Import Authorisation of Investigational Medicinal Products

L.N. 119 of 2006

MEDICINES ACT

(CAP. 458)

Good Clinical Practice and Requirements for Manufacturing or

Import Authorisation of Investigational Medicinal Products

(Human Use) Regulations, 2006

IN exercise of the powers conferred by article 106 of the Medicines

Act, the Minister of Health the Elderly and Community Care has made

the following regulations>-

(1) The title of these regulations is the Good Clinical Practice Title and scope.

and Requirements for Manufacturing or Import Authorisation of

Investigational Medicinal Products (Human Use) Regulations, 2006.

(2) These regulations shall apply in conjunction with the

Clinical Trials Regulations, 2004 and the Good Manufacturing Practice L.N. 490 of 2004.

in respect of Medicinal and Investigational Medicinal Products for

Human Use Regulations, 2004.

L.N. 485 of 2004.

(1) The following provisions shall apply to investigational Application of

provisions.

medicinal products for human use>

(a) the principles of good clinical practice and detailed

guidelines in line with those principles, as referred to in Article

1(3) of Directive 2001#20#EC, for the design, conduct and reporting

of clinical trials on human subjects involving such products<

(b) the requirements for authorisation of the manufacture

or importation of such products, as provided for in Article 13(1)

of Directive 2001#20#EC<

(c) the detailed guidelines, provided for in Article 15(5) of

Directive 2001#20#EC, on the documentation relating to clinical

trials, archiving, qualifications of inspectors and inspection

procedures.

(2) (a) When applying the principles, detailed guidelines

and requirements aforementioned, the Licensing Authority, hereinafter

referred to as “the Authority”, shall take into account the technical

implementing modalities provided for in the detailed guidance published

by the Commission in The Rules Governing Medicinal Products in the

European Union.

(b) When applying the principles, detailed guidelines

and requirements referred to in sub regulation (1) hereof to non-

commercial clinical trials conducted by researchers without the

participation of the pharmaceutical industry, the Authority may introduce

specific modalities in order to take into account the specificity of these

trials as far as regulations 8 to 19 are concerned.

(3) The Authority may take into account the special position

of trials whose planning does not require particular manufacturing or

packaging processes, carried out with medicinal products with marketing

authorisations within the meaning of Directive 2001#83#EC,

manufactured or imported in accordance with the same Directive and

conducted on patients with the same characteristics as those covered by

the indication specified in the marketing authorisation.

(4) Labelling of investigational medicinal products intended

for trials of that nature may be subject to simplified provisions laid

down in the good manufacturing practice guidelines on investigational

medicinal products>

Provided that the Authority shall inform the Commission as well

as the other Member States of any specific modalities implemented in

accordance with this sub-regulation.

(1) The rights, safety and well being of the trial subjects

shall prevail over the interests of science and society.

(2) Each individual involved in conducting a trial shall be

qualified by education, training and experience to perform his tasks.

(3) Clinical trials shall be scientifically sound and guided

by ethical principles in all their aspects.

(4) The necessary procedures to secure the quality of every

aspect of the trials shall be complied with.

(5) The available non-clinical and clinical information on

an investigational medicinal product shall be adequate to support the

proposed clinical trial.

(6) Clinical trials shall be conducted in accordance with the

latest published version of the Declaration of Helsinki on Ethical

Principles for Medical Research Involving Human Subjects, adopted

by the General Assembly of the World Medical Association.

(7) The protocol referred to in point (h) of Article 2 of

Directive 2001#20#EC shall provide for the definition of inclusion and

exclusion of subjects participating in a clinical trial, monitoring and

publication policy.

(8) The investigator and sponsor shall consider all relevant

guidance with respect to commencing and conducting a clinical trial.

(9) All clinical trial information shall be recorded, handled

and stored in such a way that it can be accurately reported, interpreted

and verified, while the confidentiality of records of the trial subjects

remains protected.

(1) Each Ethics Committee established under Article 6(1) Ethics Committees.

of Directive 2001#20#EC shall adopt the relevant rules of procedure

necessary to implement the requirements set out in that Directive and,

in particular, in Articles 6 and 7 thereof.

(2) The Ethics Committees shall, in every case, retain the

essential documents relating to a clinical trial, as referred to in Article

15(5) of Directive 2001#20#EC, for at least three years after completion

of that trial. They shall retain the documents for a longer period, where

so required under other applicable requirements.

(3) Communication of information between the Ethics

Committees and the Authority shall be ensured through appropriate and

efficient systems.

(1) A sponsor may delegate any or all of his trial-related Sponsors.

functions to an individual, a company, an institution or an organisation>

Provided that in such cases, the sponsor shall remain

responsible for ensuring that the conduct of the trials and the final data

generated by those trials comply with Directive 2001#20#EC as well as

Directive 2005#28#EC.

(2)

The investigator and the sponsor may be the same

person.

(1) The information in the investigator’s brochure, referred Investigator’s

brochure.

to in Article 2(g) of Directive 2001#20#EC, shall be presented in a

concise, simple, objective, balanced and non-promotional form that

enables a clinician or potential investigator to understand it and make

an unbiased risk-benefit assessment of the appropriateness of the

proposed clinical trial. This shall also apply to any update of the

investigator’s brochure.

(2) If the investigational medicinal product has a marketing

authorisation, the Summary of Product Characteristics may be used

instead of the investigator’s brochure.

(3) The investigator’s brochure shall be validated and

updated by the sponsor at least once a year.

(1) Authorisation, as provided for in Article 13(1) of

Directive 2001#20#EC, shall be required for both total and partial

manufacture of investigational medicinal products, and for the various

processes of dividing up, packaging or presentation.

(2) Such authorisation shall be required even if the products

manufactured are intended for export.

(3) Authorisation shall also be required for imports from

non-EU Member States into Malta.

(4) Authorisation, as provided for in Article 13(1) of

Directive 2001#20#EC, shall not be required for reconstitution prior to

use or packaging, where those processes are carried out in hospitals,

health centres or clinics, by pharmacists or other persons legally

authorised in Malta to carry out such processes and if the investigational

medicinal products are intended to be used exclusively in those

institutions.

(1) In order to obtain the authorisation, the applicant must

meet at least the following requirements>

(a) specify in his application the types of medicinal products

and pharmaceutical forms to be manufactured or imported>

Provided that for the purposes of sthis paragraph, “types of

medicinal products” include 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 active ingredients<

(b) specify in his application the relevant manufacture or

import operations<

(c) specify in his application, where relevant as in the case

of viral or non-conventional agents’ inactivation, the manufacturing

process<

(d) specify in his application the place where the products

are to be manufactured or have at his disposal, for their manufacture

or importation, suitable and sufficient premises, technical

equipment and control facilities complying with the requirements

of Directive 2003#94#EC as regards the manufacture, control and

storage of the products<

(e) have permanently and continuously at his disposal the

services of at least one qualified person as referred to in Article

13(2) of Directive 2001#20#EC.

(2) The applicant shall provide with his application

documentary evidence that he complies with sub-regulation (1) hereof.

(1) The Authority shall issue the authorisation only after Issuing of

authorisation.

verifying the accuracy of the particulars provided by the applicant

pursuant to regulation 8 by means of an inquiry carried out by its agents.

(2) The Authority shall take all appropriate measures to

ensure that the procedure for granting an authorisation is completed

within 90 days from the receipt of a valid application.

(3) The Authority may require from the applicant further

information concerning the particulars supplied pursuant to regulation

8(1), including in particular information concerning the qualified person

at the disposal of the applicant in accordance with paragraph (e) of

regulation 8(1)>

Provided that where the Authority exercises that right, the

application of the time-limits aforementioned shall be suspended until

the additional data required have been supplied.

(1) In order to ensure that the requirements laid down in Compliance

with and

regulation 8 are complied with, authorisation may be made conditional applicability of

on the carrying out of certain obligations imposed either when authorisation.

authorisation is granted or at a later date.

(2) An authorisation shall apply only to the premises

specified in the application and to the types of medicinal products and

pharmaceutical forms specified in that application pursuant to sub-

regulation 8(1)(a).

The holder of the authorisation shall at least comply with the Holder to comply

with requirements.

following requirements>

(a) have at his disposal the services of staff that comply

with the legal requirements as regards manufacture and controls<

(b) dispose of the investigational and authorised medicinal

products only in accordance with the legislation in force<

(c) give prior notice to the Authority of any changes he may

wish to make to any of the particulars supplied pursuant to

regulation 8(1) and, in particular, to inform the Authority

immediately if the qualified person referred to in Article 13(2) of

Directive 2001#20#EC is replaced unexpectedly<

(d) allow agents of the Authority access to his premises at

any time<

(e) enable the qualified person referred to in Article 13(2)

of Directive 2001#20#EC to carry out his duties, for example by

placing at his disposal all the necessary facilities<

(f) comply with the principles and guidelines for Good

Manufacturing Practice for medicinal products as laid down by

Community law.

If the holder of the authorisation requests a change in any of

the particulars referred to in points (a) to (e) of regulation 9 (1), the

time taken for the procedure relating to the request shall not exceed 30

days. In exceptional cases, this period of time may be extended to 90

days.

The Authority shall suspend or revoke the authorisation, as

a whole or in part, if the holder of the authorisation fails at any time to

comply with the relevant requirements.

(a) The documentation referred to Article 15(5) of Directive

2001#20#EC as the trial master file shall consist of essential documents,

which enable both the conduct of a clinical trial and the quality of the

data produced to be evaluated. Those documents shall show whether

the investigator and the sponsor have complied with the principles and

guidelines of good clinical practice and with the applicable requirements

and, in particular, with Annex I to Directive 2001#83#EC.

(b) The trial master file shall provide the basis for the audit

by the sponsor’s independent auditor and for the inspection by the

Authority.

(c) The content of the essential documents shall be in

accordance with the specificities of each phase of the clinical trial.

(1) The sponsor and the investigator shall retain the essential Retention of

documents.

documents relating to a clinical trial for at least five years after its

completion.

(2) They shall retain the documents for a longer period,

where so required by other applicable requirements or by an agreement

between the sponsor and the investigator.

(3) Essential documents shall be archived in a way that

ensures that they are readily available, upon request, to the Authority.

(4) The medical files of trial subjects shall be retained in

accordance with national legislation and in accordance with the

maximum period of time permitted by the hospital, institution or private

practice.

Any transfer of ownership of the data or of documents shall Transfer of data

ownership.

be documented. The new owner shall assume responsibility for data

retention and archiving in accordance with the preceding regulation.

(1) The sponsor shall appoint individuals within its Archives.

organisation who are responsible for archives.

(2) Access to archives shall be restricted to the named

individuals responsible for the archives.

(3) The media used to store essential documents shall be

such that those documents remain complete and legible throughout the

required period of retention and can be made available to the competent

authorities upon request.

(4) Any alteration to records shall be traceable.

(1) The inspectors, appointed by the Authority pursuant to Inspectors.

Article 15(1) of Directive 2001#20#EC, shall be made aware of and

maintain confidentiality whenever they gain access to confidential

information as a result of good clinical practice inspections in accordance

with applicable Community requirements, national laws or international

agreements.

(2) The Authority shall ensure that inspectors>

(a) have completed education at university level, or have

equivalent experience, in medicine, pharmacy, pharmacology,

toxicology or other relevant fields<

(b) have received appropriate training, that their training

needs are assessed regularly and that appropriate action is taken to

maintain and improve their skills<

(c) have knowledge of the principles and processes that

apply to the development of medicinal products and clinical

research.

(3) Inspectors shall>

(a) have knowledge of applicable Community and national

legislation and guidelines applicable to the conduct of clinical trials

and the granting of marketing authorisations< and

(b) be familiar with the procedures and systems for

recording clinical data, and with the organisation and regulation

of the healthcare system in the relevant Member States and, where

appropriate, in third countries.

(4) The Authority shall maintain up-to-date records of the

qualifications, training and experience of each inspector.

(5) Each inspector shall be provided with>

(a) a document setting out standard operating procedures

and giving details of the duties, responsibilities and ongoing training

requirements. Those procedures shall be maintained up to date<

and

(b) suitable means of identification.

(6) Each inspector shall sign a statement declaring any

financial or other links to the parties to be inspected. That statement

shall be taken into consideration when inspectors are to be assigned to

a specific inspection.

In order to ensure the presence of skills necessary for specific

inspections, the Authority may appoint teams of inspectors and experts

with appropriate qualifications and experience to fulfill collectively the

requirements necessary for conducting the inspection.

(1) Good clinical practice inspections may take place on Inspection

procedures.

any of the following occasions>

(a)

before, during or after the conduct of clinical trials<

(b) as part of the verification of applications for marketing

authorisation< and

(c)

as a follow-up to the granting of authorisation.

(2) In accordance with Article 15(1) and (2) of Directive

2001#20#EC, inspections may be requested and coordinated by the

European Medicines Agency (hereinafter referred to as “the Agency”)

within the scope of Regulation (EC) No 726#2004 of the European

Parliament and of the Council, especially in connection with clinical

trials relating to applications through the procedure established by

Regulation 726#2004.

(3) Inspections shall be conducted in accordance with the

inspection guidance documents developed to support the mutual

recognition of inspection findings within the Community.

(4) Improvement and harmonisation of inspection guidance

shall be achieved by the Authority, in collaboration with the Commission

and the Agency, through joint inspections, agreed processes and

procedures and sharing of experience and training.

Duties of the

The Authority shall>

Authority.

(a) make publicly available in Malta the documents relating

to the adoption of good clinical practice principles<

(b) establish the legal and administrative framework within

which good clinical inspections operate, with definitions of the

powers of inspectors for entry into clinical trial sites and access to

data< and

(c) ensure that, on request and where appropriate, inspectors

of the competent authority of other Member States also have access

to the clinical trial sites and data.

(2) The Authority shall provide for sufficient resources and

shall in particular appoint an adequate number of inspectors to ensure

effective verification of compliance with good clinical practice.

(3) The Authority shall establish the relevant procedures

for verification of good clinical practice compliance. The procedures

shall include the modalities for examining both the study management

procedures and the conditions under which clinical trials are planned,

performed, monitored and recorded, as well as follow-up measures.

(4) The Authority shall establish the relevant procedures

for the following>

(a) appointing experts for accompanying inspectors in case

of need<

(b) requesting inspections#assistance from other Member

States, in line with Article 15(1) of Directive 2001#20#EC and for

cooperating in inspections in another Member State< and

(c)

arranging inspections in third countries.

(5) The Authority shall maintain records of national and, if

applicable, international inspections including the good clinical practice

compliance status, and of their follow-up.

(6) The Authority shall ensure that national inspection

procedures are in compliance with the guidance documents published

by the Commission.

(7) The Authority shall lay down all necessary rules to

ensure that confidentiality is respected by inspectors and other experts.

With regard to personal data, the requirements of Directive 95#46#EC

of the European Parliament and of the Council shall be respected.

(8) Inspection reports shall be made available by the

Authority only to the recipients referred to in Article 15(2) of Directive

2001#20#EC, in accordance with national laws and regulations and

subject to any arrangements concluded between the Community and

third countries.

Mitbug[ fl-Istamperija tal-Gvern — Printed at the Government Printing Press