171/2010 Sb.
The DECREE
of 21 April 2004. may, 2010,
amending Decree No 228/2008 Coll., on registration of medicinal
preparations, as amended by Decree No. 13/2010 Sb.
The Ministry of health and Ministry of agriculture determined in accordance with section
paragraph 114. 2 of law No 378/2007 Coll., on pharmaceuticals and on changes of some
related laws (law on medicinal products):
Article. (I)
Decree No 228/2008 Coll., on registration of medicinal products, as amended by
Decree No. 13/2010 Coll., shall be amended as follows:
1. Footnote 1 is added:
"1) European Parliament and Council Directive 2001/83/EC of 6 May 2003.
November 2001 on the Community code relating to medicinal products for human use
preparations.
Directive of the European Parliament and of the Council 2002/98/EC of 27 June 2002. January 2003,
setting standards of quality and safety for the collection, testing,
processing, storage and distribution of human blood and blood components and
amending Directive 2001/83/EC.
Commission Directive 2003/63/EC of 25 November 2003. June 2003, amending the
European Parliament and Council Directive 2001/83/EC on the Community code
relating to medicinal products.
European Parliament and Council Directive 2004/24/EC of 31 March 2004. March
2004 amending Directive 2001/83/EC on the Community code
relating to medicinal products, as regards traditional
herbal medicinal products.
European Parliament and Council Directive 2004/27/EC of 31 March 2004. March
2004 amending Directive 2001/83/EC on the Community code
relating to medicinal products.
European Parliament and Council Directive 2001/82/EC of 6 May 2003. November
2001 on the Community code relating to veterinary medicinal products
preparations.
European Parliament and Council Directive 2004/28/EC of 31 March 2004. March
2004 amending Directive 2001/82/EC on the Community code
relating to veterinary medicinal products.
Commission directive 2009/9/EC of 10 June 1999. February 2009 amending
European Parliament and Council Directive 2001/82/EC on the Community code
relating to veterinary medicinal products.
Commission Directive 2006/130/EC of 11 July 2001. in December 2006, which shall be carried out
European Parliament and Council Directive 2001/82/EC, as regards the determination of the
the criteria for the removal of certain veterinary medicinal products for
food-producing animals from the requirement to issue on animal health
prescription.
European Parliament and Council directive 2009/35/EC of 23 December 2003. April 2009
on colours, which may be added to medicinal products.
Commission directive 2009/120/EC of 14 July 1999. September 2009 amending
European Parliament and Council Directive 2001/83//EC on a code of
Community relating to medicinal products, as regards the
advanced therapy medicinal products. ".
2. In annex 1, part IV:
"PART IV
ADVANCED THERAPY PRODUCTS
1. advanced therapy medicinal products are defined in the article. 2 (2). 1 (a).
and) Regulation (EC) no 1394/2007. Applications for registration must be in the
accordance with the format requirements as described in section I of this annex.
For modules 3, 4 and 5 shall apply the technical requirements for biological medicinal
products set out in part I of this annex. Special requirements for
advanced therapy medicinal products, as described in sections 3, 4 and 5 of this
part of the annex governing how the requirements set out in part I of this
the annex apply to advanced therapy medicinal products. In addition, the
in appropriate cases, and taking into account the specific characteristics of the
advanced therapy medicinal products in this part of the annex set out
additional requirements for these products.
Due to the specific character of the advanced therapy medicinal products is
You can determine the level of quality and non-clinical and clinical data to
be listed in the application for registration, on the basis of a risk analysis and in the
compliance svědeckými guidelines relating to the quality, safety and
efficacy of medicinal products.
The risk analysis may also be taken into account the following risk
factors: the origin of the cell, IE. autologous, allogeneic, xenogeneic, ability to
proliferation and differentiation and initiation of the immune response, the level of cellular
the handling, the combination of cells with bioactive molecules or
structural materials, the nature of the medicinal products for gene
therapy, the rate of replication capabilities for viruses or microorganisms
used in vivo, the level of integration of nucleic acids or
the genes in the genome, the long term exposure, the risk of onkogenicity and method
the submission or application.
The risk analysis may also be taken of the relevant available
the non-clinical and clinical data or experience with other related
advanced therapy medicinal products. Any derogations from the requirements of
This annex must be scientifically justified in module 2 documentation
request. The risk analysis referred to above must be in case of use also
listed and described in module 2. In this case, it is necessary to indicate the used
the methodology, the nature of the identified risks and the consequences resulting from access
based on a risk analysis for the program development and evaluation, and is
needed to describe any deviations from the requirements of this annex
resulting from the risk analysis.
2. The definition of the
For the purposes of this annex, in addition to the definitions laid down in Regulation (EC) No.
1394/2007, the following definitions shall apply
2.1. medicinal products for gene therapy ^ 18), which means
biological medicinal products, with the exception of vaccines against infectious
diseases that have the following properties:
and) contain the active ingredient, which contains recombinant nucleic
the acid used for people or people to control, correct,
the Exchange, addition or removal of genetic sequences, or from such
recombinant nucleic acid consisting of a and
(b)) their therapeutic, prophylactic or diagnostic effect
apply directly to the recombinant nucleic acid sequence, which
contain, or the product of genetic expression of this sequence,
2.2. somatic cell therapy medicinal products ^ 18), which
means a biological medicinal products, which have the following
properties:
and) contain cells or tissues that have been subject to substantial manipulation,
Thus e change of biological characteristics, physiological functions
or structural properties relevant for the intended clinical
the use of, or the cells or tissues that are not intended to be used for
the same basic function in the recipient and the donor, or of such cells, or
tissues consist, in particular, are not considered essential for the handling of
manipulations listed in annex No. 1 directly applicable regulation
Union ^ 19), and
(b)) are presented so that have properties for the treatment, prevention or
the diagnosis in the case of the disease on the basis of pharmacological,
immunological or metabolic action of its cells or tissues, or
are used for this purpose in humans or served the people.
3. specific requirements regarding module 3
3.1. Special requirements for all advanced therapy medicinal products
The application for the registration of the medicinal product for advanced therapy shall indicate
description of the system of traceability, which intends to the holder of the
create and maintain a registration in order to ensure the possibility of monitoring
the individual product and its starting and raw materials, including
all substances coming into contact with the cells or tissues that may
include, from the source, through production, packaging, storage, transport, to
delivery to a medical facility, where the product is used.
The traceability system should be complementary and compatible with the requirements of
laid down in law no 296/2008 Coll. on human tissues and cells, in the
as amended, and Regulation No. 422/2008 Coll. on the establishment of
closer to the requirements for ensuring the quality and safety of human tissues and
cells intended for human applications, in terms of human cells and tissue
other than blood cells, and in law No 378/2007 Coll. on pharmaceuticals, in
as amended, and its implementing provisions as regards
human blood cells.
3.2. Specific requirements for gene therapy medicinal products
3.2.1. the final product a medicinal substance and source materials
3.2.1.1. the gene therapy medicinal product containing the sequence
recombinant nucleic acid or a genetically modified
the micro-organism or virus.
The finished medicinal product shall consist of nucleic acid sequence or
the genetically modified micro-organism or virus in the final internal
container for the intended medical use. The finished medicinal product
can be combined with the medical device or the active
implantable medical device.
The healing substance consists of nucleic acid sequence or genetically
modified micro-organism or virus.
3.2.1.2. gene therapy medicinal product containing genetically
the modified cells
Finished medicinal product consisting of a genetically modified cells in the
final immediate container for the intended medical use.
Finished medicinal product can be combined with a medical
device or active implantable medical device.
The healing substance consists of cells genetically modified one of the
the products described in paragraph 3.2.1.1.
3.2.1.3.
In the case of products consisting of viruses or viral vectors are
source materials of the folder from which the viral vector is obtained, this means
the mother seed virus or viral vector or plasmids used to
transfekci of the host cells and cells from these basic bank
the host cells.
3.2.1.4.
In the case of products consisting of plasmids, non-viral vectors and
genetically modified micro-organisms except viruses or viral
vectors are the starting materials used to generate the folder
production cells, plasmid, it means the host bacteria and the Bank
the basic cells of recombinant microbial cells.
3.2.1.5.
In the case of genetically modified cells are the source materials
folder that is used to obtain the genetically modified cells, which are
source materials for the production of the vector, the vector and the human or
animal cells. From the Bank system used to produce the vector is
apply the principles of good manufacturing practice.
3.2.2. specific requirements
In addition to meeting the requirements set out in section 3.2.1. and 3.2.2. Part I
This annex documentation to the application for registration of a medicinal
the gene therapy product contains
and) information about all the starting materials used in the manufacture of the medicinal
substances, including those necessary for the genetic modification of human
or animal cells and, as appropriate, the subsequent cultivation and preservation
genetically modified cells, with regard to the possible absence of
purification steps,
(b) information on the genetic modification), sequential analysis, weakening the virulence,
tropism for specific tissues and cell types, dependencies of the micro-organism
or virus on cell cycle, pathogenicity and the properties of the parent
the strain in the case of preparations containing the micro-organism or virus
(c)) in the relevant sections of the documentation for a description of impurities from manufacturing
process and product-related impurities, especially viral
contaminants capable of replication, if the vector does not have to be able to
replication,
(d)) for medicinal products consisting of plasmids, the quantification of data
various forms of the plasmid throughout the period of application of the medicinal product,
(e) in the case of genetically modified cells), evaluation of the results of the tests on the
the properties of the cells before and after genetic modification, and before any
subsequent procedures or storage and freezing them.
In the case of genetically modified cells, in addition to the specific requirements
on medicinal products for gene therapy on quality requirements apply
somatic cell therapy medicinal products, and tissue preparations
Engineering referred to in section 3.
3.3. Special requirements for somatic cell therapy medicinal products
and on human tissue engineered products
3.3.1. the final product a medicinal substance and source materials
Finished medicinal product consists of medicinal substances in the inner packaging in
for the intended medical use and in the final combined in the case of
combined advanced therapy medicinal products.
The healing substance consists of engineered cells or tissues.
For the starting materials for the finished medicinal product shall be considered as other
substances, in particular supporting structures, matrix, medical devices,
biomaterials, biomolecules and other components, in combination with the manipulated
the cells, which are an integral part of, and may not be
biological origin.
The materials used in the production of medicinal substances, in particular, culture media,
growth factors, which do not have to be part of medicinal substances, shall be construed as
the raw materials.
3.3.2. specific requirements
The documentation for the registration of medicinal products, somatic cell therapy
and tissue engineered products, in addition to the requirements laid down
in sections 3.2.1. and 3.2.2. part I of this annex, requirements for:
3.3.2.1. starting materials consisting
and) of summary information about the donation, procurement and testing of human
tissues and cells, in accordance with the provisions of Act No. 296/2008 Coll., as amended by
amended, and Decree No. 422/2008 Coll., used as the default
materials; If they are used as starting materials other than healthy
the cells or tissues, in particular the cancerous tissue, you need to use them
justified,
(b)) in the case of allogeneic cell populations, from the description of the way
creating mixtures and measures to ensure their traceability,
(c)) in the context of the validation of the production process, from the characterization of medicinal substances and the
the finished product, the development of the tests, the determination of specifications and stability,
where it is necessary to take into account the potential variability caused by human or
animal tissues and cells,
(d) in the case of xenogeneic) medicinal products from animal cells from
provide information about the origin of the animals, in particular the geographical origin, breeding
animals, their age, specific acceptance criteria, measures
aimed at the prevention and monitoring of infections in animal donors,
the testing of animals for the presence of infectious agents including vertically
borne micro-organisms and viruses, and information about evidence of suitability
breeding equipment
(e)) for products derived from genetically modified animals, cells from
the description of the special properties of the cells related to the genetic modification
where shall indicate the detailed description of the methodology of creation and characterization
transgenic animal
(f)) in the case of genetic modification of cells from the technical requirements
referred to in section 3.2.
(g)) of the description of and the justification in the case of the testing of some other substances, in particular
the load-bearing structure, the matrix, medical devices, bio-materials,
biomolecules or other ingredients that are in combination with modified
the cells, which are an integral part of,
h) in the case of load-bearing structures, matrices and devices
covered by the definition of the medical device or the active
implantable medical device, of the information required in
under section 3.4. for the evaluation of a combination of the medicinal product for
modern therapy.
3.3.2.2. the manufacturing process consisting
and process validation) to ensure conformity between the lot and
the compliance process, the functional integrity of the cells during the whole production and transport to
in the time of the application or of the filing and the proper state of differentiation, and
(b) in the case of cultured cells) directly inside the matrix, the supporting structure or
medical device or on the load-bearing structure of the matrix, or
healthcare resource of information on the validation of the process of cultivation
cells in terms of growing cells, the function and integrity of the combination.
3.3.2.3. characterisation and control strategy consisting of a
and) relevant information on the characterisation of the cell population or a mixture
cells with regard to identity, purity, especially foreign microbial agent and
cellular contaminants, viability, potency, karyology, and
tumorogenitu and suitability for the intended medicinal use, including
demonstrate the genetic stability of the cells,
(b)) the qualitative and quantitative data as possible about the impurities
related to the product and impurities from the production process and of all the
the materials, which could invoke the presence during production
rozkládaných products, including the grounds for the determination of impurities, range
(c)) justification if certain tests for the release cannot be performed on the
medicinal substance or the final product, but only on the key
intermediate products or as a test during the manufacturing process,
(d) characterization of impact) of biologically active molecules such as growth
factors and Cytokines and their interactions with other components of medicinal substances,
If these are bioactive molecules part of product originating in
cells,
e) information on the State of differentiation, structural and functional arrangement
the cells and the extracellular matrix, or created if it is part of the
the intended function of three-dimensional structure; the information is part of the
characterization for those products originating in the cells; According to the needs of the
physico-chemical characterization make clinical assessments.
3.3.2.4. excipients
In the case of auxiliary substances used in cell or tissue
medicinal products, in particular transport, media folders are used
the requirements of the new auxiliary substances set out in part I of this annex, if the
There are no data on the interactions between the cells or tissues and auxiliary
substances.
3.3.2.5. developmental studies
Description of the development programme must relate to the materials and processes, and
in particular, with regard to the integrity of the cell population in the final composition.
3.3.2.6. reference materials
For the active substance and the finished product is documented and
characterized by a reference standard, which is essential for them and
specific.
3.4. Specific requirements for advanced therapy medicinal products
containing medical devices
3.4.1. advanced therapy medicinal product containing medical
the resources referred to in article 7 of Regulation (EC) no 1394/2007.
Part of the documentation to be submitted for application for marketing authorisation of a medicinal
advanced therapy product containing medical devices is
and a description of the physical characteristics and) the effect of the product,
(b) a description of the methods of product development), a description of the interaction and compatibility between the
genes, the cells or tissues, and structural components.
3.4.2. The combined advanced therapy medicinal products referred to in article. 2
paragraph. 1 (a). (d)) of Regulation (EC) no 1394/2007
For cellular or tissue part combination medicinal product for
the modern therapy of special requirements shall apply to medicinal products for
somatic cell therapy and tissue engineering on the products referred to in
section 3.3. and in the case of genetically modified cells shall apply
specific requirements for gene therapy medicinal products, as referred to in
section 3.2.
Medical device or the active implantable medical
the resource can be an integral part of the healing substance. In the case that it is
medical device or the active implantable medical
at the time of production of the resource, the application or the submission of finished product
combined with the relevant cells, it is considered an integral part of the
the finished product.
Part of the documentation presented to the application for registration of a combined
an advanced therapy medicinal product, the information concerning the
the medical device or the active implantable medical
a resource that is an integral part of the medicinal substance or the final
the product, which are essential for the evaluation of a combined medicinal
advanced therapy product. Such information shall include:
and information about choosing and) the intended function of the medical device or
implantable medical device with the other components of the product,
(b) the conformity of the medical device), which is part of the
a whole, with the essential requirements laid down in annex No. 1 of the regulation
Government No 336/2004 Coll., laying down technical requirements for
medical devices, as amended, or the conformity of
the active implantable medical device which is part of the
of the total, with the essential requirements laid down in annex No. 1.
Regulation of the Government No. 154/2004 Coll., laying down requirements on the active
implantable medical devices, as amended,
(c)) shall demonstrate compliance of the medical device or
implantable medical device with the requirements concerning TSE
laid down in Act No. 22/1997 Coll., on technical requirements for
products and amending and supplementing certain acts, as amended by Act No.
205/2002 Coll. and regulation of the Government No. 251/2003 Coll., amending certain
Government regulations issued in implementation of law No. 22/1997 Coll., on technical
requirements for products and amending and supplementing certain acts, as amended by
amended, amended by Decree-Law No 336/2004 Coll.
(d)) where available, the results of any assessment of the medical
the device, which is part of the whole, or the active
implantable medical device that is part of the
a whole, carried out by the Agency in accordance with the law No. 121/2000 Coll. on
medical devices, as amended, and its
in the implementing rules.
The body, which carried out the examination referred to in point (d) of this section,)
When prompted, provide the competent authority, which shall examine the request,
all the information related to the results of an assessment in accordance with the law
No 123/2000 Coll., as amended, and its implementing
provisions. This can include the information and documents contained in the
the application for assessment of conformity, essential for the evaluation of a combined
an advanced therapy medicinal product, as a whole.
4. specific requirements regarding module 4
4.1. Specific requirements for all advanced therapy medicinal products
Because of the unique and diverse structural and biological
characteristics of advanced therapy medicinal products may not be
Part I, module 4 of this annex with regard to the pharmacological and
toxicological tests of medicines always appropriate. Technical
the requirements in sections 4.1., 4.2. and 4.3. below explains how to
the requirements listed in part I of this annex shall apply to medicinal products
for modern therapy. Where appropriate, and taking into account the
the specific characteristics of advanced therapy medicinal products have been
set additional requirements.
In the Choose list must be explained and justified reasons
non-clinical development and the criteria used for selection of the relevant species and
modules in vitro and in vivo. The selected animal model/models may include
the animals are immunocompromised, the animals targeted include knock-out
gene, or humanized animals or transgenic. Consider the use of
homologous models, in particular the mouse cells analyzed in mice or models
simulating illness, primarily for study and imunogenity
immunotoxicity.
In addition to the requirements listed in part I is the content of the documentation to be submitted
the application for registration, proof of safety, suitability and
biocompatibility of all structural components such as the matrix, the carrier
structure and medical devices and any other substances such as
are cellular products, bio-molecules, bio-materials and chemical substances,
that are present in the final product. Take into account their physical,
mechanical, chemical, and biological properties.
4.2. Specific requirements for gene therapy medicinal products
In order to determine the extent and type of non-clinical studies necessary to
the determination of the appropriate level of non-clinical data on the safety of taking account of the
the nature and type of the gene therapy medicinal product.
4.2.1. Pharmacology
Part of the documentation presented to the application for the registration of medicinal products
medicinal products for gene therapy is
study on the operation) in vitro and in vivo of the proposed
medicinal use of pharmacodynamic studies for the proof of concept, with
using models and relevant animal species, which have demonstrated that the
nucleic acid sequence reaches its intended target. the target
authority or of the cells and place its intended function, IE. the level of
expression and functional activity. In the framework of the study shall provide data on the duration of the
the effect of nucleic acid sequence and on the proposed dosing schemes in
clinical trials,
(b) to confirm the specificity) of the study and the duration of the operation and effectiveness of the
the target cells and tissues in the case that has the medicinal product for
gene therapy Act selectively or specifically.
4.2.2. Pharmaco-kinetics
and disposition of the Study includes an assessment of) the persistence, clearance and
the mobilization. Also part of the study is proof of the disposition of the data on the
the risk of germline transmission.
(b)), together with an assessment of the risks to the environment are listed
information on the evaluation and the risk of transmission to the exclusion of a third party, if it is not
their failure to duly justified in the application on the basis of the
the type of the product.
4.2.3. Toxicology
and for the finished medicinal product) for gene therapy is judged his
toxicity. In addition, depending on the type of product, taking into account
individual testing of active substances and Excipients, and assess the effect of
in vivo for substances derived from expressed sequences, nucleic acid
which are not intended for the physiological function.
b) single dose toxicity studies can be combined with
pharmacological and farmakokinetickými studies of the safety, for example, to
assessment of persistence.
(c)) repeated dose toxicity Studies are provided in the cases, that the
It is intended to repeat the dosage for humans. Method and diagram of the submission must
exactly match the scheduled clinical dosage. In cases where the
single dosage can cause prolonged exposure in humans
nucleic acid sequence, weigh the toxicity after repeated
doses. The duration of the studies can be longer than in the case of standard studies
Depending on the persistence of the medicinal product gene
therapy and the expected potential risks. In this case, the
given the duration of the study.
(d)) part of the toxicity study is proof of the evaluation tests of a medicinal
preparation for gene therapy on genotoxicity tests. However, the standard
genotoxicity studies shall be carried out only in cases where they are necessary
for the testing of certain impurities or constituents of carrier.
(e)) part of the toxicity study is to demonstrate the evaluation tests of a medicinal
preparation for gene therapy on carcinogenicity. Standard lifetime
carcinogenicity studies in rodents is not required. However, it must be in the
assessed, depending on the product type in the relevant in vivo or in
vitro models in vivo/in vitro tumorogenní potential.
f) reproductive and developmental toxicity: is supported by studies of the effects on
fertility and reproductive function, studies of the embryonic or fetal and
perinatal toxicity studies and germline transmission, if not
their failure to duly justified in the application on the basis of the
the type of the product.
g) Additional toxicity studies
1. The study of the integration of:
For each gene therapy medicinal product shall study
integration, if it is not withholding these studies scientifically justified,
for example, because a sequence of nucleic acids cannot penetrate into the cell
the kernel. Integration studies shall be carried out in the case of medicinal products for
gene therapy, in which not expected to have the ability to integrate, but
provided data suggest risk germline transmission.
2. Imunogenita and immunotoxicity:
Part of the study on the toxicity is proof of the research potential
imunogenních and imunotoxických effects.
4.3. Special requirements for somatic cell therapy medicinal products
and on human tissue engineered products
4.3.1. Pharmacology
and the primary pharmacological studies) is illustrated by the concept of the card.
Examines the interaction of products originating in the cells with the surrounding tissue.
(b) the quantity of the product) needed to achieve the envisaged
effect, it is the effective dose and depending on the type of the product
frequency of administration.
(c)) shall take into account the secondary pharmacological study to evaluate the
the potential physiological effects, which is not related to the expected
therapeutic effect of somatic cell therapy medicinal product and
a tissue engineered product or other substances, because in addition to the
monitoring of protein may lead to the exclusion of the biologically active
molecules, or watch the protein can have unwanted destinations.
4.3.2. Pharmacokinetics
and) the conventional pharmacokinetic studies to evaluate the absorption, distribution,
metabolism and excretion is not required if you are evaluated
parameters such as viability, life expectancy, distribution, growth,
differentiation and migration, if not their nehodnocení properly justified in the
applications based on the type of the product concerned,
(b)) in the case of medicinal products and somatic cell therapy products
tissue engineering, which produce biomolecules,
to evaluate the distribution, duration and level of expression of these molecules.
4.3.3. Toxicology
and) for the finished medicinal product shall be assessed by its toxicity. Take account of the
the individual testing of active substances, excipients, other substances and
any impurities from the production process.
(b)) in the case that is longer than the duration of the observations in the case of the standard
studies of toxicity, taking into account also the expected lifetime of the medicinal
the product, pharmacodynamic and pharmacokinetic together his
profile. In this case, given the duration of the study.
(c)) the conventional studies of carcinogenicity and genotoxicity are required only in
connection with except the potential of the product.
(d)) shall be research on potential immunogenic and imunotoxické effects
of the medicinal product.
(e)) in the case of products originating in the cells and tagged animal
the cell is the need to resolve the related specific issues relating to the
security, as is the transmission of xenogeneic pathogens to humans.
5. specific requirements regarding module 5
5.1. Special requirements for all advanced therapy medicinal products
5.1.1. the special requirements in this section of part IV are additional
requirements to the requirements of module 5 in part I of this annex.
5.1.2. If clinical applications for advanced therapy medicinal products
requires a special concurrent treatment and includes surgical procedures,
therapeutic procedure to assess and describe as a whole, including information about
standardize and optimize these processes during clinical development.
If the medical devices used during surgical procedures to
application, implantation or administration of the medicinal product for advanced therapy
could have an impact on the efficacy or safety of the medicinal product for
modern therapy, it is necessary to provide information about these medical
resource.
Specific expertise required for the implementation of the application,
implantation, administration or follow-up measures. As appropriate, shall
the plan of training of health care workers regarding procedures for the use,
application, implantation or administration of these preparations.
5.1.3. If due to the nature of the medicinal products for modern
therapy of their manufacturing process during clinical development, the changes may
be requested supplementary studies to demonstrate comparability.
5.1.4. During clinical development, it is necessary to evaluate the risks
arising from potential infectious agents or the use of material
of animal origin and to take measures to reduce such risks.
5.1.5. The choice of doses and schedule of use are established on the basis of studies
the dosage.
5.1.6. the effectiveness of the proposed indication is based on the relevant results of the
clinical studies using clinically relevant parameters for
the intended use. In certain clinical conditions may be required
evidence of long-term effectiveness and provide long-term evaluation strategy
efficiency.
5.1.7. the risk management plan is given a fixed monitoring strategy
safety and efficacy.
5.1.8. In the case of combined advanced therapy medicinal products
safety and efficacy studies are designed and conducted for the
the combined product as a whole.
5.2. Specific requirements for gene therapy medicinal products
5.2.1. Human pharmacokinetic studies
Human pharmacokinetic studies shall include the following aspects:
and studies to address the excretion) of excretion of the medicinal products for
gene therapy;
(b) disposition of the study);
c) pharmacokinetic studies of the medicinal product and functional groups
responsible for the expression of genes in particular expressed proteins or
representative "signature" genomic sequence.
5.2.2. Pharmacodynamic studies in humans
Pharmacodynamic studies in humans must deal with the expression and functions of
nucleic acid sequence after administration of the medicinal product gene
therapy.
5.2.3. Safety studies will address the following aspects:
and the presence of the vector capable of replication);
(b)) the appearance of new strains;
(c)) by regrouping existing genomic sequences;
(d)) neoplastickou the proliferation caused by insertional mutagenicity.
5.3. Special requirements for somatic cell therapy medicinal products
5.3.1. a somatic cell therapy medicinal products, which is a way of
the effect is based on the production of defined active molecules.
In the case of a somatic cell therapy medicinal products, which is
the mode of action is based on the production of defined active molecules, is
need to address the pharmacokinetic profile, especially distros,
the duration and the level of expression of these molecules, if possible.
5.3.2. Biodistribution, persistence and long-term engraftment of folders
somatic cell therapy medicinal product.
During clinical development, it is necessary to deal with biodistribucí,
persistence and long-term přihojením of ingredients of the medicinal product for
somatic cell therapy.
5.3.3. Safety studies
Safety studies should address the following aspects:
and distribution and přihojením) after filing;
(b)) ektopickým přihojením;
(c)) the oncogenic transformation and the fidelity of the cells or tissues to the appropriate line.
5.4. Specific requirements for tissue engineered products
5.4.1. Pharmacokinetic study
If for the tissue engineering products are not relevant to the conventional
Pharmacokinetic studies, it is necessary in the course of clinical development
address biodistribucí, persistence and biodegradation of ingredients of products
tissue engineering.
5.4.2. Pharmacodynamic studies
Pharmacodynamic studies are designed and adapted with regard to the
properties specific to tissue engineered products, which are
accompanied by the particulars of the licence the concept and the kinetics of the preparation to achieve
the intended regeneration, repair or replacement. Appropriate pharmacodynamic
markers related to the intended functions and structure into account.
5.4.3. Safety studies
Section 5.3.3 shall apply. ".
_______________
18) Commission directive 2009/120/EC of 14 July 1999. September 2009 amending
European Parliament and Council Directive 2001/83/EC on the Community code
relating to medicinal products, as regards medicinal products
for modern therapy.
19) European Parliament and Council Regulation (EC) no 1394/2007 of 13 December.
November 2007 on advanced therapy medicinal products and amending
Directive 2001/83/EC and Regulation (EC) No 726/2004.
Article. (II)
This Decree shall take effect 15. on the day following the date of its publication.
Minister of health:
Jurásková in r.
Minister of agriculture:
Ing. Sebesta in r.
