Clinical Trials Regulations, 2004

L.N. 490 of 2004

MEDICINES ACT, 2003

( ACT NO. III OF 2003)

Clinical Trials Regulations, 2004

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

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

following regulations>-

The title of these Regulations is Clinical Trials Regulations, Title.

1. 2004.

It-titolu ta’ dawn ir-regolamenti hu Regolamenti ta’ l-2004 Titolu.

dwar Provi Kliniçi.

G[an.

(1) These regulations apply Directive 2001#20#EC and shall Scope.

regulate the conduct of clinical trials, including multi-centre trials, in

Malta on human subjects involving medicinal products as defined under

the Act and in particular relating to the implementation of good clinical

practice. These regulations shall not apply to non-interventional trials.

(2) All clinical trials including bioavailability and

bioequivalence studies shall be designed, conducted and reported in

accordance with the principles of good clinical practice. The various

aspects associated with submissions including notifications and requests

to the Licensing Authority and the Ethics Committee and any other

procedures and requirements related to clinical trials as deemed

necessary by the Licensing Authority, shall be in accordance with the

publications related to clinical trials published and, or adopted

periodically by the Commission as deemed necessary by the Licensing

Authority.

In these regulations, unless the context otherwise requires >-

Definitions.

“adverse event” means any untoward medical occurrence in

a patient or clinical trial subject who is administered a medicinal

product and which does not necessarily have a causal relationship

with this treatment<

“adverse reaction” means all untoward and unintended

responses to an investigational medicinal product related to any

dose administered<

“Agency” means the European Medicines Agency established

by Council Regulation (EC) No 726#2004<

“clinical trial” means any investigation in human subjects

intended to discover or verify the clinical, pharmacological and,

or other pharmacodynamic effects of any investigational medicinal

product and, or to identify any adverse reactions to any

investigational medicinal product and, or to study absorption,

distribution, metabolism and excretion of any investigational

medicinal product with the object of ascertaining its safety and,

or efficacy. This includes clinical trials carried out in either one

site or multiple sites, whether in one or more than one Member

State<

“the Ethics Committee” means an independent body,

consisting of healthcare professionals and non-medical members,

whose responsibility is to protect the rights, safety and wellbeing

of human subjects involved in a trial and to provide public assurance

of that protection, by, among other things, expressing an opinion

on the trial protocol, the suitability of the investigators and the

adequacy of facilities, and on the methods and documents to be

used to recruit and inform trial subjects and obtain their informed

consent<

“good clinical practice” means a set of internationally

recognized ethical and scientific quality requirements which must

be observed for designing, conducting, recording and reporting

clinical trials that involve the participation of human subjects.

Compliance with this good practice provides assurance that the

rights, safety and well being of trial subjects are protected and that

the results of the clinical trials are credible<

“informed consent” means a decision, which must be written

in one of the official languages of Malta or in a language

understandable to the clinical trial subject and, or his legal

representative, dated and signed, to take part in a clinical trial,

taken freely after being duly informed of its nature, significance,

implications and risks and appropriately documented, by any person

capable of giving consent or, where the person is not capable of

giving consent, by his or her legal representative< if such person is

unable to write, oral consent may be given in the presence of at

least one witness<

“inspection” means the act by the Licensing Authority of

conducting an official review of documents, facilities, records,

quality assurance arrangements, and any other resources deemed

to be related to the clinical trial and that may be located at the site

of the trial, at the sponsor’s and, or contract research organisation’s

facilities, or at other establishments which the Licensing Authority

sees fit to inspect<

“investigational medicinal product” means a pharmaceutical

form of an active substance or placebo being tested or used as a

reference in a clinical trial, including products already with a

marketing authorisation but used or assembled (formulated or

packaged) in a way different from the authorised form, or when

used for an unauthorised indication, or when used to gain further

information about the authorised form<

“investigator” means a doctor or a person who is suitably

qualified approved by the Licensing Authority for investigations

because of the scientific background and the experience in patient

care such investigation requires. The investigator is responsible

for the conduct of a clinical trial at a trial site. If a trial is conducted

by a team of individuals at a trial site, the investigator is the leader

responsible for the team and may be called the principal

investigator<

“investigator’s brochure” means a compilation of the clinical

and non-clinical data on the investigational medicinal product or

products which are relevant to the study of the product or products

in human subjects<

“multi-centre clinical trial” means a clinical trial conducted

according to a single protocol but at more than one site, and

therefore by more than one investigator, in which the trial sites

may be located in a single Member State, in a number of Member

States and, or in Member States and third countries<

“non-interventional trial” means a study where a medicinal

product is, prescribed in the usual manner in accordance with the

terms of the marketing authorisation. The assignment of the patient

to a particular therapeutic strategy is not decided in advance by a

trial protocol but falls within current practice and the prescription

of the medicine is clearly separated from the decision to include

the patient in the study. No additional diagnostic or monitoring

procedures shall be applied to the patients and epidemiological

methods shall be used for the analysis of collected data<

“protocol” means a document that describes the objective or

objectives, design, methodology, statistical considerations and

organisation of a trial. The term protocol refers to the protocol,

successive versions of the protocol and protocol amendments<

“serious adverse” event or “serious adverse reaction” means

any untoward medical occurrence or effect where any dose results

in death, is life-threatening, requires hospitalisation or prolongation

of existing hospitalisation, results in persistent or significant

disability or incapacity, or is a congenital anomaly or birth defect<

“sponsor” means an individual, company, institution or

organisation or its legal representative who must be established in

the Community and who takes responsibility for the initiation,

management and, or financing of a clinical trial<

“subject” means an individual who participates in a clinical

trial as either a recipient of the investigational medicinal product

or a control<

“unexpected adverse reaction” means an adverse reaction, the

nature or severity of which is not consistent with the relevant

product information (e.g. investigator’s brochure for an

unauthorised investigational product or summary of product

characteristics for an authorised product).

(1) A clinical trial may be undertaken only if, in particular>

(a) the foreseeable risks and inconveniences have been

weighed against the anticipated benefit for the individual trial

subject and other present and future patients. A clinical trial may

be initiated only if the Ethics Committee and, or 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 and

continuously monitored<

(b) the trial subject or, when the person is not able to give

informed consent, his legal representative, has had the opportunity,

in a prior interview with the investigator or a member of the

investigating team, to understand the objectives, risks and

inconveniences of the trial, and the conditions under which it is to

be conducted and has also been informed of his right to withdraw

from the trial at any time by revoking his informed consent without

suffering any detriment<

(c) the rights of the subject to physical and mental integrity,

to privacy and to the protection of the data concerning him in

accordance with the Data Protection Act and any amendments

thereto, are safeguarded<

(d) the trial subject or, when the person is not able to give

informed consent, his legal representative has given his written

consent after being informed of the nature, significance,

implications and risks of the clinical trial. However if the individual

is unable to write, oral consent may be given in the presence of at

least one witness<

(e) provision has been made for insurance or indemnity to

cover the liability of the investigator and sponsor.

(2) It shall be the responsibility of an appropriately named

qualified doctor or, where appropriate, of a named qualified dentist or

other named person with appropriate qualifications as the case may be,

to provide at all times the necessary medical care and make medical

decisions on behalf of the subjects.

(3) The subject shall be provided with a contact point where

he may obtain further information.

Without prejudice to any other relevant restriction, a clinical Clinical trials on

minors.

trial on minors may only be undertaken if>

(a) the informed consent of the parents or legal

representative has been obtained< consent must represent the

minor’s presumed will and may be revoked at any time, without

detriment to the minor<

(b) the minor has received information according to his

capacity of understanding, from staff with experience with minors,

regarding the trial, the risks and the benefits<

(c) the explicit wish of a minor who is capable of forming

an opinion and assessing this information to refuse participation

or to be withdrawn from the clinical trial at any time is given due

consideration by the investigator or, where appropriate, the

principal investigator<

(d) no incentives or financial inducements are given except

agreed compensation<

(e) some direct benefit for the group of patients is expected

from the clinical trial and only where such research is essential to

validate data obtained in clinical trials on persons able to give

informed consent or by other research methods< additionally, such

research should either relate directly to a clinical condition from

which the minor concerned suffers or be of such a nature that it

can only be carried out on minors<

(f) the corresponding scientific guidelines of the Agency

have been followed<

(g) clinical trials have been designed to minimise pain,

discomfort, fear and any other foreseeable risk in relation to the

disease and developmental stage< both the risk threshold and the

degree of distress have to be specially defined and constantly

monitored<

(h) the Ethics Committee, with pediatric expertise or after

taking advice in clinical, ethical and psychosocial problems in the

field of pediatrics, has endorsed the protocol< and

(i) the interests of the patient always prevail over those of

science and society.

(1) For the performance of clinical trials on persons incapable

of giving informed legal consent, all relevant requirements listed for

persons capable of giving such consent shall also apply. Furthermore,

clinical trials on incapacitated adults who have not given and not refused

informed consent before the onset of their incapacity, shall only be

allowed if>

(a) the informed consent of the legal representative has been

obtained< consent must represent the subject’s presumed will and

may be revoked at any time, without detriment to the subject<

(b) the person not able to give informed legal consent has

received information according to his capacity of understanding

regarding the trial, the risks and the benefits<

(c) the explicit wish of a subject who is capable of forming

an opinion and assessing this information to refuse participation

in, or to be withdrawn from, the clinical trial at any time is given

due consideration by the investigator or where appropriate the

principal investigator<

(d) no incentives or financial inducements are given except

agreed compensation<

(e) such research is essential to validate data obtained in

clinical trials on persons able to give informed consent or by other

research methods and relates directly to a life-threatening or

debilitating clinical condition from which the incapacitated adult

concerned suffers<

(f) clinical trials have been designed to minimise pain,

discomfort, fear and any other foreseeable risk in relation to the

disease and developmental stage< both the risk threshold and the

degree of distress shall be specially defined and constantly

monitored<

(g) the Ethics Committee, with expertise in the relevant

disease and the patient population concerned or after taking advice

in clinical, ethical and psychosocial questions in the field of the

relevant disease and patient population concerned, has endorsed

the protocol<

(h) the interests of the patient always prevail over those of

science and society< and

(i) there are grounds for expecting that administering the

medicinal product to be tested will benefit the patient outweighing

the risks or produce no risk at all.

(1) The Licensing Authority shall set up an Ethics Committee Ethics Committee.

which shall give its opinion, before a clinical trial commences, on any

issue requested.

(2) In preparing its opinion, the Ethics Committee shall

consider, in particular>

(a)

the relevance of the clinical trial and the trial design<

(b) whether the evaluation of the anticipated benefits and

risks as required under regulation 4 (1)(a) of these regulations is

satisfactory and whether the conclusions are justified<

(c) the protocol<

(d) the suitability of the investigator and supporting staff<

(e)

the investigator’s brochure<

(f)

the quality of the facilities<

(g) the adequacy and completeness of the written

information to be given and the procedure to be followed for the

purpose of obtaining informed consent and the justification for

the research on persons incapable of giving informed consent as

regards the specific restrictions laid down in regulation 4<

(h) provision for indemnity or compensation in the event

of injury or death attributable to a clinical trial<

(i) any insurance or indemnity to cover the liability of the

investigator and sponsor<

(j) the amounts and, where appropriate, the arrangements

for justly rewarding investigators and compensating trial subjects

and the relevant aspects of any agreement between the sponsor

and the site<

(k) the arrangements for the recruitment of subjects.

(3) (a) The Ethics Committee shall within a maximum of

60 days from the date of receipt of a valid application give its reasoned

opinion to the applicant and the Licensing Authority.

(b) Within the period of examination of the application

for an opinion, the Ethics Committee may send a single request for

information supplementary to that already supplied by the applicant.

The period mentioned in paragraph (a) shall be suspended until receipt

of the supplementary information.

(4) No extension to the 60-day period referred to in sub-

regulation (3) hereof shall be permissible except in the case of trials

involving medicinal products for gene therapy or somatic cell therapy

or medicinal products containing genetically modified organisms. In

this case, an extension of a maximum of 30 days shall be permitted. For

these products, this 90-day period may be extended by a further 90

days in the event of consultation of a group or committee. In the case

of xenogenic cell therapy, there shall be no time limit to the authorisation

period.

(1) In the case of multi-centre clinical trials limited to the

territory of Malta there shall only be in respect of such trials a single

opinion by the Ethics Committee.

(2) In the case of multi-centre clinical trials which are

carried out in more than one Member State simultaneously, a single

opinion shall be given by the Ethics Committee for each Member State

concerned by the clinical trial.

(1) It shall be an offence for the sponsor to start a clinical Commencement of

a clinical trial.

trial in Malta unless the Ethics Committee has issued a favourable

opinion and the Licensing Authority has not informed the sponsor of

any grounds for non-acceptance. The procedures to reach these decisions

can be run in parallel or not, depending on the sponsor.

(2) Before commencing any clinical trial in Malta, the

sponsor shall submit a valid request for authorisation to conduct the

clinical trial to the Licensing Authority.

(3) If the Licensing Authority notifies the sponsor of grounds

for non-acceptance, the sponsor may, on one occasion only, amend the

content of the request referred to in sub-regulation (2) in order to take

due account of the grounds given. If the sponsor fails to amend the

request accordingly, the request shall be considered rejected and the

clinical trial may not commence.

(a) Consideration of a valid request for authorisation by the

Licensing Authority shall be carried out as rapidly as possible and

may not exceed 60 days.

(b) No further extensions to the period referred to in

paragraph (a) hereof shall be permissible except in the case of

trials involving the medicinal products listed in sub-regulation (6),

hereof for which an extension of a maximum of 30 days shall be

permitted. For these products, this 90-day period may be extended

by a further 90 days in the event of consultation of a group or of

the Ethics Committee. In the case of xenogenic cell therapy there

shall be no time limit to the authorisation period.

(c) Within the period of examination of the application the

Licensing Authority may request information supplementary to

that already supplied by the applicant. The period laid down in

paragraphs (a) and (b) hereof shall be suspended until receipt of

the supplementary information.

(5) Without prejudice to sub-regulation (6), written

authorisation may be required before the commencement of clinical

trials for such trials on medicinal products which do not have a marketing

authorisation within the meaning of the Medicines Act, 2003 and any

regulations thereunder, and are referred to in Part A of the Annex to

Regulation (EEC) No 2309#93, and other medicinal products with special

characteristics, such as medicinal products the active ingredient or active

ingredients of which is or are a biological product or biological products

of human or animal origin, or contain biological components of human

or animal origin, or the manufacturing of which requires such

components.

(6) Written authorisation shall be required before

commencing clinical trials involving medicinal products for gene

therapy, somatic cell therapy including xenogenic cell therapy and all

medicinal products containing genetically modified organisms. No gene

therapy trials may be carried out which result in modifications to the

subject’s germ line genetic identity.

(7) This authorisation shall be issued without prejudice to

the application of Council Directives 90#219#EEC of the 23rd April,

1990 on the contained use of genetically modified micro-organisms

and 2001#18#EEC of the 12th March, 2001 on the deliberate release

into the environment of genetically modified organisms.

Amendments may be made to the conduct of a clinical trial

following the procedure described hereinafter>

(a) (i) After the commencement of the clinical trial, the

sponsor may make amendments to the protocol. If those

amendments are substantial and are likely to have an impact on

the safety of the trial subjects or to change the interpretation of the

scientific documents in support of the conduct of the trial, or if

they are otherwise significant, the sponsor shall preferably prior

to implementation notify the Licensing Authority and the competent

authorities of the Member States concerned of the reasons for, and

content of, these amendments and shall inform the Ethics

Committee or committees concerned in accordance with regulations

7 and 9, and where necessary<

(ii) A new informed consent has to be obtained from

the trial subjects if so required by the Ethics Committee<

(b) The Ethics Committee shall, on the basis of the details

referred to in regulation 7 (2) and in accordance with regulation 8,

give an opinion within a maximum of 35 days of the date of receipt

of the proposed amendment in good and due form. If this opinion

is unfavourable, the sponsor may not implement the amendment

to the protocol. If the opinion of the Ethics Committee is favourable

and the Licensing Authority has raised no grounds for non-

acceptance of the abovementioned substantial amendments, the

sponsor shall proceed to conduct the clinical trial following the

amended protocol. Should this not be the case, the sponsor shall

either take account of the grounds for non-acceptance and adapt

the proposed amendment to the protocol accordingly or otherwise

withdraw the proposed amendment<

(c) Without prejudice to sub-regulations (1) and (2) of this

regulation, in the light of the circumstances, notably the occurrence

of any new event relating to the conduct of the trial or the

development of the investigational medicinal product where that

new event is likely to affect the safety of the subjects, the sponsor

and the investigator shall take appropriate urgent safety measures

which include information to the subjects, in order to protect the

subjects against any immediate hazard. The sponsor shall forthwith

inform the Licensing Authority and the competent authorities of

the Member States concerned of those new events and the measures

taken and shall ensure that the Ethics Committee is notified at the

same time< and

(d) Within 90 days of the end of a clinical trial the sponsor

shall notify the Licensing Authority and the competent authorities

of the Member States concerned and the Ethics Committee, that

the clinical trial has ended. If the trial has to be terminated early,

this period shall be reduced to 15 days and the reasons clearly

explained.

(1) When the clinical trial is taking place in Malta, the Exchange of

Licensing Authority shall enter in a European database, accessible only Information.

to the competent authorities of the Member States, the Commission

and the Agency>

(a) extracts from the request for authorisation referred to in

regulation 9 (2)<

(b) any amendments made to the request, as provided for in

regulation 9 (3)<

(c) any amendments made to the protocol, as provided for

in sub-regulations (1) and (2) of regulation 10<

(d) the favourable opinion of the Ethics Committee<

(e)

the declaration of the end of the clinical trial< and

(f) a reference to the inspections carried out on conformity

with good clinical practice.

(2) At the substantiated request of any Member State, the

Agency or the Commission, the Licensing Authority shall supply all

further information concerning the clinical trial in question other than

the data already in the European database.

(1) Where the Licensing Authority has objective grounds

for considering that the conditions in the request for authorisation

referred to in regulation 9 (2) are no longer met or has information

raising doubts about the safety or scientific validity of the clinical trial,

it may suspend or prohibit the clinical trial and shall notify the sponsor

thereof. Before the Licensing Authority reaches its decision it shall,

except where there is imminent risk, ask the sponsor and, or the

investigator for their opinion, to be delivered within one week. The

Licensing Authority shall forthwith inform the other competent

authorities, the Ethics Committee concerned, the Agency and the

Commission of its decision to suspend or prohibit the trial and of the

reasons for the decision.

(2) Where the Licensing Authority has objective grounds

for considering that the sponsor or the investigator or any other person

involved in the conduct of the trial no longer meets the obligations laid

down, it shall forthwith inform him thereof, indicating the course of

action which he must take to remedy this state of affairs. The Licensing

Authority shall forthwith inform the Ethics Committee, the other

competent authorities and the Commission of this course of action.

(1) It shall not be lawful to manufacture or import any

investigational medicinal product unless there is in respect of such an

activity an authorisation issued by the Licensing Authority<

Provided that the authorisation shall be conditional to the carrying

out of such obligations as may be imposed therein. This authorization

shall also be required if the investigational medicinal product or products

is, are intended for export.

(2) (a) The authorisation shall be required for both total

and partial manufacture and for the various processes of dividing up,

packaging or presentation.

(b) However, the Licensing Authority may exclude

from sub-regulation (1) the process of making changes to the packaging

of investigational medicinal products where this process is carried out

by pharmacists or persons authorised to carry out such processes in

hospital, health centre or clinic within which solely such investigational

medicinal products are intended for use.

(3) The holder of the authorisation shall dispose of

investigational medicinal products in terms of the conditions imposed

by the Licensing Authority.

(1) The holder of the authorisation referred to in regulation Manufacture and

import of

13 shall have at his continuous and permanent disposal the services of investigational

at least one qualified person having the qualifications and experience medicinal

products.

defined under the Manufacture of Medicinal Products for Human Use

Regulations 2004, and he shall be responsible for carrying out the

duties specified in sub-regulation (2) hereof..

(2) In addition to his duties defined under the Manufacture

of Medicinal Products for Human Use Regulations, 2004 , the qualified

person shall also, for the purposes of these regulations, be responsible

for ensuring that>

(a) in the case of investigational medicinal products

manufactured in Malta, each batch of medicinal products has been

manufactured and checked in compliance with the principles and

guidelines of Good Manufacturing Practice laid down by the law

in force, the product specification file and the information notified

pursuant to regulation 9 (2) of these regulations<

(b) in the case of investigational medicinal products

manufactured in a third country, each production batch has been

manufactured and checked in accordance with standards of good

manufacturing practice at least equivalent to those laid down by

the law in force , in accordance with the product specification file,

and that each production batch has been checked in accordance

with the information notified pursuant to Regulation 9 (2) of these

Regulations<

(c) in the case of an investigational medicinal product which

is a comparator product from a third country, and which has a

marketing authorisation, where the documentation certifying that

each production batch has been manufactured in conditions at least

equivalent to the standards of good manufacturing practice referred

to above cannot be obtained, each production batch has undergone

all relevant analyses, tests or checks necessary to confirm its quality

in accordance with the information notified pursuant to regulation

9 (2) of these regulations.

(3) Insofar as the provisions laid down in paragraph (a),

(b), or (c) of sub-regulation (2) are complied with, investigational

medicinal products shall not have to undergo any further checks if they

are imported into another Member State together with batch release

certification signed by the qualified person.

(4) In all cases, the qualified person shall certify in a register or

equivalent document that each production batch satisfies the provisions

of this regulation. The said register or equivalent document shall be

kept up to date as operations are carried out and shall remain at the

disposal of the Licensing Authority for a period of five years.

The particulars on the outer packaging of investigational

medicinal products or, where there is no outer packaging, on the

immediate packaging shall appear in at least one of the official languages

of Malta and shall comply with the guidelines of good manufacturing

practice for investigational medicinal products published by the

Commission.

(1) (a) To verify compliance with the provisions on good

clinical and manufacturing practice, the Licensing Authority shall

appoint inspectors who shall on behalf of the Community carry out

medicinal products

inspections and inspect the sites concerned by any clinical trial

and manufacturing

conducted, particularly the trial site or sites, the manufacturing site of

the investigational medicinal product, any laboratory used for analyses

in the clinical trial and, or the sponsor’s premises.

(b) The Licensing Authority shall inform the Agency

of the inspections carried out and the results shall be recognised by all

the other Member States.

(c) These inspections shall be coordinated by the

Agency, within the framework of its powers as provided for in

Regulation (EEC) No 2309#93. A Member State may request assistance

from another Member State in this matter.

(2) After an inspection is performed an inspection report

shall be drawn up. The report shall be made available to the sponsor

while safeguarding confidential aspects. It may be made available to

the other Member States, to the Ethics Committee and to the Agency,

at their reasoned request.

(1) The investigator shall report all serious adverse events

immediately to the sponsor except for those that the protocol or

investigator’s brochure identifies as not requiring immediate reporting.

The immediate report shall be followed by detailed, written reports.

The immediate and follow-up reports shall identify subjects by unique

code numbers assigned to the latter.

(2) Adverse events and, or laboratory abnormalities

identified in the protocol as critical to safety evaluations shall be reported

to the sponsor according to the reporting requirements and within the

time periods specified in the protocol.

(3) For reported death of a subject, the investigator shall

supply the sponsor and the Ethics Committee with any additional

information requested.

(4) The sponsor shall keep detailed records of all adverse

events which are reported to him by the investigator or investigators.

These records shall be submitted to the Member States in whose territory

the clinical trial is being conducted, if they so request.

(1) (a) The sponsor shall ensure that all relevant Notification of

serious adverse

information about suspected serious unexpected adverse reactions that reactions.

are fatal or life-threatening is recorded and reported as soon as possible

to the competent authorities in all the Member States concerned, and to

the Ethics Committee, and in any case no later than seven days after

knowledge by the sponsor of such a case, and that relevant follow-up

information is subsequently communicated within an additional eight

days.

(b) All other suspected serious unexpected adverse

reactions shall be reported to the competent authorities concerned and

to the Ethics Committee concerned as soon as possible but within a

maximum of fifteen days of first knowledge by the sponsor.

(c) The Licensing Authority shall ensure that all

suspected unexpected serious adverse reactions to an investigational

medicinal product which are brought to its attention, shall be recorded.

(d) The sponsor shall also inform all investigators.

(2) Once a year throughout the clinical trial, the sponsor

shall provide the Member States in whose territory the clinical trial is

being conducted and to the Ethics Committee, with a listing of all

suspected serious adverse reactions which have occurred over this period

and a report of the subjectsí safety.

(3) The Licensing Authority shall ensure that all suspected

unexpected serious adverse reactions to an investigational medicinal

product which are brought to its attention are immediately entered in a

European database to which, only the competent authorities of the

Member States, the Agency and the Commission shall have access in

accordance with regulation 11 (1).

(4) The collection, verification and presentation of adverse

event or reaction reports together with the decoding procedures for

unexpected serious adverse reactions shall be carried out in accordance

with the detailed guidance published by the Commission.

(1) These regulations are without prejudice to the civil and

criminal liability of the sponsor or investigator. To this end, the sponsor

or a legal representative of the sponsor must be established in the

Community.

(2) Unless the Licensing Authority has established precise

conditions for exceptional circumstances, investigational medicinal

products and, or the devices used for their administration shall be made

available free of charge by the sponsor to the trial subjects.

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