CLINICAL TRIALS REGULATIONS

SUBSIDIARY LEGISLATION 458.43

CLINICAL TRIALS REGULATIONS

26th November, 2004

LEGAL NOTICE 490 of 2004, as amended by Legal Notice 248 of 2007.

The title of these regulations is the Clinical Trials

Regulations.

(1) These regulations apply Directive 2001/20/EC and

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

trials, in Malta on human subjects involving medicinal products as

defined under the Medicines 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 -

"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 well-being 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;

" s p o n s o r " m e a n s a n i n d i v i d u a l , c o m p a n y, i n s t i t u t i o n o r

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

p r o d u c t i n f o r m a t i o n ( e . g . i n v e s t i g a t o r ’s b r o c h u r e f o r a n

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

CLINICAL TRIALS

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 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

CLINICAL TRIALS

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 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) 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 sixty

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 sixty-day period referred to in

subregulation (3) 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 thirty days

shall be permitted. For these products, this ninety-day period may

be extended by a further ninety 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

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 subregulation (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.

(4)

(a) Consideration of a valid request for authorisation by

the Licensing Authority shall be carried out as rapidly

as possible and may not exceed sixty days.

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

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

trials involving the medicinal products listed in

subregulation (6), for which an extension of a

maximum of thirty days shall be permitted. For these

products, this ninety-day period may be extended by a

further ninety 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) shall be suspended until receipt of the

supplementary information.

(5) Without prejudice to subregulation (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,

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

thirty-five 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 above-

mentioned 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 paragraphs (a) and (b), 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 ninety 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 fifteen days and the reasons

clearly explained.

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

Licensing Authority shall enter in a European database, accessible

only 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 regulation 10(a) and (b);

(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.

(3) By way of derogation from subregulation (1), the Agency

shall make public part of the information on paediatric clinical

trials entered in the European database in accordance with the

provisions of Regulation (EC) No. 1901/2006 of the European

Parliament and of the Council of the 12th December, 2006 on

medicinal products for paediatric use.

(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.

T h e L i c e ns in g A u th o r it y s ha ll f or t h wi t h i nf o r m th e E t h ic s

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

subregulation (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 13 shall have at his continuous and permanent disposal

the services of at least one qualified person having the

qualifications and experience defined under the Manufacture of

Medicinal Products for Human Use Regulations, and he shall be

responsible for carrying out the duties specified in subregulation

(2).

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

Medicinal Products for Human Use Regulations, 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);

(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);

(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).

(3) Insofar as the provisions laid down in subregulation (2)(a),

(b), or (c) 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.

16.(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 inspections and inspect

the sites concerned by any clinical trial 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

t h e s p o n s o r a n d t h e E t h i c s C om m i t t e e w i t h a n y a dd i t i o n a l

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.

18.(1)(a) The sponsor shall ensure that all relevant information

about suspected serious unexpected adverse reactions

that are fatal or life-th reatening 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 subjects’ safety.

(3) The Licensing Authority shall ensure that all suspected

un ex pec ted serio us ad ve rse r eac ti on s to a n in v esti g ati o nal

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.