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

Type Statutory Instrument

Publication 2022-03-04

Last updated 2024-01-12

State In force superseded text

Text As published

Source Irish Statute Book

articles 63

This is the act as published. Later amendments are not folded into the text below: each one is a separate act in this repository and an entry in this law's history.

3 amending acts · 2024-01-12, S.I. No. 3/2024 - European Union (Clinical Trials on Medicinal Products for Human Use) (A…

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(ii) in respect of an application made on or before the 31^st day of January 2023, where the sponsor opted to make the application in accordance with those Regulations, and

(b) a sponsor of a clinical trial that received a favourable opinion from an ethics committee recognised by the Minister in accordance with Part 2 of those Regulations and, in relation to which trial the Authority granted an authorisation, shall continue to comply with his or her reporting obligations under those Regulations until the 31^st day of January 2025.

62.

(1) Subject to paragraph (2), any

(a) manufacturer’s licence granted under Regulation 33 of the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004 (S.I. 190 of 2004), or

(b) manufacturer’s authorisation granted under Regulation 8 of the Medicinal Products (Control of Manufacture) Regulations 2007 to 2019 in respect of investigational medicinal products,

shall continue to be in force as if granted under these Regulations.

(2) An application made in respect of the grant or variation of a manufacturer’s authorisation under the Medicinal Products (Control of Manufacture) Regulations 2007 to 2019, and which has not been determined prior to the date of coming into force of these Regulations, shall be considered as if it were an application made under Regulation 36 of these Regulations. In all cases, where the information provided in such applications is not sufficient, the Authority may require that the applicant shall update his or her application to conform to the provisions of Regulation 36.

(3) Persons referred to in Regulation 29 who had commenced their activity before 31 January 2022 shall submit the application to the Authority to be listed on the Register of Exemptions by 31^st March 2022.

63.

Subject to Regulations 61 and 62 of these Regulations, any action taken in reliance upon S.I. No. 40 of 2022 prior to the commencement of these Regulations and after the commencement of S.I. No. 40 of 2022 shall be deemed to be regulated by these Regulations.

GIVEN under my Official Seal,

2 March, 2022.

STEPHEN DONNELLY,

Minister for Health.

SCHEDULE I PROCEDURAL PROVISIONS RELATING TO DECISIONS TO REFUSE A REQUEST FOR CLINICAL TRIAL AUTHORISATION OR TO REFUSE A SUBSTANTIAL MODIFICATION TO AN AUTHORISED CLINICAL TRIAL

Where the Authority is notified of the sponsor’s wish to appeal a decision in accordance with Regulation 45, the Authority shall determine if the appeal relates to the conclusion on the Part I or Part II assessment, or both, and

(1) in the case of an appeal relating solely to the conclusion on Part I of the assessment report, process the appeal in accordance with point 2; or

(2) in the case of an appeal relating solely to the conclusion on Part II of the assessment report, refer the appeal to the National Office for processing in accordance with point 3; or

(3) in the case of an appeal relating to the conclusions of both Part I and Part II of the assessment reports, process the Part I aspects in accordance with point 2, and refer the appeal to the National Office for processing of the Part II aspects in accordance with point 3;

and shall notify the sponsor how the appeal shall be heard.

(1) The Authority shall afford an opportunity for the sponsor to make representations to the Advisory Committee for Human Medicines.

(2) The Advisory Committee may seek advice on ethical aspects of the appeal from the National Office and/or the nominated ethics committee, if relevant.

(3) After considering the representations, the Advisory Committee shall report its findings and advice, and the reasons for its advice, to the Authority.

(4) The Authority shall, after considering the report of the Advisory Committee –

(a) confirm the administrative single decision not to accept the request for authorisation of a clinical trial application or substantial modification application,

(b) accept the request for authorisation of a clinical trial application or substantial modification application.

(1) The National Office shall establish an appeals panel, and that panel shall hear the appeal, in accordance with Regulations 25 and 26 of S.I. No. 41 of 2022 .

(2) The National Office shall notify the Authority of the outcome of the appeal no later than 45 days after the appeal was referred to it pursuant to point (1).

(3) The National Office shall, after considering the report of the appeals panel—

(a) confirm the administrative single decision not to accept the request for authorisation of a clinical trial application or substantial modification application, or

(b) accept the request for authorisation of a clinical trial application or substantial modification application.

(1) In the case of an appeal to which point 1(3) applies, the Authority shall, after considering the report of the Advisory Committee pursuant to point 2(3), and the report of the appeals panel committee pursuant to point 3(2),

(a) confirm the administrative single decision not to accept the request for authorisation of a clinical trial application or substantial modification application; or

(b) accept the request for authorisation of a clinical trial application or substantial modification application.

(2) In the case of an appeal to which point 1(3) applies, if the appeal on one

aspect of the assessment report is not successful, the appeal shall not be upheld.

The Authority shall notify the sponsor of the outcome of the appeal no later than 52 days after receipt of the appeal.

SCHEDULE II PARTICULARS THAT MUST ACCOMPANY AN APPLICATION FOR A MANUFACTURER’S AUTHORISATION

The name and address of the natural or legal person proposed to be the authorisation holder.

The address of each of the premises where the manufacturing or importation of the investigational medicinal products to which the application relates, including any testing and controls associated with such activities, that are to be carried out.

The name of any organisation and address of the associated premises to which the proposed authorisation holder proposes to outsource manufacturing, testing activities concerning the investigational medicinal product.

(1) A site master file covering the premises, manufacturing, importation and quality control operations specified in the application form.

(2) A site master file shall be prepared in accordance with the guidance published by the European Commission in Part III of the EU Good Manufacturing Practice guidelines.

(1) The name, qualifications and experience of the qualified person who shall carry out the duties referred to in Article 62 of the Clinical Trials Regulation.

(2) In the case of an authorisation relating to manufacturing activities, the name, qualification and experience of the production manager other person whose duty it shall be to supervise the production operations at each of the premises referred to in point 2.

(3) In the case of an authorisation relating to manufacturing activities, that name and degrees, diplomas or other qualifications and experience of the person to be in charge of quality control over all the premises referred to in point 2.

In this Schedule, the reference to investigational medicinal products includes blood products, immunological products, cell therapy products, gene therapy products, biotechnology products, human or animal extracted products, herbal products, homeopathic products, radiopharmaceutical products and products containing chemical agents.

SCHEDULE III PROCEDURAL PROVISIONS RELATING TO PROPOSALS TO GRANT SUBJECT TO THE CARRYING OUT OF CERTAIN OBLIGATIONS, PROPOSALS TO GRANT OTHERWISE THAN IN ACCORDANCE WITH THE APPLICATION, PROPOSALS TO REFUSE TO GRANT OR VARY, PROPOSALS TO MAKE THE AUTHORISATION CONDITIONAL ON THE CARRYING OUT OF CERTAIN OBLIGATIONS, AND PROPOSALS TO SUSPEND, VARY OR REVOKE A MANUFACTURER’S AUTHORISATION

In this Schedule—

‘authorisation’ means a manufacturer’s authorisation, and

‘time allowed’ means the period of 28 days or such extended period as the Authority may in any particular case allow.

Subject to point 6, if the Authority proposes—

(1) not to grant an authorisation,

(2) to grant an authorisation subject to the carrying out of certain obligations,

(3) to grant an authorisation other than in accordance with the application,

(4) to revoke, vary or suspend an authorisation,

(5) not to vary an authorisation on the holder’s application to vary, or

(6) to make an authorisation conditional on the carrying out of certain obligations,

the Authority shall notify the applicant or authorisation holder accordingly.

Any notification given under point 2 shall include—

(1) a statement of the proposals of the Authority,

(2) a statement setting out in detail the reasons on which the said proposals are based, and

(3) a statement that the applicant or authorisation holder has the right to make representations to the Authority in response to the notification.

A person to whom notification has been given under point 2 may, within the time allowed after the notification was given, give notice to the Authority of his or her wish to do so, and make representations to the Authority with respect to the decision or proposal referred to in the notification.

The Authority shall, after considering the representations, decide whether to grant the authorisation, revoke, vary or suspend an authorisation or confirm or alter its decision, as the case may be.

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

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

SCHEDULE IV REQUIREMENTS TO BE MET BY AN AUTHORISATION HOLDER MANUFACTURING OR IMPORTING INVESTIGATIONAL MEDICINAL PRODUCTS

The authorisation holder shall—

(1) comply with the requirements set out in the Commission Delegated Regulation 2017/1569,

(2) operate only within the scope and terms defined in the authorisation.

The authorisation holder shall at all times provide and maintain such staff, premises equipment and facilities as will enable the qualified person at his or her disposal pursuant to Article 61(2)(b) of the Clinical Trials Regulation to carry out the duties referred to in Article 62(1) of the Clinical Trials Regulation.

The authorisation holder shall give prior written notice to the Authority—

(1) of any changes he or she may wish to make to any details specified in the authorisation,

(2) where it is intended to introduce significant changes to the premises or activities to which the authorisation relates, including changes which introduce significant new risks that have to be managed.

The authorisation holder shall, where manufacture is carried out under the authorisation, keep an adequate sample of each batch and of each active constituent used in the manufacture of the investigational medicinal products to which the authorisation relates, for the period which ends one year after the labelled expiry date of the product, and shall furnish on request by the Authority a sufficient sample of each such batch for the purpose of any test, examination or analysis which may be requested by the Authority. The Authority will not be charged for any such samples.

The authorisation holder shall, where manufacture is carried out under the authorisation, ensure that any human blood or blood component imported into the State and used by him or her as a starting material or as a raw material in the manufacture of an investigational medicinal product shall meet the equivalent standards of quality and safety to those laid down in Commission Directive 2004/33/EC⁸ .

The authorisation holder shall supply such information as may be requested by the Authority for the purposes of these Regulations about the manufactured or imported investigational medicinal products and about the operations being carried out under the authorisation.

The authorisation holder shall for the purpose of enabling the Authority to—

(1) verify any statement contained in an application for a manufacturer’s authorisation or clinical trial application, or

(2) ascertain whether there are any grounds for suspending, revoking or amending any such authorisation,

permit, and provide all necessary facilities to enable, authorised officers to enter and inspect his or her premises at any time and to take such samples or to take copies of any documents in relation to any such application or authorisation as may be required.

The authorisation holder shall from time to timer permit such inspection and make available such information as may be required to satisfy the Authority that the conditions of the authorisation are being complied with.

Where the authorisation holder has been informed by the Authority that any part of a batch of an investigational medicinal product to which his or her authorisation relates has been found not to conform as regards strength, quality or purity with the specifications of the relevant investigational medicinal product he or she shall, if so directed by the Authority, immediately withhold the remainder of that batch from sale, supply or exportation and, insofar as may be practicable, immediately recall all supplies already sold, supplied or exported from that batch.

10.

Where the authorisation holder has been informed by the Authority that an investigational medicinal product to which his or her authorisation relates has been found to give rise to concerns in regard to its safety or efficacy, he or she shall, if so directed by the Authority, immediately withhold that investigational medicinal product from sale, supply or exportation and, insofar as may be practicable, immediately recall all supplies of such investigational medicinal product already sold, supplied or exported.

11.

Where the authorisation holder has been informed by the Authority that any batch of an investigational medicinal product, or part thereof, to which his or her authorisation relates, has not been manufactured in accordance with the principles and guidelines of good manufacturing practice set out in the Commission Delegated Regulation 2017/1569, he or she shall, if so requested by the Authority, immediately withhold that investigational medicinal product from sale, supply or exportation and, insofar as may be practicable, immediately recall all supplies of such investigational medicinal product already sold, supplied or exported.

12.

Where the authorisation holder decides for whatever reason to recall a particular batch of an investigational medicinal product manufactured or imported by him or her, or part thereof, he or she shall forthwith inform the Authority of the decision to recall and of the reason for such recall.

13.

Where the authorisation holder considers that there may be grounds for the recall, or for the imposition of an abnormal restriction on the supply of a particular investigational medicinal product manufactured or imported by him or her, or of a batch or part of batch thereof, he or she shall consult with the Authority in relation to the action which may be considered appropriate in the circumstances.

14.

(1) The authorisation holder, in the case of manufacture of an advanced therapy investigational medicinal product, shall establish and maintain a system ensuring that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the trial site where the product is used.

(2) Where an authorisation holder manufactures an advanced therapy investigational medicinal product that contains human cells or tissues, he or she shall ensure that the traceability systems established in accordance with subparagraph 1 are complimentary to, and compatible with, the requirements laid down in Articles 8 and 14 of Directive 2004/23/EC⁹ , and Articles 14 and 24 of Directive 2002/98/EC⁸ .

(3) The authorisation holder shall keep the data referred to in paragraph (1) for a minimum of 30 years after the expiry date of the product.

(4) In the case of bankruptcy or liquidation of the authorisation holder who has manufactured an advanced therapy investigational medicinal product, and in the event that the manufacturer’s authorisation is not transferred to another legal entity, the data referred to in paragraph (1) shall be transferred to the Authority.

(5) In the event that the manufacturer’s authorisation is suspended, revoked or withdrawn, the holder of the manufacturer’s authorisation shall remain subject to the obligations laid down in paragraphs (1), (2) and (3).

(6) Paragraphs (3) to (5) shall not apply to a holder of a manufacturer’s authorisation where the holder of a marketing authorisation for the relevant advanced therapy investigational medicinal product is, by virtue of such marketing authorisation, responsible for the retention of such data.

15.

The content of the site master file shall be kept up to date at all times. Each time the site master file is updated, a copy of the updated file shall be provided to the Authority.

16.

The Authority may request the authorisation holder to confirm accuracy of details within the site master file.

EXPLANATORY NOTE

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

These Regulations give further effect to Regulation (EC) No. 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use (“Clinical Trials Regulation”) which applied from the 31^st of January 2022.

The Clinical Trials Regulation replaces and repeals Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

The National Office and National Research Ethics Committees, have been defined in separate Regulations, the European Union Clinical Trials on Medicinal Products for Human Use) (National Research Ethics Committees) Regulations 2022 ( S.I. No. 41 of 2022 ).

These Regulations also revoke S.I. No. 40 of 2022 , which was put in place as interim regulations to transpose those elements of the Clinical Trials Regulation which concerned Member State competences into Irish Law from the date of the application of the Clinical Trials Regulation. These regulations now replace S.I. No. 40 of 2022 as the Principal Regulations which give further effect to the Clinical Trials Regulation.

Footnotes

O.J. No. L 158, 27.5.2014, p. 1.

O.J. No. L 136, 30.4.2004, p. 1.

O.J. No. L 238, 16.9.2017, p. 12.

O.J. No. L 121, 1.5.2001, p. 34.

O.J. No. L 311, 28.11.2001, p. 67

O.J. No. L 119, 4.5.2016, p. 1.

O.J. No. L 80, 25.3.2017, p. 7.

O.J. No. L 91, 30.3.2004, p. 25.

O.J. No. L 102, 7.4.2004, p. 48.

O.J. No. L 33, 8.2.2003, p. 30.

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