226/2008 Coll.
DECREE


Dated June 23, 2008

On good clinical practice and detailed conditions of clinical trials of medicinal products


Ministry of Health and Ministry of Agriculture stipulates pursuant to § 114, paragraph
. 2 and to implement § 51 paragraph. 2 point. h), § 52. 6, § 53 paragraph
. 1, 8, 12 and 13, § 54 para. 1, § 55 paragraph. 7-9, § 56 par. 1
point. a) § 56 par. 7, § 57 par. 2, § 58 para. 8, § 59 para. 1, § 60 paragraph
. 2, 4, 5 and 9, § 61 paragraph. 2 point. a) and b), paragraphs 1 and 6, § 61 paragraph. 2
point. c) and § 61 paragraph. 4 point. e) of the Act no. 378/2007 Coll., on pharmaceuticals and
changes in some related laws (Act on Pharmaceuticals)
PART ONE

COMMON PROVISIONS


§ 1
Introductory provisions


(1) This Decree incorporates the relevant European Communities
^ 1) and governs the rules of good clinical practice and detailed conditions of clinical
Evaluation of Medicinal Products (hereinafter referred to as "clinical evaluation
").

(2) For the purposes of this Decree

A) a clinical trial medicinal product moment
when the first trial subjects pursuant to § 51 paragraph. 2 point. g) of the
drugs or his legal representative will sign informed consent
participation in the clinical trial in the Czech Republic;
in emergency situations according to § 52 paragraph. 9 of the Act on Pharmaceuticals the start of implementation
clinical trial shall be the moment when the examiner decides in accordance with the protocol
include the first trial subject to the
clinical evaluation and make a the written record of documentation

B) a clinical trial of a veterinary medicinal product
moment when the clinical trial has been authorized by the Veterinary Institute,

C) completion of clinical trials moment in relation to those
assessment is made in the Czech Republic last measure provided
trial protocol; as such action is not considered
follow-up trial subject;
if the protocol of the clinical evaluation provides the clinical trial differently, it is considered
end of trial time set by the Protocol,

D) all residues of active substances or their metabolites in a persistent
meat or other animal products that have been evaluated
veterinary medicinal product is applied,

E) CRFs paper documents, visual or electronic form
designed to record all of the information
according to the trial protocol forwarded to the sponsor on each trial subject
,

F), contract research organizations, natural or legal person in
contractual relationship with the sponsor to ensure the execution of one or more activities or functions
sponsor relating to the clinical evaluation
,

G) Quality Assurance: all those planned and systematic procedures
to ensure that the clinical trial is conducted and data from clinical trials
are collected, recorded and reported in accordance
with good clinical practice and related legislation

H) quality control procedures and activities within the system to ensure quality assurance
meet the quality
all activities related to the clinical trial,

I) standard operating procedures written detailed implementation methods
individual tasks within a clinical trial aimed
achieve uniform implementation of these acts,

J) the identification code of the subject
unique identifier assigned by the investigator to each trial subject
to prevent disclosure of the identity of the subject,

K) is blinding in a clinical trial means a procedure in which
trial subject, where applicable, the investigator or other persons involved
in the clinical trial have access to information about assigning
IMP individual entities ratings ,

L) significant changes to the trial protocol such change, in which
is likely to affect the safety of trial subjects or changes
scientific hypothesis of the trial.

(3) During the trial radiopharmaceuticals is
provisions of this Decree prejudice Atomic Act and regulations issued for its implementation
^ 2).

§ 2

General principles of good clinical practice

Clinical trials are conducted in accordance with the clinical protocol

Evaluation pursuant to Annex no. 1 hereto (hereinafter "the Protocol") and
protocol amendments.
PART TWO


Clinical evaluation of human medicines
CHAPTER ONE



ETHICS COMMITTEE
The establishment, composition and operation of the ethics committee

§ 3

(1) With the establishment of an ethics committee pursuant to § 53 par. 1 of the Act on Pharmaceuticals
to mean the written appointment of members of the ethics committee. The Ethics Committee is composed
least 5 members with appropriate qualifications and experience to assess and evaluate
clinical trial presented at the scientific, medical and ethical
. Before the appointment of the members of the ethics committee
a medical facility or the Ministry of Health (hereinafter
"person"), which establishes the ethics committee, require the written consent
with membership in the ethics committee and with adherence to the conditions specified in § 53 | || paragraph. 2 point. a) to c) of the Act on Pharmaceuticals.

(2) When appointing new members of the ethics committee after the committee
already been established, the procedure referred to in paragraph 1 accordingly.

(3) The Institute publishes a list of ethics committees in the Czech Republic with
indicating in particular the addresses of the ethics committee
specialization of its members, date of establishment or termination, and information on whether the ethics committee
for multicenter clinical trials and what opinions
the proposed clinical trial was issued by the ethics committee.

(4) If the ethics committee to perform the activities of the ethics committee for multi-centric trials
asks for this determination
Ministry of Health and also provide the Department a copy of the application along with
documentation on the activities of the ethics committee of the Law Pharmaceuticals and
this decree. Department within 60 days shall verify the ethics committee
meets the conditions set, and forward its opinion to the Ministry of Health
. The Ministry of Health will decide within 30 days of receipt of the opinion of the Institute
whether the ethics committee may be designated as
ethics committee for multi-centric trials. This determination
Ministry of Health notified the ethics committee, the medical facility that it
instituted, and the Constitution.

(5) If the medical facility in a clinical trial on which
consent has been given by the ethics committee constituted medical facilities
leading medical equipment will create the conditions to enable this
ethics committee pursued an activity after the entire duration of the clinical evaluation
in this medical device, and if there are changes in its composition
to ensure the continuity of its operations
as well as its rights and obligations.

§ 4

(1) Ethics Committee issues its opinions at meetings, the holding
advance reports in a manner that is described in the written operating procedures
ethics committee pursuant to paragraph 2. The opinion expressed
only the members of the ethics committee who participate in the discussion
clinical trial and are familiar with it. Ethics Committee opinion
can be accepted only if the ethics committee quorum.
For the adoption of the opinion is necessary expression of at least five members of the ethics committee
, including the present member who does not have medical training or professional
scientific qualifications, and a member who is not working
ratio, similar industrial relationship or dependent position to
healthcare facility in which the proposed clinical trial conducted
while it has to be two different people.
Its opinion, the ethics committee will not participate examiner.

(2) The Ethics Committee performs its functions according to written operating procedures, which include mainly


A) determine its composition with the name or names and surnames, and
qualifications of the members and the medical establishment, which establishes,

B) the method of planning meetings and their notification to members of the ethics committee and
leadership meetings

C) assessment of applications for approval of the ethics committee with a clinical
evaluation and implementation of continuous monitoring of the clinical trial,

D) the manner of determining ongoing oversight of clinical trials,

E) accelerated examination and issuance of an opinion on the administrative changes
in an ongoing clinical trial

F) the definition of how to approach the ethics committee report
investigators, information obtained oversight of clinical trials
or acquired in any other way, and defining the way the ethics committee

Informed in writing by the investigator or the healthcare facility
their views on the clinical trial, the reasons for their positions and possible procedures for examining
opinions

G) definition of the method and timing of how ethics committee communicates data required
law on medicines and this Decree investigator or entities
Institute and in the case of the ethics committee for multi-centric trials also
ethics committees if they are established in a clinical trial sites,

H) working practices under other laws, 3) if the Ethics
commission issues its opinions on other areas of biomedical research
than for clinical trials.

(3) The records kept by the ethics committee must be made available upon request
authorities that perform state administration in accordance with § 10 of the Pharmaceuticals Act, and
foreign control authorities in the area of ​​pharmaceuticals.

(4) The written operating procedures, a list of members of the ethics committee and a statement
that the ethics committee was established and operates in accordance with good clinical practice
and related legislation, the ethics committee
request, provide the investigator , authority or authorities referred to in paragraph 3


(5) The proceedings of the ethics committee shall contain the date, hour and place
meetings, the list of members present, a list of other invited those present
main points of discussion, recording opinions, including how
opinion was adopted , a record of the notification to conflicts of interest and signature
least one member of the committee.

(6) In case of dissolution of the ethics committee announces person ethics committee
established or determined, the Institute of whether the activities defunct ethics committee takes
another ethics committee, also communicate a list of ongoing clinical evaluation
over which the defunct ethics committee exercise supervision and how
way to ensure the retention or transfer of documentation defunct
ethics committee.

§ 5

Granting opinion on the conduct of clinical trials

(1) The Ethics Committee expressed opinion on the conduct of clinical trials
on the basis of a written application and assessment of the submitted documentation.
Request for an opinion with the conduct of clinical trials
submit the relevant ethics committee investigator or sponsor.
Papers and documents to be submitted to the ethics committee in the Czech language;
ethics committee may allow the submission of documents and materials in another language.

(2) The Ethics Committee is submitted

A) Protocol and any additions

B) the text of informed consent and other written information provided to subjects
evaluation

C) procedures for the recruitment of subjects, especially advertising,

D) the investigator's brochure containing available data on the safety
IMP

E) detailed information on compensation expenses and compensation for those
evaluation

F) curriculum vitae of the investigator or other document confirming his
qualifications

G) the proposed insurance contract or an insurance contract providing insurance for
investigator and the sponsor according to § 52 paragraph. 3 point. f) of the Act on
Pharmaceuticals,

H) other documents requested by the Ethics Committee.

(3) When assessing compensation, insurance and remuneration ethics committee assesses
always sure

) Compensation or secure indemnity trial subject
case of death or damage to health due to his participation in the clinical evaluation
are secured by the insurance contract

B) liability insurance for the investigator and the sponsor is secured
insurance contract, or whether insurance
investigator or sponsor is not part of their
labor relations

C) compensation does not exceed the expenses incurred by the trial subjects or
investigator in connection with its participation in the clinical trial and whether
reward for examiners is known in advance and fixed, and whether
sponsor submitted together with the application in writing information on the amount of
rewards

D) the amount of remuneration for trial subjects with the nature
clinical evaluation, particularly in relation to those research capacity of which is not subject
direct benefit assessment.

(4) In the case of clinical trials, which is before the inclusion of the entity
evaluation of the clinical trial can get his
informed consent, ethics committee will assess how and in what timeframe, the protocol ensures request
informed consent of the legal guardian

Trial subject or the subject itself, and consider whether it is expedient
conditional inclusion of each individual trial subject
their consent.

(5) gives its opinion to the ethics committee and the sponsor of the Institute within the period prescribed
§ 53 par. 9 and 10 of the Act on Pharmaceuticals.

(6) In case of a multicenter clinical trial, the ethics committee for multi-centric trials
forward its opinion
local ethics committees for each trial site covered by the application
sponsor and the Institute within the period specified in § 53 paragraph. 9 and 10 of the
Pharmaceuticals. The local ethics committee give their opinion
also the sponsor, the relevant ethics committee for multi-centric trials and
Institute in accordance with § 53 par. 9 and 10 of the Act on Pharmaceuticals.

(7) Opinion of the ethics committee contains

A) the identification of assessment of the clinical trial, in particular the name
clinical trial, putting sponsor and trial site
protocol number, the identification number of a European database EudraCT (
hereinafter referred to as "European database") the date of receipt of the application and a list of places
conduct of the trial, to which the ethics committee and expressed
over which supervises

B) a list of ranked documents

C) verdict and its justification,

D) Date of opinion and signature of at least one member of the ethics committee
who is authorized to do so by written procedure in accordance with § 4 para. 2

E) in the case of clinical trials, it is not possible prior to the inclusion
trial subject in a clinical trial to obtain his informed consent
, the ethics committee expressly whether they agree with the procedure
classifying subjects mentioned in Protocol and indicate whether
determines the classification of each trial subject
their consent; if the inclusion of each individual entity
reviews its approval conditional, also indicating the manner in which the investigator
this agreement will entail and how will the relevant ethics committee
statements promptly granted

F) in the event that the opinion issued by the ethics committee for multi
assessment, this fact shall, while indicating a list of places
clinical trial, to which the Commission has launched and over which supervises
.

§ 6

Changes in the conditions of a clinical trial

(1) Notification of significant changes in the protocol according to § 56 par. 1 point. a)
Law on Pharmaceuticals is made in writing with the reasons for the proposal and the revised
relevant parts of the dossier, to which such a change
protocol amendment refers. If it is a protocol amendment
administrative or organizational nature or consisting of change data, which are
as telephone, fax, e-mail address, necessary to ensure cooperation
ethics committees and the Institute sponsor,
the contracting authority shall promptly inform the Institute and the ethics committee that a given clinical trial
express their opinion. Such an amendment is not considered
significant change protocol.

(2) When assessing a protocol amendment and issue an opinion on this
Appendix ethics committee proceed in accordance with § 5 accordingly.

(3) An appeal concurring opinion of the ethics committee according to § 53 paragraph. 13
Law on Pharmaceuticals Announces Ethics Committee in writing without delay
investigator, the sponsor and the Constitution. Except when it is threatened
safety of trial subjects, the ethics committee before it decides
request the opinion of the sponsor or investigator.
Ethics committee for multi-centric trials have before deciding, also request the opinion
local ethics committees in various locations
clinical evaluation.

(4) Withdrawal of consent ethics committee contains

A) the identification of the clinical trial, including its name, putting
sponsor and the clinical trial sites for which an agreement
recalled, protocol number, the identification number of the European
database

B) the grounds for appeal consent

C) measures to end the trial, especially for the transfer of the subject
assessment to another treatment, if the agreement canceled due to threats
safety of trial subjects and if they are not already listed in the log

D) the date of withdrawal of consent and signature of at least one member of the ethics committee
which is based upon a written procedure ethics committee
entitled.
CHAPTER TWO



EXAMINERS
§ 7

The activities of the investigator ^ 4)


(1) Before commencing a clinical trial investigator familiar with
proper use and characteristics of the IMP, as
described in the Protocol and its amendments, in the information package for
investigator and other information materials
provided by the sponsor.

(2) The investigator obtained prior to the inclusion of each trial subject to
study, written informed consent of the subject or his legal representative
; in the case of clinical trials, when before
inclusion of trial subjects in clinical trials can not be
obtain such consent, to proceed according to § 52 paragraph. 9 of the Law on Pharmaceuticals and
under § 5 para. 4th

(3) The investigator, who is in a dependent relationship to the provider of medical devices
^ 5), obtained prior to the commencement of the clinical trial
consent of the operator with its implementation.

(4) The investigator in the context of good clinical practice

A) ensure that all persons involved in the conduct of clinical evaluation
locally were sufficiently experienced and appropriately qualified and
been properly informed about the Protocol and its amendments,
of medicinal preparations and their assignments in connection with
clinical trial

B) keep written records of persons carrying out the tasks entrusted
essential for the conduct of clinical trials,

C) ensures that the subject is given a reasonable
medical care in case of adverse events, including clinically significant laboratory values ​​
deviations from normal values ​​that occurred in connection
participation in the clinical trial subject evaluation

D) if it, or if it is informed about the disease coinciding
trial subject shall inform the trial subject of this fact,

E) if the consent of the subject informs about his participation in the clinical trial
his attending physician

F) shall make reasonable efforts to ascertain the reasons for premature withdrawal
the subject of the trial, without prejudice to the rights
subject.

(5) The investigator or his representative shall keep records of delivering
IMP to the trial site,
on stocks IMP in place
clinical evaluation of the use of each of the subjects and returning unused
IMP authority or by another
disposal methods. These records contain the date, amount, batch
shelf life and code numbers assigned to the investigational medicinal product and
trial subjects. Examiners shall maintain records documenting
proved that the subjects were given doses evaluated
medicinal product listed in the log, and exhibiting handling all
IMPs assumed by the client.

(6) The investigator shall ensure that the IMP
was used solely in accordance with the approved protocol, further ensure awareness
each trial subject about proper use of the evaluated
medicine and at intervals appropriate to the clinical evaluation
checks that each trial subject is following the instructions.

(7) If you are in a clinical trial conducted random selection of subjects
evaluation, examiners will ensure that the identification code will be declassified only
in accordance with the protocol.

(8) If the clinical trial is blinded, the investigator shall immediately inform
sponsor any premature unblinding of the investigational medicinal product
a fact documented.

§ 8

Lessons and informed consent of the subject

(1) The elements of the lessons of the subject and informed consent
are listed in Annex no. 2 hereof. When obtaining informed consent
not be subject evaluation unduly influenced to participate
or continue the clinical trial.

(2) To obtain informed consent in clinical trials
investigator uses and transmits only those trial subjects
informational materials that are approved by the Contracting Authority and approved
the ethics committee or the Institute. These informational materials
update, approve and agree on an whenever there are new
essential information for trial subjects.

(3) The investigator or his delegate before obtaining informed

Provide consent of the subject or his legal representative
opportunity to evaluate the information and the decision to raise queries regarding
clinical trial; These questions will be answered.

(4) The investigator or his delegate will provide the subject or his legal representative
copy of the signed and dated
provided informed consent, as well as a copy of the written information on the clinical evaluation
destined for trial subjects, including possible
any changes and additions. In the event that gave informed consent, except
legal representative also trial subject receives a copy of this consent
and trial subject.

(5) If a clinical trial on minors

A) investigator obtains informed consent according to § 52 paragraph. 6 point. a)
Law on Pharmaceuticals

B) the investigator or his delegate, who has experience working with
minors, provide a minor in the scope of its anticipated capabilities
understanding truthful information about the clinical
assessment, especially about its risks and benefits , possible discomfort and
any difficulties, as well as the authorization at any time from the clinical evaluation
withdraw

C) if permitted capabilities minors, provide it
investigator or a person authorized by written information about the clinical trial in
range corresponding to its stage of development and respects her wishes
regarding participation in the clinical trial,

D) exercise oversight ethics committee at least every six months;
If given the ethics committee has no experience in the field of paediatrics,
provide for the oversight of complicity qualified expert in the field of paediatrics
.

§ 9
Records and reports


(1) Before commencing a clinical trial in a medical facility where
a clinical trial is conducted, it must be persons involved in the clinical trial
available documents referred to in Section I of Annex
no. 3 hereof. This Annex also sets out in Sections II. and III.
Documentation that is kept during and after the clinical evaluation
. These documents must be persons involved in the clinical evaluation
available if the clinical trial is not
otherwise specified.

(2) The investigator shall ensure accurate, complete, legible and timely recording
data in the CRFs and in all messages. Records
investigator in the CRFs are in accordance with the source documents
; any irregularities must be justified.

(3) Any amendment or correction in CRFs refers
date, signature of the person who made the change, and possibly an explanation;
Change or repair connects to the original recording. Changes or repairs performed
investigator, his coworkers permissions changes or corrections
conduct, authority or person authorized by written operating procedures
contracting authority; such change or repair is confirmed
signature of the person who made the change or correction.

(4) Records associated with the clinical trial at the site of
clinical trials are open to the sponsor, the members of the ethics committee and
persons authorized inspection agencies under § 4 para. 3rd

(5) The investigator at the request of the sponsor, the person referred to in § 21 paragraph
. 3 or § 22 paragraph. 2, the ethics committee or the audit offices
allows direct access to all requested records related to the clinical evaluation
.

(6) The investigator shall promptly notify the contracting authority with a written report,
the ethics committee and the medical facility of any changes
significant impact on the conduct of clinical trials, possibly increasing the risk
subjects.

(7) Documentation of a clinical trial investigator stores so that
protect the personal data of the subject by another
legal regulation 6). After completion of the clinical trial investigator
ensure the preservation of source documents in accordance with regulations stipulating
storage of medical records ^ 7) and in accordance with § 56 paragraph
. 7 of the Act on Pharmaceuticals; identification codes
subjects are kept for at least 15 years.

§ 10

Notification of serious adverse events

(1) Notification of serious adverse events contracting entities pursuant to § 58 para. 1
the Pharmaceuticals Act contains information about the trial site, title or name

Sponsor, name and number of the clinical trial protocol identification
trial subject, description of event, name of the product
causing serious adverse event, including the administered dose and route of administration
. If the message is not made in writing, without delay, to confirm
detailed written report. The immediate and potential
subsequent written reports to the trial subjects identified priority
identification code.

(2) Adverse events including laboratory abnormalities that are listed
in the protocol as critical in terms of safety ratings are
reported in accordance with reporting requirements and deadlines specified
sponsor in the protocol.

§ 11

Interruption clinical trial and its termination before performing all tasks set protocol


(1) If a clinical trial is suspended or terminated before performing
all tasks set by the Protocol, the investigator shall forthwith
inform trial subjects and ensure their further treatment and monitoring
health.

(2) If the clinical trial is suspended or terminated under the conditions specified in paragraph
1

A) investigator without the prior consent of the sponsor, the investigator shall immediately inform
Department of the sponsor and the ethics committee, or
ethics committee, which is to reflect the given clinical trial;
Sponsor and the ethics committee or ethics committees, which are a given clinical trial
expressed, provide a detailed written explanation

B) authority or by the Institute, the investigator shall forthwith inform
ethics committee or the ethics committee that the given clinical
ratings reflect that provide a detailed written explanation.

(3) If the clinical trial is interrupted or prematurely terminated in
due to permanent or temporary withdrawal of consent ethics committee
investigator shall immediately inform the medical facility.
CHAPTER THREE



AUTHORITY
§ 12

Basic activities of the contracting authority

(1) The sponsor ensures the implementation and maintenance of systems assurance and quality control
writing and use of processed
standard operating procedures guaranteeing that the clinical trial, including the implementation with him
related laboratory testing and data handling,
will be conducted and the data will be collected, documented, processed, evaluated and reported
in accordance with the protocol, good clinical practice and other legislation
^ 8), to ensure their credibility and accuracy
. In the event that the conduct of the trial involved
contract research organization or other entity, they have a system in place
quality assurance and management like the sponsor.

(2) The contracting authority shall designate the investigator with regard to his qualifications
nature of the clinical trial and equipped medical facility in which to
clinical trial was conducted. Sponsor agree
investigator, medical facilities or other people involved
in clinical trials of a written contract which may be annexed
Protocol, the conditions of implementation of the clinical trial, including its
funding and reimbursement of expenses for treatment in the case of injury
trial subject in connection with his participation in the evaluation
responsibility for negotiations with the ethics committee or the Institute, storage
documentation and reporting and information. Before the contract of
performing clinical trials the sponsor or investigator
medical device protocol and updated set of information for
investigator to become familiar with these documents and other information provided
.

(3) The sponsor shall ensure that examiners

A) clinical trial conducted according to good clinical practice,
relevant legislation, according to a protocol agreed
authority and in accordance with the opinion of the ethics committee

B) observes the procedures for recording and reporting data.

(4) The sponsor shall also ensure that examiners ensure that

A) basic documents relating to clinical trials
will be retained until the sponsor notifies the investigator or the medical
devices that are no longer needed

B) shall be allowed access to medical facilities
conducting a clinical trial to source documents and reports for

Monitoring, audits, inspections Institute or foreign control
authorities.

(5) The sponsor also provides a written contract
clear definition of responsibilities, functions and activities which transmits
contract research organization, if such organization participates
conduct of clinical trials; responsibility for the accuracy and completeness of the data obtained
sponsor remains unaffected.

(6) Before commencing the clinical trial will define, establish and
divides all duties and functions relating to clinical
evaluation and ensures that all the activities associated with
preparation, implementation, evaluation, monitoring and auditing
clinical trial involved only suitably qualified and experienced persons
that these persons are informed of their rights, duties and functions
appropriate and that their qualifications are documented.

(7) The sponsor shall appoint for the trial subjects or their legal representative
appropriately qualified and readily available to the physician providing consultations
about health problems and issues arising in connection with
trial.

(8) The Protocol, the choice of dosage form, dosage and duration, and route of administration
IMP must be supported by sufficient data on
safety and efficacy of non-clinical studies or clinical evaluation
.

(9) If the sponsor violation of the study protocol,
standard operating procedures, good clinical practice, laws or requirements
Institute investigator, medical facilities or other
persons participating in the clinical trial, made immediately
measures to ensure the elimination of deficiencies. If
monitoring or audit revealed serious or persistent breach by
previous sentence on the part of the investigator or the healthcare facility
sponsor terminates participation in the clinical trial investigator or terminate
clinical trial at this point.

(10) If the sponsor is also the investigator, it is subject to even
provisions applicable to the investigator, with the exception of paragraph 4.

(11) In the case of a clinical trial that takes place at multiple locations
sponsor ensures that

A) before the start of the trial they are documented responsibilities
coordinating investigator, if any, and other interested
examiners

B) all examiners receive instructions for compliance with the Protocol,
uniform set of standards for the assessment of clinical and laboratory
results and completing the CRFs,

C) allow communication between investigators,

D) examiners are informed about serious unexpected adverse reactions
IMPs which have occurred in other places
clinical trial

E) in the case of changes in the clinical trial or complete the application on the basis
dissenting opinion of the ethics committee for multi
review for this evaluation, submit a new application for the same
ethics committee for multi-centric trials.

(12) The sponsor provides verification that each trial subject
provided a written consent with direct access to the original medical documentation
to monitor, audit, control and ethics committee
inspection Audit Office in connection with clinical trials.

§ 13

Application for authorization and notification of clinical trials Institute

(1) The application for clinical trial authorization or notification of a clinical evaluation
according to § 55 par. 2 Act on Medications administered sponsor Institute.
In the event that the application or notification submitted by someone other than the sponsor,
submitted with the application or notification shall sponsor for this
person. The various parts of the documentation shall be submitted separately, with
continuously numbered pages and a table of contents. The application shall be accompanied by proof
implementation costs of the assessment or request
announcement.

(2) An application for clinical trial authorization or notification
clinical evaluation shall be submitted in duplicate following documentation:

A) a list of documentation to be submitted

B) Protocol and any amendments containing the information specified in Annex
no. 1 hereof,

C) written information for the investigator, either in the form of a file

Investigator's brochure, which includes information pursuant to Annex no. 4
hereof, or as SPC,

D) written informed consent of the subject or his legal representative
in Czech language, with possible additions

E) written information for trial subjects, including lessons entity
trial or his legal representative in the Czech language

F) form CRFs,

G) whether the clinical trial has already issued some
ethics committee or external audit office
dissenting opinion

H) pharmaceutical data about medicines under Annex
no. 5 hereof,

I) in the case of a multicentric clinical trial information on how
by the ethics committee for multi-centric trials was submitted
an opinion

J) a summary of the study in the Czech language.

Case of clinical trials not aiming to obtain data for
registration or development of a medicinal product and which do not involve
manufacturers of medicinal products or persons commercially associated therewith, may, after consultation with
Institute scope of such documentation as well as its management and preservation
adjusted to reflect the nature of the clinical trial
example regarding the documentation referred to in point h).

(3) In the case of clinical trials subject to authorization and
IMP is a genetically modified organism ^ 9)
submitted together with the application or before issuing a permit, certificate of registration of genetically
modified organism in the List of genetically modified organisms and products
approved for marketing in the Czech Republic
under the law on the use of genetically modified organisms and genetic products
. The application shall be submitted
risk assessment pursuant to another legal regulation 10).

(4) Upon request of the Institute sponsor shall submit other documents
needed to assess the clinical trial, such as information required
State Office for Nuclear Safety in case
clinical trials with radiopharmaceuticals. The Institute may each part
documentation required under paragraph 2, procedures typical for individual
types of clinical trials, and the resulting requirements and documents needed
announce the publication in its information media.

§ 14

Clinical trial management, data collection and record keeping

(1) The sponsor during the clinical trial process
continuously evaluates the clinical trial, the safety of IMP
or critical parameters of efficiency and based on the findings
makes appropriate measures, including changes in the terms of conducting clinical | || ratings or its termination.

(2) The use of electronic or remote system management data on the clinical trial sponsor


A) ensure and document that these electronic systems meet him
set criteria for completeness, accuracy, reliability, and are suitable for the purpose
,

B) maintaining the standard operating procedures for the use of these systems,

C) ensure that the proposed systems allow data changes
such a way that they are documented and entered data are deleted

D) maintain a security system to prevent unauthorized access to data
,

E) maintain a list of persons who are authorized to make data changes,

F) provides adequate backup data

G) ensure blinding of data if the trial is blinded,
and for the duration of blinded clinical trial.

(3) If the data and observations collected during the clinical evaluation
further processed, it must be possible to compare the original data and observations
processed data.

(4) The client uses a unique identifier subjects
permitting identification of all the monitored data of individual entities
evaluation.

(5) The sponsor shall ensure that before and during the trial
preparation and maintenance of documentation according to Annex no. 3 hereto.
Any change in the ownership of the data obtained from clinical trials and
eventual discontinuation of clinical development of the medicinal product
sponsor shall notify the Institute.

(6), Sponsor retains after the end of trial documents

Listed in Annex no. 3 hereto.

(7) The sponsor shall establish written procedures to ensure that changes made
representatives of the contracting authority in CRFs were necessary
documented and approved by the investigator. When making such changes
representative of the sponsor shall provide the investigator
record of changes and repairs.

(8) If a clinical trial where the sponsor is the investigator,
medical facilities, university or the state via its
organizational units and which do not involve manufacturers of medicinal products
or person with him commercial connection, and if so agreed between the sponsor and the Institute
ensures entry of suspected serious
unexpected adverse reactions to a medicinal product to the European database
Department.

§ 15

Information during the trial

(1) After the commencement of clinical trial within 60 days
inform in writing the Institute and the ethics committee for multi-centric trials, if such
Commission on the concerned clinical trial
expressed its opinion, the date and location, where the clinical trial has commenced in
Czech Republic.

(2) The commencement of the clinical trial at the site informs investigator
local ethics committee that this clinical trial released
opinion of this assessment exercise supervision.

(3) Report on the progress of the clinical trial contain the information specified in Annex
no. 6 of this Decree.

(4) The annual safety report in accordance with § 58 para. 8 of the Law on Pharmaceuticals
containing the information specified in Annex no. 7 of the Decree.
The sponsor submits a report annually within 60 days after the conclusion of data collection.

§ 16

Notification of changes in the conditions of a clinical trial

(1) A significant change in terms of the clinical trial, which shall be reported
Institute and the ethics committees that the given clinical trial
express their views are considered additions protocol consisting of substantial changes
documentation, such as changes planned number of subjects
assessment, dose and duration of administration of IMPs,
changes in input and output conditions, evaluated parameters or
sampling procedures and changes IMPs
affecting their quality, such as changes in the composition , manufacturing process, specifications
storage conditions and shelf life. The announcement
changes in the conditions of a clinical trial shall be accompanied by proof of
costs of the assessment of the application.

(2) Major changes in the conditions of a clinical trial that will change
clinical trials, such as changes to the objectives of the clinical trial,
substantial changes to the selection criteria for trial subjects and substantial changes
IMPs, shall be considered as new clinical evaluation.

§ 17

Other information on the investigational medicinal product and clinical trial

Sponsor during the trial immediately it informs in writing
Institute and the ethics committee that the given clinical trial
expressed his opinion about

A) change of domicile or address

B) new findings about the medicinal product

C) actions of foreign states or ethics committees that
related to this clinical trial and may affect the safety of trial subjects
,

D) interruption of clinical trials or early termination of the Czech Republic
; In this case, information shall be provided within 15 days;
This information includes data specified in Annex no. 8 of this Order

E) stopping the development of a medicine.

§ 18

Information about the clinical trial and summary report

(1) Information about the clinical trial in the Czech Republic according to §
56 Para. 5 of the Law on medicines containing the information specified in Annex no. 8
this decree.

(2) The Contracting Authority after the end of the trial
urgently draw up a summary report stating the findings of the clinical evaluation
and their interpretation. The summary report contains the essentials
listed in Annex no. 9 hereof.

§ 19

Rated medicines and labeling

(1) The sponsor ensures that

A) medicinal products are appropriately characterized
stage of their development,

B) for medicinal products are determined by the time, temperature and

Other storage conditions and, if necessary, also designed
procedures for preparation or modification of IMPs before filing
trial subjects and tools for their application, and that
investigational medicinal products are stable throughout their use ,

C) medicinal products are packaged, distributed and stored in
compliance with good distribution practices so that they are demonstrably
protected against contamination and spoilage during transportation and storage

D) medicinal products are prepared, processed,
controlled, stored and dispensed in accordance with good pharmacy practice
, people who provide those activities must meet the technical requirements
^ 11) || |
E) medicinal products are properly labeled in accordance with paragraph 2 and
possibly coded; in the case of a blinded clinical trial
ensures that medicinal products are coded in a manner that allows
blinding and coding system that allows quick identification of
IMP in the event that it requires
state of health of the trial subject; any breach must be blinding
detectable

F) in the case of clinical trials not aiming to obtain data for
registration or development of a medicinal product and which do not involve
manufacturers of medicinal products or persons commercially associated therewith, the scope Labelling of
medicinal products, after consultation with the Department
adjust adequately the nature of the clinical trial.

(2) The designation of both inner and outer packaging of investigational medicinal product provides


A) the name of the sponsor, contract research organization or investigator

B) dosage form, route of administration, dosage amount, in the case of open
clinical trials as well as the name and strength of the medicinal product

C) batch number or code for identifying content

D) reference code allowing identification of the trial
clinical trial, trial site, investigator and sponsor
unless specified elsewhere

E) the trial subject identification number, or the number of treatment and possibly
number of visits,

F) the name of the investigator, if not included in the labeling pursuant to subparagraph a)
or d) instructions for use, that can refer to the information leaflet
or other explanatory document intended for the subject || | evaluation or person administering the IMP,

G) the words "For the purposes of the trial," or other similar wording
,

H) storage conditions,

I) shelf life (use by date expiry date
possibly checking), in the format month and year, said
manner that avoids any ambiguity

J) the text "Keep out of the reach of children" except
medicinal products used in such clinical trial where subjects
assessment is administered IMP supervised
investigator.

In justified cases to ensure the safe use
medicinal product subject to assessment on the inner cover
contain at least data enabling unambiguous identification of contents
packaging.

(3) In case of changing data determining the useful life of the package
IMP marks another label on which
indicate the new date and repeats number identifying the batch. This
designation by the person designated authority in accordance with standard operating procedure
sponsor.

(4) If in the course of clinical development of the medicinal product
made significant changes dosage forms, the sponsor shall ensure
before using the new formulation in clinical trial data on new drug
form needed to assess whether and to what extent the changes will affect
pharmacokinetic profile of the IMP.

(5) The sponsor does not provide the investigator or the healthcare facility
IMP until it received all the necessary documents
locally for trial commencement, especially
a favorable opinion of the ethics committee and the Institute permission to conduct clinical | || ratings.

(6) The sponsor provides

A) keeping records documenting transportation, receipt, storage, retrieval and disposal
IMPs,


B) creating and deploying download
medicinal products and document downloads, especially downloads of malicious
IMP returning IMPs
after the completion of clinical trials and the return of investigational medicinal products with
expired,

C) the creation and application of the treatment assessed
unused medicines, including documentation of the treatment.

(7) The sponsor shall ensure sufficient quantities of the investigational medicinal product for testing
specifications when necessary and keeping
records of analyzes and characteristics of samples of each batch;
Sponsor to ensure the preservation of samples IMP
to evaluate the data obtained in the clinical trial, if it allows
their stability.

§ 20

Change sponsor

Request for change of sponsor contains, besides the formalities required by law
following information and documentation:

A) identification of the clinical trial, of which the change applies

B) the name, surname and address of residence or domicile
outside the Czech Republic, the current sponsor,
case of a natural person or business name or name and registered office,
case of a legal person, and the name, surname and address
place of residence or domicile outside the territory of the Czech Republic,
person to whom the decision is to be transferred, if it is a physical person
or business name or name and registered office, if a legal person
, and the proposed date on which the change has been effected,

C) a statement of the contracting authority and the person to whom the decision is to be transferred
, with notarized signatures that complete and updated
documentation relating to the clinical trial or a copy of this documentation was
access or transmission the person to be transferred
decision, that this documentation corresponds
documentation submitted to the Institute within the application for authorization or notification of a clinical
assessment, including updated documentation submitted to the Institute on the date of the change
,

D) plan to ensure awareness about changing contracting authority within the
clinical trial, including for example addendum to the protocol, the investigator
information, and identification information subjektůmhodnocení
IMPs reflecting the change.
CHAPTER FOUR


MONITORING AND AUDIT OF CLINICAL TRIALS

§ 21

Monitoring of clinical trials

(1) Supervision of clinical trial sponsor ensures monitoring
clinical trial, which primarily verifies that

A) the rights and safety of all trial subjects are not violated,

B) the recorded data are accurate, complete and verifiable on the basis
source documents

C) the clinical trial is being conducted in accordance with the latest approved version
Protocol and its possible amendments, and good clinical practice
related legislation.

(2) The scope and method of monitoring authority is determined with regard to the objective, purpose,
design, complexity, blinding, scope, and target parameters of
clinical trial. Monitoring is usually done before,
during and after the trial.

(3) The Contracting Authority may appoint persons who monitor the clinical trial at the site
clinical trial prior to its commencement, during and at the end
(hereinafter referred to as "Monitor") and ensure synergy sponsor
the investigators. These persons

A) have appropriate qualifications and expertise needed to monitor
clinical trial; their expertise is documented,

B) are familiar with the IMPs, protocol
written informed consent form and other written information provided to subjects
assessment, standard operating procedures
sponsor, good clinical practice and legal regulations relating to
the clinical trial.

(4) When monitoring the trial proceed
monitor according to Annex no. 10 of this Decree.

§ 22
Audit


(1) The audit shall be deemed a systematic and independent contracting authority
assessment activities and documents relating to clinical trials,
intended to determine whether they were carried out activities related to clinical

Evaluation and whether they were recorded, analyzed and accurately reported information
according to the protocol, standard operating procedures, the sponsor, the correct
clinical practice and related legal regulations.

(2) Sponsor determines to audit those that are independent
conducted clinical trials do not ensure the monitoring or control
quality assurance (hereinafter the "auditors");
auditors have proper qualifications and knowledge required to perform audits
clinical evaluation and qualification is documented.

(3) The sponsor shall ensure that audits are carried out in accordance with written, it
developed procedures laid down by the audit scope, method of
audit, the frequency of audits, the form and content of audit reports.

(4) The plan of audits and selected procedures to adapt
nature of the clinical evaluation, particularly with regard to data submitted to the control authorities
number of subjects, type and complexity of the trial, the extent
risk for trial subjects and possibly
shortcomings in adhering to the principles of good clinical practice or legislation identified in
far during the trial.

(5) The observations and findings of the auditors shall be documented and these records are kept
in accordance with Annex no. 3 hereto.

(6) deficiencies are detected in the activities of the investigator, medical
facility or entity with respect to compliance with the Protocol,
standard procedures, good clinical practice and related legal regulations
audited entity shall promptly carry out corrective measures.

(7) If the deficiencies referred to in paragraph 6 are severe or persistent,
contracting authority to terminate the participation of the investigator or the healthcare facility in
clinical trial and immediately inform about this fact
ethics committee and the Institute. In the same way the contracting authority proceeds were
if such deficiencies are detected by monitoring the trial according to § 21 of
PART THREE


CLINICAL EVALUATION OF VETERINARY MEDICINAL PRODUCTS

§ 23


Examiner
The activities of the investigator are:

A) before a clinical trial the sponsor
submit an updated CV or further
declaration of interest statements for confidential treatment of information and other personal data
which are necessary to enable the clinical
evaluation was carried out in accordance with the protocol,

B) ensure that the clinical trial will be conducted in accordance with the protocol and
will be guided by the principles of good clinical practice

C) keep the documentation of the clinical trial
signed and dated copy of the clinical trial protocol including all amendments;
each protocol amendment prepared by the sponsor or investigator must be signed by them
with the date and must specify what was changed, including
justification

D) immediately notify the contracting authority for any deviations from the protocol
clinical trial

E) provide sufficient qualified personnel, including
activities carried out by sub-contracting for the proper conduct of the trial
and adequately inform personnel working on clinical evaluation
or caring for animals and provide him with relevant materials and
information received from the sponsor,

F) to ensure that during the trial the use of appropriate and well-maintained
equipment and appliances, and compliance with standard operating procedures
,

G) ensure informed consent from each animal breeders
prior to their inclusion in a clinical trial on the basis
adequate information concerning participation in a clinical trial

H) to oversee the housing, feeding and care of animals at
clinical evaluation and inform the breeder about animals stabled outside their
permanent housing,

I) documenting all procedures and practices, changes in animal health and
significant environmental changes

J) ensure that the requirements of the Protocol on the use of edible products
derived from food-producing animals, which were filed
rated or control of veterinary medicines and follow
set of measures for the disposal of animals evaluated,

K) immediately inform the sponsor of adverse events

L) ensure that any blinding was violated only in accordance with
protocol and consent of the sponsor,


M) to ensure receipt, storage, distribution and any other
handling of the investigational and control veterinary medicinal product and
keep the relevant records, including the remaining inventory

N) to ensure the administration evaluated and control of veterinary medicinal products
zvířatůmpouze in accordance with the trial protocol

O) to compare the after end of the trial records on the receipt, use and
residues evaluated and control of veterinary medicines and
explain any differences

P) ensure the interruption or termination of the trial
relevant documentation on the safe disposal of the reporting and control
veterinary medicinal product, including the remnants of them medicated feeds, q


) To document unforeseen events that may affect the course
clinical trial, and the measures taken,

R) keep a complete record of all visits, letters and other contacts with
authority, representatives of involved authorities and other persons
relating to organizing, leadership and clinical documentation
evaluation

S) safely stored and protected from damage or destruction of all
clinical trial documentation, including copies of it, and for a period specified
§ 61 paragraph. 4 point. e) of the Act on Pharmaceuticals,

T) provide the Contracting Authority at its request, signed documents
clinical trial or a certified copy of that one copy
retain and possibly participate in drafting the summary report

U) allow monitoring and controlling the quality of audits
clinical assessment and Veterinary Institute to carry out inspections
equipment used by investigators and provide all documentation, including copies
requested to verify compliance with the protocol of the clinical evaluation
.

§ 24
Sponsor


(1) Basic activities of the contracting authority are

A) provide scientifically substantiated information about the efficacy and safety evaluated
veterinary medicinal product on the basis of which it is possible to determine
unequivocal conclusion that there are no reasons why that could not be
clinical trial performed | ||
B) choose investigator guarantee its qualification
ensure its availability throughout the duration of the trial and verify its
agreement to assume responsibility for the clinical evaluation in accordance with
protocol and good clinical practice;

C) appoint a qualified monitor,

D) negotiate where necessary, prepare standard operating procedures
used in the clinical trial

E) to prepare, after consultation with the investigator of the clinical trial protocol
in accordance with the principles of good clinical practice and sign it together with
investigator; together with the examiner also approve and sign all
amendments to the Protocol

F) ensuring that a multicentre trial that everyone
examiners conduct this evaluation in accordance with the Protocol on the basis
uniform system of recording data on a single instruction set
procedures

G) notify the appropriate investigator for the chemical, pharmaceutical, toxicological
, security and other important information that
becomes available during the trial, and to ensure that about them
be informed and Veterinary Institute,

H) record all observed adverse events

I) to ensure proper disposal of all animals in the
clinical trial and all of them derived edible products complies with the requirements laid down
,

J) prepare and maintain records of consignments valued and control
veterinary medicinal product; in the event of interruption or termination of a clinical trial
ensure proper disposal of all their inventory
including them medicated feed

K) to keep documentation of a clinical trial
protect it from damage or destruction for a period specified by law on medicines

L) to ensure the quality and integrity of data from the trial
by audit.

(2) The contracting authority may, if appropriate, to entrust a written agreement
qualified contracting organization providing any or all of its
activities related to the trial.

§ 25
Monitor


The activity monitors are

A) provide an opinion to the contracting authority in fixing the investigator


B) provide the investigator with the necessary information regarding
clinical evaluation, through personal or telephone consultation, or other
form to be agreed with the examiner monitor, always when it
circumstances may require clinical trial

C) make sure that the investigator and staff have sufficient time
space for performing clinical trials, to ensure that the site
clinical evaluation will be adequately equipped space, equipment, and personnel
device and after its duration will be available
required number of animals

D) verify that the personnel working on clinical trials will
informed about all significant facts relating to clinical trials,

E) ensure that the investigator to understand the requirements of clinical trial and
take responsibility for its implementation,

F) work in accordance with the requirements of the client, often enough
visit examiner, before, during and after the clinical
evaluation, compliance with the protocol and good clinical practice

G) ensure that ensure informed consent before adopting
breeder animals in the clinical evaluation

H) ensure that all data are accurately, correctly and completely recorded and
illegible, missing or corrected documentation is explained fully

I) verify that the storage, delivery and inventory control
evaluated and veterinary medicinal products are safe and suitable and unused
evaluation and controlling veterinary medicinal product is returned
authority or disposed of properly, || |
J) to examine primary records and other documentation of the clinical trial
necessary for compliance with the study protocol and check whether the information stored
investigators are complete and accurate,

K) Prepare and maintain complete records of all visits, letters and other
contacts with the investigator, the sponsor and the representatives of all other participating organizations
sufficient detail for tasks that can be performed
investigator and the sponsor,

L) confirm compliance with the principles of good clinical practice investigator
through signed and dated reports on contacts that took place
visits and documented activities during the implementation
clinical trial; at the end of a trial is to submit
authorities.

§ 26
Audit


(1) The Sponsor determines to audit the auditors (§ 22 paragraph. 2)
who have the appropriate skills and knowledge to conduct the audit
clinical evaluation. Qualification of auditors is documented.

(2) The sponsor shall ensure that audits are carried out in accordance with written,
authority developed procedures that define the subject of the audit, the way
its implementation, frequency, form and content of audit reports.

(3) Audit Plan and selected procedures are governed by the meaning and purpose of the clinical evaluation
, the number of animals evaluated, type and complexity of evaluation
risk levels for judging the animals and the existing knowledge about the clinical evaluation
.

(4) If serious shortcomings carried entity shall promptly
corrective action, or terminate the clinical trial. These measures
immediately inform the Veterinary Institute. The same procedure when
finding such shortcomings monitor.

(5) The observations and findings of the auditor and the client are documented
secures confirmation of completed audits.

§ 27

Evaluation of veterinary medicinal products and their labeling

As part of good clinical practice meet
veterinary medicinal products used in clinical trials following conditions

A) are appropriately labeled according to § 19 para. 2 and the words "
Only for use in clinical trials" and "Just for Pets"

B) is determined by the time, temperature and any other conditions of their
storage

C) have adequate stability throughout their use

D) in packaging that protects against contamination and spoilage during
transportation and preservation

E) secures their sufficient quantity for inspection and further
to keep records of analyzes and characteristics
samples of each batch, and until the evaluation of the data obtained during
clinical trial,

F) in the case of blinding trial must
coding system to allow rapid identification of these products;
violations should be detectable


G) is manufactured in accordance with the principles of good manufacturing practice.

§ 28

Application for clinical trial authorization

(1) The application for clinical trial authorization submitted to the Veterinary Institute
sponsor in duplicate, on the form.

(2) The annex to the application form the following information:

A) permission to use experimental animals issued by the competent state authority
under other laws,

B) consent animal breeders,

C) clinical trial protocol, including forms for records
animals evaluated and any amendments prepared in accordance with
requirements specified in Annex no. 11 of this Decree,

D) written information for the investigator, either in the form
summary of product or set of information available on the product data
listed in Annex no. 12 of this decree,

E) written information for breeders in the Czech language, containing information
according to Annex no. 13 of this Decree, f) pharmaceutical data about
veterinary medicinal products in accordance with Annex no. 14 of this Decree,

G) proof of payment of costs

H) whether the clinical trial has already issued a dissenting opinion
foreign supervisory authority.

(3) Upon request of the Veterinary Institute, the sponsor shall submit
other documents necessary for the assessment of the clinical trial.
Any specific requirements for each of the documents are published
in the information media of the Veterinary Institute.

(4) If the assessed veterinary medicinal product
genetically modified organism, shall be submitted together with the application documents
according to § 60 par. 4 point. b) of the Act on Pharmaceuticals.

§ 29

Documents, records and reports

(1) The course of the clinical trial is conducted
documentation referred to in Annex no. 15 of the Decree.

(2) Any amendment or correction of documentation, records reviewed
animals or reports shall be marked with the date and signature, in
if necessary explanation, while the original record must be retained
. Changes or repairs are carried out according to written operating procedures
sponsor.

(3) Documents, records and reports related to clinical trials must be accessible
Contracting Authority, the Veterinary Institute, monitors and
persons performing audit.

(4) Report on the progress of the clinical trial contain the information specified in Annex
no. 16 of this Decree.

§ 30

Notification of serious adverse events

Announcement Veterinary Institute and the sponsor shall contain information on the place
clinical trial, or name, or names and surnames
sponsor, name and number of the clinical trial protocol, identification and description of the animal
reactions name and evaluated
control of veterinary medicinal product, including the administered dose and application method.
Announcement Veterinary Institute shall be made no later than 15 days after the capture
events, in case of death or life-threatening animal information
delivered within 7 days.

§ 31

Interruption and premature termination of the trial

If the clinical trial is interrupted or prematurely terminated, instructor
shall forthwith inform the sponsor, breeder, Veterinary Institute and
respective Regional Veterinary Administration and ensure further treatment and
monitoring the health of animals evaluated.

§ 32

Information about the clinical trial and summary report

(1) Information about the clinical trial sponsor shall submit
Veterinary Institute within 60 days after termination of the trial.

(2) Information on completion of the trial contains the information listed in Annex
no. 17 of this Decree.

(3) The sponsor after the termination of the trial
urgently draw up a summary report, stating the findings of the clinical trial and
their appreciation. The Annual Report contains the elements listed in Annex
no. 18 of this Decree.
PART FOUR

FINAL PROVISIONS


§ 33
Repealing provisions


Repealed:

First Decree no. 472/2000 Coll., on good clinical practice and detailed conditions
clinical trials,

Second Decree no. 301/2003 Coll., amending Decree no. 472/2000 Coll.
on good clinical practice and detailed conditions of clinical
trials.


§ 34
Efficiency


This Decree shall take effect on the first day of the calendar month following the date
publication.


Minister: Minister:
MD. Julínek, MBA vr Mgr. Gandalovič vr
Appendix 1


Clinical trial protocol and protocol amendments

Clinical trial protocol includes at least the following information in the division
said. Information specific to each trial site
may be placed on specific sites mentioned in the protocol or
separate documents. If some of the information contained in other documents
clinical trial, such as file information for
investigator, indicating the protocol appropriate links. The protocol is provided
contents and its title page or pages, states:

A) the Protocol, its identification number and date of issue; All
any amendments must be numbered and dated addendum,

B) the name and address of the sponsor and monitor

C) the name of the person authorized to sign the Protocol and its amendments on behalf
sponsor,

D) the name, address and telephone number of the qualified consultant for
consultation about health problems and issues arising in connection
clinical trial, an established authority for the clinical evaluation
,

E) the names of examiners who are responsible for conducting the clinical evaluation
, addresses and telephone numbers of trial sites,

F) the name, address, telephone number of the investigator or physician who is
responsible for medical decisions at the point of implementation
clinical evaluation

G) the name and address of the test facility performing laboratory
tests and other medical or technical department,
involved in the trial.

First Basic information

The name and description of the IMPs, summary of findings from nonclinical studies
which may have clinical importance, and
findings from clinical trials that are relevant to the study.
Summarize the known and potential risks and benefits for humans. Describe and justify
chosen route of administration, dosage, dosage regimen and duration of administration
IMP. Give the characteristics of the subjects
trials in which the clinical trial is conducted, and
references to literature and data that are associated with clinical trials and
which constitute the basis for a clinical trial.
This introductory section contains a statement that the clinical trial will be conducted in accordance with
protocol, principles of good clinical practice and legislation.

Second The objectives of the clinical trial

A detailed description of the objectives and rationale for the trial.

Third The trial

Indicate the primary and optional secondary objectives pursued during
trial. Describe the type and arrangement
conducted a clinical assessment (eg. Studies double-blind, placebo-controlled, parallel arrangement
) scheme and the procedures and steps, including the measures taken to exclude
bias (eg. The method of randomization or | || blinding). Describe the procedure for the treatment of subjects, including benefits and
dosing schedule, dosage forms, packaging and labeling of medicinal products evaluated
. Indicate the estimated duration of subject participation
evaluation and description of the sequence and duration of each part of the evaluation,
including any follow-up, and the rules and criteria for
completion and discontinuation of participation of individual subjects, parts
or the entire clinical trial. Describe the procedures for reporting
dopočitatelnosti IMPs including possibly
used reference products and placebos, procedures for handling
randomisation codes and decoding. Indicate the data that
recorded directly on the CRFs (ie. Without prior
written or electronic record), and data which are considered
source.

Fourth Choice of subjects and their removal

Give the criteria for inclusion and non-inclusion of premature termination of participation
subjects in the clinical trial.
Procedures for early termination of participation include information about when and how to disable the subject of
clinical trials or stop administration of the medicinal product
, nature and timing of data collected for scrap

Entities, and their follow-up data on whether and how subjects
replaced.

Fifth Treatment of Subjects

A description of the treatment, including the names of all medicines administered,
their dosage, dosage regimen, route of administration and duration of treatment
including follow-up of subjects evaluated for each administered medicine and
group. Give the treatment of permissible prior to or during the trial
(including emergency treatment) and the treatment that is
inadmissible at that time. Describe the procedures for monitoring compliance with all prescribed procedures
trial subjects.

6th Evaluation of efficacy

Indicate efficacy parameters and methods and timing of assessment
recording and analyzing of efficacy parameters.

7th Safety evaluation

Indicate the safety parameters, methods and timing of assessment
recording and analyzing safety parameters,
procedures for assessing, recording and reporting of adverse events
intercurrent disease and the type and duration of follow-up of subjects
after adverse events.

8th Statistics

Describe the statistical methods used, including the timing of planned interim analyzes
. Indicate the planned number of subjects that have
participate in a clinical trial in the case of multi-center trials to
specify the number of subjects projected for each trial site.
Justify the choice of sample size, including reflections or
calculating the statistical significance of the trial. Indicate the level used
significance criteria for the clinical trial, treatment procedure
missing, unused, and false information
procedures for reporting any deviation from the original statistical plan (
any deviations from the original statistical plan must be described and justified in
Protocol, possibly in the summary report). The selection of subjects for evaluation
(eg. All randomized subjects, all subjects
receiving IMP).

9th Direct access to source documents

If there is direct access to source documents secured another
written contract, indicating that investigators and medical devices
allow monitoring of clinical evaluations, audits, implementation
oversight ethics committee, inspection and control authorities access
to source documents.

10th Quality assurance and management

11th Ethical issues

Describe the ethical principles and issues considered in conjunction with clinical evaluation
.

12th Data handling and record keeping

13th Financing and insurance

Unless described in a separate contract, indicating the method of financing and insurance
.

14th Principles publications

If not addressed in a separate agreement, indicating the principles
publishing activity.
Appendix 2


The data presented in the lessons of the subject and written informed consent


The lessons of the subject and the written informed consent was
include the following information:

A) warning that the clinical trial is a research activity,

B) the objectives of the clinical trial,

C) methods of treatment and alert the likelihood of accidental inclusion
into groups differing treatment where
terms of a randomized clinical trial,

D) practices and performances during the trial, including all
invasive procedures,

E) the liability trial subject

F) emphasize those elements of the clinical trial, which has the nature
R

G) the foreseeable risks or inconveniences for trial subjects, including
potential risk to the fetus or nursing child,

H) the expected benefits; trial subject shall be informed even in cases that
no clinical benefit for him is not expected,

I) alternative treatments that may be for treating a subject
ratings are used, their advantages and risks

J) treatment and conditions of compensation, which will be the subject
given in the case of personal injury incurred in connection with its participation in the clinical trial
,

K) the estimated amount of remuneration subject for his participation in the clinical evaluation
,

L) the estimated expenditure of the body in connection with its participation in
clinical trial


M) information on that subject participation in clinical trials is
voluntary and that the subject may refuse to participate or may withdraw from
participation in a clinical trial at any time without penalty or loss of benefits to which
which is otherwise entitled

N) agree that monitors auditors, the ethics committee and
Department will have direct access to the original clinical documentation in order to verify
during clinical trials or data without causing a breach
confidentiality of information about subjects, to the extent permitted under
regulations, and by signing a written informed consent
entity or its authorized legal representative agrees with this fact,

O) agree that the records, which can be identified by the entity
evaluation will be kept confidential and will not be, to the extent guaranteed
legislation, publicly disclosed; should the results of the clinical evaluation
published, the identity of the entity will not be disclosed

P) agree that the trial subject or his legal representative
will be informed if it occurred information that might be relevant for
subject's decision to continue to participate in the clinical evaluation
,

Q) information about people, from which it will be possible to obtain further information regarding
clinical trial and the rights of trial subjects and
information about whom to contact in case of injury in connection with
clinical trials,

R) predictable circumstances and the reasons for which participation may be subject
in the clinical trial discontinued

S) the expected duration of subject participation in clinical trials,

T) the approximate number of subjects participating in a clinical evaluation
.
Appendix 3


The documents that serve to demonstrate compliance with the principles of good clinical practice and
law requirements

I. Documents available prior to the commencement of the clinical trial
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| Number | Document name | Purpose Document Retention | Posted by | Posted in |
| | | | Investigator or | sponsor |
| | | | Healthcare | |
| | | | Equipment | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 1st | The investigator's brochure | proof rating information | X | X |
| | | Product supplied examiner | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 2. | Clinical trial protocol including | proof of consent investigator and | X | X |
| | signed any supplements | sponsor protocol and its | | |
| | the investigator, the sponsor and the Head | any accessories | | |
| | medical devices and forms | | | |
| | for CRFs | | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / third | Information provided by the entity | | | |
| | Rating: | | | |
| | - Written informed consent | substantiate the contents of written informed | X | X |
| | | consent | | |
| | - Instruction and any other | proof that operators | X | X |
| | information | Ratings are poskytoványpřiměřené | | |
| | | information to allow full expression | | |
| | | Informed consent | | |
| | - Materials for the recruitment of subjects | demonstrate that the method is náborusubjektů | X | |
| | | appropriate and not coercive | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 4th | Financial aspects of the clinical trial | proof of financial contract between | X | X |
| | | investigator or medical | | |

| | | equipment and authority | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 5. | Proof of insurance and sponsor | proof under what conditions and in what | X | X |
| | investigator through | amount will be in the case of injury | | |
| | ensuring the compensation of persons | the subject of compensation granted | | |
| | ratings | | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 6th | Signed agreement between the parties | evidence of signed agreements, containing | | |
| | Parties: | For example, the definition of responsibility for | | |
| | | various activities, ensuring access | | |
| | | on documentation, archiving odpovědnostza | | |
| | | documents, dealing with the ethics committee, | | |
| | | reporting and reporting | | |
| | - The investigator / medical | | X | X |
| | equipment and the contracting authority or contractual | | | |
| | research organization | | | |
| | - Between the sponsor and the contract | | X | X |
| | research organization, it seems, if | | | |
| | account | | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 7th | Approval of the ethics committee (dated) | demonstrate that the clinical trial | X | X |
| | all details of the clinical trial | examine the ethics committee and released him | | |
| | communicated to it as presented | approval and identification numbers of versions and data | | |
| | documents | documents | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 8th | The composition of the ethics committee | proof that the ethical Commission to be set up in | X | |
| | | accordance with the principles of Good Clinical | | |
| | | practice | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 9th | Constitution permits or proof of notification | proof of consent Institute and timely | X | X |
| | | announcement | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 10th | CVs and details of qualifications | proof of qualification and eligibility for | X | X |
| | examiner / examiners and any | the trial | | |
| | Collaborators | | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 11th | Normal values ​​/ range for the results | evidence of normal value / or | X | X |
| | tests included in the protocol | range used for testing | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 12th | Proof of the quality of execution | proof of competency equipment | | X |
| | laboratory procedures / tests | and performing the required tests | | |
| | (Certificate of accreditation, established | reliability of results | | |
| | quality control and / or external | | | |
| | quality assessment or other validation) | | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 13. | Sample package labeling assessed | demonstrate compliance with the data requirements for | | X |
| | product | packaging and suitability for instructions foruse | | |
| | | trial subjects | | |

+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 14th | Instructions for handling assessed | proof of instructions required for | X | X |
| | preparations and other materials | ensuring appropriate storage, packaging | | |
| | | issuance and disposal assessed | | |
| | | products and other materials | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 15th | Records of deliveries evaluated | proof supply data, batch numbers and | X | X |
| | products and other materials | the method of delivery and hodnocenýchpřípravků | | |
| | | other materials, enabling | | |
| | | traceability of batches, control | | |
| | | transport conditions and dopočitatelnost | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 16th | Certificates delivered investigational products | proof of identity, purity and content | | X |
| | | investigational products used in | | |
| | | study | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 17th | Decryption processes for the blind | demonstrate how to detect if | X | X |
| | study | necessity identity of the blinded | | |
| | | product without breaking the blinding | | |
| | | investigational products for others | | |
| | | trial subjects | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 18th | Randomization procedure | proof method for randomization | | X |
| | | subjects | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 19th | Monitor messages before commencing | proof that the site is suitable for | | X |
| | clinical trials | clinical trial (may be associated with | | |
| | | item 20) | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +
| I / 20. | Monitor messages at the start | proof that the investigator and the person | X | X |
| | clinical trials | involved in prováděníklinického | | |
| | | Ratings were trained on implementation | | |
| | | clinical trials | | |
+ ------- + --------------------------------------- + - --------------------------------------- + ---------- ----- + ------------- +

II. Documents available during the trial (
other documents in addition to documents mentioned under I.)
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| Number | Document name | Purpose of this document | Posted in | Posted in |
| | | | investigator or | sponsor |
| | | | healthcare | |
| | | | equipment | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 1st | Additions and changes to the file information for the | evidence that the investigator is timely | X | X |
| | investigator | provided new information | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 2. | All changes to the protocol or the | evidence of the changes mentioned documents | X | X |
| | accessories, CRFs, | relating to the clinical trial |, | |
| | written informed consent | carried out during the evaluation | | |

| | instructions and any additional information | | | |
| | and advertising materials | | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 3 system. | Approval of the ethics committee (dated) | evidence that the supplements and changes to assess | X | X |
| | with amendments to the protocol, the changes | Ethics Committee and released them consent; | | |
| | written informed consent | identification of the version numbers and data document | s | |
| | instructions and any additional information | | | |
| | including promotional materials | | | |
| | other potential presented | | | |
| | documents and record of the examination of the course | | | |
| | clinical trial ethics committee | | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 4th | Announcing the changes and amendments to the protocol | proof of timely notification Institute | X | X |
| | other documents of the Institute | | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 5. | CVs and details of qualifications | proof of qualifications and competence to | X | X |
| | new investigators and | conduct of the trial, and | | |
| | Collaborators | medical supervision | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 6th | Additions and changes to normal | evidence of normal value and / or | X | X |
| | value / range of values ​​for the results | the range of tests that were changed in | | |
| | tests included in the protocol | During clinical trials | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 7th | Additions and changes to the proof of the quality | demonstrate that the test results remain | | X |
| | implementation of laboratory | credible throughout the clinical | | |
| | procedures / tests | ratings | | |
| | (Certificate of accreditation, established | | | |
| | quality control and / or external | | | |
| | quality assessment or other validation) | | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 8th | Records of deliveries evaluated | proof data delivery, and číselšarží | X | X |
| | products and other materials | the method of delivery products, and | | |
| | | other materials, enabling | | |
| | | traceability of batches, controls | u | |
| | | transport conditions and dopočitatelnost | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 9th | Certificates newly delivered batches evaluated | proof of identity, purity and content | | X |
| | products | investigational products used in | | |
| | | study | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 10th | Monitor news | evidence of visits and findings in the monitor | | X |
| | | trial site | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 11th | Communications relating to clinical | proof of any agreements or substantial | X | X |
| | evaluation, ie. letters, minutes of | negotiations regarding the clinical | | |
| | meetings, records of phone calls | evaluation, protocol violations, | | |
| | | remedial measures vedenístudie, | | |
| | | reports of adverse events / effects | | |

+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 12th | Signed written informed consents | proof that the consent of the trial subjects | X | |
| | subjects | was obtained in accordance with the principles correctly | s | |
| | | clinical practice and is protokolema data | n | |
| | | before being incorporated entity doklinického | | |
| | | assessment and evaluation of the actors don 't | s | |
| | | oppose the disclosure required | | |
| | | policy | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 13. | Source documents | proof of the existence of entities witness | X | |
| | | the integrity of the data collected involves | | |
| | | original documents relating to | | |
| | | study, and to treat subjects předchorobí | | |
| | | ratings | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 14th | CRFs filled, | proof that the investigator or by | X | X |
| | signed and dated | person authorized and properly recorded | copy | original |
| | | confirmed sighting | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 15th | Documenting repair records | proof of any changes, additions or repaired | at X | X |
|. | subjects | made in CRF zápisuúdaje | copy | original |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 16th | Notification of serious adverse events | evidence of compliance with this ustanovení§ 10 | X | X |
| | captured by the investigators and others | Decree | | |
| | safety information evaluated | | | |
| | medicines supplied | | | |
| | the sponsor | | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 17th | Notification of serious unexpected | evidence of compliance with the law ustanovení§ 58 | | X |
| | adverse reactions authority of the Institute | | | |
| | and the Ethics Committee, and other information | | | |
| | security | | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 18th | Notification of safety information | evidence of compliance with the law ustanovení§ 56 | X | X |
|. | authority investigator | | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 19th | Reports on the progress of the clinical trial | evidence of compliance with this ustanovení§ 15 | X | X |
| | submitted to the ethics committee and the Institute | Decree | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 20. | Procedure for assignment of subjects | proof of identification of bodies | X | X |
| | in the initial selection | included in the initial selection | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 21st | The list of identification codes of entities | proof that the investigator leads confidentiality | X | |
| | ratings | a list of names of all subjects with assigning | | |
| | | identification codes subjects |, | |
| | | which allows zkoušejícímuzjistit | | |
| | | the identity of any entity | | |

+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 22nd | Procedure for assignment of subjects to | evidence of a gradual including entities | X | |
| | clinical trials | by identification codes | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 23rd | Proof of dopočitatelnosti / register | proof that the products were rated | X | X |
| | evaluated products in site | used by the protocol | | |
| | ratings | | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 24th | Specimen signatures | authenticate the signatures and paraffin all persons | X | X |
| | | authorized to write and / or repair | | |
| | | information in the records of the trial subjects | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +
| II / 25th | Records of retained samples | proof marking of stored samples and | X | X |
| | body fluids and tissues, where | the place where they are stored, if it was | | |
| | kept | be repeated analysis | | |
+ ------ + --------------------------------------- + - ------------------------------------- + ------------ ----- + -------------- +

III. Documents held after the end of the trial (
other documents in addition to documents mentioned ad ad I and II)

+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| Number | Document name | Purpose of this document | Posted in | Posted in |
| | | | investigator or | sponsor |
| | | | healthcare | |
| | | | equipment | |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| III / 1st | Proof of dopočitatelnosti / register | proof that the products were rated | X | X |
| | evaluated products in site | used by the protocol, proving | | |
| | ratings | final dopočitatelnosti assessed | | |
| | | products delivered to the trial site, | | |
| | | issued and returned entities | | |
| | | the sponsor | | |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| III / 2. | Documentation disposal evaluated | proof of disposal of unused | X | X |
| | products | evaluated products made | (If | |
| | | authority or on site | liquidated in | |
| | | reviews | trial site) | |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| III / 3rd | For a complete list of identification codes | enable identification of all subjects | X | |
| | subjects | in the study if the | | |
| | | Required follow-up list | | |
| | | is maintained in a confidential manner after | | |
| | | agreed period | | |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| III / 4th | Confirmation by the audit | proof that audited | | X |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| III / 5. | The final report on the termination monitor | proof that they were all executed | | X |
| | clinical trials | activities required for completion | | |
| | | Clinical and basic copy | | |
| | | Documents are stored on respective | | |

| | | points | | |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| III / 6th | Identification method of treatment | documents returned by the sponsor to demonstrate | | X |
| | individual subjects and | All decryption occurring | | |
| | Documentation for decryption | | | |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| III / 7th | Reports on the completion of the clinical | proof of completion of the clinical trial | X | |
| | assessment submitted to the Contracting Authority | and compliance with the provisions of § 56 of the Act | | |
| | Ethics Committee and the Institute | | | |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
| III / 8th | A summary report on the clinical trial | s proof of results and interpretation | | X |
| | | clinical trials | | |
+ ------------------------------------ + ------ + ----- ------------------------------------ + ------------- ----- + -------------- +
Appendix 4


The investigator's brochure

The investigator's brochure contains at least the following data on the investigational medicinal product
(or medicinal products
) in that division. The file has a title page
which states the name of the sponsor, the name of the medicinal product or
identification code, date of issue, or file version number
IB.

First contents

Second A brief summary

At a maximum of two pages provides basic data on the physical,
chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic
, metabolic and clinical characteristics evaluated
medicine.

Third Introduction

Contains the chemical name of the medicinal product, and if
exists, and its international non-proprietary or trade name, content
drugs, pharmacotherapeutic group and the position of the medicinal product
group, justification of the research, the intended use
and indications.

Fourth Physical, chemical and pharmaceutical properties and composition

It is reported description of the active ingredient or active ingredients in the product under review
including placing the chemical (rational and structural)
formula and a brief description of their physical, chemical and pharmaceutical
properties; it shall be followed dosage form and composition including excipients
and instructions for proper storage and handling of IMP
product. Mentions structural similarity with other known drugs.

Fifth Preclinical studies

Comprehensive manner (preferably in tabular form) shall indicate the results
pharmacology, toxicology, pharmacokinetic and metabolic studies
. Mentions the methods used, results and interpretation
findings in relation to the investigational medicinal product and the possible adverse effects
humans, animal species used for nonclinical evaluation
number and sex of animals in each group, the size of the dose in
appropriate conversion (e.g. mg / kg mg / m2), dosing interval, method
administration, duration of administration, the indication of the systemic distribution, length of follow-up after completion
medicinal product. Information about the results include:
nature, frequency and severity or intensity of pharmacological and toxic effects
, time of onset, duration, and reversibility of effects and dependence
responses to the administered dose. In this section, shall be given the most serious
findings from nonclinical studies and their relevance to humans. Compared with
found an effective and non-toxic dose of the same species (
therapeutic index) and the relationship of this information to the proposed dosing in humans.
5.1 Preclinical pharmacology


It contains a summary of the pharmacological properties of the IMP
product or its significant metabolites studied in animals.
Includes studies that assess potential therapeutic effects (eg.
Efficiency model, receptor binding and specificity), and a study evaluating the safety
(eg. A special study to determine additional
pharmacological effects).

5.2 Pharmacokinetics and metabolism of a medicinal product in animals


Give a summary of the pharmacokinetics and biological transformation and distribution
medication for all species. Evaluate the absorption,
local and systemic bioavailability of the drug and its metabolites and
relation to pharmacological and toxicological findings in animal species.
5.3 Toxicology


A summary of the toxicological effects on different species of animals found in
toxicity studies after single and repeated dose, carcinogenicity
studies, special studies (eg. Irritation or sensitization
), reproductive toxicity, and genotoxicity (mutagenicity).

6th Effects in humans

Evaluate the known effects of the investigational medicinal product in humans
including pharmacokinetics, metabolism, pharmacodynamics, dependence
responses to the administered dose, safety, efficacy, and other pharmacological
data. Give the sum of all completed clinical
evaluation and possible further experience from use of the investigational medicinal product
in practice.

6.1 Pharmacokinetics and metabolism of a medicinal product in humans

Summary information on pharmacokinetics IMP
including pharmacokinetics (including metabolism, absorption, links to
plasma proteins, distribution and elimination), bioavailability when
use of the dosage form (absolute and / or relative )
population groups (eg. sex, age, organ dysfunction), interaction (eg.
interactions with other drugs and foods) and other
pharmacokinetic data.

6.2 Safety and efficacy

Summary information on the safety, pharmacodynamics, efficacy, and depending
responses to the administered dose of the investigational medicinal product or its metabolites
obtained in previous clinical trials
, both in healthy volunteers and in patients.
In the case of multiple clinical trials include clear summary
efficacy and safety in individual trials for each indication
among various population groups, summary of adverse reactions from all clinical
evaluation. Indicate significant differences in the nature and incidence of adverse events
all indications and populations, as well
possible risks and side effects that can be expected based on previous experience with
IMP with drugs or relatives.
Indicate notice or need special supervision when using
IMP.

6.3 Experience of the use of the IMP in practice

Indicate the country in which the medicinal product is authorized
or where registration is refused or canceled.
Summarize all relevant information derived from the use in practice (including dosage forms
dosage, route of administration and adverse effects).

7th conclusion

Overall evaluation clinical and clinical data on the investigational medicinal product
obtained from various sources to provide the investigator
interpretation of available data, including the implications for future clinical trials.
Evaluate the published reports on related drugs in order to allow
predict adverse reactions to medicine or other
problems in clinical trials.
Appendix 5


Pharmaceutical data about medicines
submitted with the application for clinical trial authorization

(Includes all products used in the study, including placebo)

First Preparations unregistered

A) the product name, dosage form (or forms), strength (or strength
)

B) the full qualitative and quantitative composition of the product,

C) the name and address of all manufacturers involved in the production of
product, possibly including organizations conducting blinded samples with
their function in the production chain

D) the name and address of the manufacturer performing final batch preparation

E) proof of compliance with conditions of good manufacturing practices throughout the production or preparation
IMP (eg.
Certificate certifying that the conditions of good manufacturing practice issued by the State Audit Office
or proof of continuously conducted state
inspection or permit to manufacture medicinal products for clinical evaluation
indicating the authorized activities,

f) data on the active substance / active substances:

- Chemical name and formula,


- The name and address of manufacturers stating their function in the manufacturing
chain

- Specification of the active substance

- Control analytical methods

- Certificate of analysis at least one batch of drug substance

- In the case of substances not listed in European, American and Japanese
Pharmacopoeia nor in the pharmacopoeia of one of the EU member states further:

- Identification and structure characterization of impurities

- Synthesis scheme indicating all raw materials, solvents and catalysts
,

- Analytical results from batches used for preclinical studies and clinical
previous studies

- Analytical results from batches intended for use in a clinical trial

- Stability data in the form of stability results,

G) a brief description of the production of (general description of the individual degrees
emphasis on the removal or inactivation of viruses in case
products containing substances of biological origin, including an indication of a possible blinding
)

H) the specifications of the product,

I) control of the analytical method for the preparation

J) analytical certificates

K) description of the container

L) stability data product designed shelf life, designed
storage conditions

M) evidence of security against the risk of transmission of BSE / TSE.

The extent of the information presented adapts
stage of development of the medicinal product, taking the early development with emphasis on identifying and
control of the active substance; Final specifications and complete details about
substance and preparation are expected at the end of the whole development;
Account shall be taken of the fact if it is a newly developed substance or a new product containing the substance known
and exposure of subjects with regard to
scope, objectives and anticipated duration of the study.

Second Preparations registered in the Czech Republic or any other country, in the same
dosage form, strength and package size

A) the product name, dosage form (or forms), strength (or strength
), package size,

B) the name of the active substance (or substances), the list of excipients,

C) in the case of registered in the Czech Republic
name and address or registered office of the holder of the marketing authorization or registration number
product in the Czech Republic

D) in the case of registered in another country's name and address or registered office of the Marketing Authorisation
acreage in the country, specifying the year when
the product in that country registered, and the registration number of the product.
Annex 6


Report during the trial

Report during the trial contains the following arrangement
:

A) description of the current clinical trial, a brief description
current course of clinical trial sites and investigators changes
trial in the Czech Republic, the number of patients enrolled in the Czech Republic
,

B) information on the newly discovered properties of medicinal
products, new knowledge about the investigational medicinal products in relation to their
safety and efficacy

C) measures recently adopted in relation to clinical trial carried out, for example
interventions ethics committees in the conduct of clinical trials, foreign interventions
control authorities, any restrictive interventions
sponsor in the course of the trial,

D) information on the audits performed.
Annex 7


Annual Safety Report

Annual Safety Report contains the following information in the following categories:

First The report on the safety of trial subjects in the clinical trial

In this section, the sponsor will provide an integrated analysis of safety and
assessment of risks and benefits. The evaluation should include any new
known information relating to the safety of the medicinal product and its
critical analysis with regard to the possible impact on
trial subjects included in the clinical trial, and this information, which is not
the summary of the IB or
summary of product characteristics. During the evaluation should take into account the following facts
:

A) dispensing medicine, duration of action, duration of treatment,

B) reversibility for the changes,

C) a description of previously reported toxicity in subjects

D) increase the frequency, ie the frequency of toxicity,

E) if changes or overdoses during treatment


F) the possibility of interaction and links to other risk factors

G) any specific information relating to specific population groups
eg. The elderly, children or other defined risk groups

H) positive and negative findings related to pregnancy or breastfeeding
,

I) abuse of medicinal product

J) risks associated with the study or diagnostic procedures during
trial.

The report also significant / support results from non-clinical studies and other
findings on the investigational medicinal product (eg. A spontaneous reports
literary sources) that may affect the safety of subjects, including
measures recommended to minimize risk. At the conclusion of this section is to be noted
detailed balance sheet with reasons why it is or is not necessary
perform the following actions: additions to the Protocol, additions or
update patient information and informed consent, changes
leaflet or the investigator's brochure.
Annual report on security does not replace additions to the protocol.

Second A list of all suspected serious adverse reactions including suspected
unexpected serious adverse events in this study

This section contains a specific list of all reports of suspected serious
side effects that were reported during the trial.
The list contains important information, but it is not necessary to report all the details
usually recorded in individual cases. If there u
one subject to more adverse effects for various reasons, need
is recorded as a separate message, so the body can be put in
list several times. Individual reports are listed in the table separately
according to standard organ system classification and provides data
according to the above recommendations. One list is drawn up for each
clinical trial; may include separate listings for each
IMPs (tested medicine, comparative
medicine placebo), or even lists for different dosage forms, different indications, etc.
.

Third Summary table of suspected serious adverse reactions

Summary table for serious adverse reactions should contain numbers
all reports of individual signs, symptoms or diagnoses for all trial subjects
separately for:

A) every organ system, which the report relates,

B) the various types of adverse reactions

C) each treatment arm of the trial (eg.
Tested medicinal product, placebo, comparative medicine).
Unexpected adverse effects in the table clearly marked.
Appendix 8


Information on termination, interruption or early termination of the clinical evaluation


Information on the clinical trial data contained identical information as
interruption or early termination in the following arrangement:

A) a description proběhlého clinical trial, a list of trial sites and investigators
in the Czech Republic, the total number of subjects in
Czech Republic, a brief description and an overall assessment of the course of study

B) information on the preliminary conclusions of a clinical trial
information on the safety and efficacy parameters monitored, which are available
before the final evaluation and preparation of summary reports
clinical trial, including information about where the
available a summary report after its elaboration

C) actions taken during the trial, information
interventions ethics committees in the conduct of clinical trials, foreign interventions
control authorities, any restrictive interventions sponsor
up during the trial,

D) a statement of the audits performed sponsor.

In the event of interruption or early termination of the trial
contains extra information justification and description of the modus operandi, including
ensure further treatment subjects.
Appendix 9


Summary report on the clinical trial

Summary report on the clinical trial include the following information in the division
said.

First Home page

Here you specify the name of the clinical trial, the name or code of the reporting
medicinal product for which an indication of the clinical trial
focused, very brief description of the clinical trial, unless

Obvious from the name, the name of the sponsor, protocol number, phase of clinical evaluation
starting date, the date of early termination (if the case
account), end date, name of the principal or coordinating investigator or responsible medical
representatives of the sponsor, the name of the responsible representative
sponsor and contact for queries
to the report, a statement of performing clinical trials in accordance with
principles of good clinical practice and the date the summary report.

Second summary

Brief description of the clinical trial indicating its results.

Third The contents of the summary report

Indicate pagination all part of the report, including appendices and tables.

Fourth List of abbreviations and definitions of terms used

Explain the abbreviations and terms essential for understanding the report.

Fifth Ethics conduct of the trial

5.1 Ethics committee: to prove that the clinical trial, including any changes
conducted with the approval of the relevant ethics committees;
accompanied by a list of these committees.

5.2 Duration of the study in accordance with ethical principles: confirms that
study was carried out in accordance with the ethical principles of the Helsinki Declaration.

5.3 Information subject and informed consent to participate in the study
: indicate how and when informed consent was obtained subjects
evaluation; must be accompanied by written information for trial subjects and the pattern
written informed consent.

6th The investigator and the organization of the clinical trial

Briefly describe the division of functions and activities
essential for the design, development, monitoring and evaluation of the study.
Accompanied by a list of investigators at each site evaluation along with their biographies
or information about qualifications; also be accompanied by a similar list of people who
contributed significantly to the trial.
In the case of large-scale clinical trials, giving only the most essential information.

7th Introduction

A brief inclusion of clinical trials in the overall context of development
medicine, indicating the essential characteristics
clinical trial (eg, rationale, objectives, target population,
primary evaluated parameters). Indicate the regulations or recommendations
control authorities, which were taken into account when drawing up the plan
trial.

8th The objectives of the clinical trial

Give the objectives of the clinical trial.

9th Research plan

9.1 Description of the study plan

9.2 Discussion of the study plan, including the selection of the control group

9.3 Selecting populations for clinical trials

9.3.1 Criteria for inclusion

9.3.2 Criteria for exclusion

9.3.3 Exclusion of patients from treatment or assessment

9.4 Medical care of trial subjects

9.4.1 receiving treatment

9.4.2 Identity IMPs

9.4.3 Method stratify patients into treatment groups

9.4.4 Selection of doses in the study

9.4.5 Selection and timing of doses for each patient

Blinding 9.4.6

9.4.7 Previous and concurrent therapy

9.4.8 adherence

9.5 variables characterizing the efficacy and safety

9.5.1 Determining the efficacy and safety flowchart

9.5.2 Suitability measurement methods

9.5.3 Primary efficacy variables characterizing

9.5.4 Measurement of drug concentration

9.6 Quality Assurance data

9.7 Statistical methods planned in the protocol and determine sample size

9.7.1 Statistical and analytical plans

9.7.2 Determining sample size

9.8 Changes in the study process or planned analysis

10th Patients included in the study

10.1 Evidence patients

10.2 Deviations from the protocol

11th Evaluation of efficacy

11.1 Analyzed datasets

11.2 Demographic and other basic characteristics

11.3 Measuring compliance with treatment

11.4 Efficacy Results and patient data in tabular form


11.4.1 Analysis of efficacy

11.4.2 statistical and analytical requirements

11.4.2.1 Editing covariates

11.4.2.2 treatment case of premature termination of participation in the study and missing data


11.4.2.3 Continuous monitoring and analysis of data

11.4.2.4 multicenter study

11.4.2.5 Multiple comparisons (multiplicity)

11.4.2.6 Using the "efficacy subgroups" of patients


11.4.2.7 studies demonstrating equivalence conducted with active control group


11.4.2.8 Analysis of subgroups

11.4.3 Tables for entering data on individual response

11.4.4 Dosage, drug concentrations and relationships responders

11.4.5 Interaction drug - drug and drug - disease

11.4.6 Graphical representation of information derived from data tables for each patient


11.4.7 Summary of the medicine's effectiveness

12th Safety evaluation

12.1 Length of exposure investigational medicinal product

12.2 Adverse events

12.2.1 brief summary of adverse events

12.2.2 Registration of adverse events

12.2.3 Analysis of adverse events

12.2.4 A list of adverse events in patients

03.12 deaths and other serious other significant adverse events

12.3.1 List of deaths and other serious and other major adverse events


12.3.1.1 Deaths

12.3.1.2 Other serious adverse events

12.3.1.3 Other significant adverse events

12.3.2 Case studies - deaths and other serious or significant other adverse events


12.3.3 Analysis and discussion of death and other serious adverse events


12.4 Clinical laboratory evaluation

12.4.1 Laboratory examination of individual patients (16.2.8) and all
abnormal laboratory values ​​(14.3.4)

12.4.2 Evaluation of laboratory parameters

12.4.2.1 Laboratory Values ​​in timing

12.4.2.2 Changes in laboratory values ​​for individual patients

12.4.2.3 Individual Clinically significant abnormalities

12.5 vital signs, physical findings, and other observations related to safety


12.6 Safety evaluation

13th Discussion, a general summary and conclusion

14th Tables and graphs of data from the study, but not included in the text

14.1 Demographics

14.2 Data on the efficacy of the medicinal product

14.3 Safety data

14.3.1 Registration of adverse events

14.3.2 List of deaths and other serious and significant adverse events

14.3.3 Case studies - deaths and other serious and otherwise important adverse events


14.3.4 List of laboratory abnormalities (each patient)

15th List of used materials

16th Appendices

16.1 Information on the study

16.1.1 Protocol and amendments to the Protocol

16.1.2 Specimen CRFs

16.1.3 A list of ethics committees, which are expressed
clinical evaluation, written patient information and informed consent text

16.1.4. List and description of investigators and other important participants
studies, including a brief biography and a summary or the equivalent
practice and experience relevant to the conduct of the study

16.1.5 Signatures of principal or coordinating investigator

16.1.6 list of patients who received the IMP
from specific batches if it was used more than one

16.1.7 Randomisation scheme and codes, enabling the identification of subjects
evaluation and appropriate treatment

16.1.8 audit certificates

16.1.9 Documentation statistical procedures

16 Jan. 10 Documenting laboratory standardization of methods and procedures
quality assurance, if they have been used

16 Jan. 11 publications appearing on the basis of clinical trials
16 January 12
important publications mentioned in the report

2.16 The list of patients

16.2.1 Patients who discontinued clinical trial

16.2.2 Deviations from the protocol

16.2.3 Patients excluded from the efficacy analysis

16.2.4 Demographics

16.2.5 Compliance or data on drug concentration on if the available


16.2.6 data about the drug effect on individual patients

16.2.7 A list of adverse events each patient

16.2.8 listing of individual laboratory results for each patient
if required Audit Office

16.3 Individual CRFs

16.3.1 CRFs of deaths, other serious adverse events
and exclusion due to adverse events

16.3.2 Other CRFs submitted

16.4 List of individual patient data
Annex 10


Activity monitor clinical trials

First Monitor examines the place of clinical trials before its start in

During and after its completion.

Second Monitor provides in accordance with the requirements of the client that
clinical evaluation is properly performed and documented through
following activities related to the clinical trial sites and its implementation
:

A) connection between the sponsor and the investigator,

B) verify whether in relation to the clinical trial

First the investigator has adequate qualifications and conditions for implementing
clinical trial

Second facilities, including laboratories, equipment and personnel are adequate
for safe and proper conduct of the trial,

C) verifies the IMP whether

First storage times and conditions are acceptable and whether stocks are in
during the evaluation sufficient

Second medicinal products are granted only to entities which
to be administered and in dose protocol

Third trial subjects are properly instructed on proper use,
handling, storage and return of IMPs,

Fourth acceptance, use and return of medicinal products in
trial site is adequately controlled and documented

Fifth Treatment of unused IMPs in place
assessment in accordance with the relevant regulations and requirements
sponsor,

D) verify that the investigator follows the approved protocol and possibly
approved all its amendments,

E) verify obtained written informed consent of the subject
evaluation before its inclusion in the clinical trial

F) provides that examiners will receive the latest version of the file information for
investigator, all the documents and all the elements needed for
conduct of the trial properly and in accordance with the law,

G) ensures that the investigator and his collaborators are duly informed about
clinical trial

H) verify whether the investigator and his collaborators performed within clinical


I) specified evaluation function in accordance with the protocol
or written agreement between the sponsor and the investigator / health facilities, and that
not transfer these functions to unauthorized persons,

J) verifies whether the investigator classified in clinical trials only
eligible entities and follows the recruitment of subjects in a trial,

A) verify source documents or other records from clinical
ratings are accurate, complete, timely and properly stored,

L) verifies that the investigator provides all the required reports,
announcement, applications and documents and that these documents are accurate, complete, legible
, dated and identifiable by the trial
and whether they are drawn time

M) checks and mutually compares the accuracy and completeness of data in
CRFs, source documents and other records
relating to the clinical trial.

Third Monitor verifies for example that:

A) the data required by the protocol are correctly recorded in the records
subject and are consistent with the source documents

B) any changes in dosage or treatments are properly documented for
each trial subject

C) adverse events, complementary or concomitant therapy and concomitant disease
are recorded on the CRFs in accordance with
protocol

D) in CRFs are also recorded
inspection visits by the agency did not do evaluation tests, which were conducted
and examinations that have not been implemented,

E) all removal and resignation of enrolled subjects from the clinical evaluation
are recorded and explained in the records of subjects
evaluation.

Fourth Monitor informs the investigator for any error, omission or
illegible entries in the records of the subject and ensure that
appropriate corrections, additions or cancellation of registration are made, labeled
date, explained and signed by the investigator or || | collaborator in the trial, which is authorized to carry
changes in CRFs for the investigator. This authorization
documented.

Fifth Monitor verifies whether all adverse events are properly reported
in terms of required clinical practice and protocol
ethics committee, the sponsor and the relevant legislation.


6th Monitor examines whether the investigator keeps basic documents.

7th Monitor tells the investigator deviations from the protocol,
standard operating procedures, good clinical practice and regulatory requirements
authorities and take measures to prevent recurrence of the detected deviations
.

8th Monitor progressing according to written standard operating procedures set
authority to monitor the clinical trial.

9th Monitor the sponsor shall submit a written report on each visit place
evaluation and communication related to the clinical trial, which includes
:

A) the date, site evaluation, monitor name and the name of the investigator or other
contacted people

B) a summary of what the monitor checked the monitor and statements concerning the significant findings
, deviations and deficiencies, conclusions, or carried
measures planned or recommended measures to ensure compliance.

10th Message Monitor is assessed by the contracting authority, and this assessment, as well as
consideration of the report, the authority documents.
Annex 11


Protocol clinical trial of veterinary medicinal products

Protocol should include the following information:

First Study name.

Second Identification study, which includes protocol number, protocol status
study (ie. Design, final, Appendix) and dated version of the protocol.
These data are to be placed on the front page.

Third Participants study involving investigator, sponsor and all other
collaborators responsible for the main aspects of the study including their
skills, professional profile, addresses, or telephone numbers.
Other data.

Fourth Identify the locations where they are known at the time of preparation protocol.

Fifth Objective / purpose of the study.

6th Rationale describing all relevant information if they are to
understanding of the purpose of the study (available preclinical or clinical data) and
justifying the conduct of the study.

7th Schedule (plan) study schedule showing the key moments of the study as
start date period in which they are administered drugs (evaluation, control
) follow-up period of administration, withdrawal period and end date
study.

8th The study design including overall study design (eg.
Clinical field study of the effectiveness of placebo controls or random arrangement
into blocks versus the positive control, blind study)
method of random selection procedures including accepted the division of animals into groups including || | justification, scope and methods of blinding and other techniques reducing
bias procedures used.

9th Selection and identification of animals showing specification of their resources
identification numbers, further details such as species, age, sex, breed
category, weight, physiological status and prognostic factors.

10th Criteria for inclusion / exclusion criteria for removal after
inclusion in the study, specifying that activity.

11th Handling and housing, including the method of housing animals
study, spatial conditions for the animals, climatic conditions
(heating, cooling, ventilation), admissible and inadmissible
veterinary care and treatment, method of feeding and watering, including preparation
feed and storage, inventory, availability and quality of water.

12th Animal feed showing the nutritional needs of animals and monitored
preparing fodder in accordance with these requirements, its composition (feed, mineral and vitamin supplements
, other additives) with the calculation of nutritional values ​​for
all feed used in the study, procedures
feed sampling and subsequent analysis of the determination of the criteria for determining whether
feed meets the specified requirements, feeding programs and records of present and
rejected by the amount of feed.

13th Evaluation and control of their product and its identification in order
it possible to clearly determine their composition, giving instructions for eventually.
Further handling, packaging specifications and storage conditions.
If the product is administered in feed or water, the procedure for determining the concentration
including the method used for sampling and testing methodologies
. Inspection device to identify generic or trade
name, dosage form, composition, lot number and expiration date and
store and use it in accordance with the package insert.

14th Assessed the application and control of the ground

Dosage used, describing the batch mode (the mode of application, instead of
, dose and frequency of administration) specifications
objective criteria for the potential use of concomitant therapy, describing
measures taken to ensure the safety of personnel with these zacházejícího
preparations, stating the measures to ensure the application of these products in
accordance with the study protocol.

15th Disposal, describing the method of disposal of animals
products derived from animals and debris tracked products
after the end of the study, indicating the handling of animals excluded from the study and
setting terms and conditions for the use of edible products of food-producing animals
.

16th Evaluation of efficacy in describing the effects to be achieved,
way of monitoring and recording, specifying the timing and frequency
observation, stating analyzes and tests, including the time and intervals
sampling and malting samples, defining the evaluation system
necessary for the objective capturing target response observed in animals
and to evaluate clinical response and defining methods for evaluating
and calculate the effects of the investigational product.

17th Statistics / biometrics describing in detail the statistical methods
evaluate the efficacy of the product, and test hypotheses
defined parameters, level of significance and statistical model.

18th Records indicating the procedures for recording, processing, handling and storage
primary data and other required documents.

19th Adverse events with a description of the procedures for tracking animals
with sufficient frequency to capture adverse events, indicating
appropriate action when they occur, including possible violations of blinding
in order to appropriate treatment, noting the documentation and notification
authorities.

20th Protocol amendments giving all standard operating procedures
in the study related to the management, monitoring and records with
copies of all forms and records used in the study, and the inclusion of all relevant amendments
(information provided by the breeder, instructions | || staff).

21st Changes to the study protocol with providing instructions for the preparation of amendments
records and deviations from protocol.

22nd References indicating the citations of relevant literature.
Annex 12


The investigator's brochure

In the investigator's brochure shall contain the following information:

First Name and title sponsor of the IMP,

Second chemical name of the medicinal product, and if there is,
its international non-proprietary or trade name, content of active substances
pharmacotherapeutic group

Third physical, chemical, and pharmaceutical properties and composition stating
description of the active substances contained in the reporting of chemical
(rational and structural) formula and a brief description of their
physical, chemical, and pharmaceutical properties; it shall be followed
dosage form and composition of the excipients and instructions for proper storage and handling
IMP,

Fourth nonclinical studies on results of pharmacological, toxicological
, pharmacodynamic, pharmacokinetic, metabolic and residual
studies, including the methodologies
evaluation and interpretation of findings in relation to the investigational medicinal product and the possible adverse effects on
Rated animal , humans and the environment,
compared to determine an effective dose and a toxic dose to the proposed
. All results must be reliable and valid generally.
Clinicians to be given information about the therapeutic potential
product and the hazards associated with its use.
In some cases it may be necessary to mention the metabolites default folder if
pose a risk in terms of residues. The vehicle used in the pharmaceutical
first interest is treated as an active ingredient

Fifth pharmacological indicators indicate the basic mechanisms by which applies
IMP their therapeutic effects
overall pharmacological assessment of the active ingredient, with special reference to
possibility of side effects, including route of administration, formulation, etc
. For combinations to indicate possible effects on individual components. Furthermore
shall include data on the pharmacokinetics (including metabolism, absorption, bonds

To plasma proteins, distribution and elimination), bioavailability
using the dosage form (absolute or relative), figures from different
the groups of animals (eg. By sex, age, organ dysfunction
), interactions (e.g., interactions with other preparations or food effect
) and optionally other pharmacokinetic data,

6th of toxicological indicators are indicating a single dose toxicity, repeated dose toxicity
tolerance for the evaluated species, influence
reproductive toxicity including teratogenic effects, mutagenicity and carcinogenicity
, immunotoxicity, microbiological properties of residues affect
on man and the environment,

7th Residual study demonstrating to what extent and for how long
residues persist medicinal product or its metabolites
in the tissues of the treated animal or foodstuffs that are from this animal
obtained. On this basis, in order to prevent any
risk to consumer health, quality of food from treated animals, or difficulties in
food industry provides real protection
deadlines that must be dodržovat.Souhrnným way shall
metabolism and kinetics of residues (pharmacokinetics and depletion)
.Zmíní the analytical method for the detection of residues that have a sensitivity
that allow you to establish with certainty violation
officially established maximum residue limits

8th IMP effects on animals in all
completed clinical trials and any other experience
use of the IMP in practice. It shall furthermore
all safety information and depending on the amount of the dose
medicinal product or its metabolites, which were
obtained in previous trials (healthy or sick animals
) enter summary of adverse reactions from all
clinical trials, potential risks and side effects that can
expected based on prior experience with the investigational medicinal product or
with drugs and related data on the prevalence of resistant organisms
. Indicate notice or need special supervision while
use of the IMP,

9th the experience of the use of the IMP in practice
countries where the IMP is authorized or
which registration is refused or canceled.
Summarize all relevant information gained from use in practice (including the dosage
form, dosage, route of administration and adverse effects)

10th In conclusion the overall assessment of the non-clinical and clinical data on the investigational medicinal product
obtained from various sources to provide
investigator with the interpretation of the data available
implications for future clinical trials. Evaluate the published reports on related
drugs in order to anticipate the possibility of adverse reactions assessed
medicine or other problems in clinical trials.
Annex 13


File information for breeders

The file information for breeders states:

First Name of product and contracting,

Second purpose and objective of the clinical trial,

Third range attempt, including the numbers of animals involved, the number of applications and
route of administration of the IMP and the total duration
clinical trial

Fourth monitored laboratory and clinical indicators, including the frequency of their
monitoring

Fifth The withdrawal period, if required,

6th breeders duties before, during and after the clinical evaluation
(participation in the selection of animals, animal hygiene
security conditions, mode of feeding and watering, monitoring animal health,
keeping appropriate records, etc.)

7th the need for immediate reporting of variations in health status and other
adverse side effects of the investigator.
Annex 14


Pharmaceutical data about veterinary medicines

(Applies to all products used in the study, including placebo)

First Preparations unregistered

A) the name, dosage form, strength,

B) complete formulation,

C) the names and addresses of the manufacturers involved in its production, eventually.
Organizations conducting blinded samples of their function in
manufacturing process

D) evidence of compliance with the conditions of good manufacturing practices throughout the

Production or preparation IMP

E) data on the active substance (s): the chemical name and formula,
name and address of the manufacturer, quality criteria in the case of a new substance, ie.
Substances are not contained in the product in the world have already registered, proof of identity and
structure, control analytical methods, stability data
characterization batches used for preclinical studies and intended for use in
clinical trial

F) quality criteria for the product

G) a brief description of the production,

H) control of analytical methods for drugs administered in the feed and methods
determination of the active substance in the feed,

I) stability data product designed shelf life, designed
storage conditions.

The extent of the information presented adapts stage drug development,
while the early development with emphasis on identifying and controlling
active substance. Final specifications and complete details about the substance and
product is expected at the end of the whole development. Account shall be taken of the fact
case of substance newly developed or a new product containing a substance
known and exposure valued animal with regard to the scope, objectives and
anticipated duration of the study.

Second Preparations registered in the Czech Republic or any other country, in the same
dosage form, strength and package size.

A) the name of the dosage form, strength, pack size,

B) the name of the active substance (s)

C) For products registered in the Czech Republic name, address or registered office
MAH or registration number of the product

D) For products registered in other countries name, address or registered office of the Marketing Authorisation
acreage in the country with the year of registration and registration number
.
Annex 15


Documents available for clinical trials of veterinary medicinal products


First Documents available prior to the commencement of the trial:

A) approved "Project trial" under special legislation,

B) the investigator's brochure,

C) clinical trial protocol, including any supplements
signed by the investigator and the sponsor and the forms for records of assessed
animals

D) information provided by a holder (lessons and any other
information, advertising materials)

E) the financial aspects of clinical trial

F) proof of insurance animal

G) agreements signed between the parties,

H) biographies and information on the qualifications of the investigator / investigators and potential
Collaborators

I) evidence concerning the quality of laboratory procedures / tests
(certificate of accreditation, established quality control and / or external
quality assessment or other validation)

J) sample labeling packaging investigational product labeled "
Only for use in clinical trials" and "Just for Pets"

K) instructions for handling the evaluated products and other materials

L) records of deliveries of products, and other materials

M) certificates delivered investigational products,

N) procedures for decryption blind study

O) randomization procedure.

Second Documents available during the trial:

A) additions and changes to the IB,

B) any changes to the protocol, if its accessories, records reviewed
animal breeders agree with the changes

C) notification of changes to the protocol and changes in other documents
Veterinary Institute

D) biographies and information on the qualifications of new examiners and
Collaborators

E) additions and changes to documents concerning the quality of laboratory
procedures / tests (certificate of accreditation, established quality control or other
validation)

F) records of deliveries of products, and other materials

G) attests newly delivered batches of investigational products,

H) communications relating to clinical trials (letters, minutes of meetings
, records of telephone calls)

I) source documents

J) records of the animals evaluated,

K) documenting corrections in the records of the evaluated animals

L) a record of all captured adverse effects

M) reports on the progress of clinical trials submitted to the Veterinary
Institute

N) a record of the method of identification of animals evaluated,

O) the procedure for classifying animals in the clinical evaluation


P) proof of dopočitatelnosti / register of assessed products in place
evaluation

Q) specimen signatures

R) records the activity monitor,

S) records of retained samples of body fluids and tissues, where
retained.

Third Documents available after the completion of the clinical trial:

A) evidence of dopočitatelnosti / register of assessed products in place
evaluation

B) a record of the method of identification of animals evaluated,

C) confirmation by the audit, if it was carried out,

D) identification method for the treatment of individual animals evaluated and
documentation decoding,

E) reports on the completion of clinical trials submitted to the investigator or the authority
Veterinary Institute

F) document on disposal of unused,

G) a summary report on the clinical trial.
Appendix 16


Report during the trial of veterinary medicinal products

This report contains the following information:

A) a brief description of the current course evaluations, changes
investigators and trial sites and the number of enrolled animals

B) information on the newly discovered properties
medicinal products, particularly summary serious unexpected adverse reactions
drugs from all points of the trial, new findings on the evaluated
medicinal products in relation to their effectiveness and safety for
rated animal safety of animal products intended for human
consumption and environmental impact,

C) measures recently adopted in relation to that implemented clinical trials
interventions during the trial, including their agents,

D) information about the activity monitor,

E) a statement of the audits performed.
Annex 17


Information on completion of the clinical trials of veterinary medicinal products


This information includes the following information:

A) a description proběhlého clinical trials, particularly the list
investigators and trial sites, the total number of animals evaluated, and a brief description
overall assessment during the study

B) information on the preliminary conclusions of the clinical trial, especially
efficacy and safety rated for animal
safety of animal products intended for human consumption and environmental impact, which are available
before the final evaluation and
draw up a summary report on the clinical trial

C) actions taken during the trial, particularly interventions
During clinical trials, including an indication of their authors,

D) a report on the activity monitor,

E) a statement of the audits performed.
Annex 18


Summary report of the study

First A summary report of the study is complete and comprehensive description of the study authored
after its completion. Includes description of materials and methods
presentation and evaluation of results, statistical analysis and critical clinical, scientific and statistical evaluation
. Prepares for any studies in which animals are treated
trial treatment, regardless if it was
studies completed as planned.

Second Authorship. The summary report can be prepared by the contracting authority
investigator for contracting authorities or in cooperation of both.
All individuals involved in its preparation should be considered authors.
If the investigator waive authorship, authors should provide all the necessary documentation
from where he conducted the study and signed and dated
document attached to the report describing
provided documentation and verifying the accuracy and completeness of the documents. Authors must report dated and signed
knowing that their signatures to guarantee that all data are
accordance with the study protocol, the principles of good clinical practice if necessary.
Other requirements that all opinions are accurate and complete
presentation of the study results and are fully supported by documentation study.

Third The contents of the summary report of the study:

Fourth Name and identification studies.

Fifth Objectives of the study.

6th Titles, names, qualifications and functions of all study participants.

7th Putting the study site.

8th Key figures of the study.

9th Materials and Methods used in the study.

10th Selection and identification of animals, including their detailed characteristics
history, previous diagnosis or treatment prescribed.
preventive measures and detailed criteria for inclusion and exclusion of animals from
studies with detailed information on all culled animals.


11th Handling and stabling with a detailed description of housing,
composition of feed additives used and details of any concomitant therapy
before, during and after the application of the reporting and control
product and, if necessary. interactions.

12th Destruction of animals, stating their review and disposal
edible products.

13th Treatment indicating the exact composition of the investigational product, including
strength, purity and lot or code, dosage, method and frequency of application or
. Special measures detailed data about
control of the justification for his choice, duration of treatment and observation period and
method of disposal of the remaining products.

14th Procedures studies showing the detailed description of the methods used including
methods for determination of concentrations in feed, water, body fluids and tissues
(if the subject).

15th Statistical methods indicating their detailed description.

16th Results and evaluation of specifying detailed description of the results
studies, whether favorable or unfavorable, including the relevant tables or.
Graphs and reasonable conclusions based on each individual case
or treatment group.

17th Administrative and verification tasks including a description of the procedures used to
records, processing, handling and storage of primary
data and other documentation of the study, a description of all deviations
Protocol and its amendments, including an assessment of their impact on the outcomes of the study, description || | circumstances that might affect the quality and integrity of data, a detailed description of all of the captured
adverse events, including the measures taken
and commissioning location of all documents study.

18th Additional information may be included in the reports as attachments:
study protocol, data monitoring visits, certification audits
additional reports (analytical, statistical, etc.), Copies of documentation
study.

19th Appendices to the report as rectification, erasure, other arrangements should be in the form of copyright
Appendix with a clear indication of which parts of it
concerns and signed and dated by the author. Minor mistakes (typos)
can be marked directly in the report in connection with the signature or initials of the author.

1) Directive of the European Parliament and Council Directive 2001/20 / EC of 4 April
2001 on the approximation of the laws and regulations of the Member States
relating to the implementation of good clinical practice in the conduct of clinical trials on human medicinal
products, as amended by Regulation (EC) no. 1901/2006
.

Commission Directive 2005/28 / EC of 9 April 2005 laying down
principles and detailed guidelines for good clinical practice as regards
evaluated for human medicines and also the requirements for authorization of the manufacturing or
importation of such products.

2) For example, Decree no. 307/2002 Coll., On radiation protection, as amended
Decree no. 499/2005 Coll.

3) For example, Act no. 123/2000 Coll., On medical devices and
amending certain related laws, as amended.

4) § 52 par. 2 Act no. 378/2007 Coll., On pharmaceuticals and amending
some related laws (Act on Pharmaceuticals).

5) § 6 para. 1 point. c) Act no. 378/2007 Coll.

6) Act no. 101/2000 Coll., On protection of personal data and amending certain laws
, as amended.

7) § 67b of the Act no. 20/1966 Coll., On Public Health Care, as amended
.

Decree no. 385/2006 Coll., On medical documentation, as
amended.

Act no. 499/2004 Coll., On Archives and Records Service and amending
certain laws, as amended.

8) For example, Decree no. 229/2008 Coll., On manufacturing and distribution of drugs.

9) § 2. d) of the Act no. 78/2004 Coll., on the use of genetically
modified organisms and genetic products.

) 10 § 5 of Decree no. 209/2004 Coll., On detailed conditions for the use
genetically modified organisms and genetic products.

11) § 79 para. 5 of Act no. 378/2007 Coll.