further information in accordance with paragraph (1), the sponsor may send an amended request for approval for further consideration within—

(a)the period of 60 days beginning with the day on which the notice is given; or

(b)any such extended period as the appropriate authority may in any particular case allow.

(3) An amended request for approval can be a response to the request for further information or an amendment to the request for approval.

(4) In this regulation, “ appropriate authority ” has the meaning given in regulation 18B(1).

Approval procedure for amended requests for approval

18B.—(1) An amended request for approval must be reviewed by the appropriate authority, which, for the purposes of this regulation, is either or both of the following—

(a)the licensing authority, if the request for further information relates to the licensing authority’s decision on the clinical trial authorisation;

(b)the ethics committee, if the request for further information relates to the ethics committee opinion.

(2) The appropriate authority must notify the sponsor of its decision or its opinion, or both its decision and opinion.

(3) A notice under paragraph (2) must—

(a)be in writing; and

(b)state that the appropriate authority—

(i)approves the amended request,

(ii)approves the amended request, subject to conditions specified in the notice, or

(iii)does not approve the amended request, setting out the grounds for this decision.

(4) Subject to paragraphs (6) and (7) and regulation 18C, the appropriate authority must take all reasonable steps to ensure that the notice is given within the period of 10 days beginning with the date of receipt of an amended request for approval.

(5) If a notice is given in accordance with paragraph (3)(b)(ii)—

(a)the notice must specify whether the conditions relate to either or both of the following—

(i)the licensing authority’s decision on the clinical trial authorisation;

(ii)the ethics committee opinion;

(b)the clinical trial is to be treated as approved only if the conditions specified in the notice are satisfied.

(6) The period of 10 days referred to in paragraph (4) is extended by a further—

(a)30 days, where the licensing authority or the ethics committee consults either or both of the following—

(i)a relevant committee;

(ii)a specialist group or committee;

(b)60 days, where—

(i)the investigational medicinal product is an advanced therapy medicinal product, and

(ii)the licensing authority or the ethics committee consults either or both of the groups or committees mentioned in sub-paragraph (a).

(7) If the clinical trial involves a medicinal product for xenogenic cell therapy, the time periods set out in paragraphs (4) and (6) do not apply and the appropriate authority may give written notice under this regulation at any time after receipt of an amended request for approval.

(8) The request for approval is to be treated as rejected and the authorities may not consider any further amendments to the request if—

(a)the authorities give written notice to the sponsor which contains a request for further information in accordance with regulation 18A(1) and the sponsor does not submit an amended request in accordance with regulation 18A(2); or

(b)the sponsor has submitted an amended request in accordance with regulation 18A(2), but the appropriate authority gives written notice to the sponsor in accordance with paragraph (3)(b)(iii).

Approval procedure time periods in special circumstances

18C.—(1) For the purposes of regulations 18(4) and 18B(4)—

(a)where the sponsor selects a date other than the next available ethics committee meeting, then the time periods referred to in those regulations will begin from the date that is 7 days before the chosen ethics committee meeting date; and

(b)where the clinical trial involves a medical device, then the time periods referred to in those regulations may begin from the date of formal acceptance under regulation 16(4) of the Medical Devices Regulations 2002.

(2) Where the valid request for approval or amended request for approval falls under both paragraphs (1)(a) and (1)(b), the time periods referred to in regulations 18(4) and 18B(4) will begin from the later of the dates mentioned in paragraphs (1)(a) and (1)(b).

Clinical trials conducted in countries other than the United Kingdom

19.—(1) If the licensing authority receives a request for authorisation which complies with regulations 14 and 16, relating to a clinical trial which is or is to be conducted in another country as well as the United Kingdom, the licensing authority may, if it thinks fit, require the production by the sponsor of either or both of the following—

(a)an undertaking, given by the sponsor, to permit their premises in that country to be inspected by or on behalf of the licensing authority for the purpose of establishing whether the conditions and principles of good clinical practice in accordance with Schedule 1 are satisfied or adhered to in relation to that trial; or

(b)an undertaking, given by the owner or occupier of any premises in that country at which the clinical trial is or is to be conducted, to permit those premises to be inspected by or on behalf of the licensing authority for the purpose of establishing whether the conditions and principles of good clinical practice are satisfied or adhered to in relation to that trial.

(2) If a sponsor fails to produce an undertaking required by the licensing authority in accordance with paragraph (1), that failure constitutes a ground for not approving the request for authorisation.

Modifications to clinical trial approval

20. A modification to a clinical trial approval may be made—

(a)by the licensing authority or the ethics committee, in accordance with regulation 21; or

(b)by the sponsor, in accordance with regulations 22, 22A and 22B.

Modifications by the licensing authority or the ethics committee

21.—(1) The appropriate authority may require the sponsor to make modifications to a clinical trial approval if it appears to the authority to be necessary to ensure—

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

(b)that the conditions and principles of good clinical practice are satisfied or adhered to in relation to the clinical trial.

(2) Where the appropriate authority proposes a modification in accordance with paragraph (1), that authority must, at least 7 days before the date on which it is proposed that the modification should take effect, serve a notice on the sponsor stating their proposal and the reasons for it.

(3) If, within the period of 7 days beginning with the date on which notice is served in accordance with paragraph (2), the sponsor makes representations in writing to the appropriate authority, that authority—

(a)must take those representations into account before deciding whether to require the sponsor to make the modification; and

(b)may delay the date the proposed modification is to take effect, in order to allow time for them to consider those representations.

(4) In this regulation, the “ appropriate authority ” means either or both of the following—

(a)the licensing authority;

(b)the ethics committee.

Modifications by the sponsor

22.—(1) A sponsor may make a modification to a clinical trial approval, other than a substantial modification, at any time and without the need for submitting a request under this regulation.

(2) A sponsor must—

(a)keep records of the modifications made in accordance with paragraph (1); and

(b)send those records to the licensing authority or the ethics committee, where the authority or committee (as the case may be) gives written notice requiring the sponsor to provide those records.

(3) If a sponsor makes a modification of an important detail, the sponsor must notify the authorities of the modification through an online portal made available for this purpose.

(4) If the sponsor proposes to make a substantial modification to a clinical trial approval which consists of, or includes, a substantial modification to—

(a)the terms of the request for approval of the clinical trial; or

(b)the particulars or documents that accompanied that request for approval,

the sponsor must submit a modification request to the authorities in accordance with paragraphs (6) and (7).

(5) Where the request for approval of the clinical trial was made under regulation 16(5), then a valid modification request must be submitted pursuant to paragraph (4) if the sponsor proposes to make a substantial modification to the clinical trial approval which consists of, or includes, a substantial modification to—

(a)the terms of the request for authorisation of the clinical trial;

(b)the application for an ethics committee opinion in relation to the trial; or

(c)the particulars or documents that accompanied—

(i)the request for authorisation, or

(ii)the application for an ethics committee opinion.

(6) A modification request must—

(a)be submitted to an online portal made available for this purpose;

(b)clearly identify the proposed substantial modification and whether it relates to the authorisation by the licensing authority or the ethics committee opinion;

(c)where the proposed substantial modification is a Route B substantial modification, include a statement confirming that it is a Route B substantial modification;

(d)be accompanied by—

(i)the particulars and documents specified in Part 3 of Schedule 3, and

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

(7) The modification request and accompanying material in paragraph (6) must be supplied in English.

(8) The authorities must confirm whether the modification request is valid within the period of 7 days beginning with the date of the submission of the request and notify the sponsor accordingly.

Approval procedure for substantial modifications

22A.—(1) Where the licensing authority and an ethics committee receive a valid modification request in relation to a substantial modification to a clinical trial approval—

(a)the licensing authority must—

(i)review the request in relation to the authorisation to conduct the clinical trial, and

(ii)provide its decision in accordance with this regulation;

(b)the ethics committee must—

(i)review the request in relation to the ethics committee opinion for the clinical trial, and

(ii)provide an opinion in accordance with this regulation.

(2) Where the modification request contains a statement under regulation 22(6)(c) confirming that the modification is a Route B substantial modification, the licensing authority may, if it considers appropriate and without undertaking further assessment, rely on that statement to provide its decision on the modification request.

(3) The authorities must notify the sponsor of the decision in paragraph (1)(a)(ii) or the opinion in paragraph (1)(b)(ii), or both the decision and the opinion.

(4) A notice under paragraph (3) must—

(a)be in writing; and

(b)state that the authorities—

(i)approve the proposed modification,

(ii)approve the proposed modification, subject to conditions specified in the notice, or

(iii)do not approve the proposed modification, setting out the grounds for this decision.

(5) The authorities must take all reasonable steps to ensure that the notice is given within the period of 35 days beginning with the date on which the authorities notified the sponsor that the modification request was valid in accordance with regulation 22(8).

(6) If a notice is given in accordance with paragraph (4)(b)(ii)—

(a)the notice must specify whether the conditions relate to either or both of the following—

(i)the licensing authority’s decision on the clinical trial authorisation;

(ii)the ethics committee opinion;

(b)the modification is to be treated as approved only if the conditions specified in the notice are satisfied.

(7) If a notice is given in accordance with paragraph (4)(b)(iii), regulations 22B and 22C apply.

Request for further information regarding proposed substantial modifications

22B.—(1) A notice given in accordance with regulation 22A(4)(b)(iii) may request further information required to reconsider the approval of the request.

(2) If the notice contains a request for further information in accordance with paragraph (1), then the notice must specify whether the request for further information relates to either or both of the following—

(a)the licensing authority’s decision;

(b)the ethics committee opinion.

(3) If the sponsor is given a notice in accordance with regulation 22A(4)(b)(iii) which contains a request for further information in accordance with paragraph (1), the sponsor may send an amended modification request for further consideration within—

(a)the period of 60 days beginning with the day on which the notice is given; or

(b)such extended period as the appropriate authority may in any particular case allow.

(4) An amended modification request can be a response to the request for further information or an amendment to the modification request.

(5) In this regulation, “ appropriate authority ” has the meaning given in regulation 22C(1).

Approval procedure for amended requests regarding substantial modifications

22C.—(1) An amended modification request must be reviewed by the appropriate authority, which, for the purposes of this regulation, is either or both of the following—

(a)the licensing authority, if the request for further information relates to the licensing authority’s decision;

(b)the ethics committee, if the request for further information relates to the ethics committee opinion.

(2) The appropriate authority must notify the sponsor of its decision or its opinion, or both its decision and opinion.

(3) A notice under paragraph (2) must—

(a)be in writing; and

(b)state that the appropriate authority—

(i)approves the amended request,

(ii)approves the amended request, subject to conditions specified in the notice, or

(iii)does not approve the amended request, setting out the grounds for this decision.

(4) The appropriate authority must take all reasonable steps to ensure that the notice is given within the period of 10 days beginning with the date of receipt of an amended modification request.

(5) If a notice is given in accordance with paragraph (3)(b)(ii)—

(a)the notice must specify whether the conditions relate to either or both of the following—

(i)the licensing authority’s decision;

(ii)the ethics committee opinion;

(b)the modification is to be treated as approved only if the conditions specified in the notice are satisfied.

(6) The modification request is to be treated as rejected and the authorities may not consider any further amendments to that request if—

(a)the authorities give written notice to the sponsor in accordance with regulation 22A(4)(b)(iii) and—

(i)the notice does not contain a request for further information in accordance with regulation 22B(1), or

(ii)the sponsor does not submit an amended request in accordance with regulation 22B(2); or

(b)the sponsor has submitted an amended request in accordance with regulation 22B(3), but the appropriate authority gives written notice to the sponsor in accordance with paragraph (3)(b)(iii).

Reference to the appropriate committee or the Medicines Commission

23.—(1) This regulation applies where—

(a)a sponsor has been notified under regulation 18(2) or 18B(2) that—

(i)the trial is not approved and the grounds for not approving the trial relate to the licensing authority’s decision on the clinical trial authorisation, or

(ii)the trial is approved subject to specified conditions and those conditions relate to the licensing authority’s decision;

(b)the licensing authority has modified a clinical trial approval under regulation 21; or

(c)the sponsor has been notified under regulation 22A(3) or 22C(2) that—

(i)a proposed substantial modification is not approved and the grounds for not approving the modification relate to the licensing authority’s decision, or

(ii)the proposed _dfnsubstantial modification is approved subject to conditions and those conditions relate to the licensing authority’s decision.

(2) Where this regulation applies, the sponsor may, within the period of 28 days beginning with the day on which notice is given or such extended period as the licensing authority may in any particular case allow, give notice in writing to the licensing authority of the sponsor’s wish to make written or oral representations to the appropriate committee.

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

Review and appeal relating to ethics committee opinion

24.—(1) This regulation applies where—

(a)a sponsor has been notified under regulations 18(2) or 18B(2) that—

(i)the trial is not approved and the grounds for not approving the trial relate to the ethics committee opinion, or

(ii)the trial is approved subject to specified conditions and those conditions relate to the ethics committee opinion;

(b)the ethics committee has modified a clinical trial approval under regulation 21; or

(c)the sponsor has been notified under regulation 22A(3) or 22C(2) that—

(i)a proposed substantial modification is not approved and the grounds for not approving the modification relate to the ethics committee opinion, or

(ii)the proposed _dfnsubstantial modification is approved subject to conditions and those conditions relate to the ethics committee opinion.

(2) This regulation does not apply in relation to an opinion given by—

(a)an Ethics Committee constituted by regulations made by the Scottish Ministers under section 51(6) of the Adults with Incapacity (Scotland) Act 2000; or

(b)an ethics committee pursuant to paragraph 2 of Schedule 4.

(3) Where this regulation applies, the sponsor may, within the period of 28 days beginning with the day on which notice is given or such extended period as the Authority may in any particular case allow, give notice in writing to the Authority—

(a)stating the sponsor’s wish to appeal against the opinion; and

(b)setting out their representations with respect to that opinion.

(4) Schedule 4 has effect to regulate the procedure where the Authority receives a notice in accordance with paragraph (3).

Transparency requirements

25.—(1) Subject to paragraphs (5), (7) and (10), the sponsor must register a clinical trial in a public registry by the earlier of the following—

(a)the date on which the first individual is recruited to be a participant in that trial;

(b)90 days after the date of approval of the clinical trial.

(2) Subject to paragraphs (5), (7) and (10), within the period of 12 months beginning with the day after the conclusion of the clinical trial in accordance with regulation 27, the sponsor must—

(a)publish a summary of the results of the clinical trial in the same public registry or registries (if more than one) as the trial was registered in accordance with paragraph (1); and

(b)offer to all relevant persons a summary of the results written in a manner that is understandable to laypersons.

(3) The sponsor may apply for a deferral or waiver of the requirement to register a clinical trial in accordance with paragraph (1), stating why the deferral or waiver is needed—

(a)at the time of the request for approval under regulation 16; or

(b)at any time before the date specified in paragraph (1).

(4) The sponsor may apply for a deferral or waiver of either or both of the requirements in paragraph (2), stating why the deferral or waiver is needed—

(a)at the time of the request for approval under regulation 16; or

(b)at any time before the date specified in paragraph (2).

(5) Where the sponsor applies for a deferral or a waiver in accordance with paragraphs (3) or (4), the Authority may—

(a)where they consider appropriate, defer the requirement for up to a period of 30 months beginning with the day after the conclusion of the trial, for example, in order to protect commercially confidential information; or

(b)in exceptional circumstances, waive the requirement, for example, for reasons of national defence and security.

(6) The sponsor may apply for a further deferral, stating why the deferral is needed, at any time before the expiry of the previous deferral.

(7) Where the sponsor applies for a further deferral in accordance with paragraph (6), the Authority may, where they consider appropriate, defer the requirement for up to a period of 30 months beginning with the day after the end of the previous deferral period, for example, in order to protect commercially confidential information.

(8) The Authority must give written notice of their decision to the sponsor—

(a)at the time the ethics committee provides a favourable opinion in accordance with regulation 18 or 18B, where the sponsor makes the application to defer or waive under paragraph (3)(a) or (4)(a); or

(b)subject to paragraph (9), within the period of 10 days beginning with the date of receipt of the application to defer or waive the requirement, where this application is made under paragraphs (3)(b), (4)(b) or (6).

(9) Where the sponsor makes an application under paragraph (3)(b) before the ethics committee provides a favourable opinion in accordance with regulation 18 or 18B, then the Authority may give written notice of their decision on the application for a deferral or waiver to the sponsor at the time the ethics committee provides a favourable opinion.

(10) Where the clinical trial is a Phase I trial, the Authority may provide an automatic deferral of—

(a)the requirement to register the trial in accordance with paragraph (1) for up to a period of 30 months beginning with the day after the conclusion of the trial, provided that the sponsor registers the required minimum information in a public registry before the date specified in paragraph (1);

(b)the requirements in paragraph (2) for up to a period of 30 months beginning with the day after the conclusion of the trial.

(11) The combined period of deferrals granted under paragraphs (5), (7) and (10) must not be more than the period of 10 years beginning with the day after the conclusion of the trial.

(12) In this regulation—

“ public registry ” means a a primary or partner registry of, or a data provider to, the WHO International Clinical Trials Registry Platform, provided that the registry, or the data provider, facilitates public access to information about the trial in the United Kingdom;

“ relevant person ” includes—

“ required minimum information ” includes the particulars identifying the trial and the details of the sponsor and investigator.

Lapse of clinical trial approval

26.—(1) Subject to the extension of the period in paragraphs (3) and (5), the clinical trial approval lapses at the end of the period of 24 months beginning with the date of approval of the trial if there are no participants recruited to take part in the trial.

(2) The sponsor may apply for an extension of the time period referred to in paragraph (1), stating why an extension is needed—

(a)at the time of the request for approval under regulation 16; or

(b)at any time before the expiry of the two-year period specified in paragraph (1).

(3) Where the sponsor applies for an extension in accordance with paragraph (2), the authorities may, where they consider appropriate, agree to extend the period for up to 36 months beginning with the day after the expiry of the period specified in paragraph (1), for example, where the trial involves the study of a rare disease or the trial is in anticipation of a disease causing a pandemic.

(4) The sponsor may apply for a further extension, stating why the extension is needed, at any time before the expiry of the previous extension.

(5) Where the sponsor applies for a further extension in accordance with paragraph (4), the authorities may, where they consider appropriate, agree to extend the period for up to 24 months beginning with the day after the end of the previous extension period, for example, where the trial involves the study of a rare disease or the trial is in anticipation of a disease causing a pandemic.

(6) The authorities must give written notice of their decision to the sponsor—

(a)at the time they approve the request for approval or amended request for approval in accordance with regulation 18 or 18B, where the sponsor makes the application to extend under paragraph (2)(a); or

(b)within the period of 30 days beginning with the date of receipt of the application to extend, where this application is made under paragraphs (2)(b) or (4).

(7) If the period has lapsed in accordance with paragraph (1)—

(a)the sponsor must notify the authorities in writing that the trial has ended; or

(b)the trial will be terminated in accordance with regulation 31.^F142]

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.

[^F143Information sharing

27A. The licensing authority [^F144 , the Authority^F144] and an ethics committee may disclose to each other any information acquired in carrying out their respective functions under these Regulations where disclosing such information may assist the other body in carrying out its functions under these Regulations.^F143]

[^F145Publication of information

27B.—(1) Subject to paragraph (3), the 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 approval made under regulation 16;

(b)any amended request for approval made under regulation 18A;

(c)any substantial modification to the clinical trial approval made under regulation 21, 22, 22A or 22B;

(d)the favourable opinion of the ethics committee given in accordance with regulation 18(1)(b);

(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 Authority must, after consulting such persons as they consider appropriate, publish a list of the information which may be made accessible to the public under paragraph (1).^F145]

PART 4 GOOD CLINICAL PRACTICE AND THE CONDUCT OF CLINICAL TRIALS

Good clinical practice and protection of clinical trial [^F146participants^F146]

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.

[^F147 (1A) The conditions and principles of good clinical practice include those in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, as amended from time to time.

(1B) For the avoidance of doubt—

(a)the functions of the sponsor include functions in relation to—

(i)the development and maintenance of trial specific computerised systems, and

(ii)the selection and oversight of a laboratory in relation to the analysis or evaluation of human samples collected as part of the clinical trial; and

(b)conducting a trial includes the analysis or evaluation of human samples collected as part of the clinical trial.^F147]

(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 [^F148participants^F148] of the trial free of charge.

(4) The restriction in paragraph (3) shall not apply in relation to any charge payable by a [^F149participant^F149] under regulations made under—

(a)^M17the National Health Service Act 1977 ;

(b)^M18the National Health Service (Scotland) Act 1978 ; or

(c)^M19the 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 [^F150location^F150] ; and

(b)the request for authorisation to conduct that trial specifies that in relation to one or more trial [^F151locations^F151] 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 [^F150location^F150] or those [^F151locations^F151] , 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 [^F152modified^F152] from time to time in accordance with [^F153regulations 20 to 22C^F153] ;

(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 [^F154modified^F154] from time to time in accordance with [^F155regulations 20 to 22C^F155] ; and

(c)^F156any conditions imposed ... under [^F157regulation 18(3), 18B(3), 22A(4), 22C(3)^F157] or Schedule 5.

[^F158Notification of serious breaches

29A.—(1) The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of—

(a)the conditions and principles of good clinical practice in connection with that trial; or

(b)the protocol relating to that trial, as [^F159 modified^F159] from time to time in accordance with [^F160 regulations 20 to 22C^F160] ,

within 7 days of becoming aware of that breach.

(2) For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a significant degree—

(a)the safety or physical or mental integrity of the [^F161 participants^F161] of the trial; or

(b)the scientific value of the trial.^F158]

Urgent safety measures

30.—(1) The sponsor and investigator may take appropriate urgent safety measures in order to protect the [^F162participants^F162] of a clinical trial against any immediate hazard to their health or safety.

[^F163 (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 [^F164 7 days^F164] 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.^F163]

Suspension or termination of clinical trial

31.—(1) If, in relation to a clinical trial[^F165 or part of a clinical trial^F165] —

(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)^F166any condition imposed ... under [^F167regulation 18(3), 18B(3), 22A(4), 22C(3)^F167] or Schedule 5,

is no longer satisfied (either generally or at a particular trial [^F168location);^F168]

(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 [^F169location; or^F169]

[^F170 (c)the trial has lapsed in accordance with regulation 26 and the sponsor has not notified the licensing authority that the trial has ended,^F170]

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 [^F171trial location^F171] ;

(b)in a case where the suspension or termination applies to the conduct of a trial at a particular [^F171trial location^F171] , on—

(i)the sponsor, or

(ii)the investigator at that [^F171trial location^F171] .

(3) The notice shall specify—

(a)whether the notice applies to the trial generally or to one or more of the trial [^F172locations^F172] ;

(b)whether the notice requires suspension or termination of the trial [^F173in whole or in part, and, if it applies to part of the trial, to which part it applies^F173] ;

(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 [^F174location^F174] , 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;

^F175(b). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(c)the relevant ethics committee;

^F176(d). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

^F177(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 [^F178(in whole or in part)^F178] , or the conduct of a trial at a particular [^F179location^F179] , 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 [^F179location^F179] , 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 [^F180participants^F180] of the clinical trial.

^F181(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 ....

^F182(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).

^F183(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.

[^F184Trial master file and archiving

31A.—(1) The sponsor shall keep a trial master file for a clinical trial.

(2) The sponsor shall ensure that the trial master file is readily available at all reasonable times for inspection by the licensing authority or any person appointed by the sponsor to audit the arrangements for the trial.

(3) The master file shall at all times contain the essential documents relating to that clinical trial.

(4) The essential documents relating to a clinical trial are those which—

(a)enable both the conduct of the clinical trial and the quality of the data produced to be evaluated; and

(b)show whether the trial is, or has been, conducted in accordance with the [^F185 relevant^F185] requirements of [^F186 these Regulations^F186] .

(5) The essential documents shall contain information specific to each phase of the trial.

(6) The sponsor shall ensure that any alteration to a document contained, or which has been contained, in the trial master file shall be traceable.

(7)[^F187 Subject to paragraph (7A),^F187] the sponsor and the chief investigator shall ensure that the documents contained, or which have been contained, in the trial master file [^F188 (including documents contained in electronic form)^F188] are retained for at least [^F189 the period of 25 years beginning with the day^F189] after the conclusion of the trial and that during that period are—

(a)readily available to the licensing authority on request; and

(b)complete and legible.

[^F190 (7A) If, at the date of the expiry of the 25 years referred to in paragraph (7), the data generated by the trial is being used to support an application for a UK marketing authorization, the sponsor shall ensure the documents referred to in paragraph (7) are retained for at least the period of 2 years beginning with the day after the grant of that UK marketing authorization.^F190]

(8) The sponsor and chief investigator shall ensure that the medical files of trial [^F191 participants^F191] are retained for at least [^F192 the period of 25 years beginning with the day after conclusion of the trial, or such period as is required by any other enactment, if longer^F192] .

(9) The sponsor shall appoint named individuals within his organisation to be responsible for archiving the documents which are, or have been, contained in the trial master file and, subject to paragraph (2), access to those documents shall be restricted to those appointed individuals.

(10) If there is transfer of ownership of data or documents connected with the clinical trial—

(a)the sponsor shall record the transfer; and

(b)the new owner shall be responsible for data retention and archiving in accordance with paragraphs (2), (7) and (8).

(11) For the purposes of this regulation, an individual is an individual within the sponsor’s organisation where—

(a)he is employed or engaged by the sponsor;

(b)he is acting under arrangements made with the sponsor for the purposes of managing or conducting the clinical trial;

(c)where the sponsor is an individual, he is the sponsor; or

(d)where the sponsor is a body of persons, he is—

(i)a member of the body, or

(ii)employed or engaged by such a member.^F184]

PART 5 PHARMACOVIGILANCE

[^F193Record keeping

A32.—(1) A sponsor shall keep detailed records of all serious adverse events and serious adverse reactions, including suspected unexpected serious adverse reactions, which occur during the course of a clinical trial—

(a)in the United Kingdom;

(b)conducted outside of the United Kingdom where—

(i)the sponsor of both the trial in the United Kingdom and the trial outside of the United Kingdom is the same or, where the sponsor is a company, in the same group, and

(ii)the investigational medicinal product being tested or used in the trial conducted outside of the United Kingdom is the same as the investigational medicinal product being tested or used in the clinical trial mentioned in sub-paragraph (a).

(2) A sponsor shall evaluate the events and reactions mentioned in paragraph (1), with a view to—

(a)minimising and preventing any risk presented by the use of the investigational medicinal product to which those events and reactions relate; and

(b)taking appropriate measures as soon as reasonably practicable to investigate the risks presented and implement actions for minimising and preventing those risks.

(3) For purposes of paragraph (1)(b)(i), “ group ” has the same meaning as in Part 15 of the Companies Act 2006 (see section 474(1) of that Act ). ^F193]

Notification of adverse events

32.—(1) An investigator shall report any serious adverse event which occurs in a [^F194participant^F194] 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 [^F194participant^F194] referred to in the report by a number assigned to that [^F194participant^F194] in accordance with the protocol for the trial.

(7) The number assigned to a [^F194participant^F194] in accordance with the protocol must be different from the number of any other [^F194participant^F194] in that trial, including any [^F194participant^F194] 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 [^F194participant^F194] , 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.[^F195—(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 reported as soon as possible to the licensing authority, and in any event no later than 7 days after the sponsor was first aware of the reaction.^F195]

(2) A sponsor shall ensure that within 8 days of a report in accordance with [^F196paragraph (1)^F196] , any additional relevant information is sent to the [^F197licensing authority^F197] .

[^F198 (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 the licensing authority, and in any event no later than 15 days after the sponsor is first aware of the reaction.^F198]

^F199(4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

[^F200 (4A) Paragraphs (1) to (3) do not apply to suspected unexpected serious adverse reactions specified in the protocol as not requiring immediate reporting.

(4B) The sponsor shall report suspected unexpected serious adverse reactions to which paragraph (4A) applies to the licensing authority in accordance with the reporting requirements, including the time periods for such reporting, that are specified in the protocol.^F200]

^F201(5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(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

^F202(b). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Clinical trials conducted in [^F203countries other than the United Kingdom^F203]

34. If a clinical trial is being conducted at a trial site in [^F204another country^F204] 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 [^F205reported 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.^F205]

^F206Annual ... safety report

35.[^F207—(1) Within the period of 60 days beginning with the day after the day on which the reporting year ends, a sponsor shall, in relation to each investigational medicinal product tested in clinical trials referred to in regulation A32(1), provide the licensing authority with a report on the safety of the participants of those trials.^F207]

[^F208 (1A) A report under paragraph (1) shall include—

(a)the records of, and evaluation relating to, any serious adverse reactions and serious adverse events which have occurred during the reporting year, including suspected unexpected serious adverse reactions, kept or conducted under regulation A32;

(b)the record of the taking of any measures referred to in regulation A32(2)(b);

(c)a description of how any safety concerns in the clinical trial have been assessed and managed; and

(d)a description of the overall safety profile of each investigational medicinal product being tested or used in the trials referred to in regulation A32(1), as well as a summary description of the processes adopted by the sponsor to monitor the overall safety profile of those products.

(1B) The records of serious adverse reactions and serious adverse events referred to in paragraph (1A)(a) may take the form of a list.

(1C) The licensing authority may request that the sponsor provide a list of serious adverse reactions and serious adverse events, including suspected unexpected serious adverse reactions, which have occurred at any time during the reporting year, in relation to a clinical trial referred to in regulation A32(1), where it considers it necessary to do so to investigate specific safety issues—

(a)which emerge from the report under paragraph (1); or

(b)which have otherwise come its attention, and raise concerns about the safety of the trial or the participants.

(1D) The sponsor shall provide the list requested under paragraph (1C) within the period of 30 days beginning with the day of receiving the request, or within such shorter period as the licensing authority may specify in the request.^F208]

(2) In [^F209 this regulation ^F209] , “ 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 [^F210any country^F210] .

(3) For the purposes of paragraph (2)(b), the date on which a clinical trial was authorised in [^F211a country^F211] is—

[^F212 (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.^F212]

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 [^F213 regulations 37 and 37A ^F213] , no person shall manufacture, assemble or import any investigational medicinal product except in accordance with an authorisation [^F214 of the appropriate type ^F214] granted by the licensing authority for the purposes of this regulation (“a manufacturing authorisation”).

[^F215 (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.^F215]

(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[^F216 or marketing authorisation issued by the competent authority of an EEA State in accordance with Directive relating to that product. 2001/83/EC^F216]

[^F217 (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.^F217]

[^F218Manufacture 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.^F218]

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.

[^F219Exemption for radiopharmaceuticals used for diagnostic purposes

37A.—(1) The restriction imposed by regulation 36(1) does not apply to the manufacture or assembly of a radiopharmaceutical used for diagnostic purposes where the conditions in paragraph (2) are satisfied.

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

(a)the manufacture or assembly is carried out by the holder of a manufacturer’s licence, as defined in regulation 8(1) of the 2012 Regulations, which does not relate to the manufacture of investigational medicinal products; and

(b)the radiopharmaceutical is exclusively for use in a hospital or health centre which is—

(i)a trial location for the clinical trial in which the product is to be used, or

(ii)taking part in the clinical trial.^F219]

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)[^F220 Subject to paragraph (3A), every^F220] 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 [^F221Medicines (Products for Human Use) (Fees) Regulations 2016^F221] .

[^F222 (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.^F222]

(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.

[^F223 (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.^F223]

(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,

[^F224 (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 _dfnCommission Directive 2003/94/EC[^F225 in respect of Great Britain, or of Commission Delegated Regulation 2017/1569 in respect of Northern Ireland^F225] , as regards the manufacture or import, and control, of the products to which the authorisation relates and the storage of such products,^F224]

(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)^F226the manufacturing, assembling or importation operations; ...

[^F227 (bb)in the case of an authorisation relating to the inactivation of viral or non-conventional agents, the manufacturing process; and^F227]

(c)[^F228 except in the case of an MM investigational medicinal product or a POC investigational medicinal product,^F228] 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

[^F229 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.^F229]

Qualified persons

43.[^F230—(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, [^F231 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,^F231] and

who is responsible for carrying out the duties referred to in paragraph [^F232 (1A) or^F232] 2.

[^F233 (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.^F233]

(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 [^F234 Article 62 of the EU Regulation^F234] , 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[^F235 in respect of Great Britain or Commission Delegated Regulation 2017/1569 in respect of Northern Ireland^F235] .

(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.^F230]

^M20(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 [^F236 (1A) or ^F236] (2) for the purposes of that authorisation.

[^F237 (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 [^F238 Schedule 7 to the 2012 Regulations^F238] , 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.^F237]

(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 [^F239Schedule 7 to the 2012 Regulations^F239] 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.

[^F240Approved 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.^F240]

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 [^F241change—^F241]

(i)the types of investigational medicinal products,

(ii)the manufacturing, assembling or importation operations,

[^F242 (iia)the manufacturing process,^F242]

(iii)the premises,

(iv)the technical equipment and control facilities, [^F243or^F243]

[^F244 (v)the staff, including the qualified person,^F244]

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.

[^F245 (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 [^F246 Medicines (Products for Human Use) (Fees) Regulations 2016 ^F246] ; and

“valid application” means an application—

[^F247 (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.^F247]

[^F248Variation 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.^F248]

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 [^F249or, in the case of an investigational medicinal product manufactured or assembled in Northern Ireland, any equivalent provisions in any EEA State^F249] , 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)^F250total; ...

(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;

[^F251 (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.^F251]

(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.

[^F252 (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.^F252]

[^F253Part 6A NON-INVESTIGATIONAL MEDICINAL AND NON-MEDICINAL PRODUCTS

Non-investigational medicinal and non-medicinal products

45A.—(1) A non-investigational medicinal product shall be manufactured or assembled in accordance with the principles and guidelines for good manufacturing practice which apply under these Regulations or the 2012 Regulations.

(2) A product which is not a medicinal product but which is used or to be used in a clinical trial, as described in the protocol, must—

(a)comply with safety standards applicable to that product; and

(b)be listed in the investigational medicinal product dossier with information about its properties, labelling, manufacture and safety controls, appropriate to the product.^F253]

[^F254PART 7 LABELLING

Labelling of investigational medicinal products

46.—(1) Subject to paragraph (4), where the investigational medicinal product is not an authorised medicinal product, it must be labelled with the following information—

(a) the words “for clinical trial use only”;

(b)a warning that the product must be stored out of the reach and sight of children (unless the product is to be exclusively administered in a hospital or health centre taking part in the clinical trial);

(c)information to identify the sponsor and contact persons involved in the clinical trial;

(d)information to allow identification of the clinical trial, for example the clinical trial reference code;

(e)information linking the product to the participant, for example, the participant identification number;

(f)information to allow identification of the medicinal product, including—

(i)the common name of the active substance,

(ii)the strength and pharmaceutical form,

(iii)the contents by weight, volume or number of doses, and

(iv)the batch or code number;

(g)information related to the use of the medicinal product, including—

(i)instructions for use (which may be by reference to a patient information leaflet),

(ii)method or route of administration,

(iii)expiry date, and

(iv)any special storage precautions; and

(h)in the case of trials in which blinding occurs, the name of any comparator or placebo product used alongside the investigational medicinal product.

(2) Subject to paragraph (4), where the investigational medicinal product is an authorised medicinal product, it must be labelled either—

(a)in accordance with paragraph (1); or

(b)in accordance with Part 13 of the 2012 Regulations.

(3) Paragraph (4) applies to an investigational medicinal product which is—

(a)an authorised medicinal product to be exclusively administered in a hospital or health centre taking part in the clinical trial; or

(b)a radiopharmaceutical used for diagnostic purposes.

(4) Where paragraph (3) applies, the investigational medicinal product must be labelled with at least the following information—

(a) the words “for clinical trial use only”, or equivalent wording;

(b)information linking the product to the participant, for example, the participant identification number;

(c)information to allow identification of the medicinal product, including—

(i)the common name of the active substance,

(ii)the strength and pharmaceutical form,

(iii)the contents by weight, by volume or by number of doses, and

(iv)the batch or code number;

(d)information related to the use of the medicinal product (which may be by reference to a patient information leaflet);

(e)the expiry date; and

(f)any other information relating to the clinical trial or the product that the authorities, as defined in regulation 11 (interpretation of Part 3), may require by guidelines published under paragraph (8).

(5) The sponsor may request to disapply or vary any of the requirements of this regulation at the time of the application under regulation 16.

(6) If a request under paragraph (5) is agreed—

(a)the licensing authority must inform the sponsor by a notice in writing at the time of approval under regulation 18 or 18B; and

(b)the sponsor must record that decision and any conditions in the investigational medicinal product dossier.

(7) Where—

(a)the trial is a notifiable trial; and

(b)the request concerns an authorised medicinal product which is to be exclusively administered in a hospital or health centre taking part in the trial,

the request is to be treated as agreed if no notice is given in accordance with paragraph (6)(a).

(8) The licensing authority may publish guidance on labelling of investigational medicinal products, which may include guidance on how the labelling requirements are to be met in relation to products that are—

(a)radiopharmaceuticals used for diagnostic purposes;

(b)used exclusively in a hospital or health centre;

(c)provided in differently sized or differently assembled packs, for example blister packs and small packages.

(9) For the purposes of this regulation, a medicinal product is authorised if there is a UK marketing authorisation or Article 126a authorisation, each as defined in regulation 8(1) of the 2012 Regulations, in force for the product.

(10) This regulation is subject to regulation 46B (labelling of certain POC investigational medicinal products).

Labelling of non-investigational medicinal products

46A. —(1) Subject to paragraph (2), a non-investigational medicinal product must be labelled in accordance with the requirements set out in regulation 46, and any reference in that regulation to “ investigational medicinal product ” is to be construed as a reference to “non-investigational medicinal product” accordingly.

(2) Regulation 46(4) does not apply to a non-investigational medicinal product which falls within sub-paragraph (a) of regulation 46(3).

Labelling of certain POC investigational medicinal products

46B. Regulation 46 does not apply to a POC investigational medicinal product that is to be administered in its entirety immediately after manufacture.^F254]

PART 8 ENFORCEMENT AND RELATED PROVISIONS

Application of enforcement provisions of [^F255the 2012 Regulations^F255]

47. [^F256 —(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. ^F256]

(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.

[^F257 (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.^F257]

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—

^F258(a). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(b)the relevant ethics committee; and

^F259(c). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

[^F260 (4) This regulation applies to regulations 3A, 12(1) and (2), 13(1), 22(2) to (5), 25(1) and (2)(a), 27, 28(1) to (3), 29, 29A, 30(2), 31A to 35, 36(1), 36A, 36B, 42, 43(1) and (6), 45A, 46 and 46A.^F260]

(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 [^F261 regulation 323(1) or 324(1) of the 2012 Regulations ^F261] as applied by regulation 47.

Offences

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

[^F262 (a)regulation 3A;^F262]

[^F263 (aa)^F263] regulation 12(1) and (2);

(b)regulation 13(1);

[^F264 (ba)regulation 22(2) to (5);

(bb)regulation 25(1) and (2)(a);

(bc)regulation 26(7)(a);^F264]

(c)regulation 27;

(d)regulation 28(1) to (3);

(e)regulation 29;

[^F265 (ee)regulation 29A;^F265]

(f)regulation 30(2);

[^F266 (ff)regulation 31A(1) to (3) and (5) to (10);^F266]