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

ARRANGEMENT OF REGULATIONS

PART 1

GENERAL PROVISIONS

Regulation

PART 2

ETHICS COMMITTEES

PART 3

AUTHORISATION FOR CONDUCT OF CLINICAL TRIALS AND ETHICS COMMITTEE OPINION

PART 4

GOOD CLINICAL PRACTICE AND THE CONDUCT OF CLINICAL TRIALS

PART 5

PHARMACOVIGILANCE

PART 6

MANUFACTURE AND IMPORTATION OF INVESTIGATIONAL MEDICINAL PRODUCTS

PART 7

LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS

PART 8

OFFENCES, PENALTIES AND ENFORCEMENT

PART 9

TRANSITIONAL ARRANGEMENTS

SCHEDULES

S.I.No. 190 of 2004

European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004

I, Micheál Martin, Minister for Health and Children, in exercise of the powers conferred on me by section 3 of the European Communities Act 1972 (No. 27 of 1972) and for the purpose of giving effect to Directive 2001/20/EC¹ of the European Parliament and of the Council of 4 April 2001, hereby make the following regulations:-

PART 1

GENERAL PROVISIONS

Citation

1.         These Regulations may be cited as the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004.

Commencement

2.         These Regulations shall come into force on 1 May 2004.

Scope of application of Regulations and of Control of Clinical Trials Acts 1987 and 1990

3.         (1) These Regulations shall apply to the conducting of clinical trials as defined in Regulation 4(1) of these Regulations.

(2) The Control of Clinical Trials Acts 1987 and 1990 shall not apply to clinical trials that are subject to control under these Regulations.

(3) These Regulations shall not apply to non-interventional trials.

Interpretation

4.         (1) In these Regulations:-

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

“adverse event” means any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences that do not necessarily have a causal relationship with this treatment;

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

“Advisory Committee for Human Medicines” means the Committee established under section 9 (1)(a) of the Irish Medicines Board Act 1995 (No. 29 of 1995);

“appointing authority” means the institution on whose behalf application for recognition of an ethics committee in accordance with Regulation 7(1) is made and for the purposes of this definition “institution” means a health board, a hospital, a University or other similar body involved in higher education or in the award of post-graduate specialist medical or dental qualifications or in the provision of continuing medical or dental education;

“authorised health care professional” means a registered medical practitioner or registered dentist;

“Board” means the Irish Medicines Board established by section 3 of the Irish Medicines Board Act 1995 (No. 29 of 1995);

“chief investigator” means -

(a)  in the case of a clinical trial conducted at a single trial site, the investigator for that site, or

(b)  in the case of a clinical trial conducted at more than one trial site, the authorised health care professional, whether or not he or she is an investigator at any particular site, who takes primary responsibility for the conduct of the trial;

“clinical trial” means any investigation in human subjects, other than a non-interventional trial, intended -

(a)  to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more investigational medicinal products, or

(b)  to identify any adverse reactions to one or more such investigational medicinal products, or

(c)  to study absorption, distribution, metabolism and excretion of one or more such investigational medicinal products, or

(d)  to discover, verify, identify or study any combination of the matters referred to at subparagraphs (a), (b), and (c),

with the object of ascertaining the safety or efficacy of such products, or both;

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

“Commission Directive 2003/94/EC” means Commission Directive 2003/94/EC² of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and for investigational medicinal products for human use, but only insofar as that Directive applies to investigational medicinal products;

“conditions and principles of good clinical practice” means -

(a)  the principles of and guidelines for good clinical practice set out in a measure adopted pursuant to Article 1(3) of the Directive, and

(b)  the conditions and principles for the protection of clinical trial subjects specified in Schedule 1;

“conducting a clinical trial” includes -

(a)  administering, or giving directions for the administration of, an investigational medicinal product to a subject for the purposes of that trial,

(b)  giving a prescription for an investigational medicinal product for the purposes of that trial,

(c)  carrying out any other medical or nursing procedure in relation to that trial, and

(d)  carrying out any test or analysis -

(i)   to discover or verify the clinical, pharmacological or other pharmacodynamic effects of the investigational medicinal products administered in the course of the trial,

(ii)  to identify any adverse reactions to those products, or

(iii) to study absorption, distribution, metabolism and excretion of those products,

but does not include any activity undertaken prior to the commencement of the trial which consists of making such preparations for the trial as are necessary or expedient;

“Directive” means Directive 2001/20/EC¹ of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use;

“Directive 2001/83/EC” means Directive 2001/83/EC³ of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use;

“EEA Agreement” means the Agreement on the European Economic Area signed in Oporto on the 2nd day of May, 1992 as adjusted by the Protocol to that Agreement done at Brussels on the 17th day of March, 1993⁽⁴⁾ ;

“EEA State” means a State which is a contracting party to the EEA Agreement;

“EMEA” means the European Agency for the Evaluation of Medicinal Products established by Council Regulation (EEC) No. 2309/93⁵ ;

“ethics committee” means a committee established or recognised in accordance with Part 2 of these Regulations;

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

“export” means export to a third country from the State, whether by land, sea or air;

“health board” means -

(a)  a board established under section 4 of the Health Act 1970 (No. 1 of 1970), or

(b)  the Eastern Regional Health Authority established by section 7 of the Health (Eastern Regional Health Authority) Act 1999 (No. 13 of 1999),

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

“health care professional” means -

(a)  a registered medical practitioner,

(b)  a registered dentist,

(c)  a registered nurse,

(d)  a registered pharmacist,

(e)  a person registered in the Register of Optometrists established under the Opticians Acts 1956 and 2003, or

(f)  any other person holding another such professional qualification that would entitle him or her to provide health care;

“health service body” means -

(a)  a health board,

(b)  an Area Health Board established by section 14 of the Health (Eastern Regional Health Authority) Act 1999 ,

(c)  a body established under the Health (Corporate Bodies) Act 1961 , (No. 27 of 1961), or

(d)  a body corporate established for the purpose of providing health care;

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

“import” means import to the State from a third country, whether by land, sea or air;

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

“insurance or indemnity” includes a contract of insurance, a contract of indemnity, a guarantee, a surety, a warrant and a bond and which in any case shall be available to cover the liability of the sponsor and the investigator to provide for compensation in the event of any injury, loss or damage to, or the death, of any subject arising out of the arrangement for, or conduct of, the clinical trial and which the sponsor, or investigator, shall become liable to pay to such subject, or in respect of such subject, by way of damages or costs;

“investigational medicinal product” means a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including a medicinal product that is already the subject of a marketing authorisation, but—

(a)  is used, formulated or packaged in a way different from the form that is the subject of the authorisation,

(b)  is used for an indication that is not included in the summary of product characteristics under the authorisation for the product, or

(c)  is used to gain further information about the form of the product that is the subject of the authorisation;

“investigator” means the authorised health care professional responsible for the conduct of a clinical trial at a trial site and if a trial is conducted by a team of authorised health care professionals at a trial site, the investigator is the leader responsible for that team;

“investigator's brochure” means a document containing a summary of the clinical and non-clinical data on the investigational medicinal product which are relevant to the study of the product in human subjects;

“investigator-sponsor” means, in relation to a clinical trial, a chief investigator who is also acting as the sponsor for that clinical trial;

“manufacture” includes total and partial manufacture and the various processes of dividing up, packaging and presentation;

“manufacturing authorisation” means an authorisation granted and in force in pursuance of Regulation 37 of these Regulations;

“marketing authorisation” means an authorisation granted and in force in pursuance of the Medicinal Products (Licensing and Sale) Regulations 1998 ( S.I. No. 142 of 1998 ) and includes an authorisation granted and in force under article 3 of Council Regulation (EEC) 2309/93⁵ ;

“medicinal product” has the meaning assigned to it by Directive 2001/83/EC;

“Minister” means the Minister for Health and Children;

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

“multi-centre clinical trial” means a clinical trial conducted according to a single protocol but at more than one site, and therefore by more than one investigator, in which the trial sites may be located in a single Member State, in a number of Member States or in a Member State or Member States and a third country or third countries;

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

(a)  the products are prescribed in the usual manner in accordance with the terms of that authorisation,

(b)  the assignment of any patient involved in the study to a particular therapeutic strategy is not decided in advance by a clinical trial protocol but falls within current practice,

(c)  the decision to prescribe a particular medicinal product is clearly separated from the decision to include the patient in the study,

(d)  no diagnostic or monitoring procedures are applied to the patients included in the study, other than those which are ordinarily applied in the course of the particular therapeutic strategy in question, and

(e)  epidemiological methods are to be used for the analysis of the data arising from the study;

“principles and guidelines of good manufacturing practice” means the principles and guidelines set out in Commission Directive 2003/94/EC;

“qualified person” means -

(a)  a person who as respects qualifications and experience satisfies the requirements set out in Part 1 of Schedule 6, or

(b)  a person who, without satisfying the requirements referred to in paragraph (a) has been engaged in activities equivalent to those to be performed in accordance with Regulation 40(2) in respect of investigational medicinal products for a period of at least one year prior to 1 May 2004;

“registered dentist” means a person registered in the register established under the Dentists Act 1985 (No. 9 of 1985);

“registered medical practitioner” means a person registered in the register established under the Medical Practitioners Act 1978 (No. 4 of 1978);

“registered nurse” means a person whose name is entered in the register of nurses maintained by An Bord Altranais under section 27 of the Nurses Act 1985 (No 18 of 1985);

“registered pharmacist” means a registered pharmaceutical chemist or a registered dispensing chemist and druggist, under the Pharmacy Acts 1875 to 1977;

“serious adverse event or serious adverse reaction” means any adverse event or adverse reaction that at any dose -

(a)  results in death,

(b)  is life-threatening,

(c)  requires hospitalisation or prolongation of existing hospitalisation,

(d)  results in persistent or significant disability or incapacity, or

(e)  consists of a congenital anomaly or birth defect;

“sponsor” means, in relation to a clinical trial, the person who takes on responsibility for the initiation and management (or for arranging the initiation and management) of, and the financing (or arranging the financing) for that clinical trial;

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

(a)  as a recipient of an investigational medicinal product or of some other treatment or product, or

(b)  without receiving any treatment or product, as a control;

“third country” means a country or territory outside the European Economic Area;

“trial site” means a hospital, nursing home, health centre, surgery or other establishment or facility at or from which a clinical trial, or any part of such a trial, is conducted;

“unexpected adverse reaction” means, in respect of an investigational medicinal product, an adverse reaction, the nature or severity of which is not consistent with the information about that medicinal product as set out -

(a)  in the case of a product which is the subject of a marketing authorisation, in the summary of product characteristics for that product,

(b)  in the case of any other investigational medicinal product, in the investigator's brochure relating to the particular clinical trial.

(2) A word or expression which is used in these Regulations and which is also used in the Directive has, unless the context otherwise requires, the same meaning in these Regulations as it has in the Directive.

(3) In these Regulations, unless the context otherwise requires-

(a)  any reference to a Regulation or Schedule shall be construed as a reference to a Regulation contained in these Regulations or, as the case may be, to a Schedule thereto, and

(b)  any reference in a Regulation, or a Schedule, to a paragraph shall be construed as a reference to a paragraph in that Regulation or Schedule and in a paragraph, any reference to a subparagraph shall mean a reference to a subparagraph in that paragraph.

Designation of functions under the Directive

5.         The Board shall be the competent authority for the purposes of the Directive.

PART 2

ETHICS COMMITTEES

Establishing, recognising and monitoring of ethics committees

6.         (1) The Minister shall be the Ethics Committees Supervisory Body (hereinafter in these Regulations referred to as the Supervisory Body) which shall be the body responsible in the State for recognising and monitoring ethics committees in accordance with these Regulations.

(2) Ethics committees shall be established by an appointing authority in accordance with the provisions of Schedule 2, and subject to such committees being recognised pursuant to Regulation 7, such committees shall have authority to act for the purposes of these Regulations.

(3) Ethics committees may also be established by the Supervisory Body to act—

(a)  for the whole State or part thereof; and

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

as it considers appropriate and such ethics committees shall be deemed to have been recognised pursuant to Regulation 7.

(4) The Supervisory Body may -

(a)  vary the area for which any committee it has established acts or, as the case may be, the descriptions or classes of clinical trials in relation to which such a committee acts; or

(b)  abolish any such committee.

(5) The Supervisory Body shall monitor the extent to which ethics committees adequately perform their functions under these Regulations and may provide advice and assistance to such committees in relation to the performance of their functions.

(6) Where an ethics committee is established by the Supervisory Body-

(a)  the provisions of these Regulations applicable to appointing authorities shall apply to the Supervisory Body in respect of such establishment, and

(b)  the provision of these Regulations applicable to ethics committees, shall apply to such committees,

save where otherwise indicated.

Recognition of ethics committees

7.         (1) Subject to the provisions of this Regulation, the Supervisory Body shall recognise a committee as an ethics committee for the purposes of these Regulations if -

(a)  an application in relation to that committee has been made by an appointing authority; and

(b)  it is satisfied that the proposed arrangements for the membership and operation of the committee would -

(i)   enable the committee to adequately perform the functions of an ethics committee; and

(ii)  comply with the provisions of Schedule 2.

(2) An application for recognition of an ethics committee shall be made in writing and be accompanied by such information, documentation and particulars as are necessary to enable the Supervisory Body to determine the application.

(3) In granting recognition in respect of a committee as an ethics committee, the Supervisory Body shall specify in writing -

(a)  whether the committee may act for the whole State or part of the State;

(b)  the description or class of clinical trial in relation to which the committee may act as an ethics committee; and

(c)  any other conditions or limitations that apply to that committee.

(4) The Supervisory Body may -

(a)  vary the area in respect of which the committee may act;

(b)  vary the description or class of clinical trial in relation to which the committee may act as an ethics committee; and

(c)  vary or revoke any conditions or limitations specified under paragraph (3).

(5) On granting recognition in respect of a committee as an ethics committee, the Supervisory Body shall, publish a notice in Iris Oifigiúil giving -

(a)  the name of the ethics committee;

(b)  the address for correspondence;

(c)  the date of recognition;

(d)  the area of the State for which the committee may act as an ethics committee; and

(e)  the description or class of clinical trials in respect of which the committee may act as an ethics committee.

Revocation of recognition for ethics committee

8.         The Supervisory Body may revoke a recognition of an ethics committee, granted pursuant to Regulation 7, if it is satisfied that -

(a)  the provisions of Schedule 2 are not being complied with by that committee;

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

(c)  it is otherwise necessary or expedient to do so.

Membership and operation of ethics committees

9.         The provisions of Schedule 2 shall have effect in respect of all ethics committees.

PART 3

AUTHORISATION FOR CONDUCT OF CLINICAL TRIALS AND ETHICS COMMITTEE OPINION

Requirement for authorisation and ethics committee opinion

10.       (1) A person shall not conduct, commence or cause a clinical trial to be commenced unless -

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

(b)  the Board has granted an authorisation in respect of the clinical trial; and

(c)  the sponsor of the clinical trial, or the person authorised to act on his or her behalf in relation to the trial, is established in the Community.

(2) A person shall not recruit an individual to be a subject in a clinical trial or issue an advertisement for the purpose of recruiting individuals to be subjects in a clinical trial unless the conditions specified in subparagraphs (a) and (b) of paragraph (1) have been met.

Supply of investigational medicinal products for the purpose of clinical trials

11.       (1)  A person shall not supply any investigational medicinal product for use in a clinical trial, other than in accordance with the terms of any marketing authorisation in force in relation to the product concerned, unless the conditions specified in paragraph (2) are met.

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

(a)  the Board has accepted a request for an authorisation for the purposes for which the investigational medicinal product is supplied;

(b)  in the case of an investigational medicinal product manufactured in any EEA State, the product has been manufactured by a person holding, in relation to that product—

(i)   a manufacturing authorisation, or

(ii)  an authorisation referred to in Article 13 of the Directive granted by a competent authority of any EEA State other than the State;

(c)  in the case of an investigational medicinal product imported from a third country, the product has been imported by a person holding a manufacturing authorisation relating to the importation of that product; and

(d)  the production batch of investigational medicinal product of which the product is a part has been checked and certified by a qualified person pursuant to Regulation 40.

Application for ethics committee opinion

12.       (1)  An application for an ethics committee opinion in respect of a clinical trial shall be made by the chief investigator for that trial.

(2) A chief investigator for a trial shall make only one application for an ethics committee opinion in relation to that trial regardless of the number of trial sites at which the trial is to be conducted.

(3) An application for an ethics committee opinion in relation to a clinical trial shall be made to an ethics committee recognised—

(a)  for -

(i)   the whole State,

(ii)  that part of the State in which the chief investigator is professionally based, or

(iii) a particular institution or group of institutions in which the chief investigator is professionally based; and

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

(4) An application for an ethics committee opinion shall -

(a)  be made in writing and be signed by the chief investigator making the application; and

(b)  be accompanied by -

(i)   such particulars and documentation that are set out in the detailed guidance drawn up and published by the Commission under Article 8 of the Directive, on the application format and documentation to be submitted in an application for an ethics committee opinion, including the information that is given to subjects, and on the appropriate safeguards for the protection of personal data, and

(ii)  any fee that may be payable in connection with that application.

(5) The application and any particulars and documentation shall be supplied in the English language.

(6) For the purposes of this Regulation, a chief investigator is professionally based at the hospital, health centre, surgery, clinic or other establishment or facility at or from which he or she primarily conducts his or her professional practice.

Ethics committee opinion

13.       (1) Subject to paragraphs (2) and (3), an ethics committee shall within the specified period following receipt of a valid application, give an opinion in relation to the clinical trial to which the application relates.

(2) Where following receipt of a valid application it appears to the committee that further information is required in order to give an opinion on a trial, the committee may, within the specified period and before giving its opinion, send a notice in writing to the applicant requesting that he or she furnishes the committee with that information.

(3) Where the committee sends a request in accordance with paragraph (2), the specified period shall be suspended pending receipt of the information requested.

(4) In the case of a clinical trial involving -

(a)  medicinal products for gene therapy or somatic cell therapy, including xenogenic cell therapy; or

(b)  medicinal products containing genetically modified organisms,

the ethics committee may consult a specialist committee before giving its opinion.

(5) If the clinical trial involves a medicinal product for xenogenic cell therapy, the time limits referred to in paragraphs (1) to (3) shall not apply and the ethics committee may give an opinion in relation to that trial or send a notice under paragraph (2) at any time after receipt of the valid application.

(6) In preparing its opinion, the ethics committee shall consider, in particular, the following matters:

(a)  the relevance of the clinical trial and its design;

(b)  whether the evaluation of the anticipated benefits and risks as required under paragraph 1 of Part 2 of Schedule 1 is satisfactory and whether the conclusions are justified;

(c)  the clinical trial protocol;

(d)  the suitability of the investigator and supporting staff;

(e)  the investigator's brochure;

(f)   the quality and adequacy of the facilities for the trial;

(g)  the adequacy and completeness of the written information to be given and the procedure to be followed for the purpose of obtaining informed consent to participation in the trial;

(h)  if the subjects are to include persons who because they are minors are incapable of giving informed consent, whether the research is justified having regard to the conditions and principles laid down in Part 4 of Schedule 1;

(i)   if the subjects are to include persons who are adults and who are incapable by reason of physical or mental incapacity of giving informed consent, whether the research is justified having regard to the conditions and principles laid down in Part 5 of Schedule 1;

(j)   the arrangements for the recruitment of subjects;

(k)  the provision made for indemnity or compensation in the event of injury or death attributable to the clinical trial;

(l)   any insurance or indemnity to cover the liability of the investigator and sponsor;

(m) the amounts and, where appropriate, the arrangements for rewarding or compensating investigators and trial subjects;

(n)  the terms of any agreement between the sponsor and the owner or occupier of the trial site which are relevant to the arrangements referred to in subparagraph (m).

(7) If any subject participating in a clinical trial is to be a minor and the committee does not have a member with professional expertise in paediatrics, it shall, before giving its opinion, obtain advice on the clinical, ethical and psychosocial problems in the field of paediatrics which may arise in relation to that trial.

(8) If any subject participating in a clinical trial is to be an adult incapable by reason of physical or mental incapacity of giving informed consent to participation in the trial and the committee does not have a member with professional expertise in the treatment of -

(a)  the disease to which the trial relates, and

(b)  the patient population suffering that disease,

it shall, before giving its opinion, obtain advice on the clinical, ethical and pyschosocial problems, in the field of that disease and the patient population concerned, which may arise in relation to that trial.

(9) In this Regulation -

“specified period” means-

(a)  in the case of a clinical trial involving a medicinal product for gene therapy or somatic cell therapy or a medicinal product containing a genetically modified organism-

(i)   where a specialist committee is consulted in accordance with paragraph (4), 180 days, or

(ii)  where there is no such consultation, 90 days; or

(b)  in any other case, 60 days;

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

(a)  in the case of medicinal products for gene therapy or somatic cell therapy, the use of such therapies in the treatment of humans; or

(b)  in the case of medicinal products containing genetically modified organisms, the administration of such products to humans.

“valid application” means an application which complies with the provisions of Regulation 12.

Request for authorisation to conduct a clinical trial

14.       (1)  A request for authorisation to conduct a clinical trial shall be made to the Board by the sponsor of the trial.

(2) A request shall -

(a)  be in writing and signed by or on behalf of the sponsor, whether in ink or by means of an electronic signature; and

(b)  be accompanied by -

(i)   the particulars and documents set out in the detailed guidance drawn up and published by the Commission under Article 9.8(a) of the Directive, on the format, contents and documentation to be submitted in support of a request for authorisation of a clinical trial on a medicinal product for human use, and

(ii)  any fee which may be payable in connection with that request.

(3) The request and any accompanying material shall be supplied in the English language.

Authorisation procedure for clinical trials involving general medicinal products

15.       (1) This Regulation applies to clinical trials involving medicinal products other than those to which Regulations 16 and 17 apply.

(2) The Board may, within the period of 30 days from the date of receipt of a valid request for authorisation in respect of a clinical trial to which this Regulation applies, give written notice to the sponsor -

(a)  setting out the Board's grounds for not accepting the request;

(b)  stating that the Board accepts the request for authorisation; or

(c)  stating that the Board accepts the request for authorisation, subject to the conditions specified in the notice.

(3) Subject to paragraph (4), if -

(a)  a notice is given in accordance with paragraph (2)(b); or

(b)  no notice is given in accordance with paragraph (2),

the clinical trial may be treated as if the request had been authorised.

(4) If a notice is given in accordance with paragraph (2)(c), the clinical trial may be treated as if authorisation had been granted only if the conditions specified in the notice are satisfied.

(5) If the sponsor is given a notice in accordance with paragraph (2)(a) or (c), he or she may, within the period of 14 days, or such extended period as the Board may in any particular case allow, from the date on which the notice was received, send an amended request to the Board for further consideration.

(6) The Board shall consider a valid amended request and may, within the period of 60 days from the date on which the original request was received give a written notice to the sponsor -

(a)  setting out the Board's grounds for not accepting the amended request;

(b)  stating that the Board accepts the amended request; or

(c)  stating that the Board accepts the amended request, subject to the conditions specified in the notice.

(7) Subject to paragraph (8), if a valid amended request has been received and -

(a)  a notice is given in accordance with paragraph (6)(b); or

(b)  no notice is given in accordance with paragraph (6),

the clinical trial may be treated as if the request had been authorised.

(8) If a valid amended request has been received and a notice is given in accordance with paragraph (6)(c), the clinical trial may be treated as if the request had been authorised only if the conditions specified in the notice are satisfied.

(9) If—

(a)  the Board gives written notice to the sponsor of grounds for non-acceptance in accordance with paragraph (2)(a) and the sponsor does not submit an amended request in accordance with paragraph (5), or

(b)  the sponsor has submitted an amended request in accordance with paragraph (5), but the Board gives written notice to the sponsor of grounds for non-acceptance in accordance with paragraph (6)(a),

the request shall be treated as rejected and the Board shall not consider any further amendments to the request.

 (10) In this Regulation,, “valid request” means a request which complies with the provisions of Regulation 14.

Authorisation procedure for clinical trials involving medicinal products for gene therapy etc.

16.       (1) This Regulation applies to clinical trials involving -

(a)  medicinal products for gene therapy and somatic cell therapy, including xenogenic cell therapy; and

(b)  medicinal products containing genetically modified organisms.

(2) Subject to the following provisions of this Regulation, the Board may, within the period of 30 days from the date of receipt of a valid request for authorisation of a clinical trial to which this Regulation applies -

(a)  issue a written authorisation to the sponsor; or

(b)  give a notice in writing to the sponsor setting out the grounds for not accepting the request.

(3) The Board shall not authorise a clinical trial involving products for gene therapy if the use of those products in that trial would result in modifications to any subject's germ line genetic identity.

(4) If the Board considers that it is appropriate to do so, it may consult the relevant committee before deciding whether to authorise such a clinical trial.

(5) Where the Board consults the relevant committee in accordance with paragraph (4), the period specified in paragraph (2) shall be extended by a further 90 days.

(6) Where a sponsor is given a notice in accordance with paragraph (2)(b), he or she may, within the period of 30 days, or such extended period as the Board may in any particular case allow, from the date on which the notice was received, send an amended request to the Board for further consideration.

(7) The Board shall consider a valid amended request and, not later than 90 days, or, in a case falling within paragraph (5), 180 days, from the date on which the original request was received -

(a)  issue a written authorisation to the sponsor; or

(b)  give a notice in writing to the sponsor setting out the grounds for not accepting the request.

(8) A written authorisation issued under this Regulation may contain such conditions as the Board considers appropriate.

(9) If the clinical trial involves a medicinal product for xenogenic cell therapy, the time limits set out in paragraphs (2), (5) and (7) shall not apply and the Board may issue an authorisation or notice under those paragraphs at any time after receipt of the request.

(10) In this Regulation, “the relevant committee” means -

(a)  the Advisory Committee for Human Medicines; or

(b)  any such other body or committee as the Board may consider appropriate in relation to the request under consideration.

Authorisation procedure for clinical trials involving medicinal products with special characteristics

17.      (1) This Regulation applies to clinical trials -

(a)  involving-

(i)   medicinal products which are not the subject of a product authorisation in force in pursuance of the Medicinal Products (Licensing and Sale) Regulations 1988 and are referred to in Part A of the Annex to Regulation (EEC) No. 2309/93⁵ ,

(ii)  medicinal products with special characteristics such as those which have an active ingredient -

(a)  that is a biological product of human or animal origin,

(b)  containing biological components of human or animal origin, or

(c)  the manufacturing of which requires such components, other than products falling within Regulation 16,

other than products falling within Regulation 16; or

(b)  where the Board, within 7 days from the date of receipt of a valid request for authorisation in respect of a clinical trial, issues a notice to the sponsor specifying that by virtue of the special characteristics of the medicinal product to which the trial relates, a written authorisation for that trial is required.

(2) The Board may, within the period of 30 days from the date of receipt of a valid request for authorisation in respect of a clinical trial to which this Regulation applies -

(a)  issue a written authorisation to the sponsor; or

(b)  give a notice in writing to the sponsor setting out the grounds for not accepting the request.

(3) Where a sponsor is given a notice in accordance with paragraph (2)(b), he or she may, within the period of 14 days, or such extended period as the Board may in any particular case allow, from the date on which the notice was received, send an amended request to the Board for further consideration.

(4) The Board shall consider a valid amended request and, not later than 60 days from the date on which the original request was received -

(a)  issue a written authorisation to the sponsor; or

(b)  give a notice in writing to the sponsor setting out the grounds for not accepting the request.

(5) A written authorisation issued under this Regulation may contain such conditions as the Board considers appropriate.

Clinical trials conducted in third countries

18.       (1) If the Board receives a valid request for authorisation relating to a clinical trial which is or is to be conducted in a third country as well as in the State, the Board may, if it thinks fit, require the production by the sponsor of any one or more of the following -

(a)  an undertaking, given by the sponsor, to permit the premises in that country to be inspected by or on behalf of the Board for the purpose of establishing whether the conditions and principles of good clinical practice 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 Board 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 Board in accordance with paragraph (1), that failure shall constitute a ground for not accepting the request for authorisation, for the purposes of Regulations 15 to 17.

Amendments to clinical trial protocol

19.         Subject to Regulation 26, a person shall not make an amendment to a clinical trial protocol save where -

(a)  the Board makes such an amendment in accordance with Regulation 20; or

(b)  the sponsor makes such an amendment in accordance with Regulation 21 or 22.

Amendments by the Board

20.       (1) Subject to paragraphs (2) and (3), the Board may make amendments to a clinical trial protocol if it appears to the Board 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 Board proposes to make an amendment in accordance with paragraph (1), the Board shall, at least 14 days before the date on which it is proposed the amendment should take effect, serve a notice on the sponsor stating its proposal and the reasons for it.

(3) If, within 14 days of the date a notice is served in accordance with paragraph (2), the sponsor makes representations in writing to the Board, the Board -

(a)  shall take those representations into account before deciding whether to make the amendment; and

(b)  may delay the date on which the proposed amendment is to take effect, in order to allow time for the Board to consider those representations.

Amendments by the sponsor

21.       (1) A sponsor may make an amendment to a clinical trial protocol, other than a substantial amendment, at any time.

(2) If the sponsor proposes to make a substantial amendment to a clinical trial authorisation which consists of, or includes, an amendment to -

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

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

he or she shall send a valid notice of amendment to the Board, whether or not he or she is also required to send a notice in accordance with paragraph (3).

(3) If the sponsor proposes to make a substantial amendment to a clinical trial protocol which consists of, or includes, an amendment to -

(a)  the terms of the application for an ethics committee opinion in relation to the clinical trial; or

(b)  the particulars or documents that accompanied that application,

he or she shall send a valid notice of amendment to the relevant ethics committee, whether or not he or she is also required to send a notice in accordance with paragraph (2).

(4) The Board may, within the period of 35 days from the date of receipt of a valid notice of amendment, give written notice to the sponsor -

(a)  setting out the Board's grounds for not accepting the proposed amendment; or

(b) stating that the Board accepts the application for amendment, subject to any conditions which may be specified in the notice.

(5) A relevant ethics committee shall, within the period of 35 days from the date of receipt of a valid notice of amendment, give an opinion to the sponsor.

(6) Subject to paragraph (7), if the sponsor has sent a notice in accordance with paragraph (2), he or she may make the amendment only if -

(a)  the Board has given him or her a notice in accordance with paragraph (4)(b); or

(b)  no notice has been given by the Board in accordance with paragraph (4).

(7) If the sponsor has been given a notice in accordance with paragraph (4)(b), he or she may make the amendment subject to the conditions, if any, specified in the notice.

(8) If the sponsor has sent a notice in accordance with paragraph (3), he or she may make the amendment only if the relevant ethics committee has given a favourable opinion.

(9) In this Regulation -

“valid notice of amendment” means a notice that is -

(a)  in writing; and

(b)  accompanied by -

(i)   the particulars and documents set out in the detailed guidance drawn up and published by the Commission under Article 9(8)(b) of the Directive, for the presentation and content of a proposed substantial amendment made to the protocol of a clinical trial after its commencement, and

(ii)  any fee which may be payable in connection with that notice.

Modifying or adapting rejected proposals for amendment

22.       (1) Subject to the following provisions of this Regulation, if -

(a)  the ethics committee opinion on a proposed amendment to the clinical trial protocol is not favourable; or

(b) the sponsor has been notified by the Board of any grounds for non-acceptance of a proposed amendment to the clinical trial protocol,

and it is possible to modify or adapt the proposed amendment in order to meet the concerns of the ethics committee or the Board as set out in the opinion or, as the case may be, the grounds for non-acceptance, the sponsor may amend the protocol accordingly.

(2) If a sponsor proposes to amend the clinical trial protocol in accordance with paragraph (1), the sponsor shall, not later than 30 days after receipt of the concerns referred to in paragraph (1) and at least 14 days before the date the amendment is to take effect, give a notice in writing to the Board and to the relevant ethics committee.

(3) The Board may, within the period of 14 days from the date of receipt of a notice under paragraph (2), give written notice to the sponsor setting out the Board's further grounds for not accepting the modified or adapted amendment.

(4) The relevant ethics committee may, within the period of 14 days from the date of receipt of a notice under paragraph (2), give a written notice to the sponsor stating that its opinion of the modified or adapted amendment is unfavourable.

(5) If -

(a)  the sponsor receives a written notice under paragraphs (3) or (4), he or she may not make the amendment; and

(b)  if he or she receives no such notice, he or she may make the modified or adapted amendment.

Reference to the Advisory Committee for Human Medicines

23.       (1) If -

(a)  a sponsor has been notified by the Board that -

(i)   there are grounds for not accepting a request for authorisation, or

(ii)  in accordance with Regulation 15(2) or (6), Regulation 16(8) or Regulation 17(5), the trial is authorised subject to specified conditions;

(b)  the Board has amended a clinical trial protocol under Regulation 20; or

(c)  the sponsor who has been notified by the Board in accordance with Regulation 21(4) or 22(3) that -

(i)   the Board does not accept a proposed, modified or adapted amendment to the clinical trial protocol, or

(ii)  that the Board accepts such an amendment subject to conditions,

the sponsor may within 28 days, or such extended period as the Board may in any particular case allow, of the notice being given give notice to the Board of his or her wish to make representations to the Advisory Committee for Human Medicines.

(2) The provisions of Part 1 of Schedule 3 shall have effect to regulate the procedure for reference to the Advisory Committee for Human Medicines, following receipt of a notice in accordance with paragraph (1).

PART 4

GOOD CLINICAL PRACTICE AND THE CONDUCT OF CLINICAL TRIALS

Good clinical practice and protection of clinical trial subjects

24.       (1) A person shall not -

(a)  conduct a clinical trial; or

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

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

(2) 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) 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 free of charge.

(4) Paragraph (3) shall not apply to a non-commercial clinical trial that is conducted by an investigator-sponsor, without the participation of the pharmaceutical industry, in circumstances where the investigator-sponsor has no commercial or financial interest in the outcome of the trial insofar as such products or devices have not been obtained free of charge by the investigator-sponsor.

Conduct of trial in accordance with clinical trial authorisation etc.

25.       Subject to Regulation 26, a person shall not conduct a clinical trial otherwise than in accordance with -

(a)  the clinical trial protocol relating to that trial, as may be amended from time to time in accordance with Regulations 19 to 22;

(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 clinical trial protocol, accompanying that request or that application, as may be amended from time to time in accordance with Regulations 19 to 22; and

(c)  any conditions imposed by the Board under Regulation 15(2) or (6), Regulation 16(8), Regulation 17(5) or Regulation 21(4) or Part 1 of Schedule 3.

Urgent safety measures

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

(2) If measures are taken pursuant to paragraph (1), the sponsor shall immediately, and in any event no later than 3 days from the date the measures are taken, give written notice to the Board and the relevant ethics committee of the measures taken and the circumstances giving rise to those measures.

Suspension or termination of clinical trial

27.       (1) If, in relation to a clinical trial -

(a)  the Board has objective grounds for considering that -

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

(ii)  any condition imposed by the Board under Regulation 15(2) or (6), Regulation 16(8), Regulation 17(5) Regulation 21(4) or Part 1 of Schedule 3,

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

(b)  the Board has information raising doubts about the safety or scientific validity of the trial, or the conduct of the trial at a particular trial site,

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

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

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

(i)   the sponsor, or

(ii)  the investigator at each trial site;

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

(i)   the sponsor, or

(ii)  the investigator at that trial site.

(3) The notice shall specify -

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

(b)  whether the notice requires suspension or termination;

(c)  if the notice requires suspension -

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

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

(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 Board issues a notice under paragraph (1), it shall forthwith inform -

(a)  the relevant ethics committee;

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

(c)  the EMEA; and

(d)  the European Commission.

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

(a)  inform him or her that the Board proposes to issue a notice suspending or terminating the trial, or the conduct of a trial at a particular site, and of the reasons for such proposal;

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

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

(7) A person on whom a notice has been served in accordance with paragraphs (1) and (2) may, within 28 days, or such extended period as the Board may in any particular case allow, give notice of his or her wish to make representations to the Advisory Committee for Human Medicines.

(8) The provisions of Part 1 of Schedule 3 shall have effect to regulate the procedure for reference to the Advisory Committee for Human Medicines following receipt of a notice in accordance with paragraph (7).

(9) Where the notice of suspension or termination is referred to the Advisory Committee for Human Medicines, it shall remain in force unless revoked in accordance with Part 1 of Schedule 3.

Conclusion of clinical trial

28.       (1) Subject to paragraph (2), within 90 days of the conclusion of a clinical trial the sponsor shall notify the Board 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 clinical trial 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 Board 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 information specified in the detailed guidance drawn up and published by the Commission under Article 9.8(c) of the Directive, for the declaration of the end of a clinical trial.

(4) A notification made in accordance with paragraph (2) shall include an explanation of the reasons for the early termination of the trial.

PART 5

PHARMACOVIGILANCE

Notification of adverse events

29.       (1) Subject to paragraph (4), an investigator shall report any serious adverse event which occurs in a subject at a trial site at which he or she 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 clinical trial 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 clinical trial protocol as critical to evaluations of the safety of the trial shall be reported to the sponsor in accordance with the reporting requirements, including the time periods for such reporting, specified in that protocol.

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

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

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

(a)  the sponsor, and

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

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

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

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

Notification of suspected serious unexpected adverse reactions

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

(a)  recorded; and

(b)  reported as soon as possible to—

(i)   the Board,

(ii)  the competent authorities of all EEA States, other than the State, in which the trial is being conducted,

(iii) the relevant ethics committee,

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

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

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

(a)  the Board;

(b)  the competent authorities of all EEA State, other than the State, in which the trial is being conducted, and

(c)  the relevant ethics committee,

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

(4) For the purposes of paragraphs (1) to (3), the sponsor may fulfil his or her obligations to report or provide information to the Board and the competent authorities of EEA States, other than the State, by entering the report or information in the European database established in accordance with Article 11 of the Directive.

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

(6) The Board shall—

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

(b)  ensure that the details of those reactions are entered in the European database established in accordance with Article 11 of the Directive, whether by the sponsor or the Board.

Clinical trials conducted in third countries

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

Evidential value of Certificate given by analyst

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.       (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.       (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

(ii)  responsible for quality control of the investigational medicinal products being manufactured labelled or packaged including the person named as the qualified person for the purposes of Regulation 40 and paragraph 20, or

(iii) in charge of the animals from which are derived any substances used in the production of the investigational medicinal products being manufactured, labelled or packaged, or

(iv) responsible for the culture of any living tissues used in the manufacture of the investigational medicinal products being manufactured, labelled or packaged.

10.   (1) The authorisation holder shall -

(a)  keep readily available for inspection by a person authorised by the Board durable records of -

(i)   the details of manufacture, labelling and packaging of each batch of every investigational medicinal product being manufactured, labelled or packaged under his or her authorisation, and

(ii)  the tests carried out thereon including any register or other document referred to in paragraph 3 of Part 2 of Schedule 6,

in such a form that the records will be easily identifiable from the number of the batch as shown on each container in which the investigational medicinal product is sold, supplied or exported; and

(b)  permit the person authorised to take copies or make extracts from such records.

(2) Such records shall not be destroyed within the relevant period without the consent of the Board.

11.   The authorisation holder shall keep readily available for examination by a person authorised by the Board samples of -

(a) each batch of finished investigational medicinal product manufactured, labelled or packaged under his or her authorisation for at least one year from their expiry date;

(b) each batch of bulk formulated products and of the key packaging components used for each finished product for at least a period of two years from the date on which the clinical trial, for which the relevant batch was manufactured, labelled or packaged, was completed, terminated or discontinued; and

(c) starting materials, other than solvents, gases or water, used in the manufacturing process of each finished product for at least two years after the release of the product. This period may be shortened, with the approval of the Board, if the period of stability of the material, as indicated in the relevant specification, is shorter.

12.   The authorisation holder shall make suitable arrangements to ensure that any record or sample referred to in paragraph 10 or 11 is retained for the periods specified in those paragraphs.

13.   (1) The authorisation holder shall, in cooperation with the sponsor, implement a system for recording and reviewing complaints in relation to investigational medicinal products manufactured labelled or packaged under his or her authorisation, together with an effective system for recalling promptly and at any time any such investigational medicinal product that have been distributed for use in clinical trials.

(2) The authorisation holder shall -

(a) record and investigate all complaints described in subparagraph (1) of this paragraph; and

(b) immediately inform the Board of any defect which could result in a recall of any such investigational medicinal product distributed for use in clinical trials.

14.   Where the authorisation holder has been informed by the Board that any batch of any investigational medicinal product to which his or her authorisation relates has been found not to conform as regards strength, quality or purity with -

(a)  the specification of the relevant product; or

(b)  the provisions of these Regulations,

he or she shall, if so directed by the Board, withhold such batch from distribution for use in clinical trials, so far as may be reasonably practicable, for such a period not exceeding six weeks as may be specified by the Board.

15.   The authorisation holder shall ensure that any tests for determining conformity with the standards and specifications applying to any particular product used in the manufacture shall, except so far as the conditions of the product specification for that product otherwise provide, be applied to samples taken from the investigational medicinal product after all manufacturing processes have been completed, or at such earlier stage in the manufacture as may be approved by the Board.

16.   (1) The authorisation holder shall comply with the provisions of the product specification that relate to the supply of that investigational medicinal product for the purposes of the trial.

(2) Where the authorisation relates to the labelling or packaging of an investigational medicinal product, and the authorisation holder supplies that investigational medicinal product at such a stage that it does not fully comply with the provisions of the product specification that relate to labelling, that authorisation holder shall communicate the particulars of those provisions to the person to whom that investigational medicinal product has been so supplied.

17.   Where in his or her application for a manufacturing authorisation the authorisation holder -

(a)  had specified a general classification of investigational medicinal products in respect of which that authorisation was required; or

(b)  had given particulars of manufacturing operations and of substances or articles in accordance with paragraph 4 of Schedule 4,

and there has been, or it is proposed that there shall be, a change in such general classification or such particulars, the authorisation holder shall forthwith notify the Board in writing of such change or proposed change.

18.   Where -

(a)  the manufacturing authorisation relates to the labelling and packaging of an investigational medicinal product;

(b)  that investigational medicinal product is not manufactured by the authorisation holder; and

(c)  particulars as to the name and address of the manufacturer of, or of the person who imports, that investigational medicinal product had been given by the authorisation holder to the Board,

the authorisation holder shall forthwith notify the Board in writing of any changes in such particulars.

19.   The authorisation holder, for the purpose of enabling the Board to ascertain whether there are any grounds -

(a)  for suspending, revoking or varying any authorisation granted under these Regulations;

(b)  amending the clinical trial authorisation in accordance with Regulation 20 or 21

(c)  suspending or terminating any clinical trial in accordance with Regulation 27,

shall permit, and provide all necessary facilities to enable, any person duly authorised in writing by the Board, on production if required of his or her credentials, to carry out such inspection or to take such samples or copies for the purpose of verifying any statement contained in an application for an authorisation.

20.   (1) Subject to Regulation 40, the authorisation holder shall at all times, and in accordance with that Regulation, have a qualified person to carry out the duties referred to in Regulation 40(2).

(2) The authorisation holder shall at all times provide and maintain such staff, premises, equipment and facilities as will enable the qualified person who is at his or her disposal to carry out the said duties.

PART 3

PROVISIONS WHICH MAY BE INCORPORATED IN AN AUTHORISATION RELATING TO THE IMPORTATION OF INVESTIGATIONAL MEDICINAL PRODUCTS

1.     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 avoid deterioration 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.

2.     The authorisation holder shall ensure that -

(a)  all manufacture, labelling and packaging operations have been carried out by a duly authorised manufacturer; and

(b)  the investigational medicinal products have been manufactured, labeled and packaged, and are imported, in accordance with the principles and guidelines of good manufacturing practice.

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

4.     The authorisation holder shall provide such information as may be requested by the Board concerning the type and quantity of any investigational medicinal products which he or she imports.

5.     The authorisation holder shall -

(a)  inform the Board before making any structural alterations to, or discontinuance of the use of, premises to which his or her authorisation relates; 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 responsible for quality control of the investigational medicinal products being imported including the person

named as the qualified person for the purposes of Regulation 40 and paragraph 14.

6.     (1) The authorisation holder shall -

(a)  keep readily available for inspection by a person authorised by the Board durable records of -

(i)   the details of importation of each batch of every investigational medicinal product being imported under his or her authorisation, and

(ii)  the tests carried out thereon including any register or other document referred to in paragraph 3 of Part 2 of Schedule 6,

in such a form that the records will be easily identifiable from the number of the batch as shown on each container in which the investigational medicinal product is or is to be sold, supplied or exported; and

(b)  permit the person authorised to take copies or make extracts from such records.

(2) Such records shall not be destroyed within the relevant period without the consent of the Board.

7.     The authorisation holder shall keep readily available for examination by a person authorised by the Board samples of -

(a)  each batch of finished investigational medicinal products imported under his or her authorisation for at least a period of one year from their expiry date; and

(b)  each batch of bulk formulated products and of the packaging components used for each finished product for at least a period of two years from the date on which the clinical trial, for which the relevant batch was manufactured labelled or packaged, was completed, terminated or discontinued.

8.     The authorisation holder shall make suitable arrangements to ensure that any record or sample referred to in paragraph 6 or 7 is retained for the periods specified in those paragraphs.

9.     (1) The authorisation holder shall, in cooperation with the sponsor, implement a system for recording and reviewing complaints in relation to investigational medicinal products imported under his or her authorisation, together with an effective system for recalling promptly and at any time any such investigational medicinal product that have been distributed for use in clinical trials.

(2) The authorisation holder shall -

(a)  record and investigate all complaints described in subparagraph (1) of this paragraph; and

(b)  shall immediately inform the Board of any defect which could result in a recall from distribution for use in clinical trials.

10.   Where the authorisation holder has been informed by the Board that any batch of any investigational medicinal product to which his or her authorisation relates has been found not to conform as regards strength, quality or purity with -

(a)  the specification of the relevant product; or

(b)  the provisions of these Regulations,

he or she shall, if so directed by the Board, withhold such batch from distribution for use in clinical trials, so far as may be reasonably practicable, for such a period not exceeding six weeks as may be specified by the Board.

11.   If the authorisation holder is not the sponsor of the clinical trial for which the investigational medicinal product is manufactured, labelled or packaged, he or she shall comply with the provisions of the product specification that relates to the supply of that investigational medicinal product for use in the trial.

12.   Where -

(a)  in his or her application for a manufacturing authorisation the authorisation holder had given particulars of manufacturing operations and of substances or articles in accordance with paragraph 4 of Schedule 4; and

(b)  there has been, or it is proposed that there shall be, a change in such particulars,

the authorisation holder shall forthwith notify the Board in writing of such change or proposed change.

13.   The authorisation holder shall, for the purpose of enabling the Board to ascertain whether there are any grounds -

(a)  for suspending, revoking or varying any authorisation;

(b)  amending the conduct of a clinical trial in accordance with Regulation 20 or 21

(c)  suspending or terminating any clinical trial in accordance with Regulation 27,

permit, and provide all necessary facilities to enable, any person duly authorised in writing by the Board, on production if required of his or her credentials, to carry out such inspection or to take such samples or copies, in relation to things belonging to, or any business carried on by, the authorisation holder for the purpose of verifying any statement contained in an application for an authorisation.

14.   (1) Subject to Regulation 40, the authorisation holder shall at all times, and in accordance with that Regulation, have a qualified person to carry out duties referred to in Regulation 40(2).

(2) The authorisation holder shall at all times provide and maintain such staff, premises, equipment and facilities as will enable the qualified person who is at his or her disposal to carry out the said functions.

SCHEDULE 6

PART 1

MINIMUM QUALIFICATIONS FOR QUALIFIED PERSON

The following are the minimum conditions of qualification for a qualified person:

(a)  possession of a diploma, certificate or other evidence of formal qualifications awarded on completion of a university course of study, or a course recognised as equivalent by the Board, extending over a period of at least 4 years of theoretical and practical study in one of the following scientific disciplines: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology, and biology.

However:

(i)   the minimum duration of the university course may be 3 and a half years where the course is followed by a period of theoretical and practical training of a minimum duration of one year and including a training period of at least 6 months in a pharmacy open to the public, corroborated by an examination at university level;

(ii)  where 2 university courses, or 2 courses recognised by the State in question as equivalent co-exist in an EEA State and where one of these extends over 4 years and the other over 3 years, the three-year course leading to a diploma, certificate or other evidence of formal qualifications awarded on completion of a university course or its recognised equivalent shall be considered to fulfil the condition of duration referred to in subparagraph (a) in so far as the diplomas, certificates or other evidence of formal qualifications awarded on completion of both courses are recognised as equivalent by the State in question.

The course shall include theoretical and practical study bearing upon at least the following basic subjects and shall be so balanced as to enable the person concerned to fulfil the obligations specified in Regulation 40(2):

Experimental physics

General and inorganic chemistry

Organic chemistry

Analytical chemistry

Pharmaceutical chemistry, including analysis of medicinal products

General and applied biochemistry (medical)

Physiology

Microbiology

Pharmacology

Pharmaceutical technology

Toxicology

Pharmacognosy (study of the composition and effects of the active principles of natural substances of plant and animal origin).

Insofar as certain diplomas, certificates or other evidence of formal qualifications mentioned in the first paragraph do not fulfil the criteria laid down above, the person concerned shall provide evidence to the Board of adequate knowledge of the subjects involved; and

(b)  practical experience for at least 2 years, in one or more undertakings which are authorised to manufacture medicinal products, in the activities of qualitative analysis of medicinal products, of quantitative analysis of active substances and of the testing and checking necessary to ensure the quality of medicinal products provided that the duration of practical experience may be reduced by one year where a university course lasts for at least 5 years and by a year and a half where the course lasts for at least 6 years.

or

(c)  was on or immediately before the coming into force of these Regulations, engaged in, or was entitled to be engaged in, the activities of a qualified person pursuant to the provisions of the Medical Preparations (Licensing of Manufacture) Regulations 1993⁶ , as amended by the Medical Preparations (Licensing of Manufacture) (Amendment) Regulations 1993⁷ , the Medical Preparations (Licensing of Manufacture) (Amendment) Regulations 1996⁸ and the Medicinal Products (Amendment) Regulations 1999⁹ .

PART 2

DUTIES OF QUALIFIED PERSON

1.     The qualified person referred to in Regulation 40, is responsible, without prejudice to his or her relationship with the manufacturer or importer, for ensuring:

(a)  in the case of investigational medicinal products manufactured in the State, that each batch of medicinal products has been manufactured and checked in compliance with the requirements of Commission Directive 2003/94/EC, the product specification file and the information notified pursuant to Regulation 14;

(b)  in the case of investigational medicinal products manufactured in a third country, 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, in accordance with the product specification file, and that each production batch has been checked in accordance with the information notified pursuant to Regulation 14;

(c)  in the case of an investigational medicinal product which is a comparator product from a third country, and which is the subject of a marketing authorisation, where the documentation certifying that each production batch has been manufactured in conditions at least equivalent to the standards of good manufacturing practice referred to above cannot be obtained, that each production batch has undergone all relevant analyses, tests or checks necessary to confirm its quality in accordance with the information notified pursuant to Regulation 14.

2.     Insofar as the provisions laid down in subparagraphs (a), (b) or (c) of paragraph 1 are complied with, investigational medicinal products shall not have to undergo any further checks if they are imported from another Member State together with batch release certification signed by the qualified person.

3.     In all cases, the qualified person shall certify in a register or equivalent document that each production batch satisfies the provisions of this Schedule. The said register or equivalent document shall be kept up-to-date as operations are carried out and shall be retained for not less than 5 years from the date of manufacture or for the period that ends one year after the labelled expiry date of the investigational medicinal product, whichever is the longer period.

SCHEDULE 7

( Regulation 50 )

Explanatory Note

(This note is not part of the Instrument and does not purport to be a legal interpretation)

The purpose of these Regulations is to implement Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

The Regulations provide that the Irish Medicines Board will exercise the functions of the competent authority for the purposes of the Directive and for the purposes of supervision and enforcement as required by the Regulations. The Regulations also introduce measures for the establishment and operation of Ethics Committees that are required to give an opinion before a clinical trial may commence. This includes arrangements for obtaining a single ethics committee opinion in the case of multi-centre trials. The matters to be considered by Ethics Committees are set out in Regulation 13 of the Regulations.

The Regulations also provide for an Ethics Committee Supervisory Body, the functions of which for the time being are to be discharged by the Minister. The primary function of this Body is to grant recognition in respect of Ethics Committees that are required to be established for the purposes of the Regulations. The composition of Ethics Committees, including certain procedures in regard to their operation, is set out in Schedule 2. This composition reflects the requirements set out in the Directive.

An Ethics Committee as envisaged by the Directive “is an independent body in a Member State consisting of health care professionals and non-medical members, whose responsibility it is to protect the trials, safety and wellbeing of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documentation to be used to inform trial subjects and obtain their informed consent”. All of these objectives have been provided for in these Regulations.

The conditions and principles for the protection of clinical trials subjects are set out in Schedule 1 and are consistent with the principles contained in the 1996 version of the Helsinki Declaration. The detailed conditions, that are to apply in relation to a subject giving consent, are also set out in that Schedule in relation to subjects who are able to consent, in relation to minors, and in relation to incapacitated adults. Where the conduct of a clinical trial is subject to the provisions of these Regulations, the Control of Clinical Trials Acts 1987 and 1990 will not apply.

¹ OJ L. 121, 01.05.2001, p.34.

² OJ L.262, 14.10.2003, p.22.

¹ OJ L. 121, 01.05.2001, p.34.

³OJ No. L.311, 28.11.2001, p.67.

⁴OJ No. L1, 03.01.1994, p.572.

⁵ OJ No. L214, 24.08.1993, p1.

⁵ OJ No. L214, 24.08.1993, p1.

⁵ OJ No. L214, 24.08.1993, p1.

⁶ S.I. No. 40 of 1993

⁷ S.I. No. 68 of 1993

⁸ S.I. No. 42 of 1996

⁹ S.I. No. 188 of 1999