UK Implementation of the EU Clinical Trial Directive 2001/20/EC:

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Version 09 Sept 05 1

UK Implementation of

the EU Clinical Trial

Directive 2001/20/EC:

GCP Aspects.

Dr. Colin Wilsher,

FRQA

.

BARQA GCP Committee Chairman; & Pfizer Worldwide

Development Quality Assurance

.

GIQAR , Roma, October 2005

UK Statutory Instrument

1031/2004, transposed the

European Union Directive

2001/20/EC into UK law and was

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MHRA own Summary of SI 1031/2004

Pharmacology studies in healthy human volunteers (Phase 1 studies) require authorisation from the MHRA where

previously they only needed a favourable opinion of an ethics committee;

Investigational medicinal products (IMPs) must be manufactured to good manufacturing practice (GMP)

standards and the manufacturer must have a manufacturing licence;

Each trial must have an identified sponsor who takes responsibility for its initiation, management and conduct. To establish our ethics committee system on a statutory basis (Regulations 5 to 10, and Schedule 2);

MHRA own Summary of SI 1031/2004 (cont)

To require all clinical trials to be conducted in accordance with the principles of good clinical practice (GCP)

(Regulations 28 to 31, and Schedules 1 and 5);

To provide additional protection for minors and physically or mentally incapacitated adults who are candidates for clinical trials (Regulations 14 to16 and Parts 3 & 5 of Schedule 1 for incapacitated adults and Regulation 15 and Part 4 of

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MHRA own Summary of SI 1031/2004 (cont)

To require sponsors to provide trial medicines free of charge to patients if they are not covered by a prescription charge (Regulation 28);

To provide for inspection by the MHRA for GCP and GMP to help ensure those standards are maintained (Regulations 47 to 52, Parts 2 & 3 of Schedule7,and Schedule 9; and

To provide for enforcement of these new provisions (Regulations 47 to 52 and Schedule 9).

So what are the differences

between the EU Clinical Trial

Directive (2001/20/EC) and

the UK Statutory Instrument

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Good clinical practice and protection of

clinical trial subjects

Section 28.—(1) No person shall—

(a) conduct a clinical trial; or

(b) perform the functions of the sponsor of a clinical

trial (whether that person is the sponsor or is acting

under arrangements made with that sponsor),

otherwise than in accordance with the conditions and

principles of good clinical practice.

New legal definition of adult in

the UK.

Section 2. “adult” means a

person who has attained the age

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Nurses & Pharmacists can become Investigators and Chief Investigators.

“investigator” means, in relation to a clinical trial, the authorised health professional

responsible for the conduct of that trial at a trial site, and if the trial is conducted by a team of authorised health professionals at a trial site, the investigator is the leader responsible for that team

“chief investigator” means—

(a) in relation to a clinical trial conducted at a single trial site, the investigator for that site, or

(b) in relation to a clinical trial conducted at more than one trial site, the authorised health care professional, whether or not he is an investigator at any particular site, who takes primary responsibility for the conduct of the trial;

“authorised health professional” means— (a) a doctor,

(b) a dentist, (c) a nurse, or (d) a pharmacist;

Definition of Electronic Signature

“electronic signature” means data in electronic form which are attached to or logically associated with other electronic data and which serve as a method of authentication;

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Sponsor.

Definition of sponsor changed from ICH and EU CTDir (wording changed with regard to “individual,

company, institution or organisation”)

“sponsor” means, in relation to a clinical trial, the person

who takes responsibility for the initiation, management

andfinancing (or arranging the financing)of that trial. 3(11) A person who is a sponsor of a clinical trial in accordance with this regulation must—

(a) be established in the European Community, or (b) have a legal representative who is so established.

Urgent safety measures

Reporting 3 days from date of urgent safety

measures. In contrast fatal & life threatening SUSARs

only require notification 7 day after sponsor is “first

aware”. There could be several days before a

sponsor is aware of action taken independently by the

investigator.

30.—(1) The sponsor and investigator may take appropriate urgent safety measures in order to protect the subjects of a clinical trial against any immediate hazard to their health or safety.

(2) If measures are taken pursuant to paragraph (1), the sponsor shall immediately, and in any event no later than 3 days from the date the measures are taken, give written notice to the licensing authority and the relevant ethics committee of the measures taken and the circumstances giving rise to those measures.

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NEW Principles of GCP. (Changes / differences from ICH in Red)

SCHEDULE 1 PART 2 CONDITIONS AND PRINCIPLES WHICH APPLY TO ALL CLINICAL TRIALS

Principles based on International Conference on Harmonisation GCP Guideline(a)

1. Clinical trials shallbe conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with good clinical practice and the requirements of these Regulations.

2. Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A trial should be initiated and continued only if the anticipated benefits justify the risks.

3. The rights, safety, and well-being of the trial subjects are the most important considerations andshallprevail over interests of science and society .

4. The available non-clinical and clinical information on an

investigational medicinal product shallbe adequate to support the

NEW Principles of GCP. (Changes / differences from ICH in Red) cont.

5. Clinical trials shallbe scientifically sound, and described in a clear, detailed protocol.

6. A trial shall be conducted in compliance with the protocol that has a favourable opinion from an ethics committee.

7. The medical care given to, and medical decisions made on behalf of, subjects shall always be the responsibility of an

appropriately qualified doctoror, when appropriate, of a qualified dentist.

8. Each individual involved in conducting a trial shallbe qualified by education, training, and experience to perform his or her respective task(s).

9. Subject to the other provisions of this Schedule relating to consent, freely given informed consent shallbe obtained from every subject prior to clinical trial participation.

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NEW Principles of GCP. (Changes / differences from ICH in Red) cont.

11. The confidentiality of records that could identify subjects

shallbe protected, respecting the privacy and confidentiality rules in accordance with the requirements of the Data Protection Act 1998 and the law relating to confidentiality.

12. Investigational medicinal products used in the trial shall

be—

(a) manufactured or imported, and handled and stored, in accordance with the principles and guidelines of good

manufacturing practice, and (b) used in accordance with the approved protocol.

13. Systems with procedures that assure the quality of every aspect of the trial shallbe implemented.

NEW Principles of GCP. (Changes / differences from ICH in

Red) cont.

Conditions based on Article 3 of the Directive

14. A trial shall be initiated only if an ethics committee and the licensing authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored.

15. The rights of each subject to physical and mental integrity, to privacy and to the protection of the data

concerning him in accordance with the Data Protection Act 1998 are safeguarded.

16. Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor which may

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Ethics Committee (EC)

ONE Application for ethics committee opinion

14.—(1) An application for an ethics committee opinion in relation to a clinical trial shall be made by the chief

investigator for that trial.

(2) A chief investigator for a trial shall make an application for an ethics committee opinion in relation to that trial to one ethics committee only, regardless of the number of trial sites at which the trial is to be conducted.

New UKECA United Kingdom Ethics Committees Authority formed.

Workings of Ethics Committee

(differences from the Directive in red)

Includes contract between sponsor & site.

(h) if the subjects are to include persons incapable of giving informed consent, whether the research is justified having regard to the conditions and principles specified in Part 5 of Schedule 1;

(l) the terms of any agreement between the sponsor and the owner or occupier of the trial site which are relevant to the arrangements referred to in sub-paragraph (k); and

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Workings of Ethics Committee

(Cont.)

The UK may have taken a provision from the EU

guidance note on submissions to EC

[ENTR/F2/BL D (2003) April 2003 & ENTR/CT2 revision 1 April 2004]

and put it into the UK

Law:-“6.1.2.8. Financial arrangements. This includes information on financial transactions, and compensation to subjects and

investigator/site. It might be the responsibility of either the Ethics Committee or the competent authority to review the arrangements for rewarding or compensating investigator(s) / sites and trial subjects

as well as the relevant aspects of any

agreement between the sponsor and the site

according to national provisions.”

Most importantly UK SI 1031 has given

powers for GCP Inspections.

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MHRA Inspection Findings

Most frequent non-compliances

from the Statutory Programme

UK MHRA GCP Inspection

Findings

Contracts, agreements and insurance

• Contracts not in place

• Responsibilities not clearly defined

• Unclear ownership of documents and data

• Lack of consistency between protocol and

contract

• Insurance includes exemptions which may

not cover certain patient populations

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UK MHRA GCP Inspection

Findings

Quality Systems

• Lack of essential SOPs

• SOPs not updated

• SOPs do not reflect current practice or

current legislation

• Insufficient time between SOP issues and

becoming effective, which leads to training

issues

• Lack of QA activity, no involvement in

vendor selection

• Meetings and decisions not documented

UK MHRA GCP Inspection

Findings

Investigational Medicinal Product

• Missing documentation:

– shipping records, – accountability, – dosing records

• Emergency codes not supplied prior to study start

Ethical approval

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UK MHRA GCP Inspection

Findings

Informed Consent

• Missing elements

• Inconsistencies with protocol, not

updated with protocol amendments

• Poor version control

• Incorrect form used

• Unclear process

UK MHRA GCP Inspection

Findings

Subject safety and confidentiality

• Lack of involvement of PI

• Unclear procedures (and testing of procedures)

for out of hours emergency contacts

• Subjects not provided with emergency contact

details

• Subject details sent into Sponsor company

• Ineligible subjects entered into studies

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