S.I. No. 99/2022 - European Union (Clinical Trials on Medicinal Products for Human Use) (Principal) Regulations 2022

Notice of the making of this Statutory Instrument was published in

“Iris Oifigiúil” of 4th March, 2022.

I, STEPHEN DONNELLY, Minister for Health, 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 further effect to Regulation (EC) No. 536/2014 of 16 April 2014¹ , hereby make the following regulations:

PART 1 PRELIMINARY

Citation

1.

2.

• (2) These Regulations do not apply to non-interventional studies.

Interpretation

3.

“Advisory Committee for Human Medicines” means the committee established by section 9 of the Irish Medicines Board Act 1995 (No. 29 of 1995), as amended;

“Agency” means the European Medicines Agency, established by Regulation (EC) No. 726/2004 of the European Parliament and of the Council of 31 March 2004² ;

“Assessment Report” means the report required to be drawn up by the reporting Member State or the Member State concerned, as appropriate, in the context of an application for a clinical trial under Article 6(2) and Article 7(2) of the Clinical Trials Regulation.

“Authority” means the Health Products Regulatory Authority established by section 3 of the Irish Medicines Board Act 1995 (No. 29 of 1995), as amended;

“Clinical Trials Regulation” means Regulation (EU) No. 536/2014 of the European Parliament and of the Council of 16 April 2014¹ on clinical trials on medicinal products for human use;

“Commission Delegated Regulation (EU) 2017/1569” means Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017³ ;

“clinical study” has the same meaning as it has in the Clinical Trials Regulation;

“clinical trial” has the same meaning as it has in the Clinical Trials Regulation;

“Data Protection Acts 1988 to 2018” means the Data Protection Act 1988 (No. 25 of 1988), the Data Protection Act 2003 (No. 6 of 2003) and the Data Protection Act 2018 (No. 7 of 2018);

“Declaration of Helsinki” means the Declaration of Helsinki adopted by the General Assembly of the World Medical Association in June 1964, and as amended by the General Assembly of that Association from time to time;

“Directive” means Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001⁴ ;

“Directive 2001/83/EC⁶ ” means Directive 2001/83/EC of the European Parliament and of the Council;

“EU database” means the database established under Article 81 of the Clinical Trials Regulation;

“EU portal” means the electronic portal established under Article 80 of the Clinical Trials Regulation;

“EudraGMDP database” means the EU database, maintained and operated by the European Medicines Agency, on manufacturing, import and wholesale-distribution authorisations, and good manufacturing-practice (GMP) and good-distribution-practice (GDP) certificates;

“General Data Protection Regulation” means Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016⁵ ;

“incapacitated subject” means a subject who is, for reasons other than the age of legal competence to give informed consent, incapable of giving informed consent to participate in a clinical trial;

“investigator” for the purposes of Article 49 of the Clinical Trials Regulation and these Regulations means -

• (a) a medical practitioner within the meaning of section 2 of the Medical Practitioners Act 2007 (No. 25 of 2007),

• (b) a visiting EEA practitioner within the meaning of section 2 of the Medical Practitioners Act 2007 , or

• (c) a registered dentist within the meaning of section 2 of the Dentists Act 1985 (No. 9 of 1985);

“Joint Controllership Arrangement” means the arrangement agreed by the European Commission, European Medicines Agency, Member States, sponsors and marketing authorisation applicants or holders for the purpose of processing personal data captured in the EU portal;

“legally designated representative”, for the purposes of these Regulations and the Clinical Trials Regulation only, means—

• (a) in relation to an incapacitated subject who is, or is being considered as, a subject for a clinical trial—

• (i) a person, other than a person connected with the conduct of the trial, who by virtue of his or her family or other personal relationship with the individual—

• (aa) can provide the best interpretation of the will and preferences of the individual based on their knowledge of the individual,

• (bb) is available and willing to act for that purpose, or

• (ii) if there is no such person, the medical practitioner primarily responsible for the medical treatment provided to the individual where he or she—

• (aa) can provide the best interpretation of the will and preferences of the individual based on their knowledge of the individual,

• (bb) is not involved in the conduct of the trial,

• (cc) is of the view that participation in the trial will not prejudice the health and wellbeing of the individual, and

• (dd) is available and willing to act for that purpose, and

• (b) in relation to a minor who is, or is being considered as, a subject for a clinical trial, a guardian within the meaning of the Guardianship of Infants Act 1964 (No. 7 of 1964);

“legal representative” means the natural or legal person established in the European Union as the legal representative of a clinical trial sponsor who is not established in the Union;

“manufacturer’s authorisation” means an authorisation for the manufacture or import of investigational medicinal products referred to in Article 61(1) of the Clinical Trials Regulation which is for the time being in force and which has been granted by the Authority pursuant to Regulation 38;

“marketing authorisation” means an authorisation which is for the time being in force and which has been granted by the Authority under the Medicinal Products (Control of Placing on the Market) Regulations 2007 ( S.I. No. 540 of 2007 ), or by the Commission under Regulation (EC) No. 726/2004² and includes a marketing authorisation issued by the competent authority of an EEA State, other than the State, in accordance with Directive 2001/83/EC⁶ ;

“medical doctor” for the purpose of Article 49 of the Clinical Trials Regulation means a registered medical practitioner;

“Minister” means the Minister for Health;

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

“National Office” has the meaning assigned to it by Regulation 5 of the European Union Clinical Trials on Medicinal Products for Human Use) (National Research Ethics Committees) Regulations 2022 ( S.I. No. 41 of 2022 );

“National Research Ethics Committee” has the meaning assigned to it by Regulation 13 of the European Union (Clinical Trials on Medicinal Products for Human Use) (National Research Ethics Committees) Regulations 2022 ( S.I. No. 41 of 2022 );

“nominated ethics committee” means the National Research Ethics Committee nominated by the National Office to assess and provide an opinion on a specific clinical trial application, or substantial modification to a clinical trial granted authorisation, pursuant to the Clinical Trials Regulation;

“non-commercial sponsor” means a sponsor who has no commercial or financial interest in the outcome of the clinical trial;

“non-commercial clinical trial” means a clinical trial conducted by a non-commercial sponsor which fulfils the following characteristics—

• (a) the ownership of the investigation data belongs to the non-commercial sponsor from the inception of the clinical trial, and

• (b) the design, conduct, recruitment, recording of data and reporting of the results of the investigation remain under the control of the non-commercial sponsor;

“Part I” refers to Part I of the Assessment Report;

“Part II” refers to Part II of the Assessment Report;

“premises” means any place (physical or virtual), ship or other vessel, aircraft, railway wagon or other vehicle or other mobile facility, other than a dwelling, and includes a container used to transport an investigational medicinal product and/or an auxiliary medicinal product or other relevant thing;

“qualified person” means a person with the qualifications and experience specified in Article 49(2) and (3) of Directive 2001/83/EC⁶ and named in the manufacturer’s authorisation as being responsible for the functions set out in Article 62 of the Clinical Trials Regulation;

“relevant health care provider” means –

• (a) in relation to a person receiving services in pursuance of the Health Acts 1947 to 2007—

• (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;

“registered nurse” means a person registered in the Register of Nurses and Midwives established under section 46(1)(a) of the Nurses and Midwives Act 2011 (No. 41 of 2011);

“registered pharmacist” means a person registered in the Register of Pharmacists established under section 13(1) of the Pharmacy Act 2007 (No. 20 of 2007);

“Register of Exemptions” means the register of processes specified in Article 61(6) of the Clinical Trials Regulation which are exempt from the requirements of Article 61(1) and which is established under Regulation 30 herein;

“Regulation (EC) No 726/2004² ” means regulations of the European Parliament and of the Council of 31 March 2004;

“Regulation (EU) 2017/556⁷ ” means Commission Implementing Regulation (EU) 2017/556 of 24 March 2017;

“reporting Member State” means the Member State concerned appointed as reporting Member State under Article 5 of the Clinical Trials Regulation;

“subject” means an individual who participates in a clinical trial, either as a recipient of an investigational medicinal product or as a control;

“ S.I. No. 40 of 2022 ” means the European Union (Clinical Trials on Medicinal Products for Human Use) Regulations 2022;

“ S.I. No. 41 of 2022 ” means the European Union (Clinical Trials on Medicinal Products for Human Use) (National Research Ethics Committees) Regulations 2022;

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

Roles of Authority, National Office and Nominated Ethics Committee

4.

• (a) the role of Member State, pursuant to the Clinical Trials Regulation, shall be carried out by the Authority and the National Office in conjunction with the nominated ethics committee, each of which—

• (i) may communicate information when carrying out their respective functions under the Clinical Trials Regulation, and

• (ii) shall keep such communications confidential,

• (b) where the State is the reporting Member State under the Clinical Trials Regulation, the Authority and the National Office in conjunction with the nominated ethics committee shall co-ordinate in the review of applications for the conduct of clinical trials and applications for substantial modifications to clinical trials granted authorisation, and perform the functions ascribed to the reporting Member State under the Clinical Trials Regulation within the timelines set out therein,

• (c) where the State is a Member State concerned under the Clinical Trials Regulation, the Authority and the National Office in conjunction with the nominated ethics committee shall perform the functions ascribed to the Member State concerned under the Clinical Trials Regulation within the timelines set out therein,

• (d) where the State is an additional Member State concerned pursuant to Article 14 of the Clinical Trials Regulation, the Authority and the National Office in conjunction with the nominated ethics committee shall perform the functions ascribed to additional Member States concerned under the Clinical Trials Regulation within the timelines set out therein, and

• (e) notifications to the EU portal envisaged at Article 80 of the Clinical Trials Regulation and submissions to the EU database envisaged at Article 81 thereof shall be made by either the Authority or the National Office, as appropriate.

• (f) the Authority shall—

• (i) perform the scientific review referred to in Article 4 of the Clinical Trials Regulation,

• (ii) validate the aspects covered by the Part I assessment, pursuant to Chapters II and III of the Clinical Trials Regulation,

• (iii) be the national contact point for the purposes of Article 83 of the Clinical Trials Regulation,

• (iv) perform the inspections envisaged by Articles 63 and 78 of the Clinical Trials Regulation,

• (v) collect the fees envisaged by Chapter XVI of the Clinical Trials Regulation,

• (vi) be responsible for the enforcement of these Regulations and the prosecution of any offences thereunder.

• (g) the National Office, in conjunction with the nominated ethics committee, shall—

• (i) perform the ethical review referred to in Article 4 of the Clinical Trials Regulation,

• (ii) validate the aspects covered by the Part II assessment, pursuant to Chapters II and III of the Clinical Trials Regulation.

• (h) the National Office shall have the additional functions described in S.I. No. 41 of 2022 .

• (i) a National Research Ethics Committee shall have the additional functions described in S.I. No. 41 of 2022 .

• (2) The Minister may publish guidelines as to the appropriate division of tasks prescribed by the Clinical Trials Regulation, between the Authority, the National Office and the nominated ethics committee, as appropriate.

PART 2 AUTHORISATION TO CONDUCT CLINICAL TRIALS AND AUTHORISATION OF SUBSTANTIAL MODIFICATIONS TO CLINICAL TRIALS GRANTED AUTHORISATION

Determination on role as a reporting Member State

5.

• (2) Before making its determination under paragraph (1), the Authority shall consult with the National Office.

Determination on scope of application

6.

Drafting of Reports

7.

Assessment of application – Part I of Assessment Report

8.

• (a) review the application in terms of the scientific aspects covered by Part I of the Assessment Report,

• (b) draw up Part I of the Assessment Report under Article 6(2) of the Clinical Trials Regulation, and

• (c) conclude on the application insofar as Part I of the Assessment Report is concerned, under Article 6(4) of the Clinical Trials Regulation.

• (2) In order to assist the Authority in the performance of its functions under paragraph (1)(b) and (1)(c), the nominated ethics committee shall—

• (a) review the application in terms of the ethical aspects of the matters covered by Part I of the Assessment Report, and

• (b) provide input to the Authority on those ethical aspects, in accordance with Regulation 19 of S.I. No. 41 of 2022 .

Assessment of application – Part II of Assessment Report

9.

• (1) review the application in terms of the matters covered by Part II of the Assessment Report,

• (2) draw up part II of the Assessment Report under Article 7(1) of the Clinical Trials Regulation in accordance with Regulation 7, and

• (3) conclude on Part II of the Assessment Report under Article 7(2) of the Clinical Trials Regulation.

Grant or refusal of application

10.

• (a) a clinical trial is authorised,

• (b) a clinical trial is authorised subject to certain conditions, or

• (c) authorisation of a clinical trial is refused.

• (2) Authorisation of a clinical trial shall be refused pursuant to Article 8(4) or Article 14(10) of the Clinical Trials Regulation, as appropriate, where—

• (a) the Authority or the nominated ethics committee disagrees with the reporting Member State’s conclusion as regards Part I of the Assessment Report on any of the grounds stated in the second subparagraph of Article 8(2) or Article 14(4) of the Clinical Trials Regulation, as appropriate,

• (b) the nominated ethics committee finds on duly justified grounds, that the aspects addressed in Part II of the Assessment Report are not complied with, or

• (c) the nominated ethics committee has issued a negative opinion in relation to the application.

Validation of application for authorisation of a substantial modification

11.

• (a) an aspect covered by Part I of the Assessment Report as envisaged by Article 17 of the Clinical Trials Regulation, or

• (b) aspects covered by Parts I and II of the Assessment Report, as envisaged by Article 21 of the Clinical Trials Regulation.

• (2) The National Office in conjunction with the nominated ethics committee shall validate the application and notify the sponsor of the matters at Article 20(1)(a) and (b) of the Clinical Trials Regulation, where the substantial modification concerns an aspect covered by Part II of the Assessment Report.

Assessment of application for authorisation of a substantial modification

12.

• (1) the Authority shall perform the scientific review of the Part I assessment in accordance with Articles 18 and 21, as appropriate, of the Clinical Trials Regulation,

• (2) in order for the Authority to conclude on the Part I assessment, the National Office, in conjunction with the nominated ethics committee, shall provide an opinion following ethical review of Part I, pursuant to Article 18 or 21 of the Clinical Trials Regulation and Regulation 19 of S.I. No. 41 of 2022 ;

• (3) the Authority shall conclude on the Part I assessment in accordance with Article 19 or 23 of the Clinical Trials Regulation, as appropriate,

• (4) the nominated ethics committee shall review and conclude on the Part II assessment in accordance with Article 20 or Article 23 of the Clinical Trials Regulation, as appropriate,

• (5) the Authority shall submit an administrative single decision on a substantial modification application for authorisation, in accordance with Articles 19 or 23 of the Clinical Trials Regulation,

• (6) the National Office shall submit an administrative single decision on a substantial modification application for authorisation in accordance with Article 20 of the Clinical Trials Regulation.

Grant or refusal of application for authorisation of a substantial modification

13.

• (a) the substantial modification is authorised,

• (b) the substantial modification is authorised subject to certain conditions,

• (c) authorisation of the substantial modification is refused.

• (2) In accordance with Article 20(5) of the Clinical Trials Regulation and where the substantial modification concerns an aspect covered by Part II of the Assessment Report, the National Office (through the Authority if required by the operation of the EU portal) shall notify the sponsor through the EU portal as to whether—

• (a) the substantial modification is authorised,

• (b) the substantial modification is authorised subject to conditions allowable under Article 20(5) of the Clinical Trials Regulation,

• (c) authorisation of the substantial modification is refused.

• (3) In accordance with Article 23(1) of the Clinical Trials Regulation and where the modification concerns an aspect covered by Parts I and II of the Assessment Report, the National Office will co-ordinate with the Authority to ensure that the sponsor is notified of the nominated ethics committee’s decision under Article 22 of the Clinical Trials Regulation, to facilitate notification in accordance with a method prescribed under Article 20(5) of the Clinical Trials Regulation

• (4) Authorisation of a substantial modification of an aspect covered by Part I of the Assessment Report shall be refused pursuant to Article 19(2), where—

• (a) the Authority or the nominated ethics committee disagrees with the reporting Member State’s conclusions as regards Part I of the Assessment Report, on any of the grounds stated in the second subparagraph of Article 19(2) of the of the Clinical Trials Regulation, or,

• (b) the nominated ethics committee has issued a negative opinion in relation to the substantial modification,

• (5) Authorisation of a substantial modification of an aspect covered by Part II of the Assessment Report shall be refused pursuant to Article 20(7) of the Clinical Trials Regulation, where—

• (a) the nominated ethics committee finds that aspects covered by Part II of the Assessment Report are not complied with, or

• (b) the nominated ethics committee has issued a negative opinion in accordance with Article 20(7) of the Clinical Trials Regulation.

• (6) Authorisation of a substantial modification of an aspect covered by Part I and Part II of the Assessment Report shall be refused where—

• (a) the Authority or nominated ethics committee disagrees with the reporting Member State’s conclusions as regards Part I of the Assessment Report, on any of the grounds stated in the second subparagraph of Article 23(2) of the Clinical Trials Regulation,

• (b) the nominated ethics committee finds, on duly justified grounds, that the aspects covered by Part II of the Assessment Report are not complied with, or

• (c) the nominated ethics committee has issued a negative opinion in relation to the substantial modification.

PART 3 CONDUCT OF CLINICAL TRIALS

Conduct of clinical trials within the State

14.

• (a) conduct a clinical trial,

• (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), or

• (c) perform the functions of the investigator of a clinical trial,

in the State, otherwise than in accordance with paragraph (2).

• (2) The activities at paragraph 1(a) to (c) shall be conducted in accordance with—

• (a) the Clinical Trials Regulation,

• (b) these Regulations,

• (c) the Declaration of Helsinki,

• (d) the authorisation to conduct that clinical trial as notified to the sponsor under Regulation 10 or 13 of these Regulations,

• (e) any clinical trial protocol relating to a particular clinical trial,

• (f) any particulars or documents, other than the clinical trial protocol, accompanying a clinical trial application, as may be modified from time to time in accordance with Articles 17 to 23 of the Clinical Trials Regulation,

• (g) the conditions and principles of good clinical practice, and

• (h) any other relevant guidance, including guidance published by the Agency or the European Commission.

Compliance with obligations where the sponsor is not established in European Union

15.

Charges to subjects of clinical trials

16.

• (a) any investigational medicinal products or auxiliary medicinal products used in the clinical trial, and

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

are made available free of charge to the subject of the clinical trial.

• (2) Paragraph (1) shall not apply to a non-commercial clinical trial conducted by a non-commercial sponsor, except in circumstances where the sponsor has obtained the products or devices referred to in paragraph (1) free of charge, in which case clinical trial subjects shall not bear any cost relating to such products or devices.

Damage compensation

17.

PART 4 PROTECTION OF CLINICAL TRIAL SUBJECTS AND INFORMED CONSENT

General rules, emergency rules

18.

• (2) For the purposes of Article 28(1)(d), national law in relation to privacy and data rights of individuals shall also apply, in particular the Data Protection Acts 1988 to 2018.

• (3) Article 28(1)(b) and (c), Article 31(1)(a) and (b), and Article 32(1)(a) and (b) of the Clinical Trials Regulation may be derogated from in emergency situations in the manner prescribed by Article 35 of the Clinical Trials Regulation.

Informed consent, consent in cluster trials

19.

• (2) For clinical trials in the State, the interview prescribed by Article 29(2)(c) of the Clinical Trials Regulation shall be conducted by the investigator or by—

• (a) a registered medical practitioner,

• (b) a registered dentist, or

• (c) a registered nurse

whose training, experience and qualifications have been assessed by the investigator and determined to be appropriate to qualify him, or her, to conduct the interview.

• (3) For the purposes of Article 29(8) of the Clinical Trials Regulation, in addition to the informed consent given by a guardian, a minor who is capable of forming an opinion and assessing the information given to him or her, shall also assent in order to participate in a clinical trial.

• (4) For clinical trials which are to be conducted exclusively in the State, the investigator may obtain informed consent by simplified means, in accordance with Article 30 of the Clinical Trials Regulation, provided all conditions therein are met.

PART 5 CLINICAL TRIAL MASTER FILE AND ARCHIVING

Trial master file

20.

• (1) contain information—

• (a) sufficient to demonstrate whether the principles and guidelines of good clinical practice, Annex I and, where applicable, Annex II to the Clinical Trials Regulation, have been complied with, and

• (b) which is specific to each phase of the clinical trial,

• (2) be readily available for inspection by the Authority and directly accessible upon request, and

• (3) form the basis for the Authority’s inspection as envisaged by Article 78 of the Clinical Trials Regulation.

Archiving

21.

• (1) the clinical trial master file shall be archived—

• (a) for at least 25 years after the end of a clinical trial, or such longer period as may be agreed between the sponsor and investigator, and

• (b) in a manner which ensures that it can be made available for inspection by the Authority.

• (2) the medical files of trial subjects shall be retained for the maximum period of time permitted or required by the hospital, entity, or private practice at which the trial is conducted.

PART 6 SUPERVISION AND CONTROL

Inspections in the State

22.

23.

Corrective measures

24.

• (2) Any corrective measure taken by the Authority under paragraph (1) shall be notified by the Authority to the sponsor or investigator and shall specify the date on which the measure shall take effect.

• (3) Before the Authority takes a measure under Article 77(1) of the Clinical Trials Regulation, it shall, except where immediate action is required, ask the sponsor or the investigator for their opinion, which opinion shall be delivered within 7 days.

• (4) When considering whether the requirements of the Clinical Trials Regulation continue to be met, the Authority may consult with—

• (a) the National Office, or

• (b) the nominated ethics committee, or

• (c) other Member States concerned,

before taking any of the measures referred to in Article 77(1) of the Clinical Trials Regulation.

• (5) Where a measure is taken by the Authority under Article 77(1) of the Clinical Trials Regulation and paragraph (1) of this Regulation, the Authority shall immediately inform all Member States concerned through the EU portal, in accordance with Article 77(3) of the Clinical Trials Regulation.

PART 7 SAFETY REPORTING

25.

• (1) investigators and sponsors shall comply with the reporting obligations to which they are subject under Articles 41, 42, and 43 of the Clinical Trials Regulation,

• (2) the Authority may, by way of notification, require the sponsor to send it the records referred to in Article 41(3) of the Clinical Trials Regulation, or copies thereof.

26.

• (1) shall cooperate with other Member States concerned in assessing the information reported under Articles 42 and 43 of the Clinical Trials Regulation, and

• (2) may consult with the National Office or the nominated ethics committee in the performance of its obligations under paragraph (1).

27.

PART 8 MANUFACTURING AND IMPORTATION OF MEDICINAL PRODUCTS USED IN CLINICAL TRIALS

28.

Exemptions, Register of Exemptions

29.

• (a) “pharmacists” means “registered pharmacist” as defined in Regulation 3(1) of these Regulations,

• (b) “other persons legally authorised in the Member State concerned” means a registered medical practitioner, or a registered dentist, as defined in Regulation 3(1) of these Regulations, and

• (c) a “clinic” includes a retail pharmacy business as defined in the Pharmacy Act 2007 (No. 20 of 2007).

30.

• (a) shall maintain a register of processes specified in Article 61(5) of the Clinical Trials Regulation that are undertaken in hospitals, clinics and health centres that are exempt from the requirements of Article 61(1) of the Clinical Trials Regulation, defined as “Register of Exemptions” in Regulation 3(1), and

• (b) the Minister may publish guidelines prescribing further appropriate and proportionate requirements as may be required to ensure the objectives of Article 61(6) of the Clinical Trials Regulation are met.

31.

• (2) Notwithstanding paragraph (1), a process that has not been included on the register specified in Regulation 30, may be carried out if—

• (a) the related clinical trial had commenced prior to 31 January 2022 and is being conducted under Directive 2001/20/EC, or

• (b) the process relates to a clinical trial conducted under the Clinical Trials Regulation whereby an application to be added to the Register of Exemptions has been submitted to the Authority pursuant to Regulation 32 by 31st of January 2023.

32.

• (a) made in writing, in accordance with any form and manner as the Authority at its discretion may require,

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

• (c) accompanied by any fee which may be payable in connection with the application,

• (d) subject to Regulation 31, be submitted prior to the intended commencement of the activity.

• (2) The applicant shall notify the Authority without delay of any changes to the details of the registered process.

33.

34.

• (a) conditions for entry on to the register are not satisfied,

• (b) the information submitted is false or misleading.

35.

• (a) it does not comply with these Regulations or a condition of entry on to the Register of Exemptions,

• (b) the applicant requests the withdrawal of the process,

• (c) it transpires that the information submitted in the application for entry to the Register of Exemptions is false or misleading.

Application for manufacturer’s authorisation

36.

• (a) made in writing to the Authority,

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

• (c) accompanied by—

• (i) a written undertaking that in the event of the authorisation being granted, the applicant will ensure fulfilment of the obligations arising by virtue of the terms and conditions of the authorisation, and

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

37.

• (2) Following receipt of an application, the Authority shall, by means of inspection or otherwise, confirm the accuracy of the particulars provided in the application and may give a notice in writing to the applicant requesting him or her to provide further information relating to the said particulars.

• (3) Where the Authority 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) The expiry of the period of 90 days referred to in paragraph (1) shall not confer any rights on the applicant, and in particular shall not —

• (a) confer a default or tacit manufacturer’s authorisation on an applicant, or

• (b) be taken to imply that a manufacturer’s authorisation has been granted or will be granted.

Grant or refusal of manufacturer’s authorisation

38.

• (a) the particulars supplied pursuant to Regulation 36 are accurate,

• (b) the applicant has—

• (i) complied with the requirements of Regulation 36, and of Article 61 of the Clinical Trials Regulation, and

• (ii) provided any additional information to the Authority as may have been required under Regulation 37.

• (2) Subject to paragraph (1), the Authority may—

• (a) grant a manufacturer’s authorisation in respect of any or all of—

• (i) the types and pharmaceutical forms of the investigational medicinal product manufactured or imported,

• (ii) the premises, and

• (iii) the manufacturing or importation operations specified in the application,

• (b) grant a manufacturer’s authorisation in accordance with the application, but subject to the carrying out of certain obligations by the authorisation holder,

• (c) grant a manufacturer’s authorisation otherwise than in accordance with the application, or

• (d) refuse to grant a manufacturer’s authorisation.

• (3) The provisions of Schedule III shall have effect where the Authority proposes to—

• (a) grant a manufacturer’s authorisation in accordance with the application, but subject to the carrying out of certain obligations by the authorisation holder,

• (b) grant a manufacturer’s authorisation otherwise that in accordance with the application, or

• (c) refuse to grant a manufacturer’s authorisation.

• (4) Where the Authority grants or refuses to grant an Authorisation in accordance with paragraph (2), it shall give the applicant a notice in writing stating in detail the reasons on which its decision is based.

• (5) The Authority shall enter information in the EudraGMDP database in relation to all manufacturer’s authorisations granted.

Effect of manufacturer’s authorisation

39.

• (a) the types and pharmaceutical forms of investigational medicinal products manufactured or imported,

• (b) the manufacturing or importation operations, and

• (c) the premises,

specified in the application made pursuant to Regulation 36 and in respect of which the authorisation has been granted.

Obligations of manufacturers of investigational medicinal products

40.

• (a) manufacture for supply in the EEA, or for export, any investigational medicinal product except in accordance with the requirements set down in Schedule III and with the principles and guidelines of good manufacturing practice set down in Commission Delegated Regulation (EU) 2017/1569 supplementing the Clinical Trials Regulation, or

• (b) import any investigational medicinal products except in accordance with the requirements set down in Schedule IV, and with the principles and guidelines of good manufacturing practice set down in Commission Delegated Regulation (EU) 2017/1569 supplementing the Clinical Trials Regulation.

• (2) An authorisation holder shall comply with the obligations set down in Schedule IV, as appropriate, and any further conditions or obligations as may be imposed in the authorisation.

Variation of manufacturer’s authorisation

41.

• (2) Subject to the provisions of this Regulation, if the authorisation holder makes a valid application to vary any details in respect of the manufacturer’s authorisation which has been granted, the Authority shall consider the application and may vary or refuse to vary the authorisation—

• (a) within a period not exceeding 30 days from the date the application is received if an inspection of the premises is not required, or

• (b) within a period not exceeding 90 days from the date the application is received if the Authority deems it necessary to conduct an inspection of any premises to which the variation relates.

• (3) Following receipt of a valid application to vary a manufacturer’s authorisation, the Authority 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.

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

• (5) The Authority may vary a manufacturer’s authorisation where it considers it necessary to do so for the purpose of securing compliance with the Clinical Trials Regulation, and may make a manufacturer’s authorisation conditional on the carrying out of certain obligations.

42.

• (a) proposes to vary a manufacturer’s authorisation, otherwise than in accordance with a valid application by the authorisation holder,

• (b) proposes to make a manufacturer’s authorisation conditional on the carrying out of certain obligations by the authorisation holder, or

• (c) proposes to refuse to vary a manufacturer’s authorisation, after consideration of the application of the holder.

• (2) Where the Authority—

• (a) varies a manufacturer’s authorisation, otherwise than in accordance with the valid application by the authorisation holder, or

• (b) makes a manufacturer’s authorisation conditional on the carrying out of certain obligations by the authorisation holder, or

• (c) after consideration of the application of the holder, refuses to vary a manufacturer’s authorisation,

the Authority shall notify the holder of that authorisation in writing, stating in detail the reasons on which its decision is based.

• (3) In this Regulation, “valid application” means an application—

• (a) made to the Authority 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 and supporting documentation as are necessary to enable the Authority to consider the application, and

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

Suspension and revocation of manufacturer’s authorisation

43.

• (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 or importation operations to which the authorisation relates,

• (b) the matters specified in the application in accordance with Regulation 36 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 40,

• (e) the holder has manufactured or imported investigational medicinal products otherwise than in accordance with the terms of the authorisation,

• (f) the authorisation holder does not have the staff, premises, equipment or facilities necessary for carrying out properly the handling, storage, or distribution activities to which the authorisation relates, and

• (g) the authorisation holder has failed to carry out an obligation imposed by the Authority pursuant to Regulation 38(2)(b) or Regulation 42(2)(b).

• (2) The suspension or revocation of a manufacturer’s authorisation under this Regulation may be—

• (a) total, or

• (b) limited to—

• (i) certain manufacturing or importation operations concerning medicinal products, or

• (ii) particular premises or particular parts of any premises described in the manufacturer’s authorisation.

• (3) The provisions of Schedule III shall have effect where the Authority proposes to suspend or revoke a manufacturer’s authorisation in accordance with this Regulation.

• (4) Where the Authority suspends or revokes a manufacturer’s authorisation in accordance with this Regulation, it shall notify the authorisation holder in writing, stating in detail the reasons on which its decision to suspend or revoke the authorisation is based.

PART 9 FEES

44.

• (a) without prejudice to subparagraph (b), charge a fee, or fees, to the sponsor for:

• (i) the assessment of clinical trial applications under Chapter II of the Clinical Trials Regulation and Regulations 8 and 9 of these Regulations, and

• (ii) the assessment of applications for substantial modifications under Chapter III of the Clinical Trials Regulation and Regulation 12 of these Regulations;

• (iii) consideration of an appeal submitted in accordance with Part 10 of these Regulations and Part 5 of S.I. No. 41 of 2022 ;

• (iv) the review of safety reports submitted by sponsors;

• (v) the inspection of a clinical trial site, or of a sponsor site, or of a site of any other entity involved in the conduct of a clinical trial.

• (b) charge a reduced fee, or fees, to non-commercial sponsors, for the activities under paragraph (1)(a)(i) or (ii)).

• (2) The amount of the fee, or fees, under paragraph (1)(a) and (b) shall be—

• (a) reviewed on an annual basis by the Authority and the National Office and approved by the Minister, and

• (b) published on the websites of the Authority and the National Office.

• (3) The fees under paragraph (1)(a) and (b) shall be—

• (a) payable immediately upon submission of a clinical trial application through the EU portal in accordance with Article 5 and Article 14 of the Clinical Trials Regulation;

• (b) where applicable, payable immediately upon submission of a substantial modification application through the EU portal in accordance with Article 16 of the Clinical Trials Regulation;

• (c) non-refundable once the application for a clinical trial application or substantial modification application has been validated in accordance with Article 5, Article 17 or Article 20 of the Clinical Trials Regulation, as appropriate.

• (4) The Authority shall remit a regular payment to the National Office in respect of the ethical review of applications for clinical trials and substantial modifications.

• (5) The Authority may charge fees in relation to an application for the grant or variation of a manufacturer’s authorisation and inspection of a manufacturing site.

• (6) The Authority may charge fees in relation to applications to the Register of Exemptions, and in relation to the inspection of manufacturers and processes under that Register.

PART 10 APPEALS

45.

• (a) authorise a clinical trial pursuant to Article 8(4) of the Clinical Trials Regulation, and under these Regulations,

• (b) authorise a clinical trial pursuant to Article 14(10) of the Clinical Trials Regulation, and under these Regulations, or

• (c) authorise a substantial modification pursuant to Articles 19(2), 20(7) or 23(4) of the Clinical Trials Regulation, and under these Regulations.

• (2) Any appeal shall be submitted to the Authority within 28 days of receipt of a refusal specified in paragraph (1).

• (3) The provisions of Schedule I, and of Part 5 of S.I. No. 41 of 2022 , shall apply to the submission and processing of an appeal submitted by a sponsor under paragraph (1).

PART 11 LANGUAGE

Application dossier

46.

• (1) application dossier described under Article 25 of the Clinical Trials Regulation, and

• (2) any documentation addressed to subjects,

shall be in English.

Labelling

47.

• (2) Paragraph (1) shall not preclude the information specified therein also appearing on the label in one or more languages, other than English.

PART 12 OFFENCES, PENALTIES, AND ENFORCEMENT

Offences

48.

• (a) commences a clinical trial in the State without—

• (i) notification of authorisation, in accordance with Regulation 10, or

• (ii) having in place a scheme to provide compensation for any damage suffered by a subject resulting from a clinical trial in accordance with Regulation 17,

• (b) commences a substantial modification to a clinical trial without notification of authorisation in accordance with Regulation 13,

• (c) conducts a clinical trial, other than in accordance with the requirements of Regulation 14,

• (d) performs the functions of the sponsor of a clinical trial (whether that person is the sponsor or is acting under arrangements made with that sponsor), other than in accordance with the requirements of Regulation 14,

• (e) performs the functions of the investigator of a clinical trial, other than in accordance with the requirements of Regulation 14,

• (f) charges a fee to a subject of a clinical trial other than in accordance with Regulation 16,

• (g) fails to maintain a trial master file in accordance with the requirements of Article 57 of the Clinical Trials Regulation and Regulation 20,

• (h) fails to make available to the Authority a trial master file in accordance with the time periods set out in Regulation 20(2),

• (i) fails to meet their obligations in relation to archiving under Article 58 of the Clinical Trials Regulation and Regulation 21(1),

• (j) fails to retain the medical files of clinical trial subjects in accordance with Regulation 21(2),

• (k) fails to pay a fee due under Regulation 44,

• (l) labels, sells, or supplies a medicinal product or auxiliary medicinal product other than in accordance with Regulation 47,

• (m) fails to comply with a notice of suspension or termination served under Regulation 24 or 43, unless same has been withdrawn or revoked by the Authority,

• (n) in—

• (i) an application for an ethics committee opinion,

• (ii) an application for authorisation under Chapter II of the Clinical Trials Regulation to conduct a clinical trial in the State,

• (iii) an application for a substantial modification to a previously authorised clinical trial under Chapter III of the Clinical Trials Regulation,

provides to the Authority, the nominated ethics committee, or the National Office any relevant information which is false or misleading in a material particular,

• (o) in—

• (i) the conduct of a clinical trial authorised in accordance with these Regulations,

• (ii) the sponsorship of such a clinical trial,

• (iii) the performance of the functions of a sponsor, when acting under arrangements made with the sponsor of such a clinical trial,

• (iv) the performance of the duties of a qualified person in accordance with Article 61 of the Clinical Trials Regulation,

• (v) the holding of a manufacturing authorisation,

• (vi) securing or maintaining a listing on the Register of Exemptions

provides to the Authority, the nominated ethics committee or the National Office any relevant information which is false or misleading in a material particular,

• (p) wilfully obstructs or interferes with the exercise of a power by an authorised officer pursuant to Regulation 54,

• (q) without reasonable excuse, fails to comply with any request made by an authorised officer under Regulation 54,

• (r) fails to comply with the provisions laid down in the Clinical Trials Regulations on the submission of information intended to be made publicly available to the EU database,

• (s) fails to comply with safety reporting requirements as laid down in Articles 41, 42 and 43 of the Clinical Trials Regulation,

• (t) fails to provide records requested by the Authority in accordance with Regulation 25(2),

• (u) fails to meet the requirements of Article 54 of the Clinical Trials Regulation in relation to Urgent Safety measures,

• (v) fails to establish a legal representative in accordance with Article 74(1) of the Clinical Trials Regulation when required,

• (w) fails to meet the requirements of the Clinical Trials Regulation, or of Part 4 of these Regulations, in relation to the protection of clinical trial subjects and informed consent,

• (x) fails to comply with the requirements for the manufacture and import of investigational medicinal products and auxiliary medicinal products in accordance with Regulation 40,

• (y) sells or supplies an investigational medicinal product for the purposes of a clinical trial knowing or having reasonable cause to suspect that it was manufactured, labelled, packaged or imported in contravention of Regulation 40,

• (z) 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 an investigational medicinal product knowing or having reasonable cause to suspect that it was imported in contravention of Regulation 40,

• (aa) fails to comply with the requirements for notifications and submissions laid down in Article 36, 37, and 38 of the Clinical Trials Regulation,

is guilty of an offence.

• (2) The offences listed in paragraph (1) also apply to a legal representative of a sponsor responsible for ensuring compliance with the sponsor’s obligations in the State pursuant to Article 74(1) of the Clinical Trials Regulation.

Penalties

49.

• (2) A person guilty of an offence under these Regulations shall be liable on conviction on indictment to a fine not exceeding €300,000, or to imprisonment for a term not exceeding 3 years, or both.

Body corporate

50.

Separate contraventions

51.

Infringement notices

52.

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

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

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

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

• (e) warning the person that unless the requirements of 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 Authority serves an infringement notice in accordance with paragraph (1), it shall forthwith inform the nominated ethics committee.

Defence of due diligence

53.

Enforcement generally

54.

• (2) In carrying out its compliance and enforcement role under the Clinical Trials Regulation and these Regulations, the Authority shall ensure that confidentiality is respected by authorised officers and other experts engaged in good clinical practice inspections and, with regard to personal data, that the requirements of the General Data Protection Regulation and the Data Protection Acts 1988 to 2018 are respected.

Appointment of authorised officers

55.

• (2) An authorised officer shall, when performing a function imposed on an authorised officer under these Regulations, produce his or her warrant for inspection if requested to do so by a person affected by the performance of that function.

Functions of authorised officers

56.

• (2) Without prejudice to paragraph (1), good clinical practice inspections may be carried out on any of the following occasions—

• (a) before, during or after the conduct of clinical trials;

• (b) as part of the verification of applications for a manufacturing or marketing authorisation;

• (c) as a follow-up to the granting of authorisation;

• (d) where services are provided for the support of clinical trials.

• (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 (if necessary, by the use of reasonable force) 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 General Data Protection Regulation and the Data Protection Acts 1988 to 2018,

• (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,

• (i) require any person carrying on, or 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 authorised officer such information as the authorised officer may reasonably require for the purposes of these Regulations,

• (j) take photographs of premises and equipment,

• (k) contact the subject of a clinical trial directly, in accordance with Article 10(6) of Regulation (EU) 2017/556, and

• (l) ask any representative or member of staff of the inspected entity and any party involved in the clinical trial for explanations relating to the subject matter and purpose of the inspection and record the answer.

• (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 (9) authorising such entry.

• (5) Any expert who accompanies an authorised officer may:

• (a) ask any representative or member of staff of the inspected entity and any party involved in the clinical trial for explanations relating to the subject matter and purpose of the inspection and record the answer,

• (b) review, record, and extract information from any data (including personal data) within the meaning of the General Data Protection Regulation and the Data Protection Acts 1988 to 2018.

• (6) When exercising a power under this Regulation, an authorised officer may, subject to any warrant under paragraph (9), be accompanied by such number of—

• (a) other authorised officers,

• (b) inspectors from the competent authority of another Member State,

• (c) persons with expertise relevant to the aspects being examined, or

• (d) members of An Garda Síochána or Customs and Excise Officers,

as he or she considers appropriate, in the circumstances of the case.

• (7) 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.

• (8) 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.

• (9) 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.

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

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

• (12) Any material taken away by an authorised officer under this Regulation may be retained by him or her for use in evidence in any proceedings.

Prosecution of offences

57.

PART 13 JOINT CONTROLLERSHIP ARRANGEMENT

58.

PART 14 REVOCATIONS

59.

• (a) European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004 ( S.I. No. 190 of 2004 );

• (b) European Communities (Clinical Trials on Medicinal Products for Human Use) (Amendment) Regulations 2004 ( S.I. No. 878 of 2004 );

• (c) European Communities (Clinical Trials on Medicinal Products for Human Use) (Amendment No. 2) Regulations 2006 ( S.I. No. 374 of 2006 );

• (d) European Communities (Clinical Trials on Medicinal Products for Human Use) (Amendment) Regulations 2009 ( S.I. No. 1 of 2009 ).

• (e) European Union (Clinical Trials on Medicinal Products for Human Use) Regulations 2022 ( S.I. No. 40 of 2022 ).

PART 15 ENTRY INTO FORCE AND TRANSITIONAL ARRANGEMENTS

60.

61.

• (a) those Regulations shall continue to apply until the 30th day of January 2025

• (i) in respect of an application submitted in accordance with those Regulations before the 31^st day of January 2022, and