S.I. No. 190/2004 - European Communities (Clinical Trials on Medicinal Products For Human Use) Regulations, 2004

31. If a clinical trial is being conducted at a trial site in a third country in addition to sites in the State, the sponsor for that trial shall ensure that all suspected unexpected serious adverse reactions occurring at that site are entered into the European database established in accordance with Article 11 of the Directive.

Annual list of suspected serious adverse reactions and safety report

32.

32. (1) As soon as practicable after the end of the reporting year, a sponsor shall, in relation to each investigational medicinal product tested in clinical trials in the State for which he or she is the sponsor, furnish the Board and the relevant ethics committee with -

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

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

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

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

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

• (2) In this Regulation, “reporting year”, in relation to an investigational medicinal product, means the year ending on the anniversary of the earliest date on which any clinical trial -

• (a) relating to that product, and

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

was authorised in an EEA State.

• (3) For the purposes of paragraph (2), the date on which a clinical trial was authorised in an EEA State is -

• (a) in the case of the State, the date on which -

• (i) the trial was authorised by the Board in accordance with these Regulations, or

• (ii) a permission under section 4 of the Control of Clinical Trials Act 1987 in respect of that trial was issued by the Board,

whichever is earlier; and

• (b) in the case of any other EEA State, the date on which the trial was -

• (i) authorised by the competent authority of that EEA State in accordance with the Directive, or

• (ii) authorised, approved or consented to by any public body in accordance with any provision of the law of that State relating to the regulation or control of clinical trials on medicinal products,

whichever is earlier.

PART 6 MANUFACTURE AND IMPORTATION OF INVESTIGATIONAL MEDICINAL PRODUCTS

Requirement for authorisation to manufacture or import investigational medicinal products

33.

33. (1) Subject to paragraph (2) and Regulation 34, a person shall not manufacture, label, package or import any investigational medicinal product except in accordance with an authorisation granted by the Board for the purposes of this Regulation and which is for the time being in force.

• (2) The restriction in paragraph (1) shall not apply to the manufacture, labelling or packaging of a medicinal product that is the subject of a marketing authorisation, to the extent that such manufacture is in accordance with the terms and conditions of that authorisation.

Exemption for hospitals

34.

34. (1) Subject to paragraph (3), the restriction imposed by Regulation 33(1) shall not apply to the repackaging, or the making of other changes to the labelling or packaging 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 repackaging, or other changes to the labelling or packaging, is done -

• (i) in a hospital, and

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

• (b) the investigational medicinal product is intended for use only in that hospital in respect of subjects who may be resident in the hospital or attending the hospital as non-residents.

• (3) The Board may, by a notice in writing given or sent to the hospital in question, terminate the exemption conferred by paragraph (1), insofar as it relates to that hospital, if it appears to it that -

• (a) the hospital does not have the staff, premises, equipment or facilities necessary to carry out properly the processes of repackaging, or making other changes to the packaging, of the product; or

• (b) as a result of the repackaging, or other changes to the packaging, the product can no longer be regarded either as a product which can be safely administered to subjects or as a product which is of satisfactory quality for such administration.

• (4) Where the Board terminates the exemption in relation to a particular hospital pursuant to paragraph (3), that termination shall have effect until the notice is revoked or withdrawn.

• (5) In this Regulation -

“hospital” includes a group of hospitals that may be co-operating for the purposes of the conduct of a clinical trial;

“repackaging” includes operations, such as the reconstitution of investigational medicinal products, as are normally carried out by or under the supervision of a registered pharmacist in respect of medicinal products that are the subject of marketing authorisations.

Application for manufacturing authorisation

35.

35. (1) An application for the grant of a manufacturing authorisation shall -

• (a) be made in writing to the Board; and

• (b) be signed by or on behalf of the applicant, whether in ink or by means of an electronic signature.

• (2) Every application for the grant of a manufacturing authorisation shall specify -

• (a) the descriptions of investigational medicinal products, and of the manufacturing, labelling, packaging or importation operations, in respect of which the authorisation is required;

• (b) in the case of an authorisation in respect of manufacturing, the manufacturing processes for the products in respect of which the authorisation is required;

• (c) the premises at which those products are to be manufactured, labelled, packaged or controlled; and

• (d) which, if any, of the standard provisions referred to in Regulation 37(4) it is desired shall be excluded or modified in relation to the grant of the authorisation.

• (3) Every application for the grant of a manufacturing authorisation shall be accompanied by -

• (a) the particulars specified in Schedule 4 to these Regulations; and

• (b) any fee which may be payable in connection with that application.

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

Consideration of application for manufacturing authorisation

36.

36. (1) Subject to paragraph (2), the Board 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 Board may give a notice in writing to the applicant requesting him or her to provide further information relating to —

• (a) the particulars referred to in Regulation 35(2) or (3); or

• (b) the qualified person referred to in Regulation 40.

• (3) Where the Board gives 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 Board may, if it thinks 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 Board.

• (5) In this Regulation, “valid application” means an application which complies with the provisions of Regulation 35.

Grant or refusal of manufacturing authorisation

37.

37. (1) The Board shall grant a manufacturing authorisation only if -

• (a) the applicant -

• (i) has complied with the requirements of Regulation 35,

• (ii) has at his or her disposal suitable and sufficient premises, technical equipment and control facilities complying with the requirements of Commission Directive 2003/94/EC, as regards the manufacture, labelling, packaging or import, and control, of the products specified in accordance with Regulation 35(2)(a) and as regards the storage of such products,

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

• (iv) if a notice has been given under Regulation 36(2), has provided the information requested by the Board; and

• (b) it has established that the particulars supplied pursuant to Regulation 35(2) and (3) are accurate.

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

• (a) the descriptions of investigational medicinal products;

• (b) the manufacturing, packaging, labelling or importation operations;

• (c) in respect of manufacturing, the manufacturing processes; or

• (d) the premises,

specified in the application made pursuant to Regulation 35.

• (3) The Board 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 Board considers appropriate.

• (4) The provisions specified -

• (a) in the case of a manufacturing authorisation relating to the manufacture, labelling or packaging of investigational medicinal products, in Part 2 of Schedule 5; and

• (b) in the case of a manufacturing authorisation relating to the importation of investigational medicinal products, in Part 3 of Schedule 5,

may be incorporated by the Board 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 Part 2 of Schedule 3 shall have effect where the Board proposes -

• (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 Board -

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

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

the Board shall give the applicant a notice in writing stating the reasons for its decision.

Application and effect of manufacturing authorisation

38.

38. A manufacturing authorisation shall apply only in relation to -

• (a) the descriptions of investigational medicinal products;

• (b) the manufacturing, labelling, packaging or importation operations;

• (c) in respect of manufacturing, the manufacturing processes; and

• (d) the premises,

specified in the application made pursuant to Regulation 35 and in respect of which the authorisation has been granted.

Obligations of manufacturing authorisation holder

39.

39. The manufacturing authorisation holder shall comply with -

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

• (b) the provisions referred to in Regulation 37(3).

Qualified persons

40.

40. (1) The manufacturing authorisation holder shall have permanently and continuously at his or her disposal the services of at least one qualified person who is responsible for carrying out the duties referred to in paragraph 2.

• (2) A qualified person shall be responsible for carrying out the duties specified in Part 2 of Schedule 6, in accordance with the duties so specified, in respect of the investigational medicinal products manufactured, labeled, packaged or imported in accordance with the manufacturing authorisation in question.

• (3) Where, after giving the authorisation holder and the person acting as a qualified person the opportunity of making representations to it (orally or in writing), the Board is of the opinion that -

• (a) the person so acting does not satisfy the requirements as to qualifications and experience specified in -

• (i) Part 1 of Schedule 6, or

• (ii) paragraph (b) of the definition of “qualified person” in Regulation 4(1); or

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

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

• (4) The Board may require the manufacturing authorisation holder to temporarily suspend the person acting as such qualified person upon the commencement of administrative or disciplinary proceedings against him or her for failure to fulfil his or her functions in accordance with subparagraph (2) above and the authorisation holder shall not permit that person to act as the qualified person pending the determination of such proceedings.

Variation of manufacturing authorisation

41.

41. (1) The Board may vary a manufacturing authorisation, whether on the application of the authorisation holder or otherwise.

• (2) Subject to the following provisions of this Regulation, if the manufacturing authorisation holder makes a valid application to vary the manufacturing authorisation the Board shall consider the application and -

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

• (i) descriptions of investigational medicinal products,

• (ii) the manufacturing, labelling, packaging or importation operations,

• (iii) in the case of an authorisation in respect of manufacturing, the manufacturing processes,

• (iv) the premises,

• (v) the technical equipment and control facilities,

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 Board considers appropriate.

• (3) If the application falls within paragraph (2)(a), but it appears to the Board to be necessary to conduct an inspection of any premises to which the variation relates, the Board 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 Board may give a notice in writing to the applicant requesting him or her to provide further information relating to the contents of the application or any particulars relevant to the application.

• (5) Where the Board gives 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 Part 2 of Schedule 3 shall have effect where the Board proposes to vary a manufacturing authorisation in accordance with this Regulation.

• (7) Where the Board -

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

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

the Board shall notify the holder of that authorisation in writing, stating the reasons for its decision.

• (8) In this Regulation, “valid application” means an application -

• (a) made to the Board in writing and signed by or on behalf of the applicant, whether in ink or by means of an electronic signature;

• (b) specifying the variation requested by the applicant;

• (c) accompanied by -

• (i) such particulars as are necessary to enable the Board to consider the application, and

• (ii) any fee which may be payable in connection with that application; and

• (d) where the application, and any accompanying material, is in the English language.

Suspension and revocation of manufacturing authorisation

42.

42. (1) The Board may by a notice in writing to the manufacturing authorisation holder, forthwith or from a date specified in the notice, suspend the authorisation for such period as the Board 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 or she is no longer to carry out, the manufacturing, labelling, packaging or importation operations to which the authorisation relates;

• (b) the matters specified in the application in accordance with Regulation 35(2), or the particulars accompanying the application in accordance with Regulation 35(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 authorisation holder has failed to any material extent to comply with his or her obligations under Regulation 39 or 40(1);

• (e) the holder has manufactured, labeled, packaged 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, labeled or packaged 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 14 or any equivalent provisions in any EEA State other than the State, the specification for the product provided by the person who is to act as the sponsor for 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 accompanying the request for authorisation of the clinical trial in which the products are or are to be used;

• (g) the qualified person has failed to carry out the duties referred to in Regulation 40(2), adequately or at all; and

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

• (i) the processes of manufacture labelling or packaging 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 processes or operations.

• (2) The suspension or revocation of an authorisation under this Regulation may be -

• (a) total; or

• (b) limited to investigational medicinal products -

• (i) of one or more descriptions, or

• (ii) manufactured, labeled, packaged or stored on any particular premises or in a particular part of any premises.

• (3) The provisions of Part 2 of Schedule 3 shall have effect where the Board proposes to suspend or revoke a manufacturing authorisation in accordance with this Regulation.

• (4) Where the Board suspends or revokes a manufacturing authorisation in accordance with this Regulation, it shall notify the holder of that authorisation in writing, stating the reasons for its decision to suspend or revoke the authorisation.

PART 7 LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS

Labelling

43.

43. The particulars to appear on the outer packaging of an investigational medicinal product or, where there is no outer packaging, on the immediate packaging shall be-

• (a) such as to ensure protection of the subject and traceability, to enable identification of the product and trial, and to facilitate proper use of the investigational medicinal product; and

• (b) in the English language.

PART 8 OFFENCES, PENALTIES AND ENFORCEMENT

Offences and penalties

44.

44. (1) A person who contravenes any of the following provisions of these Regulations -

• (a) Regulation 10(1) and (2);

• (b) Regulation 11(1);

• (c) Regulation 19(b);

• (d) Regulation 24(1) (2) and (3);

• (e) Regulation 25;

• (f) Regulation 26(2);

• (g) Regulations 28 to 32;

• (h) Regulation 33(1);

• (i) Regulation 39;

• (j) Regulation 40(1) and (4);

• (k) Regulation 48(8) and (9),

shall be guilty of an offence.

• (2) A person who has in his or her possession a medicinal product for the purpose of selling or supplying it in contravention of Regulation 11(1) shall be guilty of an offence

• (3) A person who fails to comply with a notice of suspension or termination served on him or her under Regulation 27(1), unless that notice has been withdrawn or revoked by the Board, shall be guilty of an offence.

• (4) Where an investigational medicinal product is manufactured, labeled, packaged or imported in contravention of Regulation 33(1), any person who sells or supplies the product for the purposes of a clinical trial knowing or having reasonable cause to suspect that it was so manufactured, labeled, packaged or imported shall be guilty of offence.

• (5) Where an investigational medicinal product is imported in contravention of Regulation 33(1), any person who, otherwise than for the purpose of performing or exercising a duty or power imposed or conferred by or under these Regulations, is in possession of the product knowing or having reasonable cause to suspect that it was so imported shall be guilty of an offence.

• (6) Any person who sells or supplies an investigational medicinal product -

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

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

the labelling of which does not comply with Regulation 43, or who procures the sale or supply of such a product, shall be guilty of an offence.

• (7) A person guilty of an offence under these Regulation shall be liable on summary conviction to a fine not exceeding €3,000 or to imprisonment for a term not exceeding six months or both.

• (8) Where an offence under these Regulations is committed by a body corporate and is proved to have been so committed with the consent, connivance or approval of or to have been attributable to the wilful neglect on the part of any person, being a director, manager, secretary or other officer of the body corporate or a person who was purporting to act in any such capacity, that person, as well as the body corporate shall be guilty of an offence and shall be liable to be proceeded against and punished as if he or she was guilty of the first mentioned offence.

• (9) For the purposes of these Regulations, every contravention of a Regulation shall be deemed a separate contravention and every contravention of a paragraph or a subparagraph shall also be deemed to be a separate contravention and shall carry the same penalty as for a single contravention of any Regulation of these Regulations.

Infringement notices

45.

45. (1) If the Board has objective grounds for considering that any person has contravened any provision to which this Regulation applies, it may serve upon that person a notice in writing (in these Regulations referred to as an “infringement notice”) -

• (a) informing him or her of the Board'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 subparagraph (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 the Board serves an infringement notice in accordance with paragraph (1), it shall forthwith inform -

• (a) the competent authorities of each EEA State, other than the State;

• (b) the relevant ethics committee; and

• (c) the European Commission.

• (4) This Regulation applies to Regulations 19(b), 24(1) to (3), 25, 26(2) and Regulations 28 to 32.

False or misleading information

46.

46. (1) A person who in the course of -

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

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

• (c) giving notice of amendment to the clinical trial protocol under Regulation 21;

• (d) giving notice of a proposal to modify or adapt such an amendment under Regulation 22; or

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

provides to the Board, to an ethics committee or to the Advisory Committee for Human Medicines any relevant information which is false or misleading in a material particular, shall be guilty of an offence.

• (2) A person who -

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

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

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

• (d) holds a manufacturing authorisation,

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

• (3) A person who, for the purpose of being engaged as a qualified person in accordance with Regulation 40, provides any information which is false or misleading in a material particular, shall be guilty of an offence.

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

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

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

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

Defence of due diligence

47.

47. In any proceedings for an offence under any of the preceding provisions of these Regulations, it shall be a good defence for a person charged to show that he or she reasonably believed that the said provisions had been complied with.

Enforcement

48.

48. (1) The Board may appoint such and so many officers as it thinks fit to be authorised officers for the purposes of these Regulations.

• (2) An authorised officer shall be furnished with a warrant of his or her appointment and when exercising a power conferred on him or her under this Regulation, he or she shall, if required by a person thereby affected, produce the warrant to that person for inspection.

• (3) Subject to paragraphs (4) and (5) an authorised officer may, for the purpose of ensuring that these Regulations are being complied with, carry out all or any of the following acts -

• (a) at all reasonable times, enter and search a premises of any class or description,

• (b) inspect any substance or product which is stored, or offered or kept for sale or supply at such premises,

• (c) require the production of, inspect and, if he or she thinks fit, take copies of any book, invoice, order, record, register, or other document or of any entry in any such book, invoice, order, record, register, or other document at such premises,

• (d) inspect and copy or extract information from any data (including personal data) within the meaning of the Data Protection Acts 1988 and 2003,

• (e) take (with or without payment) samples of any investigational medicinal product or substance stored, or offered or kept for sale or supply at such premises for test, examination or analysis,

• (f) detain and if necessary seize any investigational medicinal product, substance or article,

• (g) take any document which he or she has reasonable cause to believe to be a document which may be required as evidence in proceedings under these Regulations,

• (h) inspect and take copies, or samples of, labels used, or intended to be used on an investigational medicinal product, and

• (i) require any person carrying on, on who has carried on, an activity to which these Regulations relate, or any person currently or previously employed in connection with such an activity, to give to the officer such information as the officer may reasonably require for the purposes of these Regulations.

• (4) An authorised officer shall not other than with the consent of the occupier enter a private dwelling unless he or she has obtained a warrant from the District Court under paragraph (7) authorising such entry.

• (5) An authorised officer, for the purpose of exercising any of the powers conferred on him or her by paragraph (3), may require any other person, having authority to do so, to break open any container or package or to permit him or her to do so.

• (6) Where an authorised officer seizes any medicinal product, substance, article or document in the exercise of a power conferred on him or her by paragraph (3), he or she shall inform the person from whom it is seized.

• (7) If a judge of the District Court is satisfied, on the sworn information of an authorised officer, that there are reasonable grounds to authorise entry into any premises referred to in paragraph (4), the judge may issue a warrant authorising such an authorised officer, accompanied, if appropriate, by other authorised officers or by a member or members of the Garda Síochána, or both, at any time or times within one month from the date of issue of the warrant, on production of the warrant if requested, to enter those premises or part thereof and to exercise any of the powers conferred on such an authorised officer under this Regulation.

• (8) A person shall not wilfully obstruct or interfere with the exercise of a power by an authorised officer pursuant to this Regulation.

• (9) A person shall not, without reasonable excuse, fail to comply with any request made by an authorised officer under this Regulation.

Prosecution of offences

49.

49. An offence under these Regulations may be prosecuted by the Board.

Evidential value of Certificate given by analyst

50.

50. (1) In any proceedings for an offence under Regulation 44, a certificate signed by -

• (a) the State Chemist, or

• (b) a public analyst appointed under section 10 of the Sale of Food and Drugs Act 1875 (38 & 39 Vic., c. 63), or

• (c) a chemist or analyst appointed by the Minister for that purpose,

stating the results of any test, examination or analysis of a sample shall, with regard to that sample, be evidence for all purposes of such result.

• (2) The certificate referred to in paragraph (1) shall be in the form set out in Schedule 7 to these Regulations.

PART 9 TRANSITIONAL ARRANGEMENTS AND FEES

Transitional arrangements

51.

51. (1) Where a permission granted under section 4 of the Control of Clinical Trials Act 1987 is in force on the coming into force of these Regulations, the said permission shall continue in force and that Act shall continue to apply and on the basis that any expiry date specified in such permission is no longer applicable.

• (2) Paragraph (1) shall also apply to a permission that has been granted by the Board under section 4 of the said Act, in respect of which the required approval by the ethics committee approved by the Board in the grant of such permission, has not been obtained on the coming into force of these Regulations.

• (3) Applications made under section 3 of the Control of Clinical Trials Act 1987 but not determined by the Board on the coming into force of these Regulations, shall be deemed to have been the subject of requests made under Regulation 14.

• (4) In the case of applications referred to in paragraph (3), applicants shall be entitled to update their applications to conform with the requirements of Regulation 14 without payment of a further fee and the date of receipt of such update shall be the date of a valid request for the purposes of Regulations 15, 16 or 17 as the case may require.

• (5) In the case of investigational medicinal products that may have been manufactured, labelled, packaged or imported before the coming into force of these Regulations, for the purpose of being used in the conduct of a clinical trial in the State, the absence of a manufacturing authorisation in respect of such products shall not be an impediment to the acceptance of a request for authorisation made under Regulation 14 or to the conduct of a clinical trial involving the use of such products. In those circumstances, the standards of good manufacturing practice shall be of a standard acceptable to the Board.

• (6) The provisions of this Regulation shall also apply to clinical trials that may have been notified to the Board under subsections (2) or (3) of section 2 of the Control of Clinical Trials Act 1987 .

• (7) The provisions of this Regulation shall cease to have effect on 1 May 2006.

Fees

52.

52. (1) The fees and charges that shall be payable to the Board in connection with -

• (a) any request for authorisation made to or accepted by the Board under Regulation 14, 15, 16 or 17, or

• (b) any notice of amendment sent to the Board under Regulation 21, or

• (c) any application made to or granted by the Board under Regulation 35 or 37,

shall be determined by the Minister under sections 13 and 14 of the Irish Medicines Board Act 1995 and shall be disposed of in the same manner as for other fees and charges that are payable to the Board under the said Act.

• (2) The following fees shall be payable to the appointing authority for the ethics committee to which the application under Regulation 12 has been made:

• (a) in the case of an application under Regulation 12, a fee of €1000.00, in connection with each such application and a fee of €150 in respect of each trial site to which the application relates; and

• (b) in the case of a notification of amendment under Regulation 21(3), a fee of €200 in connection with each such notification.

• (3) The fees payable under paragraph (2) may be reduced to a single fee of €150 (in the case of the fees specified in subparagraph (a)) and €50 (in the case of the fee specified in subparagraph (b)) where the ethics committee is satisfied that the application relates to a clinical trial referred to in Regulation 24(4).

• (4) The Public Offices Fees Act 1879 (42 & 43 Vic., c. 58) shall not apply to fees payable pursuant to these Regulations.

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

PART 1 APPLICATION AND INTERPRETATION

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

• (2) If any subject of a clinical trial is an adult able to give informed consent, the conditions and principles specified in Part 3 apply in relation to that subject.

• (3) If any subject of a clinical trial is a minor, the conditions and principles specified in Part 4 apply in relation to that subject.

• (4) If any subject -

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

• (b) did not, prior to the onset of his or her incapacity, give or refuse to give informed consent to the treatment to be provided as part of the clinical trial,

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

2. In this Schedule -

“legal representative”, in relation to an adult unable by virtue of physical or mental incapacity to give informed consent and who is, or is being considered as, a subject for a clinical trial, means -

• (a) a person, other than a person connected with the conduct of the trial, who -

• (i) by virtue of his or her or her family relationship with that adult, is suitable to act as the legal representative for the purposes of that trial, and

• (ii) is available and willing to act for those purposes, or

• (b) if there is no such person, a person other than a person connected with the conduct of the trial, who is a solicitor nominated by the relevant health care provider;

“person with parental responsibility” means a natural or adoptive parent, a guardian, a person who has acted in loco parentis to a child or a person having charge or control over a child, where such person is actively involved in making decisions affecting the child's welfare;

“person connected with the conduct of the trial” means -

• (a) the sponsor of the trial,

• (b) a person employed or engaged by, or acting under arrangements made with, the sponsor and who undertakes activities in connection with the management of the trial,

• (c) an investigator for the trial,

• (d) a health care professional who is a member of an investigator's team for the purposes of the trial, or

• (e) a person who provides health care under the direction or control of a person referred to in clauses (c) and (d) above, whether in the course of the trial or otherwise;

“relevant health care provider” means -

• (a) in relation to a person receiving services in pursuance of the Health Acts 1947 to 2001 -

• (i) in a case where a health service body is providing the health care, that body, or

• (ii) in any other case, the health service body which entered the arrangements under which the health care is provided, or

• (b) in relation to any other person receiving health care, the person primarily responsible for providing that health care.

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

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

• (b) (i) in the case of a subject giving consent himself or herself -

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

• (II) if the subject is unable to sign or to mark a document so as to indicate his or her consent, is given clearly to the investigator or another member of the investigating team, in the presence of two witnesses present at the same time and recorded in writing;

• (ii) in the case of another person giving consent, is evidenced in writing, dated and signed, or otherwise marked by that person so as to indicate his or her consent.

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

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

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

PART 2 CONDITIONS AND PRINCIPLES WHICH APPLY TO ALL CLINICAL TRIALS

Conditions

1. The foreseeable risks and inconveniences have been weighed against the anticipated benefit for each subject of the clinical trial and other present and future patients.

2. The anticipated therapeutic and public health benefits justify the risks.

3. The medical care given to, and the medical decisions made on behalf of, subjects shall be the responsibility of an appropriately qualified registered medical practitioner or, where appropriate, of an appropriately qualified registered dentist.

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

Principles

5. The rights of each subject to physical and mental integrity, to privacy and to the protection of the data concerning him or her in accordance with the Data Protection Acts 1988 and 2003, are safeguarded.

PART 3 CONDITIONS WHICH APPLY IN RELATION TO A SUBJECT ABLE TO CONSENT

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

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

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

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

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

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

Conditions

1. Subject to paragraph 7, every person with parental responsibility for the minor has had an interview with the investigator, or another member of the investigating team, in which he or she has been given the opportunity to understand the nature, objectives, risks and inconveniences of the trial and the conditions under which it is to be conducted.

2. That person with parental responsibility has been provided with a contact point where he or she may obtain further information about the trial.

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

4. That person's consent represents the minor's presumed will.

5. That person's consent has been given in consultation with the registered medical practitioner who has been treating the minor.

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

7. That person may, without the minor being subject to any resulting detriment, withdraw the minor from the trial at any time by revoking his or her informed consent.

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

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

10. No incentives or financial inducements are given -

• (a) to the minor; or

• (b) to a person with parental responsibility for that minor,

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

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

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

13. The clinical trial is necessary to validate data obtained -

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

• (b) by other research methods.

14. The clinical trial cannot be properly conducted without using minors.

15. The corresponding scientific guidelines of the EMEA are followed.

Principles

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

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

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

PART 5

CONDITIONS AND PRINCIPLES WHICH APPLY IN RELATION TO AN INCAPACITATED ADULT

Conditions

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

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

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

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

5. The legal representative's consent represents the subject's presumed will.

6. The legal representative's consent has been given in consultation with the registered medical practitioner who has been treating the subject.

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

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

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

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

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

12. The clinical trial is essential to validate data obtained -

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

• (b) by other research methods.

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

14. The clinical trial cannot be properly conducted without using subjects incapable of giving an informed consent.

Principles

15. The clinical trial has been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and the cognitive abilities of the patient.

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

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

SCHEDULE 2 ADDITIONAL PROVISIONS FOR ETHICS COMMITTEES

1. (1) In this Schedule -

“expert member” means a member of an ethics committee who is a health care professional or who has professional qualifications or experience relating to the conduct of, or use of statistics in, clinical research, unless the said qualifications or experience relate only to the ethics of clinical research or medical treatment;

“lay member” means a member of an ethics committee who is not an expert member and who is not and never has been a registered medical practitioner or registered dentist and who does not in the course of his or her employment or business provide medical, dental or nursing care or participate in the promotion or conduct of clinical research.

• (2) Ethics committees shall be established by appointing authorities in accordance with the provisions of this Schedule.

2. (1) The members of an ethics committee shall be appointed by the appointing authority and shall consist of expert members and lay members.

• (2) An ethics committee shall consist of no more than twenty one members of which at least one third shall be lay members and at least one half of those lay members shall be persons who are not and never have been health care professionals.

• (3) A member of an ethics committee shall hold and vacate office as a member in accordance with the terms of the instrument appointing him or her as a member.

Chairperson, vice-chairperson and alternate vice-chairperson

3. (1) The appointing authority shall appoint—

• (a) one of the members of each ethics committee to be chairperson of the committee;

• (b) another member to be vice-chairperson; and

• (c) another member to be alternate vice-chairperson.

• (2) The members appointed as chairperson, vice-chairperson and alternate vice-chairperson shall each be appointed for such period, not exceeding the remainder of his or her term as a member, as the appointing authority may specify on appointing him or her.

• (3) Any member so appointed may at any time resign from the office of chairperson, vice-chairperson or alternate vice-chairperson.

• (4) Where the chairperson has died or has ceased to hold office, or where he or she is unable to perform his or her duties as chairperson owing to illness, absence or any other cause, references to the chairperson in this Schedule shall, so long as there is no chairperson available to perform his or her duties, be taken to include references to the vice-chairperson; or if the vice-chairperson is also is unable to perform his or her duties, the alternate vice-chairperson.

Committees, meetings and proceedings

4. (1) An ethics committee may -

• (a) appoint 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 operating procedures adopted under subparagraph (3).

• (2) Subject to subparagraph (4), the meetings and proceedings of an ethics committee and its sub-committees shall be conducted in accordance with the standing orders made, and standing operating procedures adopted, under subparagraph (3).

• (3) An ethics committee -

• (a) shall, subject to approval by the Supervisory Body, make standing orders, and adopt standing operating procedures, for the Regulation of its proceedings and business; and

• (b) may, subject to approval by the Supervisory Body, vary or revoke such orders or procedures, including provision for the suspension of the standing orders or operating procedures or any of them.

• (4) No business shall be transacted at a meeting of an ethics committee to determine, in accordance with Regulation 13, the opinion of an ethics committee in relation to a clinical trial, unless the chairperson and at least six other members (including any members co-opted under paragraph 6) are present, including at least -

• (a) one lay member who is not and never has been -

• (i) a health care professional, or

• (ii) a chairperson, member, director, officer or employee of a health service body; and

• (b) one expert member.

Deputies and co-opted members

5. (1) An ethics committee may appoint a person to act as the deputy of an expert member or a lay member provided that the person would be eligible for appointment as an expert member or, as the case may be, a lay member.

• (2) A deputy shall hold and vacate office as a deputy member in accordance with the terms of the instrument appointing him or her as a deputy.

• (3) A deputy may attend meetings and vote as a member of the committee only if the member for whom he or she acts as deputy is absent.

• (4) A deputy member and the member for whom he or she is deputy shall count as one member for the purposes of paragraphs 2(2) and 4(4).

6. (1) At any meeting of an ethics committee, the committee may co-opt up to 2 additional members for the purposes of that meeting.

• (2) At any meeting of a sub-committee of an ethics committee, the sub-committee may co-opt an additional member for the purposes of that meeting.

• (3) A person shall be eligible to be co-opted as a member only if he or she is or has been a member of an ethics committee.

• (4) A co-opted member shall hold office only in relation to the meeting for which he or she is co-opted.

• (5) A member co-opted under this paragraph shall not count as a member for any of the purposes of paragraph 2(2).

Staff, premises and facilities

7. (1) The appointing authority shall make arrangements for the appointment of such administrative and other staff for an ethics committee as it considers necessary to enable the committee to perform its functions.

• (2) The appointing authority shall -

• (a) secure the provision to an ethics committee of such accommodation and facilities as it considers necessary to enable the committee to perform its functions; and

• (b) secure that arrangements are made for such administration, maintenance, cleaning and other services as may, in its opinion, be necessary for such accommodation and facilities.

Expenses

8. (1) The appointing authority shall be responsible for the expenses of the ethics committee.

• (2) An ethics committee shall not incur expenses in excess of the amounts approved for that committee by the appointing authority under this paragraph.

9. The appointing authority may pay to members of ethics committees such traveling and other allowances as the authority may determine.

Annual report

10. (1) Within the period of six months from 31 December, each ethics committee shall prepare a report on the committee's activities during that year, which shall include a list of -

• (a) the applications made to the committee in accordance with Regulation 12; and

• (b) the decisions made by the committee in relation to those applications.

• (2) The ethics committee shall send a copy of the report to -

• (a) the Supervisory Body,

• (b) its appointing authority, and

• (c) the Board.

SCHEDULE 3

PART 1 PROCEDURAL PROVISIONS RELATING TO THE REFUSAL OR AMENDMENT OF, OR IMPOSITION OF CONDITIONS RELATING TO, CLINICAL TRIALS AUTHORISATIONS AND THE SUSPENSION OR TERMINATION OF CLINICAL TRIALS

1. Where the Board is notified of the sponsor's wish to make representations in accordance with Regulation 23(1) or 27(7) the Board shall afford an opportunity for the sponsor to make representations to the Advisory Committee for Human Medicines (hereinafter in this Schedule referred to as “the Committee”).

2. After considering the representations, the Committee shall report its findings and advice, and the reasons for its advice, to the Board.

3. In the case of a decision not to accept a request for authorisation or an amendment to the clinical trial protocol, the Board shall, after considering the report of the Committee -

• (a) confirm that it has grounds for not accepting the request or amendment; or

• (b) accept the request for authorisation or amendment to the clinical trial protocol, subject to such conditions as the Board may consider appropriate.

4. In the case of a decision to impose a condition following a request for authorisation or notice of amendment, the Board shall, after considering the report of the Committee -

• (a) confirm its decision; or

• (b) remove or alter the condition in question.

5. In the case of a notice to suspend or terminate a trial, the Board shall, after considering the report of the Committee confirm or revoke the notice.

6. The Board shall give notice to the sponsor of -

• (a) the findings and advice of the Committee and the reasons for it; and

• (b) its decision in accordance with paragraphs 3, 4 or 5.

PART 2 PROCEDURAL PROVISIONS RELATING TO PROPOSALS TO GRANT, REFUSE TO GRANT, VARY, SUSPEND OR REVOKE MANUFACTURING AUTHORISATIONS

1. In this Part of the Schedule -

“authorisation” means a manufacturing authorisation; and

“time allowed” means the period of 28 days or such extended period as the Board may in any particular case allow.

2. Subject to paragraph 6, if the Board proposes -

• (a) not to grant an authorisation;

• (b) to grant an authorisation other than in accordance with the application; or

• (c) to revoke, vary or suspend an authorisation,

the Board shall notify the applicant or authorisation holder accordingly.

3. Any notification given under paragraph 2 shall include a statement of the proposals of the Board and of the reasons for them.

4. A person to whom notification has been given under paragraph 2 may, within the time allowed after the notification was given, give notice to the Board of his or her wish to make representations to the Advisory Committee for Human Medicines with respect to the decision or proposal referred to in the notification.

5. (1) After considering the representations, the Committee shall report its findings and advice, and the reasons for its findings and advice, to the Board.

• (2) The Board shall take into account the report of the Committee and decide whether to grant the authorisation, revoke, vary or suspend an authorisation or confirm or alter its decision, as the case may be.

6. (1) Paragraph 2 shall not apply to the suspension of an authorisation where it appears to the Board that, in the interests of safety, it is necessary to suspend the authorisation with immediate effect for a period not exceeding 3 months.

• (2) If, after the aforementioned suspension has taken effect, it appears to the Board that the authorisation should be further suspended or revoked, the Board shall proceed in accordance with the provisions of paragraphs 2 to 5.

SCHEDULE 4 PARTICULARS THAT MUST ACCOMPANY AN APPLICATION FOR A MANUFACTURING AUTHORISATION

1. The name and address of the applicant, and, where the applicant is not the proposed holder of the authorisation, the name and address of the proposed holder.

2. A statement of the manufacturing, packaging, labelling or importation operations to which the authorisation is to relate, including a statement whether they include one or more of the following -

• (a) the manufacture of investigational medicinal products;

• (b) the labelling or packaging of investigational medicinal products;

• (c) the importation of investigational medicinal products.

3. (1) The address of each of the premises where the manufacturing, packaging, labelling or importation operations to which the application relates, including any testing associated with such activities, that are or are to be carried out.

• (2) The address of each of the premises if different from those referred to in the preceding subparagraph -

• (a) on which are to be kept any living animals; or

• (b) on which are to be kept or from which are to be obtained any materials of animal origin,

from which, in either case, are to be derived any substance or substances used in the production of the investigational medicinal product to which the application relates.

• (3) The address of each of the premises where the proposed holder of the authorisation proposes to store investigational medicinal products or from which he or she proposes to distribute them.

• (4) A statement indicating the facilities and equipment available at each of the premises referred to in subparagraphs (1) to (3), for storing the investigational medicinal products on, and distributing them from or between, such premises.

• (5) A separate statement in respect of each of the premises referred to in subparagraphs (1) to (3), of the manufacturing, or importation operations capable of being carried out at those premises with their existing facilities. Each statement shall specify the classes of investigational medicinal products to which the operations are relevant.

• (6) A separate statement in respect of each of the premises referred to in subparagraphs (1) to (3), of equipment available at those premises for carrying out each stage of the manufacturing, or importation operations described in subparagraph (5) of this paragraph.

4. A statement of any manufacturing operations, other than those to which the manufacturing authorisation is to relate, that are carried on by the proposed authorisation holder on or near each of the premises referred to in paragraph 3 of this Schedule, and of the substances or articles which are the subject of any such operation.

5. (1) The name and address and degrees, diplomas or qualifications and experience of the qualified person who is to carry out the duties referred to in Regulation 40(2).

• (2) In the case of an authorisation relating to manufacture, labelling or packaging, the name and address and qualifications and experience of the production manager or other person whose duty it will be to supervise the production operations at each of the premises referred to in paragraph 3 of this Schedule, and the name and function of the person to whom he or she is responsible.

• (3) The name and address and degrees, diplomas or other qualifications and experience of the person to be in charge of quality control over all the premises referred to in paragraph 3 of this Schedule and the extent of the authority to be delegated to him or her to reject unsatisfactory batches of investigational medicinal products, and the name and function of the person to whom he or she is responsible.

• (4) The name and address and degrees, diplomas or other qualifications of the person in charge of the animals referred to in paragraph 3(2) of this Schedule.

• (5) The name and address and degrees, diplomas or other qualifications of the person to be responsible for the culture of any living tissue to be used in the manufacture of investigational medicinal products.

6. An outline of the arrangements for the identification and storage of materials and ingredients before and during manufacture and for the storage of investigational medicinal products after manufacture, labelling, packaging or importation.

7. An outline of the arrangements at each of the premises where the holder of the authorisation stores or proposes to store investigational medicinal products for ensuring, so far as practicable, whether by maintaining records or other means, a satisfactory turn-over of stocks of investigational medicinal products.

8. An outline of the arrangements -

• (a) for maintaining production or importation records;

• (b) for maintaining records of analytical and other testing procedures applied in the course of manufacture, labelling, packaging or importation for ensuring compliance of materials used in the manufacture of any investigational medicinal products with the specification of such materials or medicinal products; and

• (c) for keeping reference samples of materials used in the manufacture of any investigational medicinal products and of the investigational medicinal products.

9. Where the application relates to the importation of investigational medicinal products from a third country -

• (a) the address of each of the premises where the investigational products are or are to be manufactured;

• (b) evidence to demonstrate that the products have been manufactured in conformity with good manufacturing standards at least equivalent to those laid down in the principles and guidelines of good manufacturing practice.

SCHEDULE 5 STANDARD PROVISIONS FOR MANUFACTURING AUTHORISATIONS

PART 1 INTERPRETATION

In this Schedule -

“good manufacturing practice” means the part of quality assurance which ensures that products are consistently produced and controlled in accordance with the quality standards appropriate to their intended use;

“pharmaceutical quality assurance” means the total sum of the organised arrangements made with the object of ensuring that investigational medicinal products are of the quality required for their intended use;

“product specification” means -

• (a) in the case of an investigational medicinal product manufactured before a request for authorisation to conduct the clinical trial involving those products has been made in accordance with Regulation 14 or any equivalent provisions in any EEA State other than the State, the specification for that product provided by the person who is to act as the sponsor for the proposed clinical trial,

• (b) in the case of an investigational medicinal product manufactured for the purpose of export, the specification for that product provided by the person to whose order the products are manufactured, or

• (c) in any other case, the specification for an investigational medicinal product contained in the investigational medicinal product dossier accompanying the request for authorisation of the clinical trial in which the product is or is to be used;

and

“relevant period” means the 5 years from the date on which the clinical trial, for which the relevant batch referred to in paragraphs 10(1)(a) of Part 2 of, or paragraph 6(1)(a) of Part 3 of, this Schedule was manufactured, labelled, packaged or imported, was completed, terminated or discontinued.

PART 2 PROVISIONS WHICH MAY BE INCORPORATED IN AN AUTHORISATION RELATING TO THE MANUFACTURE, LABELLING OR PACKAGING OF INVESTIGATIONAL MEDICINAL PRODUCTS

1. The authorisation holder shall -

• (a) provide and maintain such staff, premises and plant (including technical equipment) as are necessary for the carrying out, in accordance with his or her authorisation and the product specification, of such stages of the manufacture, labelling and packaging of the investigational medicinal products as are undertaken by him or her; and

• (b) not carry out any such manufacture, labelling or packaging except at the premises specified in his or her manufacturing authorisation.

2. The authorisation holder shall -

• (a) provide and maintain such staff, premises, equipment and facilities for the handling, storage and distribution of the investigational medicinal products which he or she handles, stores or distributes under his or her authorisation as are necessary to maintain the quality of the investigational medicinal products;

• (b) not use for such purposes premises other than those specified in the authorisation or which may be approved from time to time by the Board; and

• (c) ensure that any arrangements he or she makes with a person for the storage and distribution of the investigational medicinal products are adequate to maintain the quality of those products.

3. The authorisation holder shall -

• (a) conduct all manufacture, labelling and packaging operations in such a way as to ensure that the investigational medicinal products conform with the standards of strength, quality and purity applicable to them in accordance with their product specification; and

• (b) conduct all such operations in accordance with the principles and guidelines of good manufacturing practice.

4. The authorisation holder shall use, establish and implement an effective pharmaceutical quality assurance system involving the active participation of the management and personnel of the different services involved.

5. The authorisation holder shall, where animals are used in the production of any investigational medicinal products and the product specification for those products contains provisions relating to them, arrange for the animals to be housed in premises of such a nature and to be managed in such a way as will facilitate compliance with such provisions.

6. (1) The authorisation holder shall -

• (a) provide and maintain a designated quality control system having authority in relation to quality control and being independent from all other departments in the exercise of that authority; and

• (b) place the quality control system under the authority of the person notified to the Board in accordance with paragraph 5(3) of Schedule 4 being responsible for quality control.

• (2) Subject to paragraph 7, the authorisation holder shall, in order to support the quality control system, provide and maintain such staff, premises and plant as are necessary for carrying out -

• (a) such tests of the strength, quality and purity of the investigational medicinal products which he or she manufactures under the manufacturing authorisation as are required by the product specification for those products; and

• (b) any tests or controls which relate to the conditions of production and in-process controls.

• (3) Any animals used for the tests referred to in subparagraph (2) shall be suitably housed and managed.

• (4) The authorisation holder shall ensure that the quality control system, in determining whether finished investigational medicinal products are to be released for use in clinical trials takes into account, in addition to analytical results -

• (a) the conditions of production;

• (b) the result of in-process controls;

• (c) the examination of manufacturing documents; and

• (d) the conformity of products to their product specification.

7. An authorisation holder need not himself or herself provide and maintain such staff, premises and plant as are necessary for carrying out such tests as are specified in paragraph 6(2) provided that he or she makes arrangements, with a person approved in writing by the Board, to carry out such tests on his or her behalf in accordance with paragraph 6(2) and (3).

8. The authorisation holder shall provide such information as may be requested by the Board for the purposes of these Regulations -

• (a) about the products currently being manufactured, labelled or packaged under his or her authorisation; and

• (b) about the operations being carried out in relation to such manufacture, labelling or packaging.

9. The authorisation holder shall -

• (a) inform the Board before making any material alteration in the premises or plant used under his or her authorisation, or in the operations for which they are used; and

• (b) inform the Board of any change that he or she proposes to make in any personnel named in his or her authorisation as respectively -

• (i) responsible for supervising the production operations, or