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

1.	Citation
2.	Commencement
3.	Application of Regulations and of Control of Clinical Trials Acts, 1987 and 1990
4.	Interpretation
5.	Designation of functions under the Directive

PART 2 ETHICS COMMITTEES

6. & 7.	Establishing, recognising and monitoring of ethics committees
8.	Revocation of recognition for ethics committee
9.	Membership and operation of ethics committees

PART 3 AUTHORISATION FOR CONDUCT OF CLINICAL TRIALS AND ETHICS COMMITTEE OPINION

10.	Requirement for authorisation and ethics committee opinion
11.	Supply of investigational medicinal products for the purpose of clinical trials
12.	Application for ethics committee opinion
13.	Ethics committee opinion
14.	Request for authorization to conduct a clinical trial
15.	Authorisation procedure for clinical trials involving general medicinal products
16.	Authorisation procedure for clinical trials involving general medicinal products for gene therapy etc .
17.	Authorisation procedure for clinical trials involving medicinal products with special characteristics
18.	Clinical trials conducted in third countries
19.	Amendments to clinical trial protocol
20.	Amendments by the Board
21.	Amendments by the sponsor
22.	Modifying or adapting rejected proposals for amendment
23.	Reference to the Advisory Committee for Human Medicines

PART 4 GOOD CLINICAL PRACTICE AND THE CONDUCT OF CLINICAL TRIALS

24.	Good clinical practice and protection of clinical trial subjects
25.	Conduct of trial in accordance with clinical trial authorization etc .
26.	Urgent safety measures
27.	Suspension or termination of clinical trial
28.	Conclusion of clinical trial

PART 5 PHARMACOVIGILANCE

29.	Notification of adverse events
30.	Notification of suspected serious unexpected adverse reactions
31.	Clinical trials conducted in third countries
32.	Annual list of suspected serious adverse reactions and safety report

PART 6 MANUFACTURE AND IMPORTATION OF INVESTIGATIONAL MEDICINAL PRODUCTS

33.	Requirement for authorisation to manufacture or import investigational medicinal products
34.	Exemption for hospitals
35.	Application for manufacturing authorisation
36.	Consideration of application for manufacturing authorisation
37.	Grant or refusal of manufacturing authorisation
38.	Application and effect of manufacturing authorisation
39.	Obligations of manufacturing authorisation holder
40.	Qualified persons
41.	Variation of manufacturing authorisation
42.	Suspension and revocation of manufacturing authorisation

PART 7 LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS

43.	Labelling

PART 8 OFFENCES, PENALTIES AND ENFORCEMENT

44.	Offences and penalties
45.	Infringement notices
46.	False or misleading information
47.	Defence of due diligence
48.	Enforcement
49.	Prosecution of offences
50.	Evidential value of Certificate given by analyst

PART 9 TRANSITIONAL ARRANGEMENTS

51.	Transitional arrangements
52.	Fees

SCHEDULES

1.	Conditions and principles for the protection of clinical trial subjects	Conditions and principles for the protection of clinical trial subjects
	Part 1 .	Application and Interpretation
	Part 2 .	Conditions and principles that apply to all clinical trials
	Part 3 .	Conditions which apply in relation to a subject able to consent
	Part 4 .	Conditions and principles which apply in relation to a minor
	Part 5 .	Conditions and principles which apply in relation to an incapacitated adult
2.	Additional provisions for ethics committees	Additional provisions for ethics committees
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
	Part 2	Procedural provisions relating to proposals to grant, refuse to grant, vary, suspend or revoke manufacturing authorisations
4.	Particulars that must accompany an application for a manufacturing authorisation	Particulars that must accompany an application for a manufacturing authorisation
5.	Standard provisions for manufacturing authorisations	Standard provisions for manufacturing authorisations
	Part 1 .	Interpretation
	Part 2 .	Provisions which may be incorporated in an authorisation relating to the manufacture, labelling or packaging of investigational products
	Part 3 .	Provisions which may be incorporated in an authorisation relating to the importation of investigational products
6.	Qualified persons	Qualified persons
	Part 1 .	Minimum qualifications for qualified person
	Part 2 .	Duties of qualified person
7.	Certificate stating results of test, examination or analysis.	Certificate stating results of test, examination or analysis.

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.

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

Commencement

2.

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.

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.

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, 1993⁴ ;

“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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.