GOOD CLINICAL PRACTICE AND REQUIREMENTS FOR MANUFACTURING OR IMPORT AUTHORISATION OF

SUBSIDIARY LEGISLATION 458.47

GOOD CLINICAL PRACTICE AND

REQUIREMENTS FOR MANUFACTURING

OR IMPORT AUTHORISATION OF

INVESTIGATIONAL MEDICINAL PRODUCTS

(HUMAN USE) REGULATIONS

26th May, 2006

LEGAL NOTICE 119 of 2006, as amended by Legal Notice 234 of 2022.

(1) The title of these regulations is the Good Clinical

Practice and Requirements for Manufacturing or Import

Authorisation of Investigational Medicinal Products (Human Use)

Regulations.

(2) These regulations shall apply in conjunction with the

Clinical Trials Regulations and the Good Manufacturing Practice in

respect of Medicinal and Investigational Medicinal Products for

Human Use Regulations.

(1) The following provisions shall apply to investigational

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 subregulation (1) 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

IN VE S TI G ATI ON A L M ED I C I N A L PR O DU C TS ( HU MA N US E )

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 subregulation.

(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,

a d o p t e d b y t h e G e n e r a l A s s e m b l y o f t h e Wo r l d M e d i c a l

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)

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

fun ctio ns to an indi vid ual, a comp any, an in stitu tio n o r 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

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

Provided that by way of derogation from sub-regulation (1),

the Licensing Authority shall allow investigational medicinal

products to be imported from parts of the United Kingdom other

than Northern Ireland without such an authorisation provided that

all of the following conditions are fulfilled

(a) the imported investigational medicinal products have

undergone certification of batch release either in the

Union, as provided for in paragraph 3, point (a) of

Article 13 (1) of Directive 2001/20/EC, or in parts of

the United Kingdom other than Northern Ireland in

compliance with the requirements set out in paragraph

IN VE S TI G ATI ON A L M ED I C I N A L PR O DU C TS ( HU MA N US E )

3, point (b) of the same Directive;

(b) the imported investigational medicinal products are only

made available in Malta.

(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

in vest igati onal m edici nal produ cts are i ntended 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 subregulation (1).

(1) The Authority shall issue the authorisation only after

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

ninety 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

regulation 8(1)(e)

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

regulation 8 are complied with, authorisation may be made

conditional on the carrying out of certain obligations imposed

either when 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

regulation 8(1)(a).

The holder of the authorisation shall at least comply with

the 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 regulation 9(1)(a) to (e), the time

taken for the procedure relating to the request shall not exceed

IN VE S TI G ATI ON A L M ED I C I N A L PR O DU C TS ( HU MA N US E )

thirty days. In exceptional cases, this period of time may be

extended to ninety 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 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

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

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

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

col lectively t he requirements necessary for conducting the

inspection.

(1) Good clinical practice inspections may take place on

any of the following occasions

(a) before, during or after the conduct of clinical trials;

IN VE S TI G ATI ON A L M ED I C I N A L PR O DU C TS ( HU MA N US E )

(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.

(1) The Authority shall

(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.