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Regulation (EU) No 536/2014 of the European Parliament and of the CouncilShow full title

Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (Text with EEA relevance)

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  1. Introductory Text

  2. CHAPTER I GENERAL PROVISIONS

    1. Article 1.Scope

    2. Article 2.Definitions

    3. Article 3.General principle

  3. CHAPTER II AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL

    1. Article 4.Prior authorisation

    2. Article 5.Submission of an application

    3. Article 6.Assessment report — Aspects covered by Part I

    4. Article 7.Assessment report — Aspects covered by Part II

    5. Article 8.Decision on the clinical trial

    6. Article 9.Persons assessing the application

    7. Article 10.Specific considerations for vulnerable populations

    8. Article 11.Submission and assessment of applications limited to aspects covered by Part I or Part II of the assessment report

    9. Article 12.Withdrawal

    10. Article 13.Resubmission

    11. Article 14.Subsequent addition of a Member State concerned

  4. CHAPTER III AUTHORISATION PROCEDURE FOR A SUBSTANTIAL MODIFICATION OF A CLINICAL TRIAL

    1. Article 15.General principles

    2. Article 16.Submission of application

    3. Article 17.Validation of an application for the authorisation of a substantial modification of an aspect covered by Part I of the assessment report

    4. Article 18.Assessment of a substantial modification of an aspect covered by Part I of the assessment report

    5. Article 19.Decision on the substantial modification of an aspect covered by Part I of the assessment report

    6. Article 20.Validation, assessment and decision regarding a substantial modification of an aspect covered by Part II of the assessment report

    7. Article 21.Substantial modification of aspects covered by Parts I and II of the assessment report

    8. Article 22.Assessment of a substantial modification of aspects covered by Parts I and II of the assessment report — Assessment of the aspects covered by Part II of the assessment report

    9. Article 23.Decision on the substantial modification of aspects covered by Parts I and II of the assessment report

    10. Article 24.Persons assessing the application for a substantial modification

  5. CHAPTER IV APPLICATION DOSSIER

    1. Article 25.Data submitted in the application dossier

    2. Article 26.Language requirements

    3. Article 27.Update by way of delegated acts

  6. CHAPTER V PROTECTION OF SUBJECTS AND INFORMED CONSENT

    1. Article 28.General rules

    2. Article 29.Informed consent

    3. Article 30.Informed consent in cluster trials

    4. Article 31.Clinical trials on incapacitated subjects

    5. Article 32.Clinical trials on minors

    6. Article 33.Clinical trials on pregnant or breastfeeding women

    7. Article 34.Additional national measures

    8. Article 35.Clinical trials in emergency situations

  7. CHAPTER VI START, END, TEMPORARY HALT, AND EARLY TERMINATION OF A CLINICAL TRIAL

    1. Article 36.Notification of the start of a clinical trial and of the end of the recruitment of subjects

    2. Article 37.End of a clinical trial, temporary halt and early termination of a clinical trial and submission of the results

    3. Article 38.Temporary halt or early termination by the sponsor for reasons of subject safety

    4. Article 39.Update of the contents of the summary of results and summary for laypersons

  8. CHAPTER VII SAFETY REPORTING IN THE CONTEXT OF A CLINICAL TRIAL

    1. Article 40.Electronic database for safety reporting

    2. Article 41.Reporting of adverse events and serious adverse events by the investigator to the sponsor

    3. Article 42.Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency

    4. Article 43.Annual reporting by the sponsor to the Agency

    5. Article 44.Assessment by Member States

    6. Article 45.Technical aspects

    7. Article 46.Reporting with regard to auxiliary medicinal products

  9. CHAPTER VIII CONDUCT OF A CLINICAL TRIAL, SUPERVISION BY THE SPONSOR, TRAINING AND EXPERIENCE, AUXILIARY MEDICINAL PRODUCTS

    1. Article 47.Compliance with the protocol and good clinical practice

    2. Article 48.Monitoring

    3. Article 49.Suitability of individuals involved in conducting the clinical trial

    4. Article 50.Suitability of clinical trial sites

    5. Article 51.Traceability, storage, return and destruction of investigational medicinal products

    6. Article 52.Reporting of serious breaches

    7. Article 53.Other reporting obligations relevant for subject safety

    8. Article 54.Urgent safety measures

    9. Article 55.Investigator's brochure

    10. Article 56.Recording, processing, handling and storage of information

    11. Article 57.Clinical trial master file

    12. Article 58.Archiving of the clinical trial master file

    13. Article 59.Auxiliary medicinal products

  10. CHAPTER IX MANUFACTURING AND IMPORT OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS

    1. Article 60.Scope of this Chapter

    2. Article 61.Authorisation of manufacturing and import

    3. Article 62.Responsibilities of the qualified person

    4. Article 63.Manufacturing and import

    5. Article 64.Modification of authorised investigational medicinal products

    6. Article 65.Manufacturing of auxiliary medicinal products

  11. CHAPTER X LABELLING

    1. Article 66.Unauthorised investigational and unauthorised auxiliary medicinal products

    2. Article 67.Authorised investigational and authorised auxiliary medicinal products

    3. Article 68.Radiopharmaceuticals used as investigational medicinal products or as auxiliary medicinal products for a medical diagnosis

    4. Article 69.Language

    5. Article 70.Delegated act

  12. CHAPTER XI SPONSOR AND INVESTIGATOR

    1. Article 71.Sponsor

    2. Article 72.Co-sponsorship

    3. Article 73.Principal investigator

    4. Article 74.Legal representative of the sponsor in the Union

    5. Article 75.Liability

  13. CHAPTER XII DAMAGE COMPENSATION

    1. Article 76.Damage compensation

  14. CHAPTER XIII SUPERVISION BY MEMBER STATES, UNION INSPECTIONS AND CONTROLS

    1. Article 77.Corrective measures to be taken by Member States

    2. Article 78.Member State inspections

    3. Article 79.Union controls

  15. CHAPTER XIV IT INFRASTRUCTURE

    1. Article 80.EU portal

    2. Article 81.EU database

    3. Article 82.Functionality of the EU portal and the EU database

  16. CHAPTER XV COOPERATION BETWEEN MEMBER STATES

    1. Article 83.National contact points

    2. Article 84.Support by the Agency and the Commission

    3. Article 85.Clinical Trials Coordination and Advisory Group

  17. CHAPTER XVI FEES

    1. Article 86.General principle

    2. Article 87.One payment per activity per Member State

  18. CHAPTER XVII IMPLEMENTING ACTS AND DELEGATED ACTS

    1. Article 88.Committee procedure

    2. Article 89.Exercise of the delegation

  19. CHAPTER XVIII MISCELLANEOUS PROVISIONS

    1. Article 90.Specific requirements for special groups of medicinal products

    2. Article 91.Relation with other Union legislation

    3. Article 92.Investigational medicinal products, other products and procedures, free of charge for the subject

    4. Article 93.Data protection

    5. Article 94.Penalties

    6. Article 95.Civil and criminal liability

  20. CHAPTER XIX FINAL PROVISIONS

    1. Article 96.Repeal

    2. Article 97.Review

    3. Article 98.Transitional provision

    4. Article 99.Entry into force

  21. Signature

    1. ANNEX I

      APPLICATION DOSSIER FOR THE INITIAL APPLICATION

      1. A. INTRODUCTION AND GENERAL PRINCIPLES

        1. 1. The sponsor shall, where appropriate, refer to any previous applications....

        2. 2. Where a clinical trial has more than one sponsor, detailed...

        3. 3. The application shall be signed by the sponsor or a...

        4. 4. The application dossier for an application limited to Part I...

        5. 5. Without prejudice to Article 26, the application dossier for an...

      2. B. COVER LETTER

        1. 6. The cover letter shall specify the EU trial number and...

        2. 7. However, in the cover letter it is not necessary to...

        3. 8. The cover letter shall indicate where the information listed in...

        4. 9. The cover letter shall indicate if the clinical trial is...

        5. 10. The cover letter shall indicate if the methodology of the...

        6. 11. The cover letter shall indicate the location in the application...

        7. 12. In the case of a resubmission, the cover letter shall...

      3. C. EU APPLICATION FORM

        1. 13. The EU application form, duly completed.

      4. D. PROTOCOL

        1. 14. The protocol shall describe the objective, design, methodology, statistical considerations,...

        2. 15. The protocol shall be identified by:

        3. 16. The protocol shall, when possible, be written in an easily...

        4. 17. The protocol shall at least include:

        5. 18. If a clinical trial is conducted with an active substance...

        6. 19. With regard to the notification of adverse events, the protocol...

        7. 20. The protocol shall describe the procedures for:

        8. 21. In case the sponsor intends to submit a single safety...

        9. 22. Issues regarding labelling and the unblinding of investigational medicinal products...

        10. 23. The protocol shall be accompanied by the Charter of the...

        11. 24. The protocol shall be accompanied by a synopsis of the...

      5. E. INVESTIGATOR'S BROCHURE (IB)

        1. 25. An IB, which has been prepared in accordance with the...

        2. 26. The purpose of the IB is to provide the investigators...

        3. 27. The information in the IB shall be presented in a...

        4. 28. If the investigational medicinal product is authorised, and is used...

        5. 29. For a multinational clinical trial where the medicinal product to...

        6. 30. If the IB is not an SmPC, it shall contain...

      6. F. DOCUMENTATION RELATING TO COMPLIANCE WITH GOOD MANUFACTURING PRACTICE (GMP) FOR...

        1. 31. As regards documentation relating to GMP compliance, the following shall...

        2. 32. No documentation needs to be submitted where the investigational medicinal...

        3. 33. If the investigational medicinal product is not authorised, and does...

        4. 34. In all other cases, a copy of the authorisation referred...

        5. 35. For processes related to investigational medicinal products set out in...

      7. G. INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER (IMPD)

        1. 36. The IMPD shall give information on the quality of any...

        2. 1.1. Data relating to the investigational medicinal product

          1. Introduction

            1. 37. Regarding data, the IMPD may be replaced by other documentation...

            2. 38. Each section of the IMPD shall be prefaced with a...

            3. 39. The information in the IMPD shall be concise. The IMPD...

          2. Quality data

            1. 40. Quality data shall be submitted in a logical structure such...

          3. Non-clinical pharmacology and toxicology data

            1. 41. The IMPD shall also contain summaries of non-clinical pharmacology and...

            2. 42. Non-clinical pharmacology and toxicology data shall be submitted in a...

            3. 43. The IMPD shall provide a critical analysis of the data,...

            4. 44. The IMPD shall contain a statement of the good laboratory...

            5. 45. The test material used in toxicity studies shall be representative...

          4. Data from previous clinical trials and human experience

            1. 46. Data from previous clinical trials and human experience shall be...

            2. 47. This section shall provide summaries of all available data from...

          5. Overall risk and benefit assessment

            1. 48. This section shall provide a brief integrated summary that critically...

            2. 49. Where appropriate, safety margins shall be discussed in terms of...

        3. 1.2. Simplified IMPD by referring to other documentation

          1. 50. The applicant may refer to other documentation submitted alone or...

          2. Possibility of referring to the IB

            1. 51. The applicant may either provide a stand-alone IMPD or cross-refer...

          3. Possibility of referring to the SmPC

            1. 52. The applicant may submit the version of the SmPC valid...

            2. 53. If the investigational medicinal product is defined in the protocol...

        4. 1.3. IMPD in cases of placebo

          1. 54. If the investigational medicinal product is a placebo, the information...

      8. H. AUXILIARY MEDICINAL PRODUCT DOSSIER

        1. 55. Without prejudice to Article 65, the documentation requirements set out...

      9. I. SCIENTIFIC ADVICE AND PAEDIATRIC INVESTIGATION PLAN (PIP)

        1. 56. If available, a copy of the summary of scientific advice...

        2. 57. If the clinical trial is part of an agreed PIP,...

      10. J. CONTENT OF THE LABELLING OF THE INVESTIGATIONAL MEDICINAL PRODUCTS

        1. 58. A description of the content of the labelling of the...

      11. K. RECRUITMENT ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)

        1. 59. Unless described in the protocol, a separate document shall describe...

        2. 60. Where the recruitment of subjects is done through advertisement, copies...

      12. L. SUBJECT INFORMATION, INFORMED CONSENT FORM AND INFORMED CONSENT PROCEDURE (INFORMATION...

        1. 61. All information given to the subjects (or, where applicable, to...

        2. 62. A description of procedures relating to informed consent for all...

        3. 63. In the cases set out in paragraph 62, the information...

      13. M. SUITABILITY OF THE INVESTIGATOR (INFORMATION PER MEMBER STATE CONCERNED)

        1. 64. A list of the planned clinical trial sites, the name...

        2. 65. Description of the qualification of the investigators in a current...

        3. 66. Any conditions, such as economic interests and institutional affiliations, that...

      14. N. SUITABILITY OF THE FACILITIES (INFORMATION PER MEMBER STATE CONCERNED)

        1. 67. A duly justified written statement on the suitability of the...

      15. O. PROOF OF INSURANCE COVER OR INDEMNIFICATION (INFORMATION PER MEMBER STATE...

        1. 68. Proof of insurance, a guarantee, or a similar arrangement shall...

      16. P. FINANCIAL AND OTHER ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)

        1. 69. A brief description of the financing of the clinical trial....

        2. 70. Information on financial transactions and compensation paid to subjects and...

        3. 71. Description of any other agreement between the sponsor and the...

      17. Q. PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED)...

        1. 72. Proof of payment shall be submitted, if applicable.

      18. R. PROOF THAT DATA WILL BE PROCESSED IN COMPLIANCE WITH UNION...

        1. 73. A statement by the sponsor or his or her representative...

    2. ANNEX II

      APPLICATION DOSSIER FOR SUBSTANTIAL MODIFICATION

      1. A. INTRODUCTION AND GENERAL PRINCIPLES

        1. 1. Where a substantial modification concerns more than one clinical trial...

        2. 2. The application shall be signed by the sponsor or a...

      2. B. COVER LETTER

        1. 3. A cover letter with the following information:

      3. C. MODIFICATION APPLICATION FORM

        1. 4. The modification application form, duly completed.

      4. D. DESCRIPTION OF THE MODIFICATION

        1. 5. The modification shall be presented and described as follows:

        2. 6. The new version of the document shall be identified by...

      5. E. SUPPORTING INFORMATION

        1. 7. Where applicable, additional supporting information shall at least include:

      6. F. UPDATE OF EU APPLICATION FORM

        1. 8. If a substantial modification involves changes to entries on the...

      7. G. PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED)...

        1. 9. Proof of payment shall be submitted, if applicable.

    3. ANNEX III

      SAFETY REPORTING

      1. 1. REPORTING OF SERIOUS ADVERSE EVENTS BY THE INVESTIGATOR TO THE...

        1. 1. The investigator does not need to actively monitor subjects for...

      2. 2. REPORTING OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) BY THE...

        1. 2.1. Adverse Events and Causality

          1. 2. Medication errors, pregnancies and uses outside what is foreseen in...

          2. 3. In determining whether an adverse event is an adverse reaction,...

          3. 4. In the absence of information on causality provided by the...

        2. 2.2. Expectedness, unexpectedness and the RSI

          1. 5. In determining whether an adverse event is unexpected, consideration shall...

          2. 6. The expectedness of an adverse reaction shall be set out...

          3. 7. The RSI shall be contained in the SmPC or the...

          4. 8. The RSI may change during the conduct of a clinical...

          5. 9. If information on expectedness has been provided by the reporting...

        3. 2.3. Information for the reporting of SUSARs

          1. 10. The information shall at least include:

          2. 11. In addition, in order to properly process the report electronically,...

        4. 2.4. Follow-up reports of SUSARs

          1. 12. If the initial report of a SUSAR referred to in...

          2. 13. The clock for initial reporting (day 0 = Di 0)...

          3. 14. If significant new information on an already reported case is...

          4. 15. If the initial report of a SUSAR referred to in...

          5. 16. In cases where a SUSAR turns out to be fatal...

        5. 2.5. Unblinding treatment allocation

          1. 17. The investigator shall only unblind the treatment allocation of a...

          2. 18. When reporting a SUSAR to the Agency, the sponsor shall...

          3. 19. If an event is potentially a SUSAR the blind shall...

          4. 20. Unblinded information shall be accessible only to persons who need...

          5. 21. However, for clinial trials carried out in high morbidity or...

          6. 22. If following unblinding, an event turns out to be a...

      3. 3. ANNUAL SAFETY REPORTING BY THE SPONSOR

        1. 23. The report shall contain, in an appendix, the RSI in...

        2. 24. The RSI in effect at the start of the reporting...

        3. 25. If there are significant changes to the RSI during the...

    4. ANNEX IV

      CONTENT OF THE SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL

      1. The summary of the results of the clinical trial shall...

      2. A. CLINICAL TRIAL INFORMATION:

      3. B. SUBJECT DISPOSITION:

      4. C. BASELINE CHARACTERISTICS:

      5. D. END POINTS:

      6. E. ADVERSE EVENTS:

      7. F. ADDITIONAL INFORMATION:

    5. ANNEX V

      CONTENT OF THE SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL FOR LAYPERSONS

      1. The summary of the results of the clinical trial for...

      2. Clinical trial identification (including title of the trial, protocol number,...

    6. ANNEX VI

      LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS

      1. A. UNAUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS

        1. A.1. General rules

          1. 1. The following particulars shall appear on the immediate and the...

          2. 2. Symbols or pictograms may be included to clarify certain information...

          3. 3. The address and telephone number of the main contact shall...

        2. A.2. Limited labelling of immediate packaging

          1. A.2.1. Immediate and outer packaging provided together

            1. 4. When the product is provided to the subject or the...

          2. A.2.2. Small immediate packaging

            1. 5. If the immediate packaging takes the form of blister packs...

      2. B. UNAUTHORISED AUXILIARY MEDICINAL PRODUCTS

        1. 6. The following particulars shall appear on the immediate and the...

      3. C. ADDITIONAL LABELLING FOR AUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS

        1. 7. In accordance with Article 67(2), the following particulars shall appear...

      4. D. REPLACING OF INFORMATION

        1. 8. The particulars listed in sections A, B and C, other...

        2. 9. The particulars referred to in the following points shall not...

    7. ANNEX VII

      CORRELATION TABLE

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