Edited by Anne Hetherington
Insight
www.gf-associates.co.uk
Biosimilars:
an emerging
biotechnology
segment
2
Advantages of SME status
Regulatory Q&A
Guideline review
News
14
18
19
27
Issue 11 Dec 2014
EDITORIAL
Editor’s note
GFA Insight: What can you expect?
Welcome to the latest edition of GFA Insight. Our lead article in this issue takes a detailed look at
the hot topic of biosimilars, comparing the regulatory situation in Europe and the US. Another article
provides an interesting look at the incentives in place in Europe to help SMEs (small and medium sized
enterprises). The Regulatory Exchange takes a topical look at how pharmaceuticals can be developed
in order to respond to the Ebola outbreak.
As usual, we review a wide range of new guidelines issued by the FDA and EMA, including a quality
guideline regarding modified release products and a comprehensive revision of the nonclinical and
clinical guidance concerning influenza vaccines.
I hope that you find this edition of GFA Insight of interest. Please let me know if there are any topics
that you would like to see covered in future editions.
Anne Hetherington
Senior Regulatory Consultant
Key contacts
For further information on any of the articles
you have read, contact the authors Anne Hetherington, Senior Consultant
[email protected]
Leigh Shaw, Director, GFA
[email protected]
Sanjay Jain, Principal Consultant - Biologics
[email protected]
Michael Edwards, Regulatory Consultant
[email protected]
David Gubb, Regulatory Affairs Executive
[email protected]
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Whilst due care and attention has been taken in preparing this publication, GFA does not claim it to be free from error.
GFA do not accept any responsibility for actions resulting from decisions based upon the information contained herein, and
recommend that this publication should not be used in place of professional advice on regulatory and clinical issues. © GFA 2014
Page 1 GFA INSIGHT Issue 11
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Biosimilars: an emerging
biotechnology segment
By Sanjay Jain, Principal Consultant, Biologics
Abstract
As the US Food and Drug Administration (FDA) introduces a ‘purple book’ for biologics, including biosimilars;
a plethora of guidance and guidelines by regulatory bodies is available for industry to ultimately help with
the development and marketing of biosimilars; and many hundreds of biosimilars are in development
across the globe - we take a closer look at recent advances in the biosimilars arena; how these medicines
are regulated; how the apparent gaps throughout the biosimilar spectrum can be bridged; and what the
future offers for these medicines.
Introduction1-4
A recent revolution in biotechnology has resulted in a new class of medicine, the biologic – a large molecule
(200-1000 fold the size of a small molecule) typically derived from living cells and used in the treatment,
diagnosis or prevention of disease. These medicines have a successful track record in treating human
disease as nearly 200 biologics have transformed the lives of over 800 million patients with serious illnesses
across the globe. By understanding the mechanisms of diseases, e. g. multiple sclerosis, biologic medicines
can be developed to target and modify potentially altering the course of disease rather than simply treating
symptoms. The mapping of the human genome has led to an escalation in biotechnology research, e. g.
stem cell and gene therapy. Currently, over 400 biologic medicines worldwide are being studied in serious
illnesses, e. g. Alzheimer’s disease.
The on-going expiry of data protection/patents for the original bio-therapeutics have led to the development
and subsequent authorisation of copy versions, termed ‘similar biological medicinal products’ (biosimilars)
by various regulatory authorities across the globe. Recent years have demonstrated that biosimilar medicines
are a rapidly growing field and now emerging as a new segment in the biopharmaceuticals sphere. In
general, the principles of biosimilar drug development apply to all biological medicinal products. Regulatory
agencies have established a portfolio of guidance to support the increasing number of applications they
are receiving for biosimilar-related scientific advice and subsequently marketing authorisations of these
medicines.
Biologics and Biosimilars vs. Generics Drugs1-4
A ‘biosimilar’ or ‘similar biological’ or ‘follow-on’ medicine is similar to another biological medicine which
has already been authorised for use. It is a medicine that contains one or more active substances made
by or derived from a biological source (e. g. cellular or complex organisms; bacterium or yeast) often by
genetically modifying cell constructs or cell lines. Some of them may be already present in the human
body and can be relatively small molecules (e. g. human insulin), or complex molecules (e. g. monoclonal
antibody, Mab).
A biological substance is produced by or extracted from a biological source and needs a combination
of physicochemical and biological testing together with the production process and its control for its
characterisation and the determination of its quality, e. g. recombinant proteins, Mabs, medicinal products
derived from human blood and human plasma, immunological medicinal products and advanced therapy
medicinal products. The manufacturing process for biologic medicines requires dozens of steps involving
hundreds of variables and is generally more complex than manufacturing processes for chemical drugs.
The active substances of these medicines are larger and more complex than those of non-biological
medicines. Only living organisms are able to reproduce such complexity and the way they are produced may
result in a degree of variability in molecules of the same active substance, particularly in different batches
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of the same medicine. These inherent features result in greater complexity surrounding the regulation of
such products. Therefore, biosimilars cannot be considered generics. The latter have simpler chemical
structures and are considered to be identical to their reference medicines.
Biosimilar Definitions
The European Medicines Agency (EMA): A biosimilar is a biological medicinal product that contains a version
of the active substance of an already authorised original biological medicinal product (reference medicinal
product). A biosimilar demonstrates similarity to the reference product in terms of quality characteristics,
biological activity, safety and efficacy based on a comprehensive comparability exercise.
The US Food and Drug Administration (FDA)
A biological product that is highly similar to a US licensed reference biological product notwithstanding
minor differences in clinically inactive components, and for which there are no clinically meaningful
differences between the biological product and the reference product in terms of the safety, purity and
potency of the product.
The World Health Organization (WHO)
A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed
reference biotherapeutic product.
Because of the manufacturing process and the highly complex structure of the molecules included, there is
enormous complexity in proving that a biosimilar is ‘bioequivalent’ to a ‘reference product’. The EMA has
set out legislation and guidelines for biosimilars since 2007.
Biosimilars development
EMA1
General Considerations
Under the authority of the European Commission (EC), the Committee for Medicinal Products for Human
Use (CHMP) is responsible for managing the EMA’s position regarding medicines for human use, including
biosimilars. In a joint task force, the CHMP works in partnership with the Biosimilar Medicinal Products
Working Party (BMWP), the Biologicals Working Party (BWP), the Safety Working Party (SWP) and the
Pharmacovigilance Working Party (PhVWP) to provide European guidelines for biosimilars.
Compared to the FDA’s current standpoint on biosimilar legislation, the EMA has provided a more established
and experienced mechanism for consultation. A biosimilar application has to meet the “8+2+1” rule - it
cannot be filed until eight years after the reference product approval. Further to this a biosimilar cannot
be approved (or marketed) until ten years after the reference approval. The market exclusivity may be
extended by a further year for the reference product if the sponsor obtains approval for a second significant
new indication during the initial eight year exclusivity period (this is the “+1” in the rule). Biosimilars
can only be authorised (or marketed) for use once the period of data exclusivity (normally 10 years in the
European Union, EU) on the original ‘reference’ biological medicine has expired.
EMA is responsible for assessing applications from companies to market biosimilar medicines for use in the
EU. The amount of information on safety and efficacy needed to recommend a biosimilar for authorisation
is usually less than the amount needed to authorise an original biological medicine. Nevertheless, the
Agency continues to carefully monitor the safety of biosimilar medicines once they are on the market.
When approved, the variability of a biosimilar and any differences between it and its reference medicine
will have been shown not to affect safety or effectiveness. An authorised biosimilar is generally used at
the same dose to treat the same conditions as the reference medicine. A list of all biosimilar medicines
authorised centrally in the EU is shown in Table 1. The medicine’s summary of product characteristics
(SmPC) can be referred for further details.
A new EU pathway for approving biosimilar medicines has been in place for a decade now. The main part
of the evaluation is a comparison of the biosimilar with its reference medicine to show that there are
no significant differences between them. The relevant regulatory authority applies stringent criteria in
their evaluation of the studies comparing the quality, safety and effectiveness of the two medicines. The
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studies on quality include comprehensive comparisons of the structure and biological activity of their
active substances, while the studies on safety and effectiveness should show that there are no significant
differences in their benefits and risks, including the risk of immune reactions. Biosimilar medicines are
manufactured following the same stringent standards as for other medicines, and regulatory authorities
perform periodic inspections of the manufacturing sites. The regulatory authorities evaluate the safety
data that is captured directly as well as via the company’s safety monitoring system and thereafter,
take appropriate actions. For questions related to switching from one biological medicine to another,
interchangeability, patients should speak to their doctor and pharmacist.
BMWP provides recommendations to the CHMP on clinical or non-clinical matters relating directly or
indirectly to biosimilar medicines, and on the conduct of tests of biosimilar medicinal products. These
tests are needed to ensure the comparability of the old and new versions of biological medicinal products,
when manufacturers make changes to such products during their life-cycle, or choose to develop new
products which are biologically similar. The BMWP’s work covers products that are already authorised, and
those being developed. It works together with other CHMP working parties and scientific advisory groups
(SAGs), and co-operates with regulatory authorities in the Member States. The tasks of the BMWP include:
preparing, reviewing and updating guidelines to ensure that similarity and comparability issues are fully
addressed; providing scientific advice (SA) to the CHMP and SAWP on general and product-specific matters
relating to the efficacy and safety of biosimilar medicinal products and to the comparability of biological
and biotechnological medicinal products; contributing to international cooperation with other regulatory
authorities; liaising with interested parties; and contributing to comparability-related workshops and
training.
The mandatory scope of the centralised procedure (CP) applies to medicinal products developed by means
of biotechnological processes. The EMA was the first Regulatory Agency to create biosimilar guidelines in
2005, swiftly followed by the first approved biosimilar products in 2006. As of November 2014, 17 (excluding
2 withdrawn products) biosimilar products were approved by the EMA. These approvals cover five classes of
biosimilar: recombinant erythropoietins (epoetin alfa and epoetin zeta), recombinant granulocyte-colony
stimulating factors (filgrastim), recombinant human growth hormone (somatropin), recombinant follicle
stimulating hormone (follitropin alfa), and monoclonal antibodies (infliximab).
Biosimilar Guidelines and Concept Papers
To date, the EMA has published following guidelines and concept papers for biosimilars under three
classes:
• Overarching biosimilar guidelines,
• Product-specific biosimilar guidelines, and
• Other guidelines relevant for biosimilars.
There are nine product specific classes for biosimilars: alfa interferons, beta interferons, erythropoietins,
filgrastims, follitropins, growth hormones, insulins, low-molecular weight heparins, and monoclonal
antibodies. However, the development principles for each one applies in general to all biological medicinal
products.
Pre- and Post-marketing Procedures
At the time of submission of the similar biological application, the protection period of the reference
medicinal product (RMP) should have expired in order to allow the applicant to rely on the dossier of the
RMP, identified for the purpose of calculating expiry of the period of data protection, may be for a different
strength, pharmaceutical form, administration route or presentation than the similar biological medicinal
product or biosimilar. The details of the RMP used for the comparability exercise must be stated. It is a
requirement to identify a RMP which is authorised in the European Economic Area (EEA). With the aim of
facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials,
the EC has confirmed that it intends to accept batches of RMPs sourced from outside the EEA in certain
studies for the comparability exercise. The batches sourced outside the EEA must be representative of the
RMP authorised in the EEA, as demonstrated through an extensive analytical comparison and may require
comparative pharmacokinetic (PK) and pharmacodynamic (PD) data. A close collaboration with the US FDA
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is foreseen to ensure harmonisation of requirements, with regard to the acceptance of US-sourced RMP.
When a biological medicinal product that is similar to a RMP does not meet the conditions in the definition
of biosimilars, the results of appropriate preclinical tests and clinical trials must be provided. Due to the
diversity of biological medicinal products, the assessment of biosimilar products should be done on a caseby-case basis. For biosimilars the same criteria apply as for any other medicinal products in respect to the
acceptability of the proposed name by the Name Review Group (NRG). These are approved under the same
standards of quality, safety and efficacy as any other medicinal product. The SmPC structure does not have
a section to explicitly indicate the legal basis under which a product has been approved.
Normally, for biosimilar applications the appointment procedure of Rapporteur/Co-Rapporteur and her/
his assessment team will be initiated as early as 7 months prior to the Marketing authorisation applications
(MAA) submission date, to allow Rapporteur/Co-Rapporteur appointment 6 months prior to the MAA
intended submission date. At the same time the Pharmacovigilance Risk Assessment Committee (PRAC)
Co-Rapporteurs will be identified. MAA for a biosimilar should follow the structure of the CTD format. The
specific requirements are:
Module 1: Applicants should provide in Module 1.5.2, a concise document summarising the grounds and
evidence used for demonstrating that the medicinal product for which an application is submitted. The
comparability exercise of a biosimilar versus the RMP for quality, safety and efficacy should be described.
An EU Risk Management Plan is required. All the other requirements of Module 1 apply also to biosimilars.
When certain elements are not included, a justification for its absence should be provided in the respective
section.
Module 2: This section must include the Quality Overall Summary, Non-clinical Overview and Clinical Overview.
It is recommended that the Non-clinical and the Clinical Overall Summaries deal with comparability issues
in separate sections in order to facilitate the regulatory review by cross referencing the appropriate
separate sections of the dossier which contain the relevant data.
Module 3: A complete Module 3 should be submitted in accordance to the requirements set out in the Notice
to Applicants. In addition, biosimilar applications should also provide a demonstration of comparability.
Module 4 and Module 5: For a biosimilar product, results of appropriate pre-clinical and clinical studies
should be provided.
When referring to a centrally authorised RMP, the 10-year or 8-year protection period, as applicable,
should have expired and the eligibility should have been confirmed. The relevant protection period should
be counted as starting from the date of notification of the marketing authorisation (MA) decision to the
Marketing Authorisation Holder (MAH) and can be found in the Official Journal of the EU as well as in
the Community register of medicinal products for human use on the EC website. The calculation of the
protection period should take into account the notion of global MA. It contains the initial authorisation and
all variations and extensions granted to the MAH of the initial authorisation. Companies use patent law to
obtain further protection for an innovative medicine in some or all Member States. This protection applies
e. g. to new uses of the medicine, such as new indications and pharmaceutical forms. While this ‘usage
patent’ protection is in place, a biosmilar cannot be marketed for the protected indication or pharmaceutical
form, even if the period of data and market exclusivity of the RMP has expired. Applications for MA for
biosmilars can however be submitted and authorised even if some parts of the product information about
the RMP are covered by patent law.
In order to maintain harmonisation of SmPCs, the Applicant should commit as part of the MA application to
extend the indication(s)/pharmaceutical form(s) of the biosimilar MA as soon as the patent restrictions no
longer exist or should commit to withdraw the MA with restricted indications/pharmaceutical forms when
the relevant patents are no longer in force. The maximum timeframe for the evaluation of a MA application
under the CP is 210 days. However, the applicant may request an accelerated assessment procedure in
order to meet, in particular, the legitimate expectations of patients and to take account of the increasingly
rapid progress of science and therapies, for medicinal products of major interest from the point of view
of public health and therapeutic innovation. If the CHMP accepts the request, the timeframe for the
evaluation will be reduced to 150 days. Upon receipt of the application, the Agency will start the validation
on the next submission deadline stated on its website. Validation has to be completed by the corresponding
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starting date of the procedure. Applicants need to be ready to answer within a few days any issues raised
at this stage. For biosimilars of centrally authorised medicinal products, provided successful validation,
the procedure starts the same month. Where the application concerns a biosimilar of a medicinal product
authorised through a National procedure, Mutual recognition procedure (MRP) or Decentralised procedure
(DCP), the EMA will request from the Member State where the RMP received an MA to transmit within a
period of one month, a confirmation that the RMP is or has been authorised together with the information
on the full composition of the RMP and if necessary other relevant information. If, within a month from the
start of the procedure, the CHMP has not received the requested parts of the dossier from the Applicant,
the EMA will stop the clock until the problem is resolved. The EMA ensures that the opinion of the CHMP is
given within 210 days and in accordance with the standard timetable.
Mock-ups and specimens of the outer and immediate packaging together with the package leaflet must be
submitted by the Applicant to the EMA for review, before commercialisation of the medicinal product. The
package leaflet (PL) should reflect the results of consultation with target patient groups (‘user consultation’)
to ensure that it is legible, clear and easy to use and that the results of the assessment carried out in
cooperation with target patient groups are provided to the competent authority.
To verify compliance with EC Good Manufacturing Practice (GMP) Principles and Guidelines and/or to verify
specific manufacturing and control activities related to the assessment of an application, pre-authorisation
GMP inspections are possible. The Good Clinical Practice (GCP) standards applied to clinical trials carried
out for biosimilars are the same as those applied to any other medicinal product.
The requirements for submission of a summary of the pharmacovigilance system are the same as for
any MA application. Safety variations are required for safety issues, including those related to quality
problems, requiring a change of the SmPC, PL and/or labelling, which does not need to be implemented
via an Urgent Safety Restriction (USR), but should be implemented as soon as possible. A USR is an urgent
regulatory action, which is triggered by a MAH of a centrally authorised product or the EC in the event of
a safety concern, or to prevent risk to public health associated with the use of this medicinal product. The
outcome of a USR is an interim change to the product information (PI), due to the new non-clinical and/or
clinical information having a bearing on the safe use of the medicinal product, concerning particularly one
or more of the items (the indications, posology, contraindications and warnings in the SmPC). Immediately
following the finalisation of the USR for the biosimilar, the Agency will inform the MAH that the changes
may be introduced and that a subsequent type IB/II safety variation should be submitted without any delay
(no later than 15 days after the finalisation of the USR). Changes to the MA introduced by means of an
USR usually require that healthcare professionals are informed quickly about the safety concern and the
revised SmPC. MAHs are therefore requested to prepare and disseminate a Direct Healthcare Professional
Communication.
Marketing and cessation of marketing notifications as well as sunset clause monitoring apply similarly to
biosimilars. When a biosimilar is not placed on the market upon granting of the MA, the three-year period
without marketing, for the purpose of the sunset clause, will commence from the date of notification of
the MA to the MAH. However, the start of the three-year period should also take into account the date when
the medicinal product can be placed on the market by the MAH, i. e. as of the end of the 10-(or 11) year
period of market exclusivity of the RMP and at the end of other protection rules which must be respected.
MAHs are advised to inform the EMA, within 60 days from the granting of the MA, of the existence and if
known, the expiry dates of the other protection period(s) to be respected as appropriate. The need for an
exemption request will be decided based on this information.
The decisions on product interchangeability and/or substitution rely on national competent authorities and
are outside the remit of EMA/CHMP. Member States have access to the scientific evaluation performed by
the CHMP and all submitted data in order to substantiate their decisions.
The Certification of Suitability of the European Pharmacopoeia (CEP) procedure does not apply for direct
gene products (i. e. proteins), products obtained from human tissues, vaccines and blood products and
preparations. The details on other topics like use of the genetically modified organisms (GMOs), fees for
the applications etc. relevant to biosimilars can be found at EMA pre-submission guidance for users of the
centralised procedure.
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US FDA2
General Considerations
The US has been slower to provide an established legal pathway for biosimilar approvals. In the US, most,
but not all, biological products are licensed under the Public Health Service Act (PHS Act). Small-molecule
prescription drugs are approved under the Food, Drug and Cosmetic Act (the FD&C Act). The Act requires
a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product. A
biologics license application (BLA) is a submission that contains specific information on the manufacturing
processes, chemistry, pharmacology, clinical pharmacology and the medical effects of the biologic product.
If the information provided meets FDA requirements, the application is approved and a license is issued
allowing the firm to market the product.
The Patient Protection and Affordable Care Act (PP&AC Act), signed into law by President Obama on March
23, 2010, amends the Public Health Service Act (PHS Act) to create an abbreviated licencing pathway for
biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed
biological product. This pathway is provided in the part of the law known as the Biologics Price Competition
and Innovation Act 2009 (BPCI Act). Under the BPCI Act, a biological product may be demonstrated to be
“biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved
biological product.
Guidance Documents
The FDA has published the following guidance documents for industry:
Scientific considerations in demonstrating biosimilarity to a reference product: This guidance describes a
risk-based “totality-of-the evidence” approach intended to assess data and information submitted by the
sponsor to determine whether their proposed biosimilar is comparable to a reference product; and also
includes developmental advice.
Quality considerations in demonstrating biosimilarity to a reference protein product: This guidance
stresses the importance of extensive analytical, physicochemical and biological characterisation in order
to demonstrate that the proposed biosimilar is highly similar to the reference product.
Biosimilars: Questions and answers (Q&A) regarding implementation of the BPCI Act of 2009. This document
addresses early stage queries such as how to set up an advice meeting, licensing procedures, exclusivity
rights and other general questions surrounding biosimilars and reference product data comparability.
Reference product exclusivity for biological products filed under Section 351(a) of the PHS Act (draft
guidance).
Clinical pharmacology data to support a demonstration of biosimilarity to a reference product (draft
guidance).
Formal meetings between the FDA and biosimilar biological product sponsors or applicants (draft
guidance).
US FDA Considerations: Discussion by national regulatory authorities with WHO) on possible International
Non-proprietary Name (INN) policies for biosimilars (archived)
Pre- and Post-marketing Procedures
The above guidance documents are intended to assist sponsors in demonstrating that how their product
compares to a reference product with the intended purpose of submitting a MA under section 351(k) of the
Public Health Service Act (PHS Act).
Interestingly, the FDA has stated that under certain circumstances, data from animal/clinical studies
performed against a reference product that does not hold a US licence may be used to address biosimilarity.
However, data would need to be submitted to bridge to a US licensed reference product. This would clearly
be a complicated situation and would need to be discussed at an early stage with the FDA. These steps
include, but are not limited to, the comparison of a proposed product and the reference product with
respect to: structure, function, animal toxicity, human PK and PD, clinical immunogenicity, clinical safety
and clinical effectiveness. Other topics focused on include the importance of maintaining manufacturing
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processes and where this differs from the reference product, a valid assessment of the effects of these
changes is required. This should be supported through stringent analytical testing and functional assays
with additional data from animal and or clinical studies in some cases. International Conference on
Harmonisation (ICH) guidance Q5E provides a basis for the scientific principles in comparability assessment
for manufacturing changes. The FDA has strongly advised in-depth consultation for any company wishing
to develop a biosimilar so as to best optimise the procedure. Although the above guidelines are aimed at a
wider audience, the FDA is keen to emphasise the difficult nature of assessing a biosimilar application and
will, therefore, treat all advice and feedback on a case-by-case basis.
Due to the varied nature of biotechnology products and their potential risks, manufacturers of both biologic
medicines and biosimilars are required to submit pharmacovigilance and risk management plans as part of
their application. Importantly, a biosimilar may not be approved until 12 years after a reference product
is approved and in addition, a “Section 351 (k) application” of the PHS Act cannot be filed until four years
after the reference product is approved.
By and large, the FDA has openly acknowledged their lack of guidance and experience in the area of
biosimilars and is happy to consult the EMA for advice. However, there remain certain and significant
differences in legal frameworks. The EMA do not require a prelitigation procedure or a notice by the
applicant for a biosimilar with regards to the reference product sponsor. In contrast, the FDA requires a
prelitigation procedure which can last some length of time. The requirements include: notice of marketing
approval by the biosimilar applicant; disclosure of the biosimilar application and the reference product
sponsor; exchange of lists of patents where a claim of patent infringement could reasonably be asserted
by the reference sponsor; exchange of infringement claims and defences; dispute resolution negotiations
before an infringement law suit can be filed; and a period of 200-330 days between acceptance of the
biosimilar application by the FDA; and filing of any patent infringement lawsuit.
Following enactment of the BPCI Act (2009), the FDA formed a working group to plan the agency’s approach
to implementing the statute in order to ensure that the process of evaluation, review and approval of
products within this newly-defined product category, would be achieved in a consistent, efficient and
scientifically sound manner.
An “interchangeable” biological product is biosimilar to the reference product, and can be expected to
produce the same clinical result as the reference product in any given patient. If administered more
than once to an individual (as many biological products are), the risk in terms of safety or diminished
efficacy of alternating or switching between use of the biological product and the reference product will
not be greater than the risk of using the reference product without such an alternation or switch. Once
determined “interchangeable” two biological products will thus be able to be substituted for each other
(i. e. interchanged) by a pharmacist without the intervention of the health care provider. Pharmacists
will be responsible for knowing which biological products are interchangeable and which will require
prescriber prescription before substitution. To date, the FDA has not approved a biological product as a
biosimilar or interchangeable. However, since the passage of the Affordable Care Act in 2010, the FDA has
been establishing standards for licencing to ensure the safety and effectiveness of biosimilars. The FDA
understands that several companies are developing biosimilar products and may submit applications for
approval under the new law. Scientists, clinicians, and other personnel at FDA are currently working out
the details of the review and licencing process.
Purple book
Recently, the FDA has released the “Purple Book,” a list of licensed biological products with reference
product exclusivity and biosimilarity or interchangeability evaluation approved by the Center for Drug
Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The
document is produced to help state health agencies, pharmacists and prescribers determine which followons (biosimilar) can be used in place of a specific biologic product.
WHO and Other Regulatory Agencies3,4
In 2009, the WHO developed a set of globally accepted standards to assure the safety, efficacy and quality
of biosimilars. These have been developed in the wake of increased interest in these medicines by local
regulatory authorities seeking to develop national standards.
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In general, the reference product should be authorised in the country or region in question. All aspects of
quality and heterogeneity should be assessed, including direct comparisons with the reference product.
Non-clinical data should include pharmacodynamic, pharmacokinetic and comparative repeat-dose toxicity
studies in a relevant species, and clinical studies are required to demonstrate similar safety and efficacy.
Immunogenicity should always be investigated in humans before authorisation. A pharmacovigilance plan is
required when an application is submitted and a risk management plan may be necessary in some cases.
Some emerging markets have developed their own regulatory pathways for biosimilars, hoping to meet
a growing demand for biologic medicines. Singapore and Malaysia amended their guidelines mainly in
accordance with the EMA guidelines, while Brazil and Cuba chose the WHO and Canadian guidelines as the
basis for developing regulations. India released official guidelines in 2012, before which ~20 biosimilars
were approved for use within India under an ad hoc abbreviated process. The WHO will continue to monitor
progress of these medicines.
Pharmacovigilance, International Non-proprietary Name, Substitution and Interchangeability4-11
Extensive pharmacovigilance programs are needed to protect patients and ensure any adverse events
(AEs, including immunogenicity) are quickly detected, reported and attributed to the correct product and
manufacturer. Healthcare systems must ensure that all biosimilars can be rapidly and accurately identified
by national regulators, healthcare providers and patients. In Europe and the US, it is obligatory for the
manufacturers of all biosimilars to submit comprehensive pharmacovigilance and risk management plans
when applying for approval. These should include: pre and post-authorisation comparative testing, regular
tests to ensure that the manufacturing processes are the same, and risk management in case of AEs.
The WHO Program for International Drug Monitoring is based on the principle of international collaboration
in the field of pharmacovigilance. Over 100 member nations have systems in place that encourage healthcare
professionals to record and report AEs in their patients. These reports are assessed locally and may lead
to action within the country. Through membership of the WHO program, one country can identify if similar
reports are being made elsewhere.
Scientific names are the foundation of product identification and therefore, accurate record keeping and
attribution of AEs. Currently, the International Non-proprietary Name (INN) for a new biosimilar may be
the same as that of the original biologic medicine. In these cases, if only the INN, without a distinguishable
name, is used when prescribing a biologic medicine, the treating physician may not know precisely
which medicine a pharmacist gave the patient. Without distinguishable INNs, a reporter may be unable
to immediately identify which medicine was given when a patient experiences an AE. It could then be
unclear which medicine caused the AE. Regulations are being tightened to improve identification and
traceability of biologics. In 2013 the Therapeutic Goods Administration (TGA) in Australia issued guidance
for the evaluation of biosimilars including distinguishable names for biosimilars. A similar naming program
is recommended by the WHO and national regulatory bodies, e.g. Medicines and Healthcare products
Regulatory Agency (MHRA) in the UK. In 2012, the EC introduced new pharmacovigilance legislation. It
is now a legal requirement for EU Member States to take all necessary measures to clearly identify the
biological medicines that are prescribed, dispensed and sold in their country. Member States are empowered
to impose these requirements on doctors, pharmacists and other healthcare professionals.
In 2013, the WHO outlined the INN Committee’s proposed options for adopting a policy of distinguishable
non-proprietary names for biologic medicines. The objective was to improve the current INN naming system.
The FDA has concluded that the proprietary names should be different to their reference biologics, to avoid
patients receiving the incorrect product and to reduce confusion among healthcare providers.
Substitution is the practice by which a product other than that specified on the prescription is dispensed
to the patient, without the prior informed consent of the treating physician. A variation of substitution is
practiced in some countries where, if the physician prescribes by INN, the pharmacist may dispense any
product with the same active ingredient. Interchangeability is the process where two products, that are
judged to be similar, can be exchanged one with another without a significant risk of an adverse health
outcome. The FDA can designate a biosimilar as an interchangeable biologic when the biologic product is
biosimilar to the reference biologic product; it can be expected to produce the same clinical results as
the reference product in any given patient; and for a biological product that is administered more than
once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between
use of the biological product and the reference product is not greater than the risk of using the reference
Page 9 GFA INSIGHT Issue 11
emerging biotechnology segment
product without such alternation or switch. In EU, decisions on substitution are made at national level. The
WHO does not define standards on interchangeability for biologic medicines. It recognises that a number
of issues associated with the use of biologics should be defined by the national authorities. Canada does
not support automatic substitution, whereas the UK and Belgium recommend prescribing by brand name
to avoid substitution. Spain and Germany prohibit automatic substitution, but in contrast Ireland, Poland
and Portugal have no clear position. In Japan, substitution should be avoided during the post-marketing
surveillance period.
Worldwide Experience
Market Potential of Biosimilars12-17
Over the coming years, it is anticipated that a new generation of simple as well as complex biosimilars will
be developed as leading biologic medicines. These are worth an estimated US $81 billion in global annual
sales, and likely to lose their patents by 2020. The biologics market is expected to grow to US $200 billion
by 2015, with biosimilars a small but growing proportion at US $2.5 billion.
Biosimilar manufacturers are required/expected to invest in clinical trials, manufacturing and post-approval
safety monitoring programs similar to that of the original innovator companies. The cost of developing a
generic small molecule is around US $2-3 million, whereas biosimilars have been estimated to cost around
US $75-250 million to reach approval. This is largely owing to the clinical and comparability studies required
demonstrating biosimilarity.
More than 700 follow-on biologic therapies are currently in development and 245 biopharmaceutical
companies and institutes now developing or already marketing biosimilars throughout the world. Biosimilars
promise to produce big savings, typically offering 20-30% discounts on innovator biologics and likely to deliver
savings of as much as US $33 billion by 2020 across the EU alone. The US will permit interchangeability, and
this is expected to speed uptake of biosimilars there. A WHO proposal for a voluntary global naming scheme
could level the playing field for biosimilars and their reference biologics.
Germany provides the most favourable environment for biosimilar drugs, while Italy is the least favourable.
Differences in reimbursement practices and incentives, as well as variations in medical and clinical practices,
have resulted in different outcomes across EU member states. The UK is also viewed as a favourable
environment for biosimilars, with its long culture of generic utilisation and relatively high launch prices.
Italy seems to have the least favourable environment for biosimilars, with a strict price regulation system.
France also has a strict price regulation system and compulsory discounts for biosimilars. Sweden has some
of the highest manufacturer-level prices in Europe. The US market situation for biosimilars is of particular
interest because it is the centre for biotech innovation; and it spends more on biologic products than any
other nation.
Currently, there are 5 FDA-approved TNF inhibitors (infliximab, etanercept, adalimumab, certolizumab,
and golimumab), representing close to US $20 billion in sales annually. The industry is also eager to develop
follow-on biologics that are similar but cheaper than the currently existing biologics or are safer with higher
efficacy. Amgen has six biosimilar molecules in development. They expect to launch their first biosimilar in
2017. Also, US biosimilar Resima (Mab) from Celltrion is on the horizon.
Challenges for Market Penetration: Case Studies18-21
Erythropoiesis-stimulating agents (ESAs) have become a potential anaemia therapy in subjects/patients with
chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each
nephrologist should select a single ESA for an individual patient. Patents of short-acting ESAs have expired,
which has opened the field for biosimilars. Epoetin biosimilars approved by the EMA have been shown to have
a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia
(PRCA) in patients in Thailand, who were administered follow-on epoetins manufactured in Asia, indicates
that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in nonNorth American and non-EU countries are urgently needed. Two PRCA cases occurring with subcutaneous
HX575 indicate that chances of inducing a more immunogenic product are unpredictable. The differences
in glycosylation profiles between these epoetin biosimilars and their reference product, as well as the
lack of long-term safety and efficacy evaluation, could indicate a need to develop a more comprehensive
analysis of the available data, and to evaluate the post-authorisation real-life data; in order to gain a
Page 10 GFA INSIGHT Issue 11
emerging biotechnology segment
better understanding of any potential implications of molecular structural or formulation differences on
long term safety and effectiveness. Switching between an original reference ESA and a biosimilar should be
regarded as a change in clinical management. Clinicians need to be fully involved in such decisions.
FDA classifies low molecular weight heparins (LMWHs) as semi-synthetic drugs and their copies as generics
whereas the EMA views them as biological medicines and consequently their copies as biosimilars.
Consequently, FDA requires only in vivo pharmacodynamic studies, while EMA requires also clinical trials.
Because LMWHs show a high intrinsic variability and a complete characterisation is not viable, a conservative
approach is desirable.
Differences between innovator and non-innovator products can be identified analytically. This provides
a strong argument for caution before automatic substitution of conventional products (e. g. insulin
by biosimilars). Several non-innovator insulins, including insulin analogs are already available in many
countries. Many of these lack rigorous regulations for biosimilar approval and pharmacovigilance. Recently
an application for a biosimilar recombinant human insulin was withdrawn by the EMA because of safety
and efficacy concerns. Therefore, every biosimilar insulin and insulin analog should be assessed by welldefined globally harmonised preclinical and clinical studies followed by post-marketing pharmacovigilance
programs.
Summary and Conclusion1-4, 22-25
Countries around the world are experiencing the burdens associated with a growing, aging population and
an increase in chronic disease. Reconstructing human proteins into biologic medicines has revolutionised
the treatment of various diseases which have made a significant difference to the lives of patients with
serious illnesses, e.g. cancer.
Biosimilars are not generic medicinal products, since it could be expected that there may be subtle
differences between similar biological medicinal products from different manufacturers or compared with
reference products. Transforming complex therapeutic proteins from the laboratory into the large-scale
production of safe and effective medicines requires highly specialised knowledge, processes, scientific
standards and on-going investment in quality.
Biosimilar development is a potentially competitive area with high-value follow-on products. EU guidance
and experience in this field is more mature compared to the US. There is an acceptance that reduced data
packages may be acceptable, but only if appropriate justification can be made. The EMA/CHMP guidelines
are widely considered the standard, with countries such as Australia, Canada, Japan, Korea and South
Africa using them as a basis for their own regulations.
The harmonisation of the biosimilars application procedure between the FDA and EMA seems challenging in
the near future. Aside from this, now that a long wait for new US guidelines is over, the new focus is on the
future and industry widely anticipates their finalisation by the FDA, post public opinion. Whether follow-on
guidelines are more product-specific is yet to be disclosed.
Introduction of biosimilars brings hope in reducing the cost of treatment, so their availability will increase
further following the expiration of patents on biotechnologically produced drugs. The EC found that
these medicines are helping improve competition and are thus increasing access to biologic medicines for
patients. The integration of approved biosimilars into clinical practice across the globe will be instrumental
in accomplishing these goals.
Production of these new products is expected to meet worldwide demand and promote market competition,
maintain incentives for innovation, and sustain health care systems. The licencing of these products,
however, relies on the experience gained with the original biopharmaceuticals.
Biosimilars are a relatively new and emerging market. Although a number of biosimilar proteins have been
approved, especially in Europe, issues on substitutability, extrapolation to other disease indications, and
selection of reference standards and comparators, remain to be standardised at a global level. Also, in
order to support pharmacovigilance monitoring, the specific medicinal product given to the patient should
be clearly identified.
In conclusion, based on the rapid expansion of biosimilars and investment within this area, this field has
emerged as a new biotechnology segment and many more biosimilars are likely to be approved in the
coming years. Seeking scientific advice is highly recommended, and if a putative biosimilar product is not
considered ‘similar’, the developer will be facing a full development programme.
Page 11 GFA INSIGHT Issue 11
emerging biotechnology segment
Useful References/Further Reading
1. EMA’s scientific guidelines on biosimilar medicines, http://www.ema.europa.eu/ema.
2. US FDA, Guidance for Industry: quality considerations in demonstration biosimilarity to a reference protein product, 2012. http://
www.fda.gov/Drugs/DevelopmentApprovalProcess.
3. WHO, Expert Committee on Biological Standardisation. Guidelines on evaluation of similar biotherapeutic products, 2009.
4. www.amgen.com/pdfs/misc/biologics_and_biosimilar_overview, 2014.
5. EMEA CHMP Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins, EMA, 2007.
6. Schellekens H. Biosimilar therapeutics – what do we need to consider? NDT Plus, 2009, 2, (S1): i27-i36.
7. Locatelli F and Roger S. Comparative testing and pharmacovigilance of biosimilars. Nephrology Dialysis Transplantation. 2006: 21
(S5).
8. WHO, Programme for International Drug Monitoring, 2012.
9. Siegel JP. Petition to the U.S. Department of Health and Human Services, FDA, 2014.
10. CDER, US FDA, Proprietary Name Review: BLA 125418 – Zaltrap, 2012.
11. Drug Safety Update, Antiepileptic drugs: new advice on switching between different manufacturers’ products for a particular drug.
MHRA, 2013, 7(4):A1.
12. Mellstedt H. et. al. The challenge of biosimilars. Annals of Oncology, 2008, 19:411-419.
13. First Word SM Dossier, Biosimilar drugs in Europe: threat or opportunity to innovation? 2011.
14. Biosimilar Development. Sandoz, 2011. http://www.sandoz-biosimilars.com/aboutus/development.shtml.
15. Taylor L. Over_700_biosimilars_now_in_development_worldwide_report http://www.pharmatimes.com, 2014.
16. Taylor L., Germany: “EU’s most favourable market for biosimilars”, http://www.pharmatimes.com, 2014.
17. Willrich A et al. Tumor necrosis factor inhibitors: clinical utility in autoimmune diseases. Transl Res. 2014:S1931-5244.
18. Hörl WH. Differentiating factors between erythropoiesis-stimulating agents: an update to selection for anaemia of chronic kidney
disease, Drugs, 2013, 73(2):117-30.
19. Mikhail A et al. Epoetin biosimilars in Europe: five years on, Adv Ther. 2013, 30(1):28-40.
20. Minghetti P et al. Low molecular weight heparins copies: are they considered to be generics or biosimilars? Drug Discovery Today.
2013, 18 (5-6):305-11.
21. Owens DR et al. The emergence of biosimilar insulin preparations - a cause for concern? Diabetes Technol Ther. 2012, 14 (11):98996.
22. Alliance for Safe Biologic Medicines: Information Center, 2012.
23. Petrovic C. Dawn of the Biosimilars: what does the future hold for biosimilar drugs? GFA Insight, 2012.
24. MHRA, The introduction of similar biological medicinal products (biosimilars), 2012.
25. Jain, S. An expert report on ‘VIB’s Biosimilars: Capitalising on the market opportunities from biosimilars’, Belgium, IDDB Scientific
Database, Thomson Reuters, UK, 2008.
Page 12 GFA INSIGHT Issue 11
Page 13 GFA INSIGHT Issue 11
Ovaleap
Remsima
Bemfola
2013
2013
2014
** Withdrawn
Binocrit
Epoetin Alfa Hexal
Retacrit
Epoetin zeta
Silapo
Biograstim
Filgrastim
Filgrastim ratiopharm**
Ratiograstim
Tevagrastim
Filgrastim Hexal
Zarzio
Nivestim
Grastofil
Inflectra
Infliximab
2007
2007
2007
2007
2008
2008
2008
2008
2009
2009
2010
2013
2013
* Refused
Valtropin**
Alpheon*
Abseamed
2006
2006
2007
Follitropin alfa
Follitropin alfa
Infliximab
rh interferon alfa-2a
Epoetin alfa
Somatropin
Omnitrope
2006
Active
Medicine name
Year
Table 1 - List of Biosimilars authorised by the EMA1
Cancer Haematopoietic Stem Cell Transplantation
Neutropenia
Anaemia Kidney Failure, Chronic
Anaemia Cancer Kidney Failure, Chronic
Anaemia Blood Transfusion, Autologous Cancer
Kidney Failure, Chronic
Dwarfism, Pituitary Praer-Willi Syndrome Turner
Syndrome
Dwarfism, Pituitary Turner Syndrome
Hepatitis C, Chronic
Anaemia Cancer Kidney Failure, Chronic
Therapeutic area
Neutropenia
Arthritis, Psoriatic Arthritis, Rheumatoid Colitis,
Ulcerative Crohn Disease Psoriasis Spondylitis,
Ankylosing
Teva Pharma B.V.
Anovulation
Celltrion Healthcare Hungary Arthritis, Psoriatic Arthritis, Rheumatoid Colitis,
Kft.
Ulcerative Crohn Disease Psoriasis Spondylitis,
Ankylosing
Finox Biotech AG
Anovulation
BioPartners GmbH
BioPartners GmbH
Medicine Arzneimittel Pütter
GmbH & Co. KG
Sandoz GmbH
Hexal AG
Hospira UK Limited
Stada Arzneimittel AG
AbZ-Pharma GmbH
Ratiopharm GmbH
Ratiopharm GmbH
Teva GmbH
Hexal AG
Sandoz GmbH
Hospira UK Ltd.
Apotex Europe BV
Hospira UK Limited
Sandoz GmbH
Company
emerging biotechnology segment
SME STATUS
Advantages of
SME status
By Sacha Lynch, Senior Regulatory Consultant
Introduction
In 2003 the small medium sized enterprise (SME) definition was revised by the European Commission (EC)
to take account of the single market economic development and therefore harmonise the definition within
the EU alongside consideration of virtual companies thereby incorporating micro enterprises. This revised
definition came into effect in 2005 and defines an SME as enterprises which “employ fewer than 250
persons and which have an annual turnover not exceeding EUR 50 million, and/or an annual balance sheet
total not exceeding EUR 43 million”. Interestingly it is not necessary to satisfy both the annual turnover
threshold and the annual balance sheet total thresholds, such that an enterprise can exceed one of these
without losing the SME status. Although the definition is adopted in all policies, procedures and directives,
it still remains optional to implement this definition at a national level.
The definition breaks down types of enterprise into micro, small and medium sized relating to the financial
and human resource at the disposal to the entity. Figure 1 summarises the breakdown for defining the
thresholds for SME status. This includes accounting for resource which you have access to more than
25% capital and/or voting power through linked/partnered enterprises. However, there are exceptions
where the additional investment is from a non-profit source such as academic or research institutions,
public funding or venture capitalists. Conversely, SME status cannot be considered where more than 25%
is owned or controlled by a public body. Non EU entities may still benefit from the scheme, either through
establishing a subsidiary within the EU or to utilising an SME regulatory consultant.
Figure 1 - Definition of SME categories1
With more than 20 million SMEs providing employment to
67% of the private sector workforce, it provides a major
contribution to the EU economy2. Therefore the EC recognises
the need to adapt the regulatory environment to nurture the
SMEs. The adoption of the Small Business Act in 2011 meant
that when designing EU legislation the SME is kept in mind,
meaning that SMEs have a greater voice in the development
of policies and regulations within the EU.
Within the pharmaceutical industry specific provisions to
support SMEs in financing and human resourcing are laid down
in Regulation (EC) No 726/2004. With complex technologies
such as gene and cell therapies there is a continuous need to
promote the pooling of expertise to support the continuous
innovation. Within the regulation several initiatives are
employed to benefit the SME. The European Medicines Agency
(EMA) has adopted the SME office which acts a centralised
point of contact for SMEs, where several initiatives for SMEs
are promoted.
Administrative and regulatory support
SMEs can benefit from assistance with the regulatory procedures. With regard to scientific advice, the EMA
will offer SMEs additional assistance in the preparation for advice meetings including a pre submission
meeting. Furthermore regulatory procedural advice can be supported from the SME office through briefing
Page 14 GFA INSIGHT Issue 11
SME STATUS
meetings at no additional cost. Access to regulators perspectives right from early development through the
product lifecycle ensures that SMEs optimise their development plans. Advice is offered on various topics
such as criteria for centralised submissions, accelerated review processes, proposed product name review
and electronic submission.
Certificate approval
A certification process has been adopted which is open to SMEs for developing Advanced Therapy Medicinal
Products (ATMP). This initiative offers the opportunity for scientific review of the both pre-clinical and quality
data. Converse to the scientific advice where the aim is to establish the next steps in the development
programme, the certification provides a validation of the data generated within the programme and
establishes its acceptability for a marketing authorisation. Although not an approval, it provides some
confidence to future investors for the continued development of proposed ATMP.
Translations for Marketing Authorisation
The significant resource and cost involved in product information translations into various EU languages was
recognised and SME are offered translation services for product information at no extra cost.
Training Workshops
Annual training workshops are arranged by the EMA on various topics to encourage SMEs to access the
knowledge base. The workshops are designed to suit the needs of the SME and hot topics are considered
to ensure the SME have adequate support in the current legislation and scientific guidelines to meet the
regulatory changes in product development.
SME register
The SME register is a list of companies which have registered SME status. The register incorporates links to
the entities site with contact details and enables the possibility of networking and partnering opportunities.
Its aim is to create a forum for knowledge sharing between SMEs building a common resource hub.
Regulatory Fee Incentives
With the recognition that limited financial capital resource may be at the disposal of the SME the EMA
has offered various fee incentives to incorporate the range of services in the regulatory process. These
include fee reductions for regulatory procedures in order to obtain a marketing authorisation and support
post authorisation whilst the entity remains a SME. Table 1 summarises the fee incentives offered for the
regulatory procedures.
Table 1 - Summary of EMA Fee Incentives for SMEs
Regulatory procedure
Fee incentive
Scientific advice
Reduced by 90% and exemption for orphan drugs
Reduced by 90% and exemption for orphan drugs
with the option to defer with pre-authorisation
inspections
Fee deferral until approval and exemption if unsuccessful where scientific advice followed
Reduced by 40% for SME and 90% for micro enterprises
Fee exemption
Fee exemption
Inspections
Marketing authorisation application
Post authorisation applications
MedDRA licence for EUDRAVIGILANCE
Administrative services
Page 15 GFA INSIGHT Issue 11
SME STATUS
Fee Reductions
Scientific Advice
The aim of the fee reduction is to encourage companies to approach the EMA for advice in all stages of the
development programme to ensure that product applications meet the requirements of the EU directives and
lead to successful approval. Therefore companies benefit from the opportunity of unlimited advice meetings
at several stages during the development process with reduced investment in the process. However it should
be borne in mind that once scientific advice is sought there is an expectation to encompass the advice or to
justify its non-inclusion in development.
Inspections pre and post authorisation
Fee reduction for inspections is offered for SMEs. These include both the inspections prior to authorisation and
post authorisation.
Scientific Service
Scientific service fees are normally applied in cases where advice is required which is outside the scope of the
scientific advice. This includes advice for compassionate use, specifics with herbal products and certification
process for advanced therapy medicinal products.
Post Authorisation Activities
In order to support the SME in licence maintenance and encourage further development there are 40% fee
reductions offered for variations, renewals, annual fees for SMEs and this increases to 90% if the entity is
classed as a micro enterprise. There is also a similar fee reduction for transfer of ownership where the transfer
is to a further SME.
Fee Deferral
There are areas where SMEs can benefit from deferral of fee payments. This is particularly beneficial prior
to product commercialisation where product revenues are yet to be realised. Such areas include deferral of
marketing authorisation application fees and pre- authorisation inspections where the fees can be deferred
until approval of withdrawal of the marketing authorisation.
Fee Exemptions
In the case of Orphan Drug development where it is understood that the forecasted revenues from the product
commercialisation are less rewarding, SMEs can benefit from fee exemption in relation to scientific advice in
order to encourage development of medicines for rare disease. Furthermore where SMEs have sought scientific
advice prior to filing and the scientific advice was followed a fee exemption can be applied if the application
is subsequently denied.
The EMA have recognised the rising burden of drug safety requirements needed throughout the product clinical
development and subsequent commercialisation and SMEs benefit from exemption of the licence fee to for
accessing the MedDRA code database needed for Eudravigilance reporting. Further initiatives include reducing
the annual pharmacovigilance fee being implemented in 2015.
Other EU incentives open to SMEs
Several initiatives are available for SMEs to assist with resourcing of financing arrangements. These include
disseminating information on funding opportunities and links to sources of business funding networks such
as the Competitiveness and Innovation Framework Program (CIP) as well as research grants. Furthermore
encouragement of improving access to funding through initiatives such as the Seventh Framework Programme
(FP7) targeting 15% of funding to SMEs. Tax incentives are offered in individual member states with enhanced
tax relief on research and development expenditure.
Page 16 GFA INSIGHT Issue 11
SME STATUS
SMEs at a national level
Individual EU member states are bound by incorporation of the Small Business Act of Europe principles in
implementing policies and initiatives to support SMEs. There are various policies in development and
implemented in individual member states at a national level specific for the pharmaceutical industry. These
initiatives vary but include several member states offering fee reductions on certain regulatory procedures,
state funding support for pharmaceutical research and technical and administrative support either through
scientific advice or provision of user guides in many areas of research and development.
Future prospects
The EMA has surveyed the progress of the SME initiative since its adoption and from the findings further support
is needed in the pre-submission phase in order to reduce the burden in the dossier preparation. Furthermore,
additional training for SMEs is proposed for consideration through webinars is proposed and to promote further
awareness for scientific advice throughout the development programme particularly prior to clinical trials
commence. There is a need to improve the communication link with national competent authorities and to
encourage adoption of the SME definition. Finally, with the extensive pharmacovigilance legislation further
support and advice is needed with the post-authorisation activities to ensure regulatory compliance and
support product commercialisation.
References
1. Information extracted from SME User Guide
http://ec.europa.eu/enterprise/policies/
sme/files/sme_definition/sme_user_guide_
en.pdf
2. Commission communication - Model
declaration on the information to the
qualification of an enterprise as an SME
Page 17 GFA INSIGHT Issue 11
Q&A
Regulatory
Q&A
By Leigh Shaw, Director
Question
We want to apply for ODD status in the EU for a prophylactic vaccine for Ebola infection, what do we need to think
about?
Answer
With any application for Orphan Drug Designation (ODD) in the EU there are a number of key areas which a company
should consider and address in their submission to the regulatory authorities. In particular:
1) whether the product is for the treatment, prevention or diagnosis of a particular condition,
2) that there is a plausible scientific argument based on in vitro and in vivo data (in animals and / or
humans) that the product will do what the company seeks designation for,
3) that the orphan condition is life threatening or debilitating in nature,
4) that there are no products already available for the condition, or that if there are, your new product
will be of significant benefit,
5) if the application is based on prevalence, that the condition affects less than 5 in 10,000 persons in
the EU,
6) if the application is based on the fact that without incentives it is unlikely that the product will
generate a sufficient return to cover the development costs, that an estimate of those development
costs is clearly presented.
Since your product is a prophylactic vaccine the ODD would be for the prevention of Ebola infection, and this would
have implications for how the other areas of the application were approached. It is interesting however to note
that the European Medicines Agency (EMA) recently issued a press release1 encouraging Sponsors to apply for ODD
for products to either prevent and treat Ebola and also noting a number of other initiatives and measures they have
in place to combat this outbreak. Therefore it would be expected that the EMA would be pleased to receive you
application.
As regards medical plausibility you would need to present in vitro and animal model data to demonstrate that your
new vaccine does appear to have the potential to prevent Ebola infection. Clearly if you also have data from human
studies too, for example immunogenicity and tolerability data from healthy volunteers, then this should be included
and would add significantly to the case for designation.
Providing literature which demonstrates that Ebola is life threatening would clearly not be an issue. In addition, since
there are no current vaccines for the prevention of this deadly infection, demonstrating significant benefit would not
be required.
Assuming that the application was to be made on the basis of prevalence rather than a lack of return of investment,
then this would be an interesting part of the application and not without its challenges. Presentation of prevalence
data is often challenging for orphan conditions because it is based on literature and by definition as these are
rare diseases there may often be few epidemiology papers which have been published, making an estimate of the
prevalence difficult to obtain. The EMA recognise that there
can be difficulties and have therefore produced specific
References
guidance just on this issue2. Because this is a prophylactic
vaccine the key issue would be to consider the number of
people that may be vaccinated rather than the prevalence
1. Speeding up development of Ebola
of the disease itself (which thankfully would be very low in
treatments and vaccines, EMA 20th Oct
the EU currently). So for example one could imagine health
2014, http://www.ema.europa.eu/ema/
care workers that might be exposed to Ebola either in the EU
index.jsp?curl=pages/news_and_events/
or if providing support in Africa may be vaccinated. Indeed
news/2014/10/news_detail_002190.
other travellers to regions affected by Ebola may also be
jsp&mid=WC0b01ac058004d5c1
vaccinated and these would therefore need to be taken into
2. Points to consider on the calculation and
account when calculating the prevalence for ODD. The
reporting of the prevalence of a condition
prevalence would be a key section and would clearly be an
for orphan designation, EMA, 2002
area for discussion at an ODD pre-submission meeting.
Page 18 GFA INSIGHT Issue 11
GUIDELINE REVIEW
Guideline
Review
By Michael Edwards, Regulatory Consultant, David Gubb, Regulatory Affairs Executive and
Celine Courtay-Cahen, Regultory Affairs Executive, Sacha Lynch, Senior Regulatory Consultant
and Sanjay Jain, Principal Consultant - Biologics
Guideline on quality of oral modified release products EMA/CHMP/QWP/428693/2013
Although the existing guideline CPMP/QWP/604/94 is still valid, Section A on oral modified release products
has been updated through this new guideline. Coming into effect in September 2014, the guideline
provides further clarification in relation to the in vitro dissolution data requirements and the in vitroin vivo correlation (IVIVC) justifications. There is a clear stipulation that tablets cannot be scorelined
or recommended for subdivision due to the nature of the product and any proposal for scorelines would
require robust justification for consideration.
In vitro dissolution testing is clarified with a wider normal pH range of pH1-7.5 to be considered and
specific guidance is given regarding the use of buffers, surfactants and enzymes in the dissolution media
to ensure batch to batch consistency and using the results for biowaivers. Further guidance is provided on
the approaches to consider for ensuring the discriminatory power of the dissolution test methods. Other
updates in the dissolution testing criteria are the need to provide information on the rate of dissolution over
time for products with zero order kinetics and establishing similarity with comparators with a minimum of
12 time points, particularly when extrapolating for approval of different strengths.
Guidance changes in relation to IVIVC include a discussion surrounding variability in the data and development
of the model to produce the estimates. Whereas the original guidance suggested three levels for establishing
correlation the updated guidance in this area determine only Level A to establish IVIVC. There needs to be
validation of the model to show that the in vivo model can reliably predict the in vitro dissolution results in
order to act as a substitute for in vivo studies. However, results cannot be extrapolated outside the range
of data from development such as the range of active release or dosing range.
When setting the specification, depending whether the product has zero order release kinetics, it is
recommended to propose a dissolution rate/time rather than a cumulative dissolved amount at each time
point. For delayed release products there should be consideration for at least 2 time points considering
the acidic medium and therefore less than 2 hours and later to ensure complete dissolution, ensuring that
the gastro-resistance is maintained for at least 2 hours.
Overall the guideline provides more clarity on the requirements for specific quality aspects when developing
modified release oral dosage forms and when biowaivers can be considered justified.
The guideline can be reviewed here
Guideline on clinical investigation of medicinal products for prevention of stroke and systemic
embolic events in patients with non-valvular atrial fibrillation EMA/CHMP/341363/2014
Coming into effect in December 2014 this new guideline has been developed to provide guidance for
conducting clinical trials for medicinal products to prevent stroke and systemic embolism in patient with
non-valvular atrial fibrillation. Existing guidelines for development of antiarrhythmic medicines do not
provide guidance for data required to justify the indication for stroke prevention. Treatment for patients
diagnosed with atrial fibrillation involves consideration of anticoagulant and/or anti-thrombotic agents to
reduce the risk of stroke and embolisms. Therefore, guidance has been developed to support the industry
and regulators in compiling the data needed for products that are indicated in prevention of stroke and
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systemic embolisms. It provides appropriate methods to assess efficacy and safety including recommendations
for the appropriate endpoints, suitable eligibility criteria for patient selection and appropriate control groups
to ensure robust trial design.
Defining the primary endpoint as time to first stroke or systemic embolism there is a mandatory requirement
to consider clinically relevant secondary analysis. Classification of stroke is defined in order to understand the
impact of treatment on stroke development. Included in the guideline are specifics on inclusion criteria for
studies to ensure a true representation of the population, such that patients where atrial fibrillation occurs
as a result of reversal disorders such as myocardial infarction are excluded as this is considered a secondary
event.
The guideline provides a resource for information on the assessment of safety aspects in the clinical trial
splitting between bleeding and non-bleeding events. It provides recommended bleeding definitions to be
used and guidance on appropriate collection of these events. There are requirements for development of the
appropriate antidote treatment and the provisions for post authorisation safety studies to be incorporated in
the development plan in considering the antidote for the product.
The guideline complements existing guidance on clinical investigations for anti-arrhythmia treatments
CPMP/EWP/237/95 and addendum CHMP/EWP/213056/2010, providing more clarification for designing the
development programme specifically for proposed anticoagulant treatments.
Full guidance document here
Draft Guideline on the clinical investigation of medicinal products to prevent development/slow
progression of chronic renal insufficiency EMA/CHMP/355988/2014
Consultation has begun on the draft guideline aimed at providing guidance to the industry on design and
conduct of clinical trials for development products indicated in the prevention or slowing the progression
of renal disease. It focuses on defining the endpoints to establish the meaningful outcomes for primary or
secondary prevention of chronic kidney disease, alongside establishing a suitable comparator for studies.
Specific consideration is given to the use of biomarkers for early detection of nephrotoxicity. Industry is
invited to comment on the draft with the deadline for comments due on 01 January 2015.
The draft guideline can be reviewed here
Concept paper on transferring quality control methods validated in collaborative trials to a
product/laboratory specific context EMA/CHMP/CVMP/JEG-3Rs/94304/2014
The concept paper proposes developing a guideline on the use of the datasets from laboratory testing in
order to support product specific method validation. Currently even with methods incorporated in the Ph.
Eur. the method still needs to be validated within the individual laboratory and for each specific product
before a method can be routinely implemented. This creates a hurdle when considering the need for the 3Rs
(replace, reduce and refine) in in vivo testing. As large collaborative studies already acquire data on methods
employed, this data could be utilised and applied to laboratory/product specific validation. The guideline
aims to establish the criteria for the data that can be applied to support laboratory or product specific
method validation needed for quality control tests on products both in development and on the market.
It is anticipated that the draft guideline will be published in Q3 2015. It is envisaged that such a guideline
with clarify the implementation of the validated 3R methods in quality control testing and encourage the
development of new methods.
Review the concept paper here
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Concept paper on good genomics biomarker practices EMA/CHMP/PGxWP/415990/2014
The EMA has opened a consultation for a guideline to be established on the use of genomic biomarkers in order
to improve transparency; adopt a best practice for their use within clinical trials; translate the information
for better technology development and improve the validity of pharmacogenomics trials. The aim would
be to incorporate guidance on appropriate genomic methodology selection, analysis and testing standards
for technology and justification and procedural guidance for genomic biomarkers in clinical trials. The
Pharmacogenomics working party will undertake a consultation to develop the draft guideline and anticipates
the draft guideline to be available within the next 12 months.
Review the concept paper here
Questions and answers on wheat starch containing gluten as an excipient in the context of the
revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for
human use’ (CPMP/463/00 Rev.1) EMA/CHMP/704219/2013
EMA has released a questions and answers for the consultation review of the guidelines on ‘Excipients in the label
and package leaflet of medicinal products for human use’ (CPMP/463/00 Rev. 1). The review of this guideline
involved setting up a multidisciplinary team in March 2012 who would look to update the recommended
warnings for listed excipients to incorporate special populations, different routes of delivery and additional
excipients needing enhanced warning in the interest of safety. This question and answer document provides an
overview of the current recommended warnings to be placed on labelling for wheat starch. Gluten content is
only considered as a component of wheat starch and currently there is no guidance to consider the acceptable
levels of gluten. The Ph. Eur. monograph for wheat starch controls the protein level to not more than 0.3% and
based on the total protein levels and communication from the EDQM indicates that this level would assume
gluten content of not more than 100 ppm. Medicinal products are unlikely to reach exposure levels that would
lead to coeliac disease activity alone but there is a need to consider the gluten level alongside the daily dietary
intakes and therefore it is proposed to update the wheat starch warnings to consider the known thresholds for
gluten. Therefore the proposal is to update the wording for the package leaflet to include information on the
gluten content where wheat starch is used as an excipient.
The question and answer document can be found here
Reflection paper on the use of cocrystals and other solid 6 state forms of active substances in
medicinal products EMA/CHMP/CVMP/QWP/136250/2014
This reflection paper considers the appropriate data needed to ensure the quality and safety of various solid
states and in particular for the newer solid states emerging, like co-crystals. The development of co-crystals
allows the possibility to improve the properties of the active thereby enhancing the stability, bioavailability and
improving both flexibility and robustness to alternative manufacturing processing. However from a regulatory
viewpoint there is little guidance on the data requirements for co-crystals.
Co-crystals are a solid state where the product consists of more than one molecule in a crystalline structure.
In contrast to polymorphs where an active can present in various crystal structures for the active moiety the
co-crystal also has a neutral molecule present in the crystal structure. This neutral molecule is referred to
as the conformer. It exists in the structure with weak interactions such as hydrogen bonding or van der Waals
forces and there is no ionic bonding as is the case with active salts. Therefore no proton transfer present
distinguishing it from salt forms.
With the evidence of proton transfer providing evidence of salt form the EMA proposes that a co-crystal can be
indicated where a ΔpkA <0 can be demonstrated. With a ΔpkA between 0 and 3 there is a need to demonstrate
further evidence of structure through stereoscopic confirmation. In contrast the guidance published from the
FDA proposes a wider limit for defining a co-crystal without further stereoscopic confirmation as ΔpkA <1.
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Solid state differences have implications for the interpretation for both new chemical entities and generic
applications. The reflection paper clarifies the current view that where there is weak association which
can be broken through dissolution then these solid states can be considered the same active substance and
reference can be made to different solid state in terms of an abridged generic application. This also clarifies
when different solid states cannot be claimed as new chemical entities which would be subject to data
exclusivity.
Further consideration is given to whether different solid states can be encompassed under one marketing
authorisations with the view that it should be clear what the active moiety is associated with. This means
that it would not be possible to interchange between different salts or co-crystals under the same marketing
authorisation and would need to be considered as a line extension with the Annex II of the regulation
no 1084/2003 and no 1085/2003. However, the exception to this interpretation is with the hydrate form.
Since the amount of water delivered to the patient lacks clinical significance then these can be considered
interchangeable as long as the free base form is clearly expressed within the product information. Other
crystal forms where there are no associated compounds such as polymorphs can also be interchangeable
where there is no significant difference in the properties.
When considering that co-crystals share similar concepts as salts which the association of other components
then similar principles with respect to the quality documentation can be applied. Being an alternative solid
state, the quality information is encompassed with the drug substance section of the dossier and subject to
compliance with the Part II GMP requirements for active substances. However it is important to consider that
adequate justification that the crystal structure is indeed present and that it is not a physical mixture of two
or more crystal compounds through several independent approaches in analytical testing.
The reflection paper can be found here
European Medicines Agency – Guideline on bioanalytical method validation. EMA/CHMP/
EWP/192217/2009 Rev.1 Corr.
The guideline issued by the EMA was adopted by the Committee for Human Medicinal Products in July 2011
and came into effect in February 2012. The recently revised guideline details the key requirements for the
validation of bioanalytical methods.
Bioanalysis is the quantitative measurement of drug concentrations in biological matrices (i.e. serum, plasma,
blood, urine and saliva), and is important in drug development to understand the behaviour of an active drug
and/or their metabolites for the purpose of pharmacokinetics, toxicokinetics, bioequivalence and exposure
–response. The results of animal toxicokinetic studies and of clinical trials, including bioequivalence studies,
can be used to support safety and efficacy, then this data from bioanalysis can then be used to support
marketing for new active substances or support variations to authorised drug products.
The bulk of the guidance paper gives details on the full validation of specific analytical methods. The main
objective of method validation is to demonstrate the reliability of a method to determine the concentration
of an analyte in a given biological matrix. When developing an analytical method, full validation should
be conducted for each species and matrix concerned. Reference standards for the use in the validation
methods are described, and details the quality requirements of these references, be they certified standards
or internal standards.
The guidance describes the specific validation areas in detail, including:
• Selectivity – the ability to differentiate the analyte of interest and reference from endogenous components
in the matrix, and possible interference from metabolites, degradation products or back conversion of
metabolites into parent analytes.
• Calibration curve – detailing the response of the instrument used against a known concentration of
analyte, then used to determine analyte levels in the sample.
• Accuracy – the closeness of the determined value obtained by the method to the nominal concentration
of the analyte.
• Precision – the repeatability of the values (the closeness) of repeated individual measurements.
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• Stability – ensuring that all preparation and storage conditions do not affect the concentration of the
analyte.
Further information is then presented on the analysis of study samples, giving advice on how to conduct
analytical runs, acceptance criteria, calibration and reanalysis of samples.
Ligand binding assay guidance is presented in the latter part of the document, giving details on methods and
testing design including reference standards, specificity of binding reagents, selectivity and matrix selection.
Ligand binding assays are commonly used for macromolecules, however due to the complexity and inherent
characteristics of macromolecules, guidance is more detailed and comprehensive.
The final part of the guidance document details the report structure for validation of analytical methods,
presented as a systematic checklist to ensure that all activities are detailed and reported on, including
details of any analysis that should then cross refer to the appropriate validation.
More information can be found here
Draft guideline on influenza vaccines - Non-clinical and clinical module EMA/CHMP/
VMP/457259/2014
This draft guideline covering non-clinical and clinical requirements for new influenza vaccines (consultation
opened 31st July 2014, deadline for comments 31st January 2015) forms one module of the current update
of guidance on this topic, with the aim of producing a single modular guideline covering regulatory, quality,
non-clinical and clinical aspects. The revision includes re-evaluation of serological testing methodology
& standardisation issues, and acknowledges the paucity of definitive evidence supporting immunological
correlates of influenza protection. Key topics addressed are:
• Non-clinical & clinical data required in support of an initial marketing authorisation (MA) for a seasonal,
pandemic, or zoonotic influenza vaccine (see below),
• Application requirements for vaccine composition (strain) changes,
• Recommendations on characterising immune response,
• Circumstances under which pre-authorisation clinical efficacy and/or post-authorisation vaccine
effectiveness studies would be required,
• Safety data considerations pre- and post-MA,
• Guidance on content of risk-management plans (RMP).
Pre-pandemic vaccines to an emerging influenza strain of animal origin with pandemic potential are referred
to as zoonotic vaccines, and the term pandemic preparedness vaccines is applied to those products prepared
for potential pandemics (formerly known as pandemic mock-up). The guideline is primarily applicable to
vaccines containing live attenuated influenza viruses (LAIV), inactivated viruses, and adjuvants.
Detailed guidance is given as to non-clinical and clinical studies to be conducted according to the type
(i.e. seasonal/pandemic/zoonotic) and nature (eg LAIV, inactivated adjuvanted/non-adjuvanted) of vaccine,
and intended target population. Non-clinical data should cover primary pharmacodynamics (including
immunogenicity, protection/challenge, and passive immunisation studies) and toxicology (excepting
genotoxicity and carcinogenicity, which are not usually required). Pharmacokinetic and specific safety
studies are generally not needed, unless indicated by the nature of the product (for example use of new
formulations or adjuvants, particular requirements for LAIV). Inactivated vaccine products are also exempted
from environmental risk assessment requirements.
Clinical studies discussed comprise clinical immunogenicity [immunological testing assays, analysis of data, and
essential studies for MA application (MAA)], clinical efficacy where necessary and feasible (with considerations
on study design, endpoints and duration), vaccine effectiveness (focusing primarily on seasonal influenza
vaccines, and covering design, population and data management), and clinical safety (particularly the size of
safety population required pre-MAA according to vaccine indication, and which applicants are recommended
to discuss with competent authorities during clinical development). Post-authorisation pharmacovigilance
activities will vary according to the type of vaccine, but as a minimum a RMP should address requirements
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in immunocompromised patients (if not previously studied, and to determine if a different immunisation
schedule is needed) and monitoring of the elderly and frail population. Again, applicants are advised
to request scientific advice as to design and conduct of post-MA studies. No core summary of product
characteristics (SmPC) is proposed for individual influenza vaccines, as SmPCs should be prepared according
to product-specific data.
More information can be found here
FDA Guidance for Industry – Draft Guidance: Design and Analysis of Shedding Studies for Virus
or Bacteria-Based Gene Therapy and Oncolytic Products
This draft guidance contains recommendations on how to conduct shedding studies during pre-clinical and
clinical development of virus or bacteria-based gene therapy (VBGT products) and oncolytic viruses or
bacteria (oncolytic products). For this guidance, “shedding” means release of product-based viruses or
bacteria from the patient, leading to the possibility of transmission to untreated individuals. Studies are
conducted to provide information about the likelihood of such transmission and about measures to prevent
it. Typically, preclinical and clinical shedding studies are not stand-alone studies but are integrated in
safety, biodistribution (preclinical), or efficacy (clinical) studies.
Pre-clinical studies can help estimate the likelihood and potential shedding profile in humans, especially if
humans have not been previously exposed to the product (product based on a non-human bacterial or viral
strain). In cases where humans have been previously exposed, pre-clinical studies are also recommended if
the product has been modified to achieve a different in vivo tropism than the parent strain, or if the route
of administration has changed.
Shedding of each oncolytic or VBGT product should be studied during clinical development. The shedding
profile is not always predictable due to the influence of many product-specific variables and patient-specific
factors. Furthermore, oncolytic or VBGT products may be derived from human-specific strains, so animal
models may not adequately predict shedding in human.
The main considerations in the design of the studies are:
• The choice of clinical samples
• The periodicity of sample collection
• The duration of the period of collection
• The assay methodology
The types of clinical samples collected to assess shedding include urine, faeces, nasal swabs and skin biopsy.
The choice of clinical samples might be based on the natural route of transmission and shedding of the
parent virus and/or the biodistribution and shedding data from pre-clinical studies. In addition, the route
of administration should be considered, especially in case of intradermal or intranasal administration.
The duration of a shedding study will take into account biological characteristics of the product, as well as
factors such as the immune status of the patient at the time of treatment. If the product elicits a strong
immune response, it may be more rapidly cleared from the body than a poorly immunogenic product.
Persistence and latency-reactivation in the host are possible in the case of herpes virus-based products.
Shedding of such products may be intermittent and unpredictable. For products classified as replication
competent, able to multiply and amplified in the host, the extent and duration of shedding might be
significantly increased.
Analytical assays used to measure shedding are designed to detect nucleic acids, or the presence of infectious
viral particles or dividing bacteria. At least one of the chosen assays should be quantitative and often
quantitative polymerase chain reaction (qPCR) is used because of ease of performing and assay sensitivity.
For replication competent products, detection of nucleic acids should be followed up with infectivity or
growth-based assays. In all cases, the assays conditions should be optimized to avoid false positive or false
negative results, to not underestimate the extent of shedding, and to selectively analyse the product
under investigation. Clinical samples such as faeces and urine are rich in complex organic matter that can
adversely affect the performance of the assay. Also, samples such as saliva and nasal swabs are rich not only
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in host proteins and nucleic acids, but also in the body’s natural flora and circulating strains of viruses and
bacteria from the environment.
In conclusion, data collected in clinical studies provides a shedding profile of an oncolytic or VBGT product in
a target patient population, and these data are used to estimate the potential of transmission to untreated
individuals. The FDA’s current understanding is that, in most cases, this potential of transmission is extremely
low, because of the derivation methods and/or modifications that are designed for attenuation of the product.
When there is a potential to cause disease in humans, it may be appropriate to include information on
shedding in the Investigator Brochure, the Informed Consent for Investigational New Drug studies and the
package insert for licenced products, to inform patients and physicians on the potential for transmission and
the measures to prevent it.
More information can be found here
EMA Guideline CPMP/EWP/785/97 Rev. 1: Guideline on the Evaluation of Medicinal Products for
the Treatment of Irritable Bowel Syndrome (IBS)
This guideline replaces the previous “Points to Consider on the Evaluation of Medicinal Products for the
Treatment of Irritable Bowel Syndrome”, in operation since 2003.
IBS is considered to be one of the most frequent clinical problems in gastroenterology with an estimated
prevalence in the Western world of up to 20%, with female predominance in those seeking health care. The
pathophysiology of the symptoms is still incompletely understood, but the diagnosis must include abdominal
discomfort or pain associated with changes in bowel habits and stool consistency, and must exclude structural
or biochemical abnormalities of the gut. Currently the Rome III criteria are regarded to be the standard
diagnostic criteria, with sub-typing of the patients according to their predominant stool pattern.
Candidate compounds should be evaluated for their pharmacodynamics properties in humans in the early
development, as this may help to understand the mode of action and thus support the biological plausibility
of the clinical effects. Moreover, pharmacodynamic endpoints in different patient subtypes can be useful in
the determination of the final target population.
Pivotal clinical studies could be designed according to the intended use: either long-term continuous use, or
short-term repeated treatment may be investigated. Both types of treatment schedules should be investigated
in placebo-controlled, randomised, double-blind trials. The inclusion of an active comparator cannot currently
be recommended. However, a 10-14 day lead-in period should be part of the study, to determine the fulfilment
of the inclusion and exclusion criteria.
It is still recommended to combine two major IBS symptoms in the primary endpoint, in line with the
Rome III definitions. Those two endpoints should be the evaluation of abdominal pain and the evaluation
of stool frequency/consistency (depending on the IBS subtype). The global symptom evaluation, subject to
controversy, should no longer be part of the primary evaluation, unless the compound studied is intended for
the treatment of two or more IBS subtypes. Patient reported outcome instruments are currently not available
and this guideline recommends the development and validation of such instruments suitable for different
disease subtypes.
Secondary endpoints are required to be generally supportive of the primary endpoints. A global symptom
evaluation (if not included in the primary endpoints) should be defined as the main secondary endpoint, using
a numerical evaluation scale of changes. Further secondary endpoints should also be included.
Extrapolation of trial results from adults to children or to elderly patients appears to be questionable. Ideally,
separate trials should be conducted in different age range children in order to prove efficacy and safety of
drug candidate. Also, the intent to include a relevant proportion of elderly subjects should be part of all
future trials in adults, as elderly people might be more prone to the dangers of potentially exaggerated effects
of IBS treatments (bowel obstruction, disturbance of water/electrolyte balance). Finally, the development
of drug candidates for one gender only is considered fully acceptable if a different therapeutic response is
expected.
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In conclusion, the mains changes introduced in this guideline refer to the patient population to be selected
for trials, the flexibility towards future changes in the definition of the disease and the recommendation on
primary endpoints and the introduction of special patients groups.
More information can be found here
Guideline on clinical evaluation of medicinal products used in weight control EMA/
CHMP/311805/2014
Obesity, a chronic clinical condition, is the result of interactions between genetic, metabolic, environmental
and behavioural factors and is associated with increases in morbidity and mortality. The scope of this guideline
[which replaces ‘Guideline on clinical evaluation of medicinal products used in weight control’ (CPMP/
EWP/281/96 Rev.1)] is restricted to the development of pharmacological options (e. g. centrally acting
anorectic agents, drugs that inhibit the absorption of nutrients, drugs which modulate incretin receptor
activity such as glucagon like peptide 1 receptor agonists) for treatment of obesity. These therapies are not
recommended until non-pharmacological options (e. g. nutritional education and modification, behaviour
modification, increased activity and exercise) are tried. This Guideline should be read in conjunction with
the Annex I of Directive 2001/83/EC, and relevant ICH guidelines for conducting clinical trials.
This draft guideline (consultation period started 31 July 2014) aims to provide guidance to industry for the
clinical evaluation of new medicinal products used to promote weight loss in obese adult patients. It clarifies
the requirements for clinical documentation needed to support a marketing authorisation for weight loss,
notably the recommended methods of assessing efficacy (reduction in body weight as the primary efficacy
endpoint, and reduced cardiovascular risk as well as weight-related comorbidities as secondary efficacy
endpoints), selection of patients (BMI ≥30 kg/m2 with a relevant proportion of patients with cardiovascular
risk factors), strategy and design of clinical trials (pharmacokinetic and pharmacodynamic studies in patients
and appropriate sub-groups e. g. patients with comorbidities or risk factors as well as the older population),
pre-clinical and clinical safety aspects (e. g. neuropsychiatric safety, abuse potential, cardiovascular disease
and valvulopathy and pulmonary hypertension) and overall development strategy. The deadline for comments
on this draft is 31 January 2015.
More information can be found here
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NEWS
News
Snippets
Germany tops Global Patient Poll looking at Ease of Access to Medicines
Germany has come top of a new international league table in terms of access to medicines for patient
organisations, with Italy and France in joint second place and the UK coming fourth. The survey, conducted
by the medical information organisation PatientView, asked patient groups in 12 countries or regions about
their ability to gain access to medicines, for example, by influencing the health technology assessment
process in their country. The fifth-best access, after that in the UK, was found in the Nordic countries,
followed by Canada in sixth place. The US and central and south America are next, in joint seventh place,
followed by the Netherlands and Australasia, joint ninth, then Spain in eleventh place and finally, placed
twelfth, with the worst access, is Eastern Europe.
The survey also asked patient groups representing individual diseases and conditions how able they are
to influence access-to-medicines processes, and the top performers in this table are groups representing
people with HIV/AIDS. Only 19% of these patient groups now regard access to medicines to be a hurdle,
compared to 38% which reported that they did so in PatientView’s last survey, in 2012. However, a large
proportion of cancer patient groups find access to medicines to be a problem, with 41% reporting this to
be the case in 2014 compared with 28% in 2012. Many cancer patient groups today clearly feel unable to
negotiate better access to medicines, and incapable of influencing government healthcare policies which
reject the most modern cancer therapies on cost grounds.
‘Harbingers of Disruptive Change’ in Healthcare
The IMS Institute for Healthcare Informatics has identified what it calls “harbingers of disruptive change”
which it sees as having a significant long-term impact on the role or use of medicines in the future. These
include:
• Consumer technology companies such as Google and Apple are rushing to healthcare to transform
patient engagement, e.g. by use of mobile, cloud and wearable technology.
• Governments are unshackling data to aid research and spark innovation e.g. US and Korean governments
have advanced healthcare data availability.
• Medicines spending growth is returning to developed countries, signalling a new phase in the life
sciences innovation cycle.
• US clinicians are being encouraged to consider costs in clinical treatment decisions, e.g. this year, the
American Society of Clinical Oncology announced a value initiative, in which cost is explicitly marked
out as a factor that will influence clinical decision-making.
• China has loosened the price caps of 530 low-cost essential drugs, which could allow prices to rise to a
level that encourages companies to offer these medicines at acceptable quality standards.
• The recent formation of mega trans-Atlantic supply-chain purchasing groups has radically shifted the
balance of power, particularly in the US and Europe, with buyers now exercising leverage on the global
market.
Other key events noted in the report include the wave of innovation in the hepatitis C arena; new
breakthrough vaccines which could mean a new era of improved public health for low and middle-income
countries; the growing use of biological products that bring new treatment options and expanded markets,
and the shift of focus for US payment and delivery systems towards outcomes and performance.
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NEWS
Patent law changes could boost Clinical Research in the UK
A recent change to patent law could help to attract drug research back to the UK. The legal amendment
removes the risk of infringement claims and allows companies to use a patented product when carrying out
clinical trials. This rule is in addition to the so-called ‘Bolar Exemption’, which protects generic companies
from the risk of infringement lawsuits if they are conducting clinical trials on a patented drug. The new
law removes intellectual property barriers to the research-based pharmaceutical industry carrying out
clinical trials in the UK, putting them on the same level as other EU countries and generic companies.
A spokesman for an IP practice said “one of the issues that drives location for clinical trials is whether that
work will escape the risk of patent infringement claims, injunctions stopping trials part way through or
‘stop-go’ injunctions and damages after the event. This is now a much more straightforward exercise to
clear trials in the UK for patent purposes, giving research-based companies more certainty in the planning
stage.” A patent attorney confirmed that this is good news for the UK “and it is likely to lead to more
research projects taking place here, which should enable us to retain research skills and expertise and it
should also help to avoid delays when bringing new drugs and treatments to market.”
Aspirin helps to treat schizophrenia
It has been found that anti-inflammatories such as aspirin, oestrogen and N-acetylcysteine can improve the
efficacy of existing schizophrenia treatments. In a comprehensive meta-analysis conducted by researchers
at the University of Utrecht, there was significant evidence that some, but not all, anti-inflammatories
can improve symptoms in schizophrenia patients. It is known that the immune system is linked to certain
psychiatric disorders and that schizophrenia in particular is linked to the HLA gene system.
Treatment of schizophrenia has not changed much in over 50 years and relies mainly on correcting the
regulation of dopamine in the brain. This has been shown to help symptoms such as hallucinations and
delusions, but has been unable to help many other symptoms such as decreased energy, lack of motivation
and poor concentration. It is estimated that 20%-30% of all patients do not respond to antipsychotic
treatment, but co-treatment with anti-inflammatories holds the possibility of improving patients’ response
to treatment. Prof Sommer, of the University of Utrecht commented “This study makes us realise that
we need to be selective about which anti-inflammatory we use. Now that we know that some effects are
replicated, we need to refine our methods to see if we can turn it into a real treatment.”
Conducting R&D in Rare Cancer Patients
The EMA recently met with the Rare Cancers Europe (RCE) group, to discuss the group’s consensus paper,
which is calling for innovative approaches in collecting and summarising evidence for potential new
treatments for rare cancers. The group called for earlier access to promising experimental drugs and
suggested that rules need to be “relaxed” to allow for greater use of compassionate and off-label use of
drugs. It was noted that patients’ attitudes towards risk may differ from that of regulatory agencies and
health authorities. Kathy Oliver, of the International Brain Tumour Alliance noted that “Medical decisions
are usually risk-averse, for many reasons, but rare-cancer patients often argue in favour of relaxing rules
so that new treatments can be tried”.
RCE point out that as large trials are not feasible in rare cancers so initiatives such as low-power randomised
clinical trials and adaptive trials should be considered. Research should focus on biomarkers and the
usefulness of electronic patient records should be explored. The report also suggests that surrogate endpoints could replace clinical end-points.
Page 28 GFA INSIGHT Issue 11
SPOTLIGHT SERVICES
Spotlight Services
Each edition we put a spotlight on two of the services we offer, and explore them in more detail.
Spotlight Service 1:
Training
We all have to ensure that our training files are kept up-to-date to show that we are staying abreast
of the changes in practice in the industry. As a provider of best practice guidance, GFA can make this
process easy for you. We offer a combination of off-the-shelf and bespoke training services, tailored
to your needs. Training can be delivered at your premises, hosted at our office in Ely, UK or at another
venue convenient to your location. More companies are approaching us to assist in providing such
programmes and the list of topics we can provide includes (but is not limited to) the following:• Good Clinical Practice (Introductory and Refresher courses)
• European / US Regulatory Environment (including; regulatory considerations for clinical
development, Biosimilars legislation in the EU and US, Orphan Drug Designation, Paediatric
Regulations)
• GCP Inspection Readiness
• Pharmacovigilance (up-to-date overview of current safety reporting requirements)
• Regulatory Affairs for Academics, SMEs and Spin-Outs
Spotlight Service 2:
Product development strategy and programme management
Formulating a cost-effective, efficient programme of services to get a product to market can be a
difficult task for start-ups, virtuals and SMEs. As a consultancy, we are meticulous in our attention to
detail so as to provide you with the best advice and plan of action possible. Ensuring your goals are
achieved in a timely manner is a firm priority and our team will assist you in interpreting an array of
regulatory scenarios. From informal consultation to major multinational projects, our award winning
expert advice is readily available. Once your strategy and programme has been developed, we can
then manage and co-ordinate it on your behalf, liaising with the providers of the component parts of
the programme. These services include:• In depth regulatory strategy advice
• Best route to market recommendations
• Formal project planning, analysis and delivery for non-clinical and Clinical Phase I-III projects
• Study design and protocol preparation
• Sourcing of radiosynthesis, manufacturing, toxicology and analytical chemistry capabilities.
Fact SHEETS
GFA fact sheets
Did you know that GFA can provide you with fact
sheets on a wide range of regulatory topics? In this
we are looking at the Fact Sheets that summarise
the main regulatory routes in Europe. You may
be eligible for the centralised route, which gives
a single authorisation covering the whole of
Europe. Alternatively, you may consider using
the decentralised route or the mutual recognition
procedure.
Page 29 GFA INSIGHT Issue 11
Please contact GFA for a fact sheet index and
to obtain copies at [email protected] The
following fact sheets are available on request:
• Fact Sheet No. 7
Centralised Procedure
• Fact Sheet No. 8
Mutual Recognition Procedure
• Fact Sheet No. 9
Decentralised Procedure
Gregory Fryer Associates Ltd
Phone : +44 (0) 1353 645590
Fax: +44 (0) 1353 645599
[email protected]
www.gf-associates.co.uk
30 St Thomas Place, Cambridgeshire Business Park, Ely, Cambridgeshire, CB7 4EX, UK

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