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5.7 Chapter Review 105
5.6.4 Labelling of Investigational Drugs
Drugs intended for use in clinical trials should bear a label containing the following
statement:
Caution: New Drug–Limited by Federal (or United States) law to investiga-
tional use.
Drugs shipped for non-clinical trials should be labelled with one of the following
statements:
CAUTION: Contains a new drug for investigational use only in laboratory
research animals, or for tests in vitro. Not for use in humans. Or
CAUTION: Contains a biological product for investigational in vitro diagnos-
tic tests only
5.6.5 Registry of Clinical Trial Information
The 1997 Food and Drug Administration Modernization act mandated the US
department of health and human services (HSS), through its National Institute
of Health (NIH), to establish a registry containing information on clinical trials.
The registry is available via www.clinicaltrials.gov and can be used by patients for
example to nd trials conducted in both the US and 221 countries across the globe
that they may be able to participate in and benet from.
5.7 Chapter Review
This chapter described the purpose and design of the dierent types of studies con-
ducted during the clinical phase of drug development. It then proceeded to examine
the principles of GCP and outlined how these are incorporated into the regulations
governing the conduct of clinical trials in the EU. Finally, the chapter examined
some of the distinctive aspects of the regulations that govern clinical trials in the
US. Finally, an overview of clinical ndings reported in respect of an exemplar drug
(Emgality) is presented as a case study (Box 5.1).
Box 5.1 Emgality Clinical Studies
Emgality is the tradename given to a biotech drug approved in both the EU and
US in 2018 for the prophylactic treatment of migraine. Known as LY2951742
while in development, its nonproprietary name is galcanezumab in the EU
and galcanezumab gnlm in the USA. The active i ngredient is a monoclonal
(Continued)
106 5 Clinical Trials
Box 5.1 (Continued)
antibody (Mab), which binds and hence inactivates calcitonin gene-related
peptide (CGRP). Elevated levels of CGRP in the blood has been associated with
migraine. It is administered by SC injection once monthly.
The efficacy of galcanezumab in treating migraine was assessed in three piv-
otal phase three randomized, double-blind, placebo-controlled multinational
clinical trials. The first two studies involved a total of 1,784 participants, who
suffered from migraine 4–14 days per month. Participants in those two studies
reported four to five fewer days with migraine every month (as compared to two
to three fewer days per month in the case of participants receiving a placebo
injection). The third study involved a total of 1,117 participants who reported
migraine for more than 15 days per month (chronic migraine). In this study, par-
ticipants treated with galcanezumab reported five fewer days with migraine per
month, compared with three fewer days for participants receiving placebo. The
most common side effect noted during trials is injection site reactions, such as
pain and redness.
Additional clinical trials have been undertaken/initiated, both pre- and
post-product approval. These are most conveniently accessed via the www
.clinicaltrials.gov website, which can be searched via key words (LY2951742/
Emgality/galcanezumab). A summary of Emgality clinical (and also non-clinical
and quality) data submitted to the regulatory agencies by the company seeking
marketing authorization (Eli Lilly) is usually available on the regulatory agency’s
website. For example, an Emgality European Public Assessment Report (EPAR)
is available o n the EMA website. The FDA host a database of approved drugs
(‘drugs@fda’), which is searchable by drug name/key word. Drug entry data
invariably include a ‘reviews’ section, which will present (partially redacted)
review information.
Finally, a summary of clinical and additional pertinent information is pre-
sented in a drug’s full prescribing information/package insert, which is usually
easily accessed via drug regulatory agencies websites, via an internet search,
and is also usually published by the company on a dedicated product website.
Such websites are generally based upon the product’s tradename (e.g. www
.emgality.com).
5.8 Further Reading
ICH Guidelines
Good Clinical Practice, ICH E6
www.ich.org
European Legislation and Guidance on Clinical Trials
The Rules Governing Medicinal Products in the European Union, Volume 10, Clinical
Trials
https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-10_en
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5.8 Further Reading 107
Clinical Trials Information System (CTIS) Website
https://euclinicaltrials.eu/home
Evans, S. (2010) Fundamentals of clinical trial design. Journal of Experimental Stroke &
Translational Medicine. 3(1): 19–27.
El-Hagrassy, M.M. et al. (2018) Principles of designing a clinical trial: optimizing
chances of trial success. Current Behavioural Neuroscience Reports. (2018) 5(2):
143–152.
Scavone, C. et al. (2019) The European clinical trials regulation (No 536/2014): changes
and challenges. Expert Review of Clinical Pharmacology. 12 (11) 1027–1032.
US IND Regulations
Code of Federal Register, Title 21, Part 312
www.fda.gov
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109
6
Marketing Authorisation
6.1 Chapter Introduction
This chapter looks at the process of obtaining a marketing authorisation, the nal
step in bringing a drug to the marketplace. This requires that the data collected dur-
ing the non-clinical and clinical studies be organised into a comprehensive dossier
for submission to the regulatory authorities. The authorities subject the dossier to a
thorough review to ensure that there is satisfactory evidence as to the quality, safety,
and ecacy of the drug so that they can then grant a marketing authorisation with
condence that it can contribute to public health without undue risk. It is only then
that commercial sales of the product can commence and the developer can start to
recoup some of the expenditure that was required to bring it this far.
6.2 The Application Dossier
To obtain a marketing authorisation, the applicant must submit a dossier to the
regulatory authorities containing extensive technical data on the quality, safety,
and ecacy of the drug, together with administrative and other documents such
as application forms, declarations, labels, and leaets. The volume of information
that must be assembled is quite large, and can easily run up to 120,000 pages.
To facilitate the review process, dierent regulatory authorities specied their
own format for how the dossier should be assembled. This meant that, although
all regulatory authorities require essentially the same technical information,
applicants had to expend considerable time and eort presenting the information
in the format specied by each authority. However, through the ICH process, a
common format was agreed between EU, US and Japanese regulatory authorities
and adopted in 2003. This is known as the Common Technical Document (CTD).
It is now also accepted by a wider group of regulatory authorities that were not
actively involved in its original development. Specications were also developed to
allow for electronic submissions of the application dossier in what is referred to as
an electronic common technical document (eCTD)
Medical Product Regulatory Aairs: Pharmaceuticals, Diagnostics, Medical Devices,
Second Edition. John J. Tobin and Gary Walsh.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
110 6 Marketing Authorisation
6.3 CTD
The CTD is organised into ve modules. A schematic representation of the structure
and hierarchy is shown in Figure 6.1.Module 1 isdesigned to containregion-specic
information such as application forms and other administrative provisions that may
apply. As such it is not harmonised and is not considered part of the core CTD. The
other four modules present the technical data in a harmonised format. Module 2
should contain critical overview assessments of the quality, non-clinical and clinical
data, together with summaries of the non-clinical and clinical data. The objective of
this section is to provide reviewers with an introduction to the submission and to
orient them as to how the applicant believes the data support the granting of a mar-
keting authorisation. Modules 3, 4 and 5 provide the detailed quality, non-clinical,
and clinical data, to which thereviewer may then refer. Each module should be com-
prised individual documents as the fundamental unit and each document should
have its own internal page numbering.
The CTD format was incorporated into the EU regulations and is set out in the
revised version of Annex I to directive 2001/82/EC, which was published as Com-
mission Directive 2003/63/EC. It is also supported by detailed guidance in the Rules
Governing Medicinal Products in the European Union, Volume 2B – Presentation
and content of the dossier. Since 2016 submissions must be made electronically.
The FDA did not directly incorporate the CTD format into the US regulatory
requirements that are detailed in Title 21 CFR, Part 314.50 in the case of a New
Drug Application (NDA), or Title 21 CFR Part 601.2 (a) in the case of a Biologics
License Application (BLA). Rather, they introduced the CTD format via ‘Guidance
Module 2
The CTD
Not part
of the CTD
Regional
administrative
information
Quality overall
summary
Qualtiy
Non-clinical
overview
Clinical
overview
Non-clinical
summary
Non-clinical
study reports
Clinical study
reports
Clinical
summary
Module 1
Module 3 Module 4 Module 5
Figure 6.1 Diagrammatic representation of the organization of the CTD.
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6.3 CTD 111
Table 6.1 Correlation between the requirements of 21 CFR Part 314.50
and the CTD format .
21 CFR Part 314.50 Requirements CTD
(a) Application form 1
(b) Index 2
(c) Summary
(c)(2)(i) Annotated draft labeling
(c)(2)(ii) Pharmacologic class
(c)(2)(iii) Marketing history
(c)(2)(iv) CMC summary
(c)(2)(v) Non-clinical pharmacology & toxicology summary
(c)(2)(vi) Human pharmacokinetics & bioavailability summary
(c)(2)(vii) Microbiology summary (Anti-infectives only)
(c)(2)(viii) Clinical data & statistics summary
(c)(2)(ix) Concluding discussion
1
2
1
2
2
2
2
2
2
(d) Technical Sections
(d)(1) Chemistry, manufacturing, and controls section
(d)(2) Nonclinical pharmacology and toxicology section
(d)(3) Human pharmacokinetics and bioavailability section
(d)(4) Microbiology section (anti-infectives only)
(d)(5) Clinical data section
(d)(6) Statistical section
(d)(7) Pediatric use section
3
4
5
5
5
5
5
(e) Samples of labels and drugs (when requested) 1
(f) Case report forms and tabulations 5
(g) Other
(h) Patent information 1
(i) Patent certication 1
(j) Claimed exclusivity 1
(k) Financial certication or disclosure statement 1
for Industry’ documents. Through binding guidance, mandated by the section
745A(a) of the FD&C Act, NDAs and certain BLAs must be submitted electronically
since May 2017. The correlation between the requirements in 21 CFR Part 314.50
and the CTD format is shown in Table 6.1.
As noted elsewhere in this chapter regulatory authorities now require electronic
submission of marketing applications. This was also facilitated through the ICH pro-
cess which developed specications (M8) for submission of an eCTD. These speci-
cations basically address thedirectory structures and le formats that should be used
112 6 Marketing Authorisation
to enable regulatory authorities to handle electronic submissions without encoun-
tering software issues. Documents should be provided, where possible, as individual
Portable Document Format (PDF) les, while Extensible Markup Language (XML)
must be used to provide a user interface that enables navigation and viewing via a
standard web browser. As such the specications have been developed to facilitate
reviewers who may wish to:
● Copy and paste.
● View and print documents.
● Annotate documentation.
● Export information to databases.
● Search within and across applications.
● Navigate throughout the eCTD and its subsequent amendments/variations.
An update of the specication (v4.0) has been agreed and is in the process of being
adopted by regulatory authorities.
It is worthwhile to note, that in the US, where the applicant will just be dealing
with a single authority, there is no need to resubmit data that was previously sub-
mitted as part of an IND application to conduct clinical trials. Instead, the applicant
can cross-reference the IND le. This does not apply in Europe, because clinical
trial applications will have been submitted to individual Competent Authorities,
whereas marketing authorisation applications are usually submitted centrally to the
EMA or collectively to a number of Competent Authorities. Thus, the les need to
be self-supporting.
6.3.1 Module Structure
The ICH has issued guidelines onhow to organisethe data in the modules. These are
shown in Table 6.2. These guidance documents deal primarily with how the infor-
mation should be organised, whereas advice on how to generate the data is provided
in the quality, safety, and ecacy guidelines that were discussed in the previous
chapters. We shall now look at the structure of the modules in a little more detail,
starting with the basic data modules.
Table 6.2 ICH CTD guidance documents.
Document Topic covered
M4(R4)
Common Technical Document Superstructure and document
granularity
Quality – M4Q(R1) Module 3: Quality + Module 2 Quality Overall Summary
Safety – M4S(R2) Module 4: Non-clinical + Module 2 Non-clinical Overview and
Summary
Ecacy – M4E(R2) Module 5: Clinical + Module 2 Clinical Overview and
Summary
eCTD – M8 (3.2.2)
ICH Electronic Common Technical Document Specication, v3.2.2
implemented, (v4.0 agreed and proceeding to implementation)
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6.3 CTD 113
6.3.2 Module 3 – Quality
The quality module must contain information on the identity, characteristics, man-
ufacturing methods, control, packaging and stability of both the drug substance
and nal drug product. The standard headings used to present this information are
shown in Figure 6.2.
Identity: The drug substance should be identied as appropriate by its:
● Recommended International Nonproprietary Name (INN),
● Other nonproprietary names such as United States Adopted Name (USAN),
Japanese Accepted Name (JAN); British Approved Name (BAN),
● Compendial name,
● Chemical name,
● Company or laboratory code (Proprietary name) and
● Chemical Abstracts Service (CAS) registry number.
Characterisation: Typical data that may be provided to describe the physical and
chemical characteristics of the drug substance are shown in Figure 6.3. The
description of the drug product should include the recipe detailing all the other
ingredients (excipients) that are used to formulate the nal product. It is vital
to provide adequate data on dissolution behaviour of the drug product as the
reviewer may wish to tie this in with pharmacokinetic or bioavailability data
submitted in the other modules.
Manufacturing process: The descriptions of the manufacturing steps for the drug
substance and product should include process ow diagrams and discussions of
critical scale-up steps and process development history and process validation
activities, together with assessment of the equivalence or dierences in batches
used for various studies.
Control: All control points starting with the basic raw materials right through to
the nished product must be identied. Descriptions of the specications, test
methods, reference standards, and methods validation data should be included.
Packaging: Similarly, information on the closure/packaging systems must be
provided in terms of material specication, suitability/compatibility with the
pharmaceutical product, dimensional specications, water impermeability, etc.
Defence against microbial contamination should be discussed in the context of
either packaging of sterile products or use of preservatives as appropriate.
Stability: Stability protocols and data should be submitted along with the commit-
ment and protocols to continue stability testing post-approval.
Appendices: This section is most likely to contain additional data associated with
biological-based products. It should contain information as regards the facilities
and equipment used for the manufacture of biotech products. Assessment of the
risk of contamination from adventitious agents such as transmissible spongi-
form encephalopathy agents (TSEs), bacteria, mycoplasma, fungi, or viruses
should also be provided. Additional information on novel excipients that have
not been used before should also be included in this section.
Regional: This section is used to include region-specic quality information. In
a US submission, this should contain samples of executed batch records, the
114 6 Marketing Authorisation
1. TableofContentsofModule3
3.2. Body of Data
3.2.S Drug Substance
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General Properties
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
3.2.S.2.2 Description of Manufacturing Process and Process Controls
3.2.S.2.3 Control of Materials
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and/or Evaluation
3.2.S.2.6 Manufacturing Process Development
3.2.S.3 Characterisation
3.2.S.3.1 Elucidation of Structure and other Characteristics
3.2.S.3.2 Impurities
3.2.S.4 Control of Drug Substance
3.2.S.4.1 Specication
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justication of Specication
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment
3.2.S.7.3 Stability Data
3.2.P Drug Product
3.2.P.1 Description and Composition of the Drug Product
3.2.P.2 Pharmaceutical Development
3.2.P.2.1 Components of the Drug Product
3.2.P.2.1.1 Drug Substance
3.2.P.2.1.2 Excipients
3.2.P.2.2 Drug Product
3.2.P.2.2.1 Formulation Development
3.2.P.2.2.2 Overages
3.2.P.2.2.3 Physicochemical and Biological Properties
3.2.P.2.3 Manufacturing Process Development
3.2.P.2.4 Container Closure System
3.2.P.2.5 Microbiological Attributes
3.2.P.2.6 Compatibility
3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer(s)
3.2.P.3.2 Batch Formula
3.2.P.3.3 Description of Manufacturing Process and Process Controls
3.2.P.3.4 Controls of Critical Steps and Intermediates
3.2.P.3.5 Process Validation and/or Evaluation
3.2.P.4 Control of Excipients
3.2.P.4.1 Specications
Figure 6.2 Headings structure of Module 3.
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