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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5978_Библиотеки_им_академика_М_И_Перельмана
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6.3 CTD 115
3.2.P.4.2 Analytical Procedures
3.2.P.4.3 Validation of Analytical Procedures
3.2.P.4.4 Justication of Specications
3.2.P.4.5 Excipients of Human or Animal Origin
3.2.P.4.6 Novel Excipients
3.2.P.5 Control of Drug Product
3.2.P.5.1 Specication(s)
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of Analytical Procedures
3.2.P.5.4 Batch Analyses
3.2.P.5.5 Characterisation of Impurities
3.2.P.5.6 Justication of Specication(s)
3.2.P.6 Reference Standards or Materials
3.2.P.7 Container Closure System
3.2.P.8 Stability
3.2.P.8.1 Stability Summary and Conclusion
3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment
3.2.P.8.3 Stability Data
3.2.A Appendices
3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Excipients
3.2.R Regional Information
Examples include:
Executed Batch Records (USA only)
Method Validation Package (USA only)
Comparability Protocols (USA only)
Process Validation Scheme for the Drug Product (EU only)
Medical Device (EU only)
3.3. Literature References
Figure 6.2 (Continued)
● Structural information: chemical formula and stereochemistry in the case of a New
Chemical Entity (NCE) or amino acid sequence and glycosylation sites in the case of
a biotech product.
● Chemical and Physical Properties: appearance, colour, odour, molecular weight, melt-
ing point, refractive index, ionisation constants, partition coecients, solubility under
dierent conditions of pH or solvent.
● Spectral Properties: infrared, UV–visible, X-ray, NMR, etc.
● Chromatographic Properties: TLC, HPLC, GC-MS.
● Electrophoretic Properties: Isoelectric point, SDS-PAGE prole.
Figure 6.3 Typical data that may be submitted to characterise the drug substance.
method validation package, and comparability protocols. In an EU submission,
this should contain a process validation scheme for the drug product, specic
forms relating to theprevention of TSE’s from animal-derived materialsor other
infections from materials of humanorigin, relevant certicates of suitability and
Medical Device info if such is used as part of the drug delivery system.
116 6 Marketing Authorisation
6.3.3 Drug Master Files
It should be noted that all technical data submitted in support of marketing
authorisations remains condential between the applicant and the regulatory
authorities. In situations where the manufacturer of a drug substance is a dierent
commercial entity to the applicant seeking approval of a drug product incorporating
the substance, the substance manufacturer may submit quality data on the sub-
stance directly to the authorities as a Drug Master File. This enables the authorities
to review information on the quality of the drug substance as part of the overall
review of the product marketing application, without requiring the substance
manufacturer to disclose his manufacturing procedures to the marketing applicant.
However, the substance manufacturer must provide the substance user with all
the relevant procedures necessary to assess the quality of the substance before it is
incorporated into the drug product.
6.3.4 Module 4 – Non-clinical Study Reports
This module should contain data from all the non-clinical studies that were
conducted to investigate the pharmacological and toxicological properties of the
drug substance/product. The standard headings used to present this information
are shown in Figure 6.4. Study reports should be presented in the following order
according to species and route of administration:
Species Route of administration
Mouse Oral
Rat Intravenous
Hamster Intramuscular
Other rodent Intraperitoneal
Rabbit Subcutaneous
Dog Inhalation
Non-human primate Topical
Other non-rodent mammal Other
Non-mammals
6.3.5 Module 5 – Clinical Study Reports
This module should contain reports of all the clinical studies and other related
data that were conducted to demonstrate the safety and ecacy of the drug in
human subjects. The standard headings used to present this information are shown
in Figure 6.5. An example of headings for a tabulated listing of clinical studies is
shown in Table 6.3.
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6.3 CTD 117
4.1 Table of Contents of Module 4
4.2 Study Reports
4.2.1 Pharmacology
4.2.1.1 Primary Pharmacodynamics
4.2.1.2 Secondary Pharmacodynamics
4.2.1.3 Safety Pharmacology
4.2.1.4 Pharmacodynamic Drug Interactions
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4.2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)
4.2.2.7 Other Pharmacokinetic Studies
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity
4.2.3.2 Repeat-Dose Toxicity
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
4.2.3.3.2 In vivo
4.2.3.4 Carcinogenicity
4.2.3.4.1 Long-term studies
4.2.3.4.2 Short- or medium-term studies
4.2.3.4.3 Other studies
4.2.3.5 Reproductive and Developmental Toxicity
4.2.3.5.1 Fertility and early embryonic development
4.2.3.5.2 Embryo-fetal development
4.2.3.5.3 Prenatal and postnatal development, including maternal
function
4.2.3.5.4 Studies in which the ospring (juvenile animals) are dosed
and/or further evaluated.
4.2.3.6 Local Tolerance
4.2.3.7 Other Toxicity Studies (if available)
4.2.3.7.1 Antigenicity
4.2.3.7.2 Immunotoxicity
4.2.3.7.3 Mechanistic studies (if not included elsewhere)
4.2.3.7.4 Dependence
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 Other
4.3 Literature References
Figure 6.4 Headings structure of Module 4.
The following points are worthy of note in terms of placement of data. In the
case of studies with multiple objectives, reports should be placed in the section
corresponding to their primary purpose. Reports of laboratory studies conducted
with human materials to investigate pharmacokinetic eects should be placed in
Section 5.3.2 of the clinical module as opposed to the nonclinical module. A US sub-
mission requires that the individual case report forms of all trial subjects that died
118 6 Marketing Authorisation
TableofContentsofModule5
5.2 Tabular Listing of All Clinical Studies
5.3 Clinical Study Reports
5.3.1 Reports of Biopharmaceutic Studies
5.3.1.1 Bioavailability (BA) Study Reports
5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports
5.3.1.3 In vitro–In vivo Correlation Study Reports
5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human
Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
5.3.2.3 Reports of Studies Using Other Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
5.3.3.2 Patient PK and Initial Tolerability Study Reports
5.3.3.3 Intrinsic Factor PK Study Reports (sex, age, race, weight, etc.)
5.3.3.4 Extrinsic Factor PK Study Reports (diet, smoking, alcohol use, etc.)
5.3.3.5 Population PK Study Reports
5.3.4 Reports of Human Pharmacodynamic (PD) Studies
5.3.4.1 Healthy Subject PD and PK/PD Study Reports
5.3.4.2 Patient PD and PK/PD Study Reports
5.3.5 Reports of Ecacy and Safety Studies
5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed
Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies
5.3.5.3 Reports of Analyses of Data from More Than One Study
5.3.5.4 Other Clinical Study Reports
5.3.6 Reports of Post-Marketing Experience
5.3.7 Case Report Forms and Individual Patient Listings
5.4 Literature References
Figure 6.5 Headings structure of Module 5.
or were dropped from a study due to adverse events are included in Section 5.3.7.
Copies of referenced documents, including important published articles, ocial
meeting minutes, or other regulatory guidance or advice should be provided in the
reference section.
6.3.6 Module 2 – Summaries
This module should be prefaced by a brief introduction outlining the pharmacolog-
ical class, mode of action and the proposed clinical use of the drug. The overview
reports form the most important part of this module as they introduce the reviewer
to the case that the applicant wishes to put forward in favour of authorisation of the
drug for the proposed indications for use. They should be written by experts and
provide reasoned and integrated evaluations and assessments of the data. As such it
is expected that the authors will draw on data from dierent studies to substantiate
particular points in terms of ecacy, safety or quality. Similarly, they should
highlight any limitations or areas of concern that may exist. Quality aspects should
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Table 6.3 Example of a tabulated listing of clinical studies.
Type o f
study
Study
identifier Location of study report
Objective(s) of
the study
Study design and
type of control
Test product(s);
dosage regimen;
route of
administration
Number of
subjects
Healthy subjects
or diagnosis of
patients
Duration of
treatment
Study status;
Type of report
BA 001 Vol 3, Sec. 1.1, p. 183 Absolute BA IV
vs. Tablet
Cross-over Tablet, 50 mg
single dose, oral,
10 mg IV
20 Healthy
subjects
Single dose Complete;
Abbreviated
BE 002 Vol 4, Sec. 1.2, p. 254 Compare
clinical study
and
to-be-marketed
formulation
Cross-over Two tablet
formulations,
50 mg, oral
32 Healthy
subjects
Single dose Complete;
Abbreviated
PK 1010 Vol 6, Sec. 3.3, p. 29 Dene PK Cross-over Tablet, 50 mg
single dose, oral
50 Renal
Insuciency
Single dose Complete;
Full
PD 020 Vol 6, Sec. 4.2, p. 147 Bridging study
between regions
Randomised
placebo-
controlled
Tablet, 50 m g,
multiple-dose,
oral, every 8 h
24 (12 drug,
12 placebo)
Patients with
primary
hypertension
2 wk Ongoing;
Interim
Ecacy 035 Vol 10, Sec. 5.1, p. 1286 Long term;
Ecacy and
Safety;
Population PK
analysis
Randomised
active-
controlled
Tablet, 50 m g,
oral, every 8 h
300 (152 test
drug, 148
active
control)
Patients with
primary
hypertension
48 wk Complete;
Full
120 6 Marketing Authorisation
Non-clinical Overview
Overview of the nonclinical testing strategy
Pharmacology
Pharmacokinetics
Toxicology
Integrated overview and conclusions
List of literature references
Non-clinical Summaries
Introduction
Written Summary of Pharmacology
Tabulated Summary of Pharmacology
Written Summary of Pharmacokinetics
Tabulated Summary of Pharmacokinetics
Written Summary of Toxicology
Tabulated Summary of Toxicology
Clinical Overview
Product Development Rationale
Overview of Biopharmaceutics
Overview of Clinical Pharmacology
Overview of Ecacy
Overview of Safety
Benets and Risks Conclusions
Literature References
Clinical Summaries
Summary of Biopharmaceutic Studies and Associated Analytical Methods
Summary of Clinical Pharmacology Studies
Summary of Clinical Ecacy
Summary of Clinical Safety
Literature References
Synopses of Individual Studies
Figure 6.6 Structure of non-clinical and clinical overview and summary sections.
be covered in a single Quality Overall Summary document, that summarises and
justies the quality measures specied. It should follow the structure of module 3.
The reviews of the nonclinical and clinical aspects are each split into two sections.
The nonclinical overview and clinical overview sections should present critical
discussions and assessments of results with conclusions, whereas the non-clinical
and clinical summaries provide abbreviated factual data presented as written
summaries supported by summary tables. The structure of these sections is shown
in Figure 6.6.
6.3.7 Module I – Region Specific
The content of information submitted in this module will vary depending on the
requirements of the dierent regional authorities. We shall examine some of
the specic features that apply to EU and US submissions.
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6.3 CTD 121
6.3.8 Module 1 – EU
Since 1 January 2016 electronic submission of marketing authorizations appli-
cations is mandatory in the EU. To facilitate this the EMA has created an
electronic submissions website at https://esubmission.ema.europa.eu/eaf/index
.html from which portals for submission of data to the EMA (eSubmission
Gateway) and National Competent Authorities (Common European Submis-
sion Portal – CESP) may be accessed. Their use is mandatory unless making
a submission to a single national authority, in which case direct submission
through their own portal site may be required. Practical guidance on electronic
submissions is available on the EMA submissions site, while guidance relating
to national submissions can be found on a Heads of Medicines Agencies site at
https://www.hma.eu.
The headings for an EU submission are shown in Figure 6.7 and a summary
of the information captured by the application form is shown in Figure 6.8. Elec-
tronic signatures in accordance with Regulation (EU) No. 910/2014 on electronic
1.0 Cover Letter
1.1 Comprehensive Table of Contents
1.2 Application Form
1.3 Product Information
1.3.1 SPC, Labeling, and Package Leaet
1.3.2 Mock-up
1.3.3 Specimen
1.3.4 Consultation with Target Patient Groups
1.3.5 Product Information already approved in the Member States
1.3.6 Braille
1.4 Information about the Experts
1.4.1 Quality
1.4.2 Non-clinical
1.4.3 Clinical
1.5 Specic Requirements for Dierent Types of Applications
1.5.1 Information for Bibliographical Applications
1.5.2 Information for Generic, ‘Hybrid’ or Bio-similar Applications
1.5.3 (Extended) Data/Market Exclusivity
1.5.4 Exceptional Circumstances
1.5.5 Conditional Marketing Authorisation
1.6 Environmental Risk Assessment
1.6.1 Non-GMO
1.6.2 GMO
1.7 Information relating to Orphan Market Exclusivity
1.7.1 Similarity
1.7.2 Market Exclusivity
1.8 Information relating to Pharmacovigilance
1.8.1 Pharmacovigilance System
1.8.2 Risk-management System
1.9 Information relating to Clinical Trials
1.10 Information relating to Paediatrics
Figure 6.7 Module 1 headings – EU submission.
122 6 Marketing Authorisation
Declaration and signature
1. TYPE OF APPLICATION
(Relevant subsections of electronic form to be completed as appropriate depending on
whether it is a centralised or decentralised application or concerns extensions, orphan
or paediatric status, etc.)
2. MARKETING AUTHORISATION APPLICATION PARTICULARS
2.1 Name(s) and ATC code
2.2 Strength, pharmaceutical form, route of administration, container and
pack sizes
2.3 Legal status
2.4 Marketing authorisation holder, Contact persons, Company
2.5 Manufacturers
2.6 Qualitative and quantitative composition
3. SCIENTIFIC ADVICE
(Received from CHMP or CA’s)
4. OTHER MARKETING AUTHORISATION APPLICATIONS
(Applications or authorisations in other member states or outside the EU)
5. ANNEXED DOCUMENTS (where appropriate)
(Proof of payment, rights of reference letters, ow charts of production sites, manufac-
turing authorisations, GMP certicates, etc.)
Figure 6.8 Outline of information captured by an EU Marketing Authorisation Application
form.
identication and trust services for electronic transactions in the internal market
are generally acceptable for any declarations that are required.
EU regulations require the submission of a Summary of Product Characteristics
(SPC) as part of the product information section. Specic templates and guidance
are available to prepare the document, which must adhere to the headings shown
in Figure 6.9. The SPC is a pivotal document in terms of how the medicinal product
1. Name of the Medicinal Product, followed by the strength and pharmaceutical form
2. Qualitative and Quantitative composition
3. Pharmaceutical form
4. Clinical Particulars: (therapeutic indications, administration, contraindications,
special warnings and precautions, interaction with other drugs, use in pregnancy or
lactation, eects on driving, undesirable eects, overdose)
5. Pharmacological Properties: (pharmacodynamics, pharmacokinetics, pre-clinical
safety data)
6. Pharmaceutical particulars: (excipients, major incompatibilities, shelf life, storage
precautions, nature and contents of container, disposal precautions)
7. Marketing authorisation holder.
8. Marketing authorization number(s).
9. Date of the rst authorisation or renewal of the authorisation.
10. Date of revision of the text.
11. Dosimetry information for radiopharmaceuticals
12. Instructions for preparation of radiopharmaceuticals
Where relevant, the statement ‘This medicinal product is subject to additional monitoring’
must also be included
Figure 6.9 Summary of Product Characteristics (SPC) headings.
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6.3 CTD 123
Identication of the medicinal product: (name, form, strength, pharmacotherapeutic
group)
Therapeutic indications
Information before use: (contraindications, precautions, interactions with drugs alcohol,
warnings)
Usage instructions: (dosage, method of taking, frequency, duration,overdose, missed dose,
Adverse reactions
Information on: (usage within expiry date, storage, signs of deterioration, qualitative com-
position, pharmaceutical form and content, name and address of marketing authorisation
holder and manufacturer)
Additional names under which the product is authorised in other member states, if
applicable.
Date of last revision of leaet
Where relevant, the statement ‘This medicinal product is subject to additional monitoring’
must also be included
Figure 6.10 Information to be provided in the package leaflet.
can be presented and promoted. The authorities must approve the SPC as part of the
granting of a marketing authorization and thus it will usually require amendment
over the course of the review process so that a nal agreed version can be authorised
as part of the licensing decision.
The package leaet and label or other information provided to health profession-
als on the safe and eective use of the product must be drawn up in accordance
with the SPC. The information that must be provided in the package leaet and
outer package label are shown in Figures 6.10 and 6.11 respectively. The languages
used should be appropriate to the locations where authorizations are sought,
and target groups should be consulted to ensure that text is legible, clear, and
easy to use. Specic approval of labels and leaet text is an integral part of the
authorisation process. Additional non-harmonised information that individual
member states may require, such as price, reimbursement conditions, legal status
and identication/authenticity should be placed in a boxed area known as the
‘blue’ box.
Declarations as regards the credentials of the experts who wrote the Module 2
summaries, must be provided as this is a specic legal requirement of the EU sys-
tem. The applicant must submit an environmental risk assessment, evaluating any
potential risks of the environment arising from use, storage, and disposal of medic-
inal products. In the case of products containing genetically modied organisms,
the information must be presented in accordance with the provisions of Directive
2001/18/EC on the deliberate release into the environment of genetically modied
organisms.
6.3.9 Module 1 – US
Selected elements of the contents of a US submission are shown in Figure 6.12.
A single 2-page application form covers all drug submissions for human use,
whether they are a NDA, a BLA or an Abbreviated New Drug Application
124 6 Marketing Authorisation
Name form and strength of medicinal product
Active substance per dosage
Quantity by weight, volume or dosage
Excipients with a recognised action (if required)
Method of administration
Warning to store out of reach and sight of children
Special warnings, if necessary
Expiry date
Special storage conditions
Special precautions about disposal, if applicable
Name and address of the marketing authorisation holder
Marketing authorisation number
Batch number
Instructions for use if non-prescription
Safety features to allow verication of the authenticity of the product and detection of
tampering
Figure 6.11 Information to be provided in the outer package label.
FDA form 356h
Patent information: existing patents, Patent certications Statements of claimed
exclusivity and associated certications
Department certication
Financial disclosure information
Letters of authorization for reference to other applications or drug master les
Waiver requests
Environmental assessment or request for categorical exclusion
Promotional information
Labeling: Annotated labeling text, Labeling comparison (for ANDA)
Figure 6.12 Module 1 contents – US submission.
(ANDA). The form should be used with each submission communication and
serves as a submission checklist and a commitment to comply with applicable
regulations and other requirements. A sample is shown in Figure 6.13. Financial
disclosure information on investigators must be submitted on specic forms.
Environmental assessments can be avoided if it is estimated that the active
ingredient will not reach 1 part per billion in the aquatic environment after the
fth year of marketing. The specic labelling requirements are set out in 21
CFR Parts, 201, 606, 610 and 660. The annotated version of the labelling should
show annotations cross-referencing to the data that substantiate each of the
statements contained in the labelling. The promotional material is required to
ensure that the drug is being marketed to medical professionals in line with the
supporting data.
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