RAHB unit III European union

Introduction to biologics
Biological medicines
Biological medicines (‘biologicals’) contain active substances from a biological
source, such as living cells or organisms. Biological medicines are well
established in clinical practice and in many cases they are indispensable for the
treatment of serious and chronic conditions such as diabetes, autoimmune
diseases and cancers.
Key features of biological medicines
Most biological medicines in current clinical use contain active substances made
of proteins. These can differ in size and structural complexity, from simple
proteins like insulin or growth hormone to more complex ones such as
coagulation factors or monoclonal antibodies
Biosimilar medicines
A biosimilar medicine (‘biosimilar’) is a medicine highly similar to another
biological medicine already marketed in the EU (the so-called ‘reference
medicine’)1, 2. Companies can market approved biosimilars once the period of
market protection of the reference medicine expires (after 10 years).
Since biosimilars are a type of biological medicine, all features pertinent to
biological medicines apply
Due to the natural variability of the biological source and to the manufacturing
process unique to each manufacturer, minor differences can occur between the
biosimilar and its reference medicine. Strict controls are always in place during
manufacturing to ensure that minor differences do not affect the way the medicine
works or its safety. Thus, these differences are not clinically meaningful in terms
of safety or efficacy

Directives

Directive 2001/83/EC of the European Parliament and of the Council of 6

November 2001 on the Community code relating to medicinal products for
human use (CELEX_32001L0083_en_TXT.pdf)

Scientific guidelines and guidance related to biologics in EU

The European Medicines Agency's scientific guidelines on biological human
medicines help applicants prepare marketing authorisation applications.
Guidelines reflect a harmonised approach of the EU Member States and the
Agency on how to interpret and apply the requirements for the demonstration of
quality, safety and efficacy set out in the Community directives.
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The Agency strongly encourages applicants and marketing authorisation holders
to follow these guidelines. Applicants need to justify deviations from guidelines
fully in their applications at the time of submission. Before that, they should seek
scientific advice, to discuss any proposed deviations during medicine
development.
Scientific advice
The European Medicines Agency (EMA) can provide medicine developers
advice on the most appropriate way to generate robust evidence on a medicine's
benefits and risks. EMA provides scientific advice to support the timely and
sound development of high-quality, effective and safe medicines, for the benefit
of patients.
At any stage of a medicine's development, a developer can ask guidance and
direction from EMA on the best methods and study designs to generate robust
information on how well a medicine works and how safe it is, regardless of
whether the medicine is eligible for the centralised authorisation procedure or not.
Scientific advice helps to ensure that developers perform the appropriate tests and
studies, so that no major objections regarding the design of the tests are likely to
be raised during the evaluation of the marketing authorisation application. This
also helps avoid patients taking part in studies that will not produce useful
evidence.
For human medicines, scientific advice and protocol assistance are given by the
Committee for Medicinal Products for Human Use (CHMP) on the
recommendation of the Scientific Advice Working Party (SAWP). However, in
the case of medicines that are intended to treat, prevent or diagnose a disease
causing a declared public health emergency, scientific advice is given by the
CHMP based on recommendation of the Emergency Task Force (ETF).
How scientific advice works
EMA gives scientific advice by responding to specific questions posed by the
medicine developer on the development of a particular medicine.
The developer of a medicine presents the way it plans to develop its medicine and
identifies questions and possible solutions. EMA then gives advice on the
developer’s proposals.
Scientific advice is prospective in nature. EMA does not pre-evaluate the results
of the studies and in no way concludes on whether the benefits of the medicine
outweigh the risks.
Scientific advice from EMA is not legally binding on EMA or on the medicine
developer with regard to any future marketing authorisation applications for the
medicine concerned.
When is scientific advice most useful

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Scientific advice and protocol assistance are particularly useful to medicine
developers when:
• they are developing an innovative medicine and there appears to be no or
insufficient relevant detail in EU guidelines or guidance documents, or in
Pharmacopoeia monographs, including draft documents or monographs
released for consultation;
• they are developing new or repurposed medicines targeting (re)emerging
pathogens for which there is an unmet medical need but insufficient or no
guidance is available;
• the developer chooses to deviate from scientific guidelines in its
development plan;
• the medicine developer has limited knowledge about medicine regulation,
such as some academic groups or micro, small and medium sized
enterprises (SMEs).
Medicine developers can request scientific advice or protocol assistance either
during the initial development of a medicine before submission of a marketing
authorisation application or later on, during the post-authorisation phase
Biological guidelines are provided for:
• Active substance
• Finished product
Guideline on similar biological medicinal products
(guideline-similar-biological-medicinal-products-rev1_en.pdf)

https://www.ema.europa.eu/en/human-regulatory/research-
development/scientific-guidelines/biological-guidelines

Comparability/ biosimilarity assessment

(Biosimilar development and approval in the EU: Comparability studies: the
cornerstone of biosimilar development)

Plasma master file:

Introduction
• The plasma master file (PMF) is a compilation of all the required scientific
data on the quality and safety of human plasma relevant to the medicines,
modical devices and investigational products that use humun plasma in
their manufacture. These data cover all aspects of the use of plasma, from
collection to plasems pool.
• The concept of the PMF was established by European legislation in June
2003

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 • The PMF is a separate set of documentation from the dossier for a
medicine's marketing authorisation.
General Principle
The PMF is stand-alone documentation, which is separate from the dossier for
marketing authorisation, which provides all detailed information on the
characteristics of the entire human plasma
• The PMF information should therefore not be additionally included
integrated into section 3.2.2.3 of the product-specific eCTD dossiers.
• The PMF will be updated at least annually with the submission of the
Annual update.
Plasma Master File (PMF) submissions
When shall submit my application? What is the timetable for my procedure?
• The appropriate time and planning of submission and the timetable for
assessment of applications is important for applicants, the European
Medicines Agency, CPMP members and experts for a better and efficient
working plan
• The submission deadlines and full procedural timetables are published as
a generic calendar and are for the information and use of Applicant/PMF
Holder, the European Medicines Agency. CPMP members and assessment
teams. The published timetables identify the submission, start and finish
dates of the procedures as well as other interim dates/milestones that occur
during the procedure.
• Timetables are classified under 90, 60 or 30 day evaluation procedure and
individual links are provided on this page. The initial PMF certification
procedure is run on a 90 day evaluation timetable. The timetable for annual
update is 60 day (or 90 day) and is decided in consultation with the
coordinator. Depending on the extent of the responses, their evaluation will
follow a 30 or 60 day timetable.
• The submission/start/CPMP dates are generally fixed; other dates may be
subject to adjustments until the CPMP Scientific committee proceeds to
their adoption for every individual application.
Pre submission activities
Prior the submission of application the applicant should inform the relevant
competent authorities
1. Letter of intent to EMEA
2. Appointment of coordinators
3. Submission and Validation
4. Evaluation
Structure of the eCTD Dossier for the PMF

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 • The complete PMF scientific data package is made up of multiple files.
The PMF data should be placed in module 3 under 3-2-s-2-3 control-of-
materials within the eCTD structure.
• Documentation should be included as per the CPMP guideline on the
scientific requirements for the PMF
Module 1 EU
1.0 Cover Letter
1.2 Application Form.
1.3 Product Information
1.3.1 SPC, Labelling and Package Leaflet
1.3.2 Mockup
1.3.3 Specimen
1.3.4 Consultation with Target Patient Groups
1.3.5 Product Information already approved in the Member States
Procedure
• The first step of the PMF certification procedure is similar to the
marketing- authorisation evaluation procedure. Following the satisfactory
outcome of an evaluation, the Agency issues a PMF certificate of
compliance with European legislation. This certificate is valid throughout
the European Union.
• In the second step, after certification, it is the responsibility of the
marketing- authorisation holder to update its medicinal product licences
and to incorporate the certified PMF in its marketing authorisations.

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Documents required for the PMF 2nd Step Submission within the Product
eCTD Structure
• For a 2nd step PMF submission within a Marketing Authorization, only,
the following documents should be provided for the corresponding eCTD:
• Module 1 EU
1.0 Cover letter
1.2 Application form
1.2 Certificate of Compliance
• Module 2
2.3 Expert Statement regarding the impact (if any) of the PMF on the concerned
medicinal product(s) 16
Envelope Elements and Metadata for the PMF Certification/Recertification
Dossiers
• This section describes how the envelope elements and leaf metadata
should be used in the eCTD when submitting PMF dossiers.

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2.<Submission Description>
• In all cases, the free-text envelope element <submission description>
should be used to describe
• the scope related to the PMF and to further identify the submission as
relating to a Plasma
• Master File, or a PMF 2nd Step. The contents of the <submission
description> envelope element
• should be concise but clearly indicative of the exact content of the
submission. The submission description should not exceed 200 characters.
3. <Application Number>
• This is key envelope element which identifies and allows sorting of the
PMF certification submissions/application procedures. The <Application
Number envelope should always be filled in populated to indicate that the
submission relates to the PMF.
• The <Application Number should follow this convention:
<EMEA>/<H>/<PMF holder ref. number><initial submission year 18>/<type of
change for variations or transfers>/<procedure number (if applicable), all
separated by slashes e.g,
➢ EMEA/H/PMF/000123/08
➢ EMEA/H/PMF/000123/08/1/01
4. <Invented Name>
➢ This envelope element is not applicable for the PMF dossier.
➢ Where an envelope element is not applicable, please indicate "Not
Applicable' rather than leaving the element blank (particularly as this
element is mandatory so cannot be left blank).
6. <INN>
➢ This envelope element is not applicable for the PMF dossier.
➢ Where an envelope element is not applicable, please indicate Not
Applicable' rather than leaving the element blank

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Updates to the PMF Dossier Sections
➢ When there is any change to the PMF data, in line with general eCTD
principles, only changed sections should be submitted, not the entire PME.
➢ If the PMF-Holder wishes to covert to eCTD at the time of a variation, it
is recommended that before the actual variation is submitted, a full baseline
eCTD sequence 0000 is first submitted.
➢ Any updated sections for review associated with the variation should be
subsequently sent as a following sequence 0001

TSE/ BSE evaluation

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TSE/BSE Regulation in Europe:
• Through Scrapie in the middle of the 1980s, Europe was the first region to
be victimized by the TSE/BSE situation. The guidelines were then initially
evaluated from Europe. In any case, WHO also warned the globe about the
epidemic in 1997. In light of this, WHO also entered the scene with the aim
of educating and guiding people all around the world. Canada and the
USFDA also distributed their rules.
• The European Parliament and Council passed Regulation (EC) No.
999/2001 on May 22, 2001, which established guidelines for the
avoidance, reduction, and abolition of specific transmissible spongiform
encephalopathies (Figure 3). It lays out guidelines for the European
Association to shun, exterminate, and govern Transmissible spongiform
encephalopathies (TSEs). Additionally, it deals with the manufacture,
distribution, and occasionally the sale of creatures and creature-related
goods. According to their level of risk of BSE, EU Member States or areas
are ranked by the European Commission as follows:
• As per European Pharmacopeia, General Part 5.2.8., Chance Appraisal
shows "Risk minimization as opposed to take a chance with disposal" as
underneath. The total end of chance at source is seldom conceivable, proper
measures and contemplations ought to be taken to deal with the gamble of
communicating creature TSEs by means of restorative items imply the
danger minimization instead of the gamble disposal. The well-known cow
illness, BSE, which has killed a sizable number of cows in the UK and the
rest of Europe, raised the level of concern. As a result, actions have been
taken across Europe, and the EU has issued early orders to restrict
TSE/BSE. The EU administrative consistency mandates' Add-on I
principles have given the note for direction the power to regulate
throughout Europe
• Among CEPs, TSE compliance certificates are one type (Certificate of
Suitability to the European Pharmacopoeia). When handling products that
might be contaminated with TSE, they are employed to maximize safety.
The European Directorate for the Quality of Medicines has validated that
any item that carries a TSE CEP is appropriately controlled under the
pertinent monographs produced by the European Pharmacopoeia.
• The guidelines for combating, controlling, and eliminating TSEs in bovine
and caprine wildlife are outlined in Regulation (EC) No 999/2001. It covers
the development of living things, their release into the world, and in some
circumstances, their trade. The Regulation also provides a legal basis for
the classification of Part States and third-party nations or territories into

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 those having a negligible BSE risk, a controlled BSE risk, and a subverted
BSE risk based on their BSE infection status, as stated in Commission
Decision 2007/453/EC3
• The conditions for introducing live animals, embryos, eggs, and other
products of animal conception into the Association are set forth in Annex
IX of Regulation (EC) No 999/2001. The conditions for the imports of
bovine animals are expressly stated in Chapter B of the Annex, which takes
into account the BSE status of the third nations or areas. Furthermore,
Chapter D of that Annex outlines the specifications for the creation of a
verification regarding the TSE related risk in the health certification
necessary for the importation into the Association of specific animal by-
products and inferred items, including, among other things, handled animal
protein.

Development and regulatory approval of biologics (Investigational medicinal

products and biosimilars)
IMP development and approval in EU
➢ In the European Union, A biological substance is referred as the active
ingredient in biological products.
➢ A "biological substance" is defined as "a substance that is produced by or
extracted from a biological source
➢ That requires a combination of physico-chemical-biological testing, along
with the production process and its control, for its characterization and the
determination of its quality.
➢ Examples: immunologic medicine
1. Medicines derived from human blood and plasma
2. Medicines developed by means of recombinant DNA technology
3. Hybridoma and mAb methods
4. Advanced therapy medicinal products

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Nonclinical Studies
➢ CHMP has adopted ICH S6 as a guideline governing preclinical testing of
biologics. "Preclinical safety evaluation of biotechnology-derived
pharmaceuticals - Scientific guideline
➢ The CHMP adopted the addendum to this guideline The addendum
complements, clarifies, and updates ICH S6 and is intended to further
harmonize the standards for nonclinical studies.
➢ The addendum covers the following five topics: species selection, study
design, immunogenicity, reproductive and developmental toxicity, and
carcinogenicity

Nonclinical Studies contents

Species selection

Study design

Immunogenicity

Reproductive and developmental toxicity

carcinogenicity

1. Species Selection:
• Discusses the factors that sponsors should consider in selecting relevant
species for nonclinical testing
• This testing should permit identification of a species model that can
demonstrate potentially adverse consequences of target modulation.
2. Study Design:
• Sponsors should consider PK-PD approaches
• When no PD endpoint is available, the sponsor should select the high dose
based on PK data
• The sponsor may need to assess subject recovery from the medicine's
pharmacologic and toxicologic effects when these effects occur at
clinically relevant exposures.
3. Immunogenicity:
• Nonclinical studies are not useful in predicting potential immunogenicity
of human or humanized proteins in humans.
• The addendum provides more detail than ICH S6 regarding situations when
the sponsor should measure antidrug antibodies

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4. Reproductive and Developmental Toxicity:
• The addendum first provides general advice on reproductive and
developmental testing and then discusses more specific recommendations
for fertility studies, embryo-fetal development (EFD) studies and pre- and
postnatal development (PPND) studies, and the timing of studies in
nonhuman primates (NHPs).
5. Carcinogenicity:
• The sponsor may design a strategy addressing potential carcinogenicity based
on a weight of evidence approach, including a review of relevant information,
such as literature information on class effects, target biology, and mechanisms of
action; in vitro data clinical data and data from chronic toxicity studies.
Clinical Studies
Biologics need to undergo clinical trials before a marketing authorization
application. The Clinical Trials Directive sets forth the general requirements for
clinical trials of medicinal products, including biologics.
Clinical trial authorization

GCP and other consideration for clinical trials

Study design consideration

Consultation with European medicinal agency

1. Clinical Trial Authorization

1. A clinical trial may commence only if-
• The trial subjects understand the objectives and risks of the trial and give
informed, written consent to participate.
• The trial safeguards the physical and mental integrity of the subjects
• Insurance covers the liability of the sponsor and investigator
2. GCP and Other Considerations for Clinical Trials
• Clinical trials of biologics must comply with GCP, as described in
Directive 2005 /28/EC on Good Clinical Practice.
• Investigators must obtain freely given informed consent from every trial
subject before each subject is enrolled.
• Clinical trial information must be handled, recorded, and stored with
respect for relevant confidentiality and privacy rules. Trials must comply
with the ethical principles of the world medical associations declaration of
Helsinki

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3. Study Design Considerations
General guidance on study design applies to biologics as well as small molecule
medicines.
Phase I usually involves the initial safety and PK studies
Phase II study is therapeutic exploratory study that explores efficacy
Phase III Typically involves therapeutic conformity studies
4. Consultation with the European Medicines Agency
A sponsor may obtain, scientific advice regarding clinical trial protocols from the
EMA.
The agency's remarks will only address scientific issues and will generally focus
on matters such as the selection of endpoints and comparator, the duration of
treatment or follow-up, and the design of pivotal studies.
Marketing Authorization Application
1. The requirements of the EU centralized procedure.
• The approval standards for biotechnology products are the same as for
chemically synthesized medicines.
• Both types of products must be safe and effective and have appropriate
quality.
2. MAA for a biotechnology product must meet the standard dossier
submission requirements
MAA must generally comply with the CTD format, including with respect
to
Module I (administrative information, including labelling)
Module 2 (various summaries)
Module 3 (chemical, pharmaceutical, and biological information)
Module 4 (nonclinical reports)
Module 5 (clinical study reports)

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Regulatory Pathway for Biological Investigational Medicinal Products

Clinical Trial Application (CTA)

Overview of Contents of Clinical Trial Application (CTA):
1. Covering Letter
2. Application Form
• Module 1 - Contains information on the administration of the trial, trial
site(s) with principal investigator(s), the trial design and on the
investigational medicinal products (IMP).
• Module 2 - Represents national or local Ethics Committee application form
3. Clinical Trial Protocol
4. Information on Investigational Medicinal Products (IMP)
5. Recruitment Arrangements
6. Subject information and the informed consent procedure
7. Suitability of the investigator and quality of the facilities
8. Insurance and indemnity
9. Financial Arrangements

Biosimilar development and approval in the EU

Biosimilar development
1. EMA's scientific committees evaluate the majority of marketing
authorisation applications for biosimilar medicines before they can be
approved and marketed in the EU.
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 2. EMA evaluates biosimilars according to the same standards of
pharmaceutical quality, safety and efficacy that apply to all biological
medicines approved in the EU.
3. Developers of biosimilars are required to demonstrate through
comprehensive comparability studies with the 'reference' biological
medicine that:
• their biological medicine is highly similar to the reference medicine,
notwithstanding natural variability inherent to all biological medicines;
• there are no clinically meaningful differences between the biosimilar and
the reference medicine in terms of safety, quality and efficacy.
4. This allows avoiding the unnecessary repetition of clinical trials already
carried out with the reference medicine.
5. Biosimilar competition should improve patient access to safe and effective
biological medicines with proven quality.
Regulatory approval of biosimilars in the EU include:
regulatory framework for biosimilars
Process for approval of biosimilars in the EU
Data requirements for approval
Immunogenicity
Extrapolation
Regulatory framework for biosimilars
The EU has approved the highest number of biosimilars worldwide, and
consequently has the most extensive experience of their use and safety.
EMA has issued scientific guidelines to help developers conform to the strict
regulatory requirements for approving biosimilars.
The guidelines have evolved to keep pace with rapid advances in biotechnology
and analytical sciences, and they take on board increasing experience of clinical
use.
Process for approval of biosimilars in the EU
• All medicines produced using biotechnology and those for specific
indications must be approved in the EU through EMA
• Some biosimilars may be approved at national level, such as some low-
molecular weight heparins derived from porcine intestinal mucosa.
• When a company applies for marketing authorisation at EMA, data are
evaluated by EMA's scientific committees on human medicines and on
safety, as well as by EU experts on biological medicines and specialists in
biosimilars.
• The review by EMA results in a scientific opinion, which is then sent to
the European Commission, which ultimately grants an EU-wide marketing
authorisation
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Data requirements for approval
• For any biological medicine with a new active substance, a positive
benefit-risk balance is determined mainly from evidence of safety and
efficacy in pivotal trials in humans.
• A positive benefit-risk balance is based on demonstrating biosimilarity, i.e.
that the active substance is highly similar to the reference medicine.
• This is achieved via comprehensive comparability studies with the
reference medicine

• The non-clinical and clinical data needed to approve a biosimilar are

different from those needed for a biological medicine with a new active
substance.
• This is because, by demonstrating biosimilarity, the biosimilar relies on the
safety and efficacy experience gained with the reference medicine

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Same pharmaceutical quality standards for all medicines
The studies to prove pharmaceutical quality should provide detailed data on:
structural characterisation and other physicochemical properties
purity (traces of residues from the manufacturing process have to be controlled
and must not exceed acceptable levels)
biological activity
excipients and starting materials
strength and formulation
the control of the manufacturing process (to ensure that the active substance and
finished product conform with the accepted ranges for technical specifications)

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stability of the active substance and finished product during shelf-life under
defined storage conditions
Comparability studies: the cornerstone of biosimilar development
Comparability is conceived as a step-wise process that is tailor-made for each
product (figure 5); knowledge from the initial quality comparability studies1 (step
1) is used to determine the extent and type of non-clinical (step 2) and clinical
studies2 (step 3) required in the next step of development, always with the aim of
ruling out differences in clinical performance between the biosimilar and the
reference medicine.
Comparability is a well-established scientific principle of regulatory science:
comprehensive comparative quality studies prove that physicochemical
properties and biological activity are highly similar.
Comparative clinical and non-clinical studies that support the approval of a
biosimilar rule out differences which may affect the medicine’s safety and
efficacy.
Step 1 Comparative quality studies
In vitro studies compare the protein structure and biological function using
sensitive techniques capable of detecting minor differences with clinical
relevance between the biosimilar and its reference medicine. These studies are
much more sensitive than clinical trials for detecting such differences, as there is
often variability among human subjects participating in trials. Differences that
may affect clinical safety, efficacy or immunogenicity need to be further studied
(e.g. in comparative non-clinical or clinical studies, step 2 and 3).
Step 2 Comparative non-clinical studies
These studies include pharmacodynamic studies in vitro, which look at binding
and activation (or inhibition) of physiological targets and immediate
physiological effects in cells. Pharmacodynamic studies in vivo (animal models)
are only done if no suitable in vitro model exists. In vivo toxicological studies are
only required in certain cases, for example when the biosimilar is produced in a
new type of cell or organism, or when the formulation includes new excipients
not used previously.
Step 3 Comparative clinical studies
The aim of studies in humans is not to demonstrate safety and efficacy in patients,
as these have already been established for the reference medicine. Clinical trials
are tailored to confirm biosimilarity and to address any questions that may remain
from previous analytical or functional studies.

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Approval of biosimilars builds on existing scientific knowledge on safety and
efficacy of the reference medicine gained during its clinical use, so fewer clinical
data are needed.
From a scientific and regulatory point of view, the reference medicine’s entire
clinical development programme does not need to be repeated. This means that
patients and healthy volunteers will not be subjected to unnecessary clinical trials.

Comparability: a scientific principle routinely used after manufacturing

changes to medicines on the market

Comparability is not a new regulatory concept, but a well-established scientific

principle that has been used for decades in the manufacture of medicines made
by biotechnology3, 4, 5. Companies producing biological medicines are likely to
adapt or improve the manufacturing process several times during the commercial
life of a product (e.g. by increasing production scale). Comparing batches before
and after a manufacturing change ensures consistency, so that there are no
changes in safety or efficacy. A change to the manufacturing process must always
be approved by regulators. The extent of the comparability studies required
following a manufacturing change to a biological medicine will depend on the
expected impact on quality, safety and efficacy of the medicine. Most often,
analytical and functional data are sufficient, and clinical trials to prove safety and
efficacy are not needed (table 5, scenario 1 and 2). Clinical trials are needed only
if an impact on safety and efficacy is anticipated (scenario 3)

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Most of the widely used biological medicines on the market have seen several
changes to their manufacturing process and these often result in minor differences
from the version initially approved or the version used in the clinical trials filed
for approval. Regulators have built up extensive experience to conclude that such
differences do not affect the medicine’s quality, safety and efficacy
Comparative trials are designed to confirm biosimilarity and clinical
performance
Comparison of the biosimilar with the reference medicine involves extensive
comparability studies to assess any possible impact on safety and efficacy. The
approach is equivalent to when major changes are introduced to the
manufacturing process for a medicine made by biotechnology (scenario 3 in table
5).
Clinical trials for biosimilars do not need to include all the pivotal studies
conducted for the reference medicine to prove safety and efficacy in humans.
Comparative clinical trials are specifically designed to rule out clinically relevant
differences in safety or efficacy between the biosimilar and the reference
medicine, and to confirm biosimilarity.
There are certain key aspects that need to be considered for the design of
comparative clinical trials:
• The goal is to rule out potential product-related differences that could affect
pharmacokinetics (PK), efficacy or safety, including immunogenicity.

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• PK studies should be conducted in a homogeneous and sensitive
population (healthy volunteers or patients) to detect any possible
differences between the biosimilar and its reference medicine. Healthy
volunteers can be selected if they represent the most appropriate population
to detect such differences and if the medicines’ toxicity is not a cause of
concern.
• To compare the pharmacological effects, a sensitive endpoint that allows
detection of product-specific differences should be chosen
• Endpoints measuring pharmacodynamic activity (‘PD endpoints’) can be
used when available and when relevant for the medicine’s clinical effect.
In many settings, these endpoints are more sensitive than clinical outcomes
to detect potential differences between a biosimilar and the reference
medicine. PD endpoints are usually based on laboratory tests. Examples
include: glucose infusion rate in a glucose clamp study for biosimilar
insulins (rather than measures of HbA1c or long-term consequences of
diabetes)
• absolute neutrophil count for biosimilar granulocyte-colony stimulating
factor (rather than number of serious infections)
• number of oocytes retrieved during in vitro fertilisation for biosimilar
follicle stimulating hormone (rather than pregnancies or live births)
• If there are no suitable PD endpoints, a clinical efficacy trial comparing the
biosimilar and its reference medicine is generally needed. This trial should
be adequately powered, randomised, parallel-group, preferably double
blind, and should use efficacy endpoints. These endpoints should
preferably measure the pharmacological activity of the medicine and be
less influenced by patient- or disease-related factors
• Adequate equivalence margins should be chosen for the primary efficacy
endpoint. Margins are established on the basis of knowledge of efficacy
with the reference medicine, as well as on clinical judgement. Equivalence
margins are set specifically for the indication studied and depend on the
endpoint chosen. They should represent the largest difference in efficacy
that would not matter in clinical practice; treatment differences within this
range would thus be acceptable because they have no clinical relevance.
The principles of selecting equivalence margins are not unique to
biosimilar testing: they are routinely used in clinical trials when comparing
treatment alternatives, or when comparing the same medicine before and
after manufacturing changes that may have a clinical effect3
• As for all clinical trials, legal requirements (e.g. Good Clinical Practice)
have to be met.

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The extent of clinical studies needed for approval depends on several
factors, including those outlined in table 6.

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Immunogenicity
• Immunogenicity is always studied for biological medicines.
• This is because of the intrinsic ability of proteins and other biological
medicines to cause an unwanted immune response, which, in rare cases,
could cause a serious adverse reaction (e.g. anaphylaxis or delayed
hypersensitivity) or reduced efficacy.
Key considerations on potential immunogenicity of biological medicines
1. Immunogenicity is not a safety concern in itself
In most cases, an immune reaction against a biological treatment is not
responsible for serious problems that result from a higher immune response,
Connected to clinical outcomes
2. The nature of immune reactions depends on many factors
Changes to the structure of the protein may occur during improper storage or
transport, or proteins could form aggregates
3.Harmful immunogenicity is unlikely after manufacturing changes or after
switching

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A harmful immune response is unlikely after a change to the manufacturing
process of a biological medicine
4. Immunogenicity is always monitored post marketing
Particularly important to learn of rare immune reactions that can only be detected
after a long follow-up period in larger numbers of patients.
Immunogenicity data needed for approval of a biosimilar
• The type of biological medicine and its intended use
• Product characteristics
• Previous knowledge of immunogenicity
Extrapolation
• If a biosimilar is highly similar to a reference medicine and has comparable
safety and efficacy in one therapeutic indication, safety and efficacy data
may be extrapolated to other indications approved for the reference
medicine.
• No trials at all need to be carried out with the biosimilar in certain
indications.
Criteria for extrapolation
Before an indication for a biosimilar may be approved based on extrapolated
safety and effectiveness, several factors need to be taken into account.
These include:
Mechanism of action
The mechanism of action of the active substance should be mediated by the same
receptor(s) in both the initial and the extrapolated indication.
If the mode of action of the active substance is complex and involves multiple
receptors or binding sites (as is often the case with monoclonal antibodies), it may
be difficult to establish the contribution of each receptor or binding site to each
indication. In this case, additional studies (nonclinical or clinical) will be needed
to prove that the biosimilar and reference medicine will behave similarly in the
extrapolated indication.
Relevant study population
Comprehensive comparability studies must show that the biosimilar is highly
similar to the reference medicine (by means of safety, efficacy and
immunogenicity data) in a key indication in a population in which potential
differences in clinical performance can be detected
Extrapolation across different clinical settings
Data from a given indication (e.g. rheumatoid arthritis) may not be directly
applicable in terms of safety or efficacy to an indication falling within another
therapeutic area where the mode of action, posology or pharmacokinetics may be
different (e.g. oncology). In this case, additional studies may be needed

28
Extrapolation of safety data
Safety data can only be extrapolated after a comparable safety profile has been
established for the biosimilar in one therapeutic indication. If comparability is
shown at structural, functional, pharmacokinetic and pharmacodynamic level,
and efficacy is comparable, then adverse reactions due to the biosimilar’s
pharmacological action can be expected to be the same and to occur at similar
frequencies
Extrapolation of immunogenicity data
Extrapolation of immunogenicity data is not automatic, as it always requires
justification. This is because immunogenicity is determined by more than
product-related characteristics. Factors relating to patients (age, immune status),
disease (comorbidities, concomitant treatments) or treatment-related factors
(route of administration, length of exposure) also have to be considered.
EMA's scientific committees assess most marketing authorization applications
for biosimilar medicines in the EU, applying the same rigorous standards of
quality, safety, and efficacy as for all biological medicines. Biosimilar developers
must prove their product's high similarity to the reference medicine through
extensive comparability studies, ensuring there are no clinically significant
differences in safety, quality, and effectiveness.
1. The EU leads in biosimilar approvals globally, with substantial experience in
their safe use. EMA provides scientific guidelines to assist developers in meeting
strict regulatory standards, adapting them to match rapid advancements in
biotechnology and analytical sciences while incorporating growing clinical
experience.
2. In the EU, approval is required for all biotechnology-based medicines and
those designed for specific uses, which is overseen by the EMA. While some
biosimilars can receive national-level approval, such as certain low-molecular
weight heparins derived from porcine intestinal mucosa, most go through a
rigorous process. When a company seeks marketing authorization from the EMA,
their data undergo evaluation by EMA's scientific committees for human
medicines and safety, along with assessments by EU experts in biological
medicines and biosimilar specialists. This thorough review by the EMA leads to
a scientific opinion, which is subsequently forwarded to the European
Commission for the final grant of EU-wide marketing authorization.
3. To gain approval for a new biological medicine with a new active ingredient,
it's crucial to establish a positive benefit-risk balance primarily through pivotal
human trials. This balance relies on proving biosimilarity, indicating that the
active substance closely resembles the reference medicine.

29
Pre-clinical and clinical development considerations
Pre-clinical development considerations
Nonclinical Studies Similar to the FDA,168 the CHMP has adopted ICH S6 as a
guideline governing preclinical testing of biologics.169 In July 2011, the CHMP
adopted the addendum to this guideline, and the addendum came into effect in
Europe in December 2011. The addendum complements, clarifies, and updates
ICH S6 and is intended to further harmonize the standards for nonclinical studies.
As explained in Section 2.2, we discuss the addendum here in light of the
CHMP’s earlier approval of it. The addendum and ICH S6 are applicable in both
the United States and EU, however, and readers interested in understanding the
nonclinical standards in either jurisdiction should review both sections.
General Principles
Although the addendum does not alter the scope of the ICH S6, it prevails
whenever there are differences between the two. The addendum covers the
following five topics: species selection, study design, immunogenicity,
reproductive and developmental toxicity, and carcinogenicity
Species Selection
The addendum discusses the factors that sponsors should consider in selecting
relevant species for nonclinical testing. According to the addendum, initial testing
should compare target sequence homology between species, with subsequent in
vitro assays making qualitative and quantitative cross species comparisons of
relative target binding affinities, receptor–ligand occupancy, and kinetics.
Sponsors also should assess functional activity. This testing should permit
identification of a species model that can demonstrate potentially adverse
consequences of target modulation. When the preceding approaches cannot be
used to determine relevant species, the sponsor may conduct tissue cross-
reactivity studies. If no relevant species exists, the sponsor may consider
homologous molecules or transgenic models, as noted in ICH S6. Specific
instructions are provided for mAbs, for which a short-term safety study in one
species—and no additional toxicity studies—are recommended. If there are two
relevant species (one rodent and one nonrodent), the sponsor should conduct
short-term studies in both. If the toxicologic findings from these studies are
similar for both species, long-term studies may involve one of those species,
usually the rodent species.
Study Design
Sponsors should consider PK–PD approaches—such as exposure–response
relationships, modeling, or simulation approaches—when selecting the high dose
for toxicity testing. The high dose should be the higher of (1) the dose providing
the maximum intended pharmacologic effect in the preclinical species and (2) the
dose providing “an approximately 10-fold exposure multiple over the maximum
30
exposure to be achieved in the clinic. ”When no PD endpoint is available, the
sponsor should select the high dose based on PK data, as well as available in vitro
binding and/or pharmacology data. Generally, repeat-dose toxicity tests should
have a duration of 6 months; studies of longer duration are not considered
valuable. Finally, the sponsor may need to assess subject recovery from the
medicine’s pharmacologic and toxicologic effects when these effects occur at
clinically relevant exposures. One approach is to include, in at least one study, a
nondosing period assessing the reversibility of the toxic effects.
Immunogenicity
As noted in ICH S6, nonclinical studies are not useful in predicting potential
immunogenicity of human or humanized proteins in humans. The addendum
provides more detail than ICH S6 regarding situations when the sponsor should
measure antidrug antibodies (ADAs), namely when (1) there is evidence of
altered PD activity, (2) there are unexpected changes in exposure in the absence
of a PD marker, or (3) there is evidence of immune-mediated reactions.
Collection of appropriate samples during the study is recommended, because it is
hard to predict the need for ADA measurement before the completion of the in-
life phase of the study
Reproductive and Developmental Toxicity
The addendum first provides general advice on reproductive and developmental
testing and then discusses more specific recommendations for fertility studies,
embryo–fetal development (EFD) studies and pre- and postnatal development
(PPND) studies, and the timing of studies in nonhuman primates (NHPs).
The addendum first discusses appropriate species for testing.182 Reproductive
studies should occur in a relevant species, but no such studies are required for
products directed at foreign targets, such as bacteria and viruses. If the product is
pharmacologically active in both rodents and rabbits, EFD studies should occur
in both species unless teratogenicity or embryo–fetal lethality is identified in one
of them. Sponsors should not use NHPs in developmental testing unless they are
the only relevant species, and even then, the sponsor can provide scientific
justification to use an alternative model. If no relevant species exists, the sponsor
may consider using transgenic mice or homologous proteins. If the weight of the
evidence (e.g., information regarding the mechanism of action, phenotypic data
from genetically modified animals, or class effects) suggests an adverse effect on
fertility or pregnancy, this information may permit communication of the risks,
and additional studies might not be warranted.
Fertility studies should occur in mice or rats when either is a relevant species.
Mating studies are impractical for NHPs, but sponsors can evaluate the
reproductive tract in repeat-dose toxicity studies of sexually mature NHPs that
last at least 3 months.183 Concerns about effects on conception or implantation
31
should be addressed through studies of NHPs, a transgenic model, or a
homologous protein or through risk management, informed consent, and labeling.
With respect to EFD and PPDN, the sponsor may conduct separate studies or may
consider one study that covers day 20 of gestation to birth (an enhanced PPDN or
ePPND).
If the candidate enters clinical trials before completion of EFD studies,
appropriate risk management techniques (e.g., contraception) should be used in
any clinical trial involving women of childbearing potential.185 If these
precautions are in place and NHPs are the only relevant species, the sponsor can
conduct EFD and ePPND studies during phase III. When these precautions are
not possible, the sponsor should submit the complete EFD report or interim
ePPND study before beginning phase III.186 When the product’s mechanism of
action raises serious developmental toxicity concerns and NHPs are the only
relevant species, no study is necessary; instead, the labeling should disclose the
concern, and the sponsor should avoid administering the candidate to women of
childbearing potential
Carcinogenicity
As noted, carcinogenicity assessments of biologics are not always warranted, but
the addendum provides advice for use in situations when they are appropriate.187
According to the addendum, the sponsor may design a strategy addressing
potential carcinogenicity based on a weight of evidence approach, including a
review of relevant information, such as literature; information on class effects,
target biology, and mechanisms of action; in vitro data; clinical data; and data
from chronic toxicity studies.188 In some cases, this review will be sufficient to
address the carcinogenic potential.189 In situations when the mechanism of
action raises concerns and the weight of the evidence supports them, the hazard
should be addressed through product labeling and risk management practices.190
If the weight of the evidence regarding a mechanism-based concern is instead
unclear, the sponsor can propose additional studies to address it.191 When
insufficient information exists on product characteristics and mechanism of
action, a more extensive assessment might be appropriate, including, for example,
additional endpoints in toxicity studies.192 If this assessment suggests a
carcinogenicity concern, sponsors may propose additional studies or labeling to
address the concern.193 If this assessment instead suggests no carcinogenicity
concern, additional nonclinical testing is not recommended

clinical development considerations

Clinical Studies in Compliance with the Clinical Trials Directive
After complying with the preclinical testing requirements, biologics also need to
undergo clinical trials before a marketing authorization application (MAA) can
32
be submitted. The Clinical Trials Directive sets forth the general requirements for
clinical trials of medicinal products, including biologics.195 Because some
general standards may not be relevant or appropriate for biologics, however,
regulators must take a flexible approach to trials of these products. This section
summarizes the requirements of the Clinical Trials Directive, noting special
considerations for biologics when necessary
Clinical Trial Authorization
The Clinical Trials Directive and European Commission guidance196 describe
the steps that a sponsor must take before commencing a clinical trial. According
to these documents, a clinical trial may commence only if (1) the anticipated
therapeutic and public health benefits outweigh any foreseeable risks and
inconveniences to the subjects; (2) the trial subjects understand the objectives and
risks of the trial and give informed, written consent to participate; (3) the trial
safeguards the physical and mental integrity of the subjects; and (4) insurance
covers the liability of the sponsor and investigator. To comply with these
requirements, the trial sponsor must take certain steps. In general, the sponsor
must take responsibility for the following: trial conduct, appointment of an
appropriate investigator, selection of the institution that will conduct the trial,
quality control, data collection standards, protocol drafting, and creation of the
investigator’s brochure. The sponsor then must apply for approval from both the
ethics committee in the country where the trial will be conducted and competent
authorities of the Member States. Written authorization may be required for all
biologics trials and is required for trials involving medicines containing
genetically modified organisms, medicines for gene therapy, and medicines for
somatic cell therapy (including xenogenic cell therapy). The opinion of the ethics
committee should be issued within 60 days. A review period of 30 days can be
added for medicines requiring written authorization noted earlier, and for
xenogenic cell therapy, there are no time limits for authorization. This time frame
can be extended by an additional 90 days (in addition to the original 90 days) if
the ethics committee consults a national group or committee. The trial may begin
only if (1) the ethics committee has issued a favorable opinion and (2) no
competent authority has informed the applicant of grounds for non-acceptance.
Good Clinical Practices and Other Considerations for Clinical Trials
Clinical trials of biologics must comply with GCP, as described in Directive 2005
/28 /EC on Good Clinical Practice and the ICH E6 guideline, which the CHMP
has adopted. The directive and guideline describe general governing principles
for clinical trials. The rights, safety, and well-being of trial subjects must prevail
over the interests of science and society. Investigators must obtain freely given
informed consent from every trial subject before each subject is enrolled. Clinical
trial information must be handled, recorded, and stored with respect for relevant
33
confidentiality and privacy rules. Trials must comply with the ethical principles
of the World Medical Association’s Declaration of Helsinki. Specific GCP
guidelines apply to trials of advanced therapy medicinal products. These
guidelines regulate issues such as the donation, procurement, and testing of
human tissues and cells; the implementation of a traceability system; and specific
rules on safety reporting and long-term follow-up. Under the Clinical Trials
Directive, special requirements apply to clinical trials conducted on minors and
other persons not able to give informed legal consent. These requirements are
intended to preserve the dignity of the trial subjects, confirm that the benefits of
the trial outweigh the risks, and ensure that subjects’ representatives give consent
with as much involvement of the subject as possible. Competent authorities must
record information regarding trials in the European database of clinical trials
(EudraCT), which is accessible only to other competent authorities, the European
Medicines Agency (EMA), and the European Commission.
CHMP has issued a guideline on quality requirements during the clinical trial
period for investigational medicinal products (IMPs) containing biological or
biotechnology-derived substances.205 The guideline describes quality
documentation that should be submitted to the competent authority as part of the
sponsor’s investigational medicinal product dossier (IMPD). Given the
importance of the production process for a biologic’s properties, as described in
Section 3, theguideline states that the IMPD should include, among other things
(1) an adequate description of the process and process controls, including a flow
chart of all successive steps and details of in-process testing, and (2) a description
and justification of “any reprocessing during manufacture of the drug substance
The guideline also recognizes that sponsors will improve and optimize their
manufacturing processes during clinical development and describes the steps
sponsors should take following these changes.207 Specifically, the sponsor must
compare the quality attributes of the pre- and postchange biological active
substances and relevant intermediates, and “[d]epending on the consequences of
the change introduced and the stage of development, a comparability exercise
may be necessary.” For first-in-human (FIH) clinical trials, sponsors should use
product representative of the material used during the nonclinical testing
phase.209 Finally, with regard to characterization, the guideline requires details
on the biological activity to be provided, recognizing that the extent of
characterization data will further increase in later phases.
Study Design Considerations
General guidance on study design applies to biologics as well as small molecule
medicines.211 According to the guidance, there is a “close, but variable
correlation” between phase of development and type of study, but one type of

34
trial can occur in several different phases.212 The guidance therefore identifies
the “[m]ost typical kind of study for each phase.
Phase I usually involves the initial introduction of the investigational product into
human subjects, and studies in this phase usually have nontherapeutic objectives.
Specifically, phase I studies typically investigate one or more of the following:
(1) initial safety and tolerability; (2) PK, which are “particularly important to
assess the clearance of the drug and to anticipate possible accumulation of parent
drug or metabolites and potential drug-drug interactions”; (3) PD; and (4) drug
activity, to preliminarily determine the potential therapeutic benefit of a
medicine.214 The most typical phase I study is the human pharmacology study.
According to the guidance, phase I studies may be conducted in healthy
volunteers or certain types of patients (e.g., patients with mild hypertension). If
the medicine has significant potential toxicity (e.g., cytotoxic products), the trial
will usually be conducted in patients.
The CHMP introduced new guidelines on FIH studies after the 2006 TeGenero
incident. That case involved a FIH clinical trial of a novel mAb, during which
subjects experienced severe adverse events, including multiorgan failure.215 The
new guideline describes risk factors helpful in identifying potential severe
adverse reactions, including concerns derived from knowledge or lack thereof
regarding (1) the product’s mode of action, (2) the nature of the target, or (3) the
relevance of animal models.216 The guideline also discusses quality, nonclinical,
and clinical study design considerations for minimizing risk to human subjects.
The most typical phase II study is a therapeutic exploratory study that explores
efficacy in narrowly defined, relatively homogenous groups of patients. Initially,
studies may use a variety of designs (e.g., concurrent controls and comparisons
with baseline status). Subsequent phase II trials usually are randomized and
concurrently controlled, allowing for evaluation of the medicine’s safety and
efficacy for a particular indication. A major goal of this phase is to determine the
dose(s) for phase III trials.
Phase III typically involves therapeutic confirmatory studies that are designed to
verify the preliminary evidence obtained in phase II and to provide a sufficient
basis for marketing authorization. Phase III studies “may also further explore the
doseresponse relationship, or explore the drug’s use in wider populations, in
different stages of disease, or in combination with another [medicine].”219 With
regard to medicines administered for long periods, extended exposure trials
ordinarily occur during phase III, although the sponsor may start them in phase
II.
To ensure that clinical trials in all three phases of development will be adequate
to support an MAA, sponsors should design these trials with the MAA
requirements in mind. Biologics in general need to comply with the requirements
35
set out in Part III of the CTD, and advanced therapy medicinal products need to
comply with the requirements described in Part IV of the CTD. Section 3.3, infra,
provides more information regarding the MAA.
Consultation with the European Medicines Agency
A sponsor may obtain, from the EMA, scientific advice regarding clinical trial
protocols. Although this advice does not bind the ethics committee and national
competent authority and is not binding for purposes of a future MAA, it can be
useful to guide revisions to the protocol. The agency’s remarks will only address
scientific issues and will generally focus on matters such as the selection of
endpoints and comparator, the duration of treatment or follow-up, and the design
of pivotal studies
Advice also might address a sponsor’s proposal to deviate from a CHMP
guideline. If the applicant decides not to follow the EMA’s advice, it should
justify this decision in its MAA. EMA guidance details the procedures for
requesting scientific advice.
The fact that an applicant requests advice from EMA does not preclude it from
also seeking advice from national competent authorities or from foreign
regulators, such as the FDA. The process of obtaining advice from the national
competent authorities is often less formal than requesting advice from the EMA,
and such advice can prove helpful. Consequently, seeking such advice is a
common choice among applicants
Applicants also may seek parallel scientific advice from the EMA and FDA.
Generally, the parallel scientific procedure is available for “important
breakthrough drugs,” products that the EMA and FDA have identified as falling
within therapeutic areas of overlapping interest (e.g., oncology products,
vaccines, and blood products), and products with “significant clinical safety,
animal toxicology, or unique manufacturing concerns that could impede . . .
development.” The goal of these meetings is to provide clarity regarding the
regulatory requirements of each region and the reasons for any differences
between them. A sponsor requesting parallel advice should authorize the agencies
to exchange all information about the product, including trade secrets. After the
parallel scientific advice procedure, each agency will provide its own independent
advice on the questions at issue. There is no guarantee of harmonized advice or
identical regulatory decisions on the approvability of the product. Nevertheless,
sponsors are increasingly requesting parallel scientific advice. For example, in
the period ranging from September 2009 to September 2010, the agencies
received seven requests for such advice
The fact that an applicant requests advice from EMA does not preclude it from
also seeking advice from national competent authorities or from foreign
regulators, such as the FDA. The process of obtaining advice from the national
36
competent authorities is often less formal than requesting advice from the EMA,
and such advice can prove helpful. Consequently, seeking such advice is a
common choice among applicants
Applicants also may seek parallel scientific advice from the EMA and FDA.
Generally, the parallel scientific procedure is available for “important
breakthrough drugs,” products that the EMA and FDA have identified as falling
within therapeutic areas of overlapping interest (e.g., oncology products,
vaccines, and blood products), and products with “significant clinical safety,
animal toxicology, or unique manufacturing concerns that could impede . . .
development.” The goal of these meetings is to provide clarity regarding the
regulatory requirements of each region and the reasons for any differences
between them. A sponsor requesting parallel advice should authorize the agencies
to exchange all information about the product, including trade secrets. After the
parallel scientific advice procedure, each agency will provide its own independent
advice on the questions at issue. There is no guarantee of harmonized advice or
identical regulatory decisions on the approvability of the product. Nevertheless,
sponsors are increasingly requesting parallel scientific advice. For example, in
the period ranging from September 2009 to September 2010, the agencies
received seven requests for such advice.
The Marketing Authorization Application: Contents and Approval
Standard
Many biologics fall under the scope of the centralized marketing authorization
procedure, which is mandatory for medicines developed through
biotechnological methods (recombinant DNA technology; controlled expression
of genes coding for biologically active proteins in prokaryotes and eukaryotes,
including transformed mammalian cells; and hybridoma and mAb methods).235
For example, the following are subject to the centralized procedure: cell therapy,
gene therapy, vaccines from strains developed through recombinant DNA
technology (including gene deletion), and “any medicinal product for which a
monoclonal antibody is used at any stage in the manufacturing process.
Nonetheless, some biologics are still approved at the Member State level. For
example, many vaccines do not fall within the scope of the centralized procedure.
The EMA has published a guideline intended to harmonize the summaries of
product characteristics and patient information leaflets for human vaccines. This
chapter discusses the requirements of the EU centralized procedure
The approval standards for biotechnology products are the same as for chemically
synthesized medicines. Both types of products must be safe and effective and
have appropriate quality. Because of their special characteristics, however,
biotechnology products must comply with several additional dossier
requirements.
37
The MAA for a biotechnology product must meet the standard dossier submission
requirements, as described in Article 8 of the Medicines Directive.238
Consequently, the MAA must generally comply with the CTD format, including
with respect to Module I (administrative information, including labeling and
mock-ups), Module 2 (various summaries), Module 3 (chemical, pharmaceutical,
and biological information), Module 4 (nonclinical reports), and Module 5
(clinical study reports)
MAAs for biologics also must meet special requirements. The applicant must
thoroughly describe the manufacturing process and must (1) provide information
on the origin and history of the starting materials; (2) demonstrate that the active
substance complies with specific measures for preventing the transmission of
animal spongiform encephalopathies; (3) if cell banks are used, demonstrate that
cell characteristics remain unchanged at the passage level for production (and
beyond); (4) provide information as to whether there are adventitious agents in
seed materials, cell banks, pools of serum or plasma, and all other materials of
biological origin, and, if it is not possible to avoid the presence of potentially
pathogenic adventitious agents, show that further processing ensures elimination
or inactivation of the agents; (5) if possible, base vaccine production on a seed lot
system and established cell banks; (6) in case of medicines derived from human
blood or plasma, describe the origin, criteria, and procedures for the collection,
transportation, and storage of the starting material; and (7) describe the
manufacturing facilities and equipment
Other special rules apply certain types of biological medicines. For example, for
plasma-derived medicinal products, the applicant must provide an information
dossier, the Plasma Master File. MAAs for vaccines other than for influenza need
to contain a Vaccine Antigen Master File. Special rules also apply to advanced
therapy medicinal products, including gene therapies, somatic cell therapies, and
tissue-engineered products.

Stability, safety, advertising, labelling and packing of biologics in EU

Stability
ICH Topic Q 5 C Quality of Biotechnological Products: Stability Testing of
Biotechnological/Biological Products
(ttps://www.ema.europa.eu/en/documents/scientific-guideline/ich-topic-q-5-c-
quality-biotechnological-products-stability-testing-biotechnological/biological-
products_en.pdf)
1. Preamble
2. Scope of the annex
3. Terminology
4. Selection of batches
38
4.1 Drug Substance (Bulk Material)
Where bulk material is to be stored after manufacture but prior to formulation and
final manufacturing, stability data should be provided on at least three batches for
which manufacture and storage are representative of the manufacturing scale of
production. A minimum of six months stability data at the time of submission
should be submitted in cases where storage periods greater than six months are
requested. For drug substances with storage periods of less than six months, the
minimum amount of stability data in the initial submission should be determined
on a case-by-case basis. Data from pilot-plant-scale batches of drug substance
produced at a reduced scale of fermentation and purification may be provided at
the time the dossier is submitted to the regulatory agencies with a commitment to
place the first three manufacturing scale batches into the long-term stability
program after approval. The quality of the batches of drug substance placed into
the stability program should be representative of the quality of the material used
in pre-clinical and clinical studies and of the quality of the material to be made at
manufacturing scale. In addition, the drug substance (bulk material) made at pilot-
plant scale should be produced by a process and stored under conditions
representative of that used for the manufacturing scale. The drug substance
entered into the stability program should be stored in containers which properly
represent the actual holding containers used during manufacture. Containers of
reduced size may be acceptable for drug substance stability testing provided that
they are constructed of the same material and use the same type of
container/closure system that is intended to be used during manufacture.
4.2 Intermediates
During manufacture of biotechnological/biological products, the quality and
control of certain intermediates may be critical to the production of the final
product. In general, the manufacturer should identify intermediates and generate
in-house data and process limits that assure their stability within the bounds of
the developed process. While the use of pilot-plant- scale data is permissible, the
manufacturer should establish the suitability of such data using the
manufacturing-scale process.
4.3 Drug Product (Final Container Product)
Stability information should be provided on at least three batches of final
container product representative of that which will be used at manufacturing
scale. Where possible, batches of final container product included in stability
testing should be derived from different batches of bulk material. A minimum of
six months data at the time of submission should be submitted in cases where
storage periods greater than six months are requested. For drug products with
storage periods of less than six months, the minimum amount of stability data in
the initial submission should be determined on a case-by-case basis. Product
39
expiration dating will be based upon the actual data submitted in support of the
application. Since dating is based upon the real-time/real-temperature data
submitted for review, continuing updates of initial stability data should occur
during the review and evaluation process. The quality of the final container
product placed on stability studies should be representative of the quality of the
material used in the preclinical and clinical studies. Data from pilot-plant scale
batches of drug product may be provided at the time the dossier is submitted to
the regulatory agencies with a commitment to place the first three manufacturing
scale batches into the long-term stability program after approval. Where pilot-
plant scale batches were submitted to establish the dating for a product and, in the
event that product produced at manufacturing scale does not meet those long-
term stability specifications throughout the dating period or is not representative
of the material used in pre-clinical and clinical studies, the applicant should notify
the appropriate regulatory authorities to determine a suitable course of action.
4.4 Sample selection criteria
Where one product is distributed in batches differing in fill volume (e.g., 1
milliliter (ml), 2 ml, or 10 ml), unitage (e.g., 10 units, 20 units, or 50 units), or
mass (e.g., 1 milligram (mg), 2 mg, or 5 mg) samples to be entered into the
stability program may be selected on the basis of a matrix system and/or by
bracketing. Matrixing, i.e., the statistical design of a stability study in which
different fractions of samples are tested at different sampling points, should only
be applied when appropriate documentation is provided that confirms that the
stability of the samples tested represents the stability of all samples. The
differences in the samples for the same drug product should be identified as, for
example, covering different batches, different strengths, different sizes of the
same closure and possibly, in some cases, different container/closure systems.
Matrixing should not be applied to samples with differences that may affect
stability, such as different strengths and different containers/closures, where it
cannot be confirmed that the products respond similarly under storage conditions.
Where the same strength and exact container/closure system is used for three or
more fill contents, the manufacturer may elect to place only the smallest and
largest container size into the stability program, i.e., bracketing. The design of a
protocol that incorporates bracketing assumes that the stability of the intermediate
condition samples are represented by those at the extremes. In certain cases, data
may be needed to demonstrate that all samples are properly represented by data
collected for the extremes.
5. STABILITY-INDICATING PROFILE
On the whole, there is no single stability-indicating assay or parameter that
profiles the stability characteristics of a biotechnological/biological product.
Consequently, the manufacturer should propose a stability-indicating profile that
40
provides assurance that changes in the identity, purity and potency of the product
will be detected. At the time of submission, applicants should have validated the
methods that comprise the stability-indicating profile and the data should be
available for review. The determination of which tests should be included will be
product-specific. The items emphasised in the following subsections are not
intended to be all-inclusive, but represent product characteristics that should
typically be documented to adequately demonstrate product stability
5.1 Protocol
The dossier accompanying the application for marketing authorisation should
include a detailed protocol for the assessment of the stability of both drug
substance and drug product in support of the proposed storage conditions and
expiration dating periods. The protocol should include all necessary information
which demonstrates the stability of the biotechnological/biological product
throughout the proposed expiration dating period including, for example, well-
defined specifications and test intervals. The statistical methods that should be
used are described in the Tripartite Guideline on stability.
5.2 Potency
When the intended use of a product is linked to a definable and measurable
biological activity, testing for potency should be part of the stability studies. For
the purpose of stability testing of the products described in this guideline, potency
is the specific ability or capacity of a product to achieve its intended effect. It is
based on the measurement of some attribute of the product and is determined by
a suitable quantitative method. In general, potencies of
biotechnological/biological products tested by different laboratories can be
compared in a meaningful way only if expressed in relation to that of an
appropriate reference material. For that purpose, a reference material calibrated
directly or indirectly against the corresponding national or international reference
material should be included in the assay. Potency studies should be performed at
appropriate intervals as defined in the stability protocol and the results should be
reported in units of biological activity calibrated, whenever possible, against
nationally or internationally recognised standard. Where no national or
international standards exists, the assay results may be reported in in-house
derived units using a characterised reference material. In some
biotechnological/biological products, potency is dependent upon the conjugation
of the active ingredient(s) to a second moiety or binding to an adjuvant.
Dissociation of the active ingredient(s) from the carrier used in conjugates or
adjuvants should be examined in real-time/real-temperature studies (including
conditions encountered during shipment). The assessment of the stability of such
products may be difficult since, in some cases, in vitro tests for biological activity
and physicochemical characterisation are impractical or provide inaccurate
41
results. Appropriate strategies (e.g., testing the product prior to
conjugation/binding, assessing the release of the active compound from the
second moiety, in vivo assays) or the use of an appropriate surrogate test should
be considered to overcome the inadequacies of in vitro testing.
5.3 Purity and Molecular Characterisation
For the purpose of stability testing of the products described in this guideline,
purity is a relative term. Due to the effect of glycosylation, deamidation, or other
heterogeneities, the absolute purity of a biotechnological/biological product is
extremely difficult to determine. Thus, the purity of a biotechnological/biological
product should be typically assessed by more than one method and the purity
value derived is method-dependent. For the purpose of stability testing, tests for
purity should focus on methods for determination of degradation products. The
degree of purity, as well as individual and total amounts of degradation products
of the
biotechnological/biological product entered into the stability studies, should be
reported and documented whenever possible. Limits of acceptable degradation
should be derived from the analytical profiles of batches of the drug substance
and drug product used in the pre-clinical and clinical studies.
5.4 Other Product Characteristics
The following product characteristics, though not specifically relating to
biotechnological/biological products, should be monitored and reported for the
drug product in its final container:
• Visual appearance of the product (colour and opacity for solutions/suspensions;
colour, texture and dissolution time for powders), visible particulates in solutions
or after the reconstitution of powders or lyophilised cakes, pH, and moisture level
of powders and lyophilised products.
• Sterility testing or alternatives (e.g., container/closure integrity testing) should
be performed at a minimum initially and at the end of the proposed shelf-life.
• Additives (e.g., stabilisers, preservatives) or excipients may degrade during the
dating period of the drug product. If there is any indication during preliminary
stability studies that reaction or degradation of such materials adversely affect the
quality of the drug product, these items may need to be monitored during the
stability program.
• The container/closure has the potential to adversely affect the product and
should be carefully evaluated (see below).
6. STORAGE CONDITIONS
6.1 Temperature
Since most finished biotechnological/biological products need precisely defined
storage temperatures, the storage conditions for the real-time/real-temperature
stability studies may be confined to the proposed storage temperature.
42
6.2 Humidity
Biotechnological/biological products are generally distributed in containers
protecting them against humidity. Therefore, where it can be demonstrated that
the proposed containers (and conditions of storage) afford sufficient protection
against high and low humidity, stability tests at different relative humidities can
usually be omitted. Where humidity-protecting containers are not used,
appropriate stability data should be provided.
6.3 Accelerated and stress conditions
As previously noted, the expiration dating should be based on real-time/real-
temperature data. However, it is strongly suggested that studies be conducted on
the drug substance and drug product under accelerated and stress conditions.
Studies under accelerated conditions may provide useful support data for
establishing the expiration date, provide product stability information for future
product development (e.g., preliminary assessment of proposed manufacturing
changes such as change in formulation, scale-up), assist in validation of analytical
methods for the stability program, or generate information which may help
elucidate the degradation profile of the drug substance or drug product. Studies
under stress conditions may be useful in determining whether accidental
exposures to conditions other than those proposed (e.g., during transportation) are
deleterious to the product and also for evaluating which specific test parameters
may be the best indicators of product stability. Studies of the exposure of the drug
substance or drug product to extreme conditions may help to reveal patterns of
degradation; if so, such changes should be monitored under proposed storage
conditions. While the Tripartite Guideline on stability describes the conditions of
the accelerated and stress study, the applicant should note that those conditions
may not be appropriate for biotechnological/biological products. Conditions
should be carefully selected on a case-by-case basis.
6.4 Light
Applicants should consult the appropriate regulatory authorities on a case-by-case
basis to determine guidance for testing.
6.5 Container/Closure
Changes in the quality of the product may occur due to the interactions between
the formulated biotechnological/biological product and container/closure. Where
the lack of interactions cannot be excluded in liquid products (other than sealed
ampoules), stability studies should include samples maintained in the inverted or
horizontal position (i.e., in contact with the closure), as well as in the upright
position, to determine the effects of the closure on product quality. Data should
be supplied for all different container/closure combinations that will be marketed.
In addition to the standard data necessary for a conventional single-use vial, the
applicant should demonstrate that the closure used with a multiple-dose vial is
43
capable of withstanding the conditions of repeated insertions and withdrawals so
that the product retains its full potency, purity, and quality for the maximum
period specified in the instructions-for-use on containers, packages, and/or
package inserts. Such labelling should be in accordance with relevant
national/regional requirements.
6.6 Stability after Reconstitution of Freeze-Dried Product
The stability of freeze-dried products after their reconstitution should be
demonstrated for the conditions and the maximum storage period specified on
containers, packages, and/or package inserts. Such labelling should be in
accordance with relevant national/regional requirements.
7. TESTING FREQUENCY
The shelf-lives of biotechnological/biological products may vary from days to
several years. Thus, it is difficult to draft uniform guidelines regarding the
stability study duration and testing frequency that would be applicable to all types
of biotechnological/biological products. With only a few exceptions, however,
the shelf-lives for existing products and potential future products will be within
the range of 0.5 to five years. Therefore, the guidance is based upon expected
shelf-lives in that range. This takes into account the fact that degradation of
biotechnological/biological products may not be governed by the same factors
during different intervals of a long storage period. When shelf-lives of one year
or less are proposed, the real-time stability studies should be conducted monthly
for the first three months and at three-month intervals thereafter. For products
with proposed shelf-lives of greater than one year, the studies should be
conducted every three months during the first year of storage, every six months
during the second year, and annually thereafter.While the testing intervals listed
above may be appropriate in the pre-approval or pre-license stage, reduced testing
may be appropriate after approval or licensure where data are available that
demonstrate adequate stability. Where data exist that indicate the stability of a
product is not compromised, the applicant is encouraged to submit a protocol
which supports elimination of specific test intervals (e.g., nine-month testing) for
post-approval/post- licensure, long-term studies.
8. SPECIFICATIONS
Although biotechnological/biological products may be subject to significant
losses of activity, physicochemical changes, or degradation during storage,
international and national regulations have provided little guidance with respect
to distinct release and end of shelf-life specifications. Recommendations for
maximum acceptable losses of activity, limits for physicochemical changes, or
degradation during the proposed shelf-life have not been developed for individual
types or groups of biotechnological/biological products but are considered on a
case-by-case basis. Each product should retain its specifications within
44
established limits for safety, purity, and potency throughout its proposed shelf-
life. These specifications and limits should be derived from all available
information using the appropriate statistical methods. The use of different
specifications for release and expiration should be supported by sufficient data to
demonstrate that clinical performance is not affected as discussed in the Tripartite
Guideline on stability.
9. LABELLING
For most biotechnological/biological drug substances and drug products,
precisely defined storage temperatures are recommended. Specific
recommendations should be stated, particularly for drug substances and drug
products that cannot tolerate freezing. These conditions, and where appropriate,
recommendations for protection against light and/or humidity, should appear on
containers, packages, and/or package inserts. Such labelling should be in
accordance with relevant national regional requirements

Safety
Safety of biosimilars
General considerations on safety for biosimilars
Since the introduction of the first biosimilar in clinical use in 2006, an increasing
number of biosimilars have been approved and safely used in the EU.
Apart from reactions of an immunological nature, most adverse drug reactions
(ADRs) can be predicted from the pharmacological action, and occur with both
the reference medicine and the biosimilar (e.g. high haemoglobin levels with
epoetins). Of more than 50 biosimilars approved in the EU to date, none has been
withdrawn or suspended for reasons of safety or efficacy.
Safety monitoring for all biological medicines, including biosimilars
A robust regulatory framework to protect patients’ safety
The EU has a well-established system for monitoring, reporting, assessing and
preventing adverse drug reactions for all medicines, including all biological
medicines. Authorities continuously evaluate the benefit-risk balance of all
medicines and take necessary regulatory action (e.g. introducing new warnings in
the product information or restricting use) to safeguard public health.
Same safety monitoring for all biological medicines
Safety monitoring of biosimilars follows the same requirements that apply to all
biological medicines. There is no specific requirement just for biosimilars.
A plan to manage risks always in place
Companies applying for marketing authorisation in the EU must submit a risk
management plan (RMP) for each new medicine, including biological medicines.
The RMP, which is tailored for each product, includes a pharmacovigilance plan
and risk minimisation measures to identify, characterise and minimise a
45
medicine’s important risks. The RMP of a biosimilar is based on knowledge and
experience gained with the reference medicine. For all medicines approved in the
EU, in addition to the conditions of use in the product information, additional
measures (e.g. educational brochures, patient alert cards or inclusion of patients
in registries) may be needed to manage a specific risk. When any extra measure
is applied to the reference medicine (e.g. educational material), it should also be
considered for the biosimilar
Safety studies after marketing
Post-marketing studies allow monitoring of known risks and also permit detection
of rare adverse drug reactions that emerge only when large numbers of patients
have been treated for a long period. This is why at the time of approval regulators
may impose on the company an obligation to carry out a postauthorisation safety
study (PASS). This also binds the company to register the study in the publicly
available EU PAS Register: http://www.encepp.eu/
encepp_studies/indexRegister.shtml. The criteria for deciding whether a post-
marketing safety study is needed are the same for all medicines, including
biosimilars and their reference medicines. If a PASS has been requested for a
reference medicine, it will normally be requested also for the biosimilar.
Collecting spontaneous adverse drug reactions and submitting PSURs
As for all medicines, companies marketing biosimilars must collect all reports of
suspected adverse drug reactions and submit periodic safety update reports
(PSURs) to regulators. Regulatory authorities review reports for any signal
suggestive of a possible unwanted effect. If a signal is suspected, it is evaluated
by EMA’s scientific committees, which will determine if any action is needed
Additional monitoring and black triangle
All new medicines are closely monitored after being introduced to the market.
Biological medicines approved after 1 January 2011 are subject to socalled
‘additional monitoring’ and are included in a list of medicines under ‘additional
monitoring’. This list includes medicines authorised in the EU that are being
monitored particularly closely by regulatory authorities, for example because the
active substance is new to the market or there are limited data on its long-term
use. In this case, they are monitored particularly closely during the first years after
approval.
The black triangle symbol identifies medicines under additional monitoring. It is
displayed in the SmPC and package leaflet together with the sentence: “This
medicinal product is subject to additional monitoring” Additional monitoring
encourages healthcare professionals and patients to report any suspected adverse
drug reactions of new medicines. This enables prompt identification and analysis
of information about the medicines to add to the knowledge gained during clinical

46
trials. If a biological medicine (or biosimilar) is labelled with a black triangle, it
does not necessarily mean that there are additional safety concerns with it
Monitoring long-term or long-latency adverse events
Safety monitoring of long-term or long-latency events for biological medicines
follows the same principles as for small-molecule medicines. However, detecting
and characterising the longterm adverse drug reactions of biological medicines
may be difficult using only spontaneous reporting. This is why additional
pharmacovigilance activities (such as including patients in registries) could be
required in certain cases.
Traceability: importance of identifying biological medicines by tradename
and batch number
An important requirement for the safety monitoring of all biological medicines is
the need for product and batch traceability during clinical use and at all levels in
the supply chain10. This covers the time from release by the manufacturer and
progress through the entire distribution chain until the medicine is administered
to the patient. As required by EU law, every medicine will have an invented name
(tradename or brand name) together with the active substance name (i.e. the
international nonproprietary name, or INN, which is assigned by WHO). For
identifying and tracing biological medicines in the EU, medicines have to be
distinguished by the tradename and batch number and this is particularly
important in cases where more than one medicine with the same INN exists on
the market. This ensures that, in line with EU requirements for ADR reporting,
the medicine can be correctly identified if any product-specific safety (or
immunogenicity) concern arises. Healthcare professionals play an essential role
in contributing to the understanding of a medicine’s safety profile during clinical
use. Biological medicines are approved on the basis of an acceptable safety
profile and they should be used according to the recommendations in the
summary of product characteristics (SmPC) and package leaflet. If a suspected
ADR is identified for a biological medicine, healthcare professionals should
report it, taking care to include the tradename and batch number of the medicine.
It is important that healthcare professionals report any suspected ADR of a
biosimilar even if the reaction is already listed in the reference medicine’s SmPC.
For a biological medicine, its tradename, INN and batch number can be found in
the product packaging. A statement has been introduced in the SmPC to remind
healthcare professionals of the need to clearly record the tradename and batch
number in the patient’s healthcare records.

LABELLING AND PACKAGE LEAFLET

Article 54

47
The following particulars shall appear on the outer packaging of medicinal
products or, where there is no outer packaging, on the immediate packaging:
(a) the name of the medicinal product followed by the common name where the
product contains only one active substance and if its name is an invented name;
where a medicinal product is available in several pharmaceutical forms and/or
several strengths, the pharmaceutical form and/or the strength (baby, child or
adult as appropriate) must be included in the name of the medicinal product;
(b) a statement of the active substances expressed qualitatively and quantitatively
per dosage unit or according to the form of administration for a given volume or
weight, using
their common names;
(c) the pharmaceutical form and the contents by weight, by volume or by number
of doses of the product:
(d) a list of those excipients known to have a recognized action or effect and
included in the guidelines published pursuant to Article 65. However, if the
product is injectable, or a topical or eye preparation, all excipients must be stated;
(e) the method and, if necessary, the route of administration;
(f) a special warning that the medicinal product must be stored out of reach of
children;
(g) a special warning, if this is necessary for the medicinal
product;
(h) the expiry date in clear terms (month/year);
(i) special storage precautions, if any;
(j) special precautions for disposal of unused medicinal
products or waste materials from medicinal products, if appropriate;
(k) the name and address of the holder of the authorization for placing the
medicinal product on the market;
(l) the number of the authorization for placing the medicinal product on the
market;
(m) the manufacturer's batch number;
(n) in the case of self-medication, instructions on the use of the medicinal
products.
Article 55
1. The particulars laid down in Articles 54 and 62 shall appear on immediate
packagings other than those referred to in paragraphs 2 and 3.
2. The following particulars at least shall appear on immediate packagings which
take the form of blister packs and are placed in an outer packaging that complies
with the requirements laid down in Articles 54 and 62.
- the name of the medicinal product as laid down in Article 54(a),

48
- the name of the holder of the authorization for placing the product on the
market,
- the expiry date,
- the batch number.
3. The following particulars at least shall appear on small immediate packaging
units on which the particulars laid down in Articles 54 and 62 cannot be
displayed:
-the name of the medicinal product and, if necessary, the strength and the route
of administration,
- the method of administration,
- the expiry date,
- the batch number,
- the contents by weight, by volume or by unit.
Article 56
The particulars referred to in Articles 54, 55 and 62 shall be easily legible, clearly
comprehensible and indelible.
Article 57
Notwithstanding Article 60, Member States may require the use of certain forms
of labelling of the medicinal product making it possible to ascertain:
- the price of the medicinal product,
- the reimbursement conditions of social security organizations,
- the legal status for supply to the patient, in accordance with Title VI,
- identification and authenticity
Article 58
The inclusion in the packaging of all medicinal products of a package leaflet shall
be obligatory unless all the information required by Articles 59 and 62 is directly
conveyed on the outer packaging or on the immediate packaging
Article 59
The package leaflet shall be drawn up in accordance with the summary of the
product characteristics; it shall include, in the following order:
(a) for the identification of the medicinal product:
- the name of the medicinal product, followed by the common name if the product
contains only one active substance and if its name is an invented name; where a
medicinal product is available in several pharmaceutical forms and/or several
strengths, the pharmaceutical form and/or the strength (for example, baby, child,
adult) must be included in the name of the medicinal product,
—a full statement of the active substances and excipients expressed qualitatively
and a statement of the active substances expressed quantitatively, using their
common names, in the case of each presentation of the medicinal product,

49
— the pharmaceutical form and the contents by weight, by volume or by number
of doses of the product, in the case of each presentation of the product,
— the pharmaco-therapeutic group, or type of activity in terms easily
comprehensible for the patient,
— the name and address of the holder of the authorization for placing the
medicinal product on the market and of the manufacturer;
(b) the therapeutic indications;
c) list of information which is necessary before taking the medicinal product:
—contra-indications,
—appropriate precautions for use,
— forms of interaction with other medicinal products and other forms of
interaction (e.g. alcohol, tobacco, foodstuffs) which may affect the action of the
medicinal product,
—special warnings; this list must:
— take into account the particular condition of certain categories of users (e.g.
children, pregnant or breastfeeding women, the elderly, persons with specific
pathological conditions), —mention, if appropriate, potential effects on the ability
to drive vehicles or to operate machinery,
— detail those excipients, knowledge of which is important for the safe and
effective use of the medicinal product and included in the guidelines published
pursuant to Article 65;
(d) the necessary and usual instructions for proper use, in particular:
—the dosage,
—the method and, if necessary, route of administration,
— the frequency of administration, specifying if necessary, the appropriate time
at which the medicinal product may or must be administered, and, as appropriate,
depending on the nature of the product:
—the duration of treatment, where it should be limited,
— the action to be taken in the case of an overdose (e.g., symptoms, emergency
procedures), —the course of action to take when one or more doses have not been
taken,
—indication, if necessary, of the risk of withdrawal effects;
(e) a description of the undesirable effects which can occur under normal use of
the medicinal product and, if necessary, the action to be taken in such a case; the
patient should be expressly invited to communicate any undesirable effect which
is not mentioned in the leaflet to his doctor or to his pharmacist;
(f) a reference to the expiry date indicated on the label, with:
—a warning against using the product after this date,
—where appropriate, special storage precautions,
—if necessary, a warning against certain visible signs of deterioration
50
(g) the date on which the package leaflet was last revised.
2. Notwithstanding paragraph 1(b), the authority competent may decide that
certain therapeutic indications shall not be mentioned in the package leaflet,
where the dissemination of such information might have serious disadvantages
for the patient
Article 60
Member States may not prohibit or impede the placing on the market of medicinal
products within their territory on grounds connected with labelling or the package
leaflet where these comply with the requirements of this Title
Article 61
1. One or more specimens or mock-ups of the outer packaging and the immediate
packaging of a medicinal product, together with the draft package leaflet, shall be
submitted to the authorities competent for authorizing marketing when the
marketing authorization is requested.
2. The competent authority shall refuse the marketing authorization if the
labelling or the package leaflet do not comply with the provisions of this Title or
if they are not in accordance with the particulars listed in the summary of product
characteristics.
3. All proposed changes to an aspect of the labelling or the package leaflet
covered by this Title and not connected with the summary of product
characteristics shall be submitted to the authorities competent for authorizing
marketing. If the competent authorities have not opposed a proposed change
within 90 days following the introduction of the request, the applicant may put
the change into effect.
4. The fact that the competent authority do not refuse a marketing authorization
pursuant to paragraph 2 or a change to the labelling or the package leaflet pursuant
to paragraph 3 does not alter the general legal liability of the manufacturer or as
appropriate the marketing authorization holder.
Article 62
The outer packaging and the package leaflet may include symbols or pictograms
designed to clarify certain information mentioned in Articles 54 and 59(1) and
other information compatible with the summary of the product characteristics
which is useful for health education, to the exclusion of any element of a
promotional nature.
Article 63
1. The particulars for labelling listed in Articles 54, 59 and 62 shall appear in the
official language or languages of the Member State where the product is placed
on the market. The first subparagraph shall not prevent these particulars from
being indicated in several languages, provided that the same particulars appear in
all the languages used.
51
 2. The package leaflet must be written in clear and understandable terms for the
users and be clearly legible in the official language or languages of the Member
State where the medicinal product is placed on the market. The first subparagraph
shall not prevent the package leaflet being printed in several languages, provided
that the same information is given in all the languages used. 3. The competent
authorities may exempt labels and package leaflets for specific medicinal
products from the obligation that certain particulars shall appear and that the
leaflet must be in the official language or languages of the Member State where
the product is placed on the market, when the product is not intended to be
delivered to the patient for self-administration
Article 64
Where the provisions of this Title are not complied with, and a notice served on
the person concerned has remained without effect, the competent authorities of
the Member States may suspend the marketing authorization, until the labelling
and the package leaflet of the medicinal product in question have been made to
comply with the requirements of this Title
Article 65
As necessary, the Commission shall publish guidelines concerning in particular:
— the formulation of certain special warnings for certain categories of medicinal
products,
—the particular information needs relating to self-medication,
—the legibility of particulars on the labelling and package leaflet,
—methods for the identification and authentication of medicinal products,
—the list of excipients which must feature on the labelling of medicinal products
and the way these excipients must be indicated.
These guidelines shall be adopted in the form of a Directive, in accordance with
the procedure referred to in Article 121(2).
Article 66
1. The outer carton and the container of medicinal products containing
radionuclides shall be labelled in accordance with the regulations for the safe
transport of radioactive materials laid down by the International Atomic Energy
Agency. Moreover, the labelling shall comply with the provisions set out in
paragraphs 2 and 3.
2. The label on the shielding shall include the particulars mentioned in Article
54. In addition, the labelling on the shielding shall explain in full, the codings
used on the vial and shall indicate, where necessary, for a given time and date,
the amount of radioactivity per dose or per vial and the number of capsules, or,
for liquids, the number of millilitres in the container.
3. The vial shall be labelled with the following information:

52
— the name or code of the medicinal product, including the name or chemical
symbol of the radionuclide,
—the batch identification and expiry date,
—the international symbol for radioactivity,
—the name of the manufacturer,
—the amount of radioactivity as specified in paragraph 2. Article 67
Article 67
The competent authority shall ensure that a detailed instruction leaflet is enclosed
with the packaging of radiopharmaceuticals, radionuclide generators,
radionuclide kits or radionuclide precursors. The text of this leaflet shall be
established in accordance with the provisions of Article 59. In addition, the leaflet
shall include any precautions to be taken by the user and the patient during the
preparation and administration of the medicinal product and special precautions
for the disposal of the packaging and its unused contents.
Article 68
Without prejudice to the provisions of Article 69, homeopathic medicinal
products shall be labelled in accordance with the provisions of this title and shall
be identified by a reference on their labels, in clear and legible form, to their
homeopathic nature
Article 69
1. In addition to the clear mention of the words
‘ homeopathic medicinal product
’ , the labelling and, where appropriate, the package insert for the medicinal
products referred to in Article 14(1) shall bear the following, and no other,
information:
—the scientific name of the stock or stocks followed by the degree of dilution,
making use of the symbols of the pharmacopoeia used in accordance with
Article 1(5),
— name and address of the registration holder and, where appropriate, of the
manufacturer,
—method of administration and, if necessary, route,
—expiry date, in clear terms (month, year),
—pharmaceutical form,
—contents of the sales presentation,
—special storage precautions, if any,
—a special warning if necessary for the medicinal product,
—manufacturer's batch number,
—registration number,
—homeopathic medicinal product without approved therapeutic indications,

53
 — a warning advising the user to consult a doctor if the symptoms persist
during the use of the medicinal product.
2. Notwithstanding paragraph 1, Member States may require the use of certain
types of labelling in order to show:
—the price of the medicinal product,
—the conditions for refunds by social security bodies

Advertising
Article 86
1. For the purposes of this Title, advertising of medicinal products shall
include any form of door-to-door information, canvassing activity or
inducement designed to promote the prescription, supply, sale or
consumption of medicinal products; it shall include in particular:
—the advertising of medicinal products to the general public,
— advertising of medicinal products to persons qualified to prescribe or
supply them, —visits by medical sales representatives to persons qualified
to prescribe medicinal products,
— the provision of inducements to prescribe or supply medicinal products
by the gift, offer or promise of any benefit or bonus, whether in money or in kind,
except when their intrinsic value is minimal,
— sponsorship of promotional meetings attended by persons qualified to
prescribe or supply medicinal products
, — sponsorship of scientific congresses attended by persons qualified to
prescribe or supply medicinal products and in particular payment of their
travelling and accommodation expenses in connection therewith
2. The following are not covered by this Title:
—the labelling and the accompanying package leaflets, which are subject
to the provisions of Title V,
— correspondence, possibly accompanied by material of a non-
promotional nature, needed to answer a specific question about a particular
medicinal product,
— factual, informative announcements and reference material relating, for
example, to pack changes, adverse-reaction warnings as part of general
drug precautions, trade catalogues and price lists, provided they include no
product claims,
— statements relating to human health or diseases, provided there is no
reference, even indirect, to medicinal products.
Article 87

54
 1. Member States shall prohibit any advertising of a medicinal product in
respect of which a marketing authorization has not been granted in
accordance with Community law.
2. All parts of the advertising of a medicinal product must comply with the
particulars listed in the summary of product characteristics.
3. The advertising of a medicinal product:
— shall encourage the rational use of the medicinal product, by presenting
it objectively and without exaggerating its properties,
—shall not be misleading.
Article 88
1. Member States shall prohibit the advertising to the general public of
medicinal products which:
—are available on medical prescription only, in accordance with Title VI
—contain psychotropic or narcotic substances, such as the United Nations
Conventions of 1961 and 1971,
— may not be advertised to the general public in accordance with the
second subparagraph of paragraph 2.
2. Medicinal products may be advertised to the general public which, by
virtue of their composition and purpose, are intended and designed for use
without the intervention of a medical practitioner for diagnostic purposes
or for the prescription or monitoring of treatment, with the advice of the
pharmacist, if necessary.
Member States shall prohibit the mentioning in advertising to the general
public of therapeutic indications such as:
—tuberculosis,
—sexually transmitted diseases,
—other serious infectious diseases,
—cancer and other tumoral diseases,
—chronic insomnia,
—diabetes and other metabolic illnesses.
3. Member States shall be able to ban, on their territory, advertising to the
general public of medicinal products the cost of which may be reimbursed
4. The prohibition referred to in paragraph 1 shall not apply to vaccination
campaigns carried out by the industry and approved by the competent
authorities of the Member States.
5. The prohibition referred to in paragraph 1 shall apply without prejudice to
Article 14 of Directive 89/552/EEC.
6. Member States shall prohibit the direct distribution of medicinal products
to the public by the industry for promotional purposes; they may, however,
authorize such distribution in special cases for other purposes.
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 Article 89
1. Without prejudice to Article 88, all advertising to the general public of a
medicinal product shall: (a) be set out in such a way that it is clear that the
message is an advertisement and that the product is clearly identified as a
medicinal product;
(b) include the following minimum information:
— the name of the medicinal product, as well as the common name if the
medicinal product contains only one active substance
—the information necessary for correct use of the medicinal product,
— an express, legible invitation to read carefully the instructions on the package
leaflet or on the outer packaging, as the case may be
2. Member States may decide that the advertising of a medicinal product to the
general public may, notwithstanding paragraph 1, include only the name of the
medicinal product if it is intended solely as a reminder
Article 90
The advertising of a medicinal product to the general public shall not contain any
material which:
(a) gives the impression that a medical consultation or surgical operation is
unnecessary, in particular by offering a diagnosis or by suggesting treatment by
mail;
(b) suggests that the effects of taking the medicine are guaranteed, are
unaccompanied by adverse reactions or are better than, or equivalent to, those of
another treatment or medicinal product;
(c) suggests that the health of the subject can be enhanced by taking the medicine;
(d) suggests that the health of the subject could be affected by not taking the
medicine; this prohibition shall not apply to the vaccination campaigns referred
to in Article 88(4);
(e) is directed exclusively or principally at children;
(f) refers to a recommendation by scientists, health professionals or persons who
are neither of the foregoing but who, because of their celebrity, could encourage
the consumption of medicinal products;
(g) suggests that the medicinal product is a foodstuff, cosmetic or other consumer
product;
(h) suggests that the safety or efficacy of the medicinal product is due to the fact
that it is natural;
(i) could, by a description or detailed representation of a case history, lead to
erroneous self-diagnosis;
(j) refers, in improper, alarming or misleading terms, to claims of recovery;

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(k) uses, in improper, alarming or misleading terms, pictorial representations of
changes in the human body caused by disease or injury, or of the action of a
medicinal product on the human body or parts thereof;
(l) mentions that the medicinal product has been granted a marketing
authorization.
Article 91
1. Any advertising of a medicinal product to persons qualified to prescribe or
supply such products shall include
— essential information compatible with the summary of product
characteristics;
— the supply classification of the medicinal product. Member States may
also require such advertising to include the selling price or indicative price
of the various presentations and the conditions for reimbursement by social
security bodies
2. Member States may decide that the advertising of a medicinal product to
persons qualified to prescribe or supply such products may,
notwithstanding paragraph 1, include only the name of the medicinal
product, if it is intended solely as a reminder.
Article 92
1. Any documentation relating to a medicinal product which is transmitted as part
of the promotion of that product to persons qualified to prescribe or supply it shall
include, as a minimum, the particulars listed in Article 91(1) and shall state the
date on which it was drawn up or last revised.
2. All the information contained in the documentation referred to in paragraph 1
shall be accurate, up-to-date, verifiable and sufficiently complete to enable the
recipient to form his or her own opinion of the therapeutic value of the medicinal
product concerned.
3. Quotations as well as tables and other illustrative matter taken from medical
journals or other scientific works for use in the documentation referred to in
paragraph 1 shall be faithfully reproduced and the precise sources indicated.
Article 93
1. Medical sales representatives shall be given adequate training by the firm
which employs them and shall have sufficient scientific knowledge to be able to
provide information which is precise and as complete as possible about the
medicinal products which they promote.
2. During each visit, medical sales representatives shall give the persons visited,
or have available for them, summaries of the product characteristics of each
medicinal product they present together, if the legislation of the Member State so
permits, with details of the price and conditions for reimbursement referred to in
Article 91(1).
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3. Medical sales representatives shall transmit to the scientific service referred to
in Article 98(1) any information about the use of the medicinal products they
advertise, with particular reference to any adverse reactions reported to them by
the persons they visit
Article 94
1. Where medicinal products are being promoted to persons qualified to prescribe
or supply them, no gifts, pecuniary advantages or benefits in kind may be
supplied, offered or promised to such persons unless they are inexpensive and
relevant to the practice of medicine or pharmacy.
2. Hospitality at sales promotion shall always be reasonable in level and
secondary to the main purpose of the meeting and must not be extended to other
than health professionals.
3. Persons qualified to prescribe or supply medicinal products shall not solicit or
accept any inducement prohibited under paragraph 1 or contrary to paragraph 2.
4. Existing measures or trade practices in Member States relating to prices,
margins and discounts shall not be affected by paragraphs 1, 2 and 3.
Article 95
The provisions of Article 94(1) shall not prevent hospitality being offered,
directly or indirectly, at events for purely professional and scientific purposes;
such hospitality shall always be reasonable in level and remain subordinate to the
main scientific objective of the meeting; it must not be extended to persons other
than health professionals.
Article 96
1. Free samples shall be provided on an exceptional basis only to persons
qualified to prescribe them and on the following conditions:
(a) the number of samples for each medicinal product each year on prescription
shall be limited;
(b) any supply of samples shall be in response to a written request, signed and
dated, from the prescribing agent;
(c) those supplying samples shall maintain an adequate system of control and
accountability;
(d) each sample shall be identical with the smallest presentation on the market;
(e) each sample shall be marked ‘ free medical sample — not for sale’ or shall
show some other wording having the same meaning;
(f) each sample shall be accompanied by a copy of the summary of product
characteristics;
(g) no samples of medicinal products containing psychotropic or narcotic
substances within the meaning of international conventions, such as the United
Nations Conventions of 1961 and 1971, may be supplied.

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2. Member States may also place further restrictions on the distribution of
samples of certain medicinal products.
Article 97
1. Member States shall ensure that there are adequate and effective methods to
monitor the advertising of medicinal products. Such methods, which may be
based on a system of prior vetting, shall in any event include legal provisions
under which persons or organizations regarded under national law as having a
legitimate interest in prohibiting any advertisement inconsistent with this Title,
may take legal action against such advertisement, or bring such advertisement
before an administrative authority competent either to decide on complaints or to
initiate appropriate legal proceedings.
2. Under the legal provisions referred to in paragraph 1, Member States shall
confer upon the courts or administrative authorities powers enabling them, in
cases where they deem such measures to be necessary, taking into account all the
interests involved, and in particular the public interest:
— to order the cessation of, or to institute appropriate legal proceedings for an
order for the cessation of, misleading advertising, or
— if misleading advertising has not yet been published but publication is
imminent, to order the prohibition of, or to institute appropriate legal proceedings
for an order for the prohibition of, such publication, even without proof of actual
loss or damage or of intention or negligence on the part of the advertiser.
3. Member States shall make provision for the measures referred to in the second
subparagraph to be taken under an accelerated procedure, either with interim
effect or with definitive effect.
It shall be for each Member State to decide which of the two options set out in
the first subparagraph to select.
4. Member States may confer upon the courts or administrative authorities powers
enabling them, with a view to eliminating the continuing effects of misleading
advertising the cessation of which has been ordered by a final decision:
— to require publication of that decision in full or in part and in such form as
they deem adequate,
—to require in addition the publication of a corrective statement.
5. Paragraphs 1 to 4 shall not exclude the voluntary control of advertising of
medicinal products by self-regulatory bodies and recourse to such bodies, if
proceedings before such bodies are possible in addition to the judicial or
administrative proceedings referred to in paragraph 1.
Article 98
1. The marketing authorization holder shall establish, within his undertaking, a
scientific service in charge of information about the medicinal products which he
places on the market.
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2. The marketing authorization holder shall: — keep available for, or
communicate to, the authorities or bodies responsible for monitoring advertising
of medicinal products, a sample of all advertisements emanating from his
undertaking together with a statement indicating the persons to whom it is
addressed, the method of dissemination and the date of first dissemination,
— ensure that advertising of medicinal products by his undertaking conforms to
the requirements of this Title,
— verify that medical sales representatives employed by his undertaking have
been adequately trained and fulfill the obligations imposed upon them by Article
93(2) and (3),
— supply the authorities or bodies responsible for monitoring advertising of
medicinal products with the information and assistance they require to carry out
their responsibilities,
— ensure that the decisions taken by the authorities or bodies responsible for
monitoring advertising of medicinal products are immediately and fully complied
with
Article 99
Member States shall take the appropriate measures to ensure that the provisions
of this Title are applied and shall determine in particular what penalties shall be
imposed should the provisions adopted in the execution of Title be infringed.
Article 100
Advertising of the homeopathic medicinal products referred to in Article 13(2)
and Article 14(1) shall be subject to the provisions of this Title with the exception
of Article 87(1). However, only the information specified in Article 69(1) may be
used in the advertising of such medicinal products. Moreover, each Member State
may prohibit in its territory any advertising of the homeopathic medicinal
products referred to in Article 13(2) and Article 14(1)

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