Commission Implementing Regulation (EU) 2017/556
of 24 March 2017
on the detailed arrangements for the good clinical practice inspection procedures pursuant to Regulation (EU) No 536/2014 of the European Parliament and of the Council
(Text with EEA relevance)
THE EUROPEAN COMMISSION,
Having regard to the Treaty on the Functioning of the European Union,
Whereas:
Regulation (EU) No 536/2014 lays down the legal framework for the conduct of clinical trials on medicinal products for human use in the Union to ensure that the rights, safety and well-being of the subjects are protected, and the data generated in clinical trials are robust and reliable. In particular, the sponsor of a clinical trial and the investigator are to ensure that the clinical trial is conducted in accordance with the relevant protocol and the principles of good clinical practice. Compliance with the applicable legal requirements, the protocol and the principles of good clinical practice, including with standards relating to data integrity and ethical conduct of the clinical trial, is to be verified by means of inspections conducted under the responsibility of the Member State where the inspection takes place.
The inspection in the context of clinical trials may concern good manufacturing practices as regards the manufacturing of the investigational medicinal products or good clinical practice as regards the conduct of clinical trials. Article 63 of Regulation (EU) No 536/2014 empowers the Commission to adopt delegated acts specifying the detailed arrangements for good manufacturing practice inspections as regards investigational medicinal products. Therefore, this Regulation should only lay down detailed arrangements for good clinical practice inspections procedures and requirements regarding training and qualifications of good clinical practice inspectors.
Member States may conduct inspections of clinical trials performed in third countries, either because a clinical trial is related to a clinical trial authorised in the Union or because the data of the clinical trial is being referred to in a clinical trial authorisation application in the Union. Those inspections should allow verifying whether such clinical trials were conducted in accordance with standards equivalent to Union standards. Inspections of clinical trials in third countries may also be conducted in order to verify whether the clinical trials, whose results are referred to in marketing authorisation applications in the Union, meet the ethical requirements set out in Regulation (EU) No 536/2014. Therefore, provisions on detailed arrangements for the inspection procedures should apply also to inspections conducted outside the Union in accordance with Regulation (EU) No 536/2014.
The International Conference on Harmonisation (‘ICH’) reached a consensus in 1995 to provide a harmonised approach for good clinical practice. Pursuant to Article 47 of Regulation (EU) No 536/2014, the ICH guidelines should be appropriately taken into account by the sponsor when drafting the clinical trial protocol and conducting the clinical trial. To the extent that those guidelines are compatible with the relevant Union law and EU guidelines, inspectors should refer to the ICH guidelines, taking into account the characteristics of each trial.
Member States should be required to set up quality systems to ensure that the inspection procedures are observed and consistently monitored. A well-functioning quality system should comprise an organisational structure, clear processes and procedures, including the standard operating procedures to be followed by inspectors when performing their tasks, clearly defined details of the inspectors' duties and responsibilities and ongoing training requirements, as well as adequate resources and mechanisms which aim at eliminating non-compliance.
It is necessary to enable inspectors to ensure the practical effectiveness of provisions on good clinical practice. That objective should be reflected in the minimum requirements for the qualification of inspectors, in particular as regards their education and training. For the same reasons, detailed rules on inspection procedures should be laid down.
In order to safeguard the effectiveness of inspection, the inspectors should be granted the necessary powers of access to the premises and data. This includes in particular any laboratory used for analysis in the clinical trial, any contract research organisation's facilities or the sponsor's premises. They should also be empowered to contact the trial subjects in justified cases.
In order to ensure the compliance with arrangements for good clinical practice inspections and in accordance with Article 77 of Regulation (EU) No 536/2014 Member States should take corrective measures if necessary. When during an inspection a major non-compliance or breach is identified, or the inspectors' investigatory powers are not recognised by the sponsors, Member States should have recourse to penalties.
This Regulation should become applicable at the same time as Regulation (EU) No 536/2014.
The measures provided for in this Regulation are in accordance with the opinion of the Standing Committee on Medicinal Products for Human Use,
HAS ADOPTED THIS REGULATION:
CHAPTER IGENERAL PROVISIONS
Article 1Scope
This Regulation applies to inspections of:
- (a)
clinical trials conducted in the Union, including clinical trial sites related to those trials but located outside the Union;
- (b)
clinical trials referred to in the applications for clinical trial authorisations pursuant to Article 25(5) of Regulation (EU) No 536/2014;
- (c)
clinical trials conducted in third countries and referred to in marketing authorisation applications in the Union.
Article 2Time frame for inspections
Inspections may take place in any of the following circumstances:
- (a)
before, during or after the conduct of a clinical trial;
- (b)
as part of the verification of applications for marketing authorisation;
- (c)
as a follow-up to the granting of a marketing authorisation.
Article 3Quality system
1.
Each Member State shall set up a properly designed quality system ensuring that the inspection procedures are observed and consistently monitored.
Member States shall maintain those quality systems up to date.
2.
Each inspector shall have access to and comply with standard operating procedures, details of their duties, responsibilities and training requirements.
CHAPTER IIINSPECTORS
Article 4Qualifications, training and experience
1.
Inspectors shall have completed education at university level, or have equivalent experience, in medicine, pharmacy, pharmacology, toxicology or other fields relevant to the principles of good clinical practice.
2.
Inspectors shall receive appropriate training, including participation in inspections. Their training needs, necessary to maintain or improve their skills, shall be assessed regularly by a person appointed for that task.
3.
Inspectors shall have knowledge of principles and processes that apply to the development of medicinal products and clinical research and have knowledge of applicable Union and national legislation and guidelines on the conduct of clinical trials and the granting of marketing authorisations.
4.
Inspectors shall have the ability to make professional judgments in relation to the compliance with applicable Union and national legislation and guidelines. They shall be able to assess data integrity as well as aspects related to ethical conduct of clinical trials.
5.
Inspectors shall be familiar with the procedures and technical methods for the recording and management of clinical data, and with the organisation and regulation of the healthcare systems in the relevant Member States and, where appropriate, in third countries.
6.
Inspectors shall be able to assess the degree of risk as regards the safety of the subjects enrolled in the clinical trial as well as the data integrity.
7.
Inspectors shall be aware of the applicable rules as regards confidentiality and protection of personal data.
8.
Member States shall keep records of the qualifications, training and experience of each inspector and maintain those records up-to-date for as long as inspector is in active duty.
Article 5Conflict of interest and impartiality
1.
Inspectors shall be free from any influence which could affect their impartiality or their judgement.
2.
Inspectors shall not have conflicts of interest. In particular, they shall be independent of all of the following parties:
(a)
the sponsor;
(b)
the investigators involved in the clinical trial;
(c)
persons financing the clinical trial;
(d)
any other party involved in the conduct of the clinical trial.
3.
Each inspector shall make an annual declaration of their financial interests and other links to the parties to be potentially inspected. That declaration shall be taken into consideration for the purposes of assigning an inspector to a specific inspection.
CHAPTER IIIINSPECTION PROCEDURES
Article 6Subject matter of inspections
Inspectors shall verify the compliance with the requirements of Regulation (EU) No 536/2014, including protection of the rights and well-being of the clinical trial subjects, the quality and integrity of data generated in clinical trial, the compliance with principles of good clinical practice, including the ethical aspects and the relevant national legislation.
Article 7Procedures to be established by Member States
1.
Member States shall establish the relevant procedures for at least the following:
(a)
appointing experts to accompany inspectors, if additional expertise is required for an inspection;
(b)
arranging inspections outside the Union;
(c)
verification of good clinical practice compliance, including the modalities for examining the study management procedures and the conditions under which the clinical trial is planned, performed, monitored and recorded, as well as follow-up measures, such as a review of an analysis of the root cause of a significant non-compliance and verification of corrective and preventive actions implemented by the sponsor.
Member States shall make those procedures and rules publicly available.
2.
Member States shall also define the powers of experts appointed to accompany inspectors.
Article 8Unannounced inspections
The inspections may, where necessary, be carried out unannounced.
Article 9Collaboration between Member States
1.
Member States shall collaborate with each other, with the Commission and with the European Medicines Agency to develop and improve commonly recognised standards of good clinical practice inspections. This collaboration may take the form of joint inspections, agreed processes and procedures and sharing of experience and training.
2.
The Commission shall make publicly available any guidance documents on the commonly recognised standards for the conduct of inspections, developed in collaboration with Member States and the European Medicines Agency.
3.
The European Medicines Agency shall process and make available to Member States information on inspections that are envisaged, scheduled, or conducted, in order to assist Member States to ensure the most efficient use of inspection resources when planning their inspections.
4.
Member States may request assistance from the national competent authority of another Member State in the matter of inspection.
Article 10Powers of inspectors
1.
Inspections shall be carried out by inspectors appointed by Member States.
In order to ensure the availability of necessary skills for each inspection, Member States may appoint teams of inspectors and appoint experts with appropriate qualifications to accompany inspectors.
2.
Inspectors shall be entitled to inspect the clinical trial sites, documents, facilities, records, including individual patients' records, quality arrangements, data and any other resources and entities that are deemed by the competent authority to be related to the clinical trial.
3.
When performing an inspection, the inspectors shall be empowered to enter into sites, other related premises, and to access to data, including individual patients' records.
4.
Inspectors shall be entitled to make copies of records and hard copies, print-outs of electronic records and take photos of premises and equipment.
5.
Inspectors shall be entitled to 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 to record the answer.
6.
Inspectors shall be empowered to contact the trial subjects directly, in particular in case of reasonable suspicion that they were not informed adequately of their participation in the clinical trial.
7.
Member States shall provide inspectors with suitable means of their identification.
8.
Member States shall establish a legal and administrative framework to ensure that inspectors from other Member States, on request and where appropriate, have access to sites, any premise of any entity related to the clinical trial as well as to related data.
Article 11Recognition of inspection conclusions
Inspectors shall carry out inspections on behalf of the Union. The results of those inspections shall be recognised by all Member States.
Article 12Resources
Member Sates shall appoint an adequate number of inspectors to ensure effective verification of compliance of clinical trials with applicable requirements, as well as the timely reporting of inspection findings.
Article 13Inspection reports and records
Without prejudice to the obligation to submit the inspection reports via the EU Portal in accordance with Article 78(6) of Regulation (EU) No 536/2014, Member States shall keep for at least 25 years relevant records of national inspections as well as of the inspections performed outside their territory, including information on the outcome of the inspection as regards good clinical practice compliance status as well as any action taken by the sponsor or Member State in the follow-up of the inspection. The inspection reports submitted through the EU portal shall not contain personal data of clinical trials' subjects.
Article 14Confidentiality
The inspectors and experts appointed to the inspection team shall maintain the confidentiality of information to which they gain access as a result of good clinical practice inspections.
CHAPTER IVFINAL PROVISIONS
Article 15Repeal
Directive 2005/28/EC is repealed from the date referred to in the second paragraph of Article 17.
Article 16Transitional provisions
Directive 2005/28/EC, except for its Chapters 5 and 6, shall continue to apply to the clinical trials governed by Directive 2001/20/EC pursuant to Article 98 of Regulation (EU) No 536/2014.
Article 17Entry into force
This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.
It shall apply from 6 months after the date of publication in the Official Journal of the European Union of the notice referred to in Article 82(3) of Regulation (EU) No 536/2014.
This Regulation shall be binding in its entirety and directly applicable in all Member States.
Done at Brussels, 24 March 2017.
For the Commission
The President
Jean-Claude Juncker