1. business and industrial
2. pharmaceutical industry

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Focus – Pharmaceutical Symposium
Annual Pharmaceutical
Symposium 2014
Held in conjunction with the Federal Agency for Medicines and Health Products (FAMHP),
Belgium, this year’s Annual Symposium posed the question: “Matching modern
regulation with modern medicine – a patient-centred approach to regulatory affairs?”
The first session on the new clinical trial regulation was chaired by
Kristof Bonnarens, Head of Division R&D, FAMHP, Belgium, who gave
a brief overview of the new regulation (due to apply from mid-2016)
and its key principles, namely a single submission to a European IT
platform where EU member state (MS) approval is scientifically and
ethically harmonised with patient involvement.
Stefano Soro, Head of Unit, Medicinal Products – Quality, Safety
and Efficacy, Health and Consumers Directorate-General, European
Commission, described some of the procedures relating to the
regulation in more detail. Describing the three step authorisation
procedure: validation (ten days), assessment (45 days) and decision
(five days), it was noted that the MS must determine their individual
language requirements for documents in the Annex to the regulation.
The presentation examined each of the steps in more detail, including
the selection of the reporting MS during the validation period and the
parallel assessment of the joint MS review and independent MS review
of national and local elements.
The grounds for decisions for refusal were also outlined, including the
need for MS to implement appeal procedures. During the discussions
it was noted that the voluntary harmonisation procedure (VHP) really
formed the blueprint for the regulation and that language from the
Declaration of Helsinki was mirrored in sections of the regulation. It was
highlighted that the regulation was not intended to provide a European
homogenisation of ethics committees and that the role and composition
of each MS’s ethics committees will follow national rules.
Further information was provided on the current progress on
development of the portal which underpins the roll-out of the regulation,
and consideration of the wide variety of delegated powers given to the
Commission were discussed, including principles of good manufacturing
practice (GMP), details of good clinical practice (GCP) inspections
and qualifications of inspectors, GMP guidelines, guidelines on the
formatting and sharing of information, rules on cooperation for the
assessment of safety information.
Fergus Sweeney, Head of Inspections and Human Medicines
Pharmacovigilance, European Medicines Agency (EMA), first looked
at the formation of the EU portal, database and medicinal product
dictionary discussing Articles 80, 81, 82 and 84 of the regulation. The
formation of the safety reporting database (Articles 40 and 44) and
the EudraCT and EU Clinical Trials Register (EU CTR) Legacy databases
(Article 98) were also briefly discussed. The EU database will be publicly
accessible by default, although there are exceptions including those
justified on the grounds of protection of personal data, protection of
commercially confidential information, and protection of confidential
communication between MS in relation to the preparation of the
Regulatory Rapporteur – Vol 11, No 12, December 2014
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SESSION 1: The New EU Clinical Trial Regulation
Reported by Sarah Roberts, Vice President, Global
Regulatory Affairs, PRA Health Sciences, UK.
Focus – Pharmaceutical Symposium
assessment report. The release of the EMA public consultation on
functional specifications on 10 October 2014 (with comments due on
31 October 2014) was highlighted and delegates were encouraged
to participate in the consultation process. Process workflows
documenting every step are currently being established (eg, how the
assessment procedure for Parts I and II will work). For each sponsor,
access to the portal and database is via a Trial Related Sponsor
Superuser (+ backup). The superuser can assign user access to
the portal allowing them to assign work packages to other users,
and to modify other users’ work packages. All users (including
the Sponsor Super User) will be required to register with the EMA
using its identification scheme. In conclusion, there is a need for a
streamlined, coordinated and transparent approach to the clinical
trial regulation and its tools and processes.
Martyn Ward, Chair, Clinical Trials Facilitation Group (CTFG) and
Clinical Trials Unit, MHRA, spoke about the regulation’s impact at
both a national and European level. For MS, implementation of the
regulation will require new legislation and IT systems and processes
to be developed at the national and EU levels. The new regulation
states, “Member states shall…” and “Member states may…” which will
require new legislation to be implemented in many areas including
establishment, constitution and procedures for ethics committees,
appeal mechanisms, legal representatives for incapacitated persons
and minors, informed consent, investigators, auxiliary medicinal
products, fees, sanctions, penalties and inspections. In addition,
there is a need for secondary EU legislation and guidance such
as delegated acts (GMP), implementing acts (collaboration on
assessment of safety data, modalities for inspection) and guidelines
(GMP, sharing data on a voluntary basis).
Finally, a panel discussion (chaired by Anne De Bock, AstraZeneca,
Belgium, and including the speakers and Greet Musch, Director
General DG Pre authorisation, FAMHP, Belgium, Professor Patrick
Cras, University Ziekenhus Antwerpen, Anne Vergison, Mutualités
Socialistes, Belgium and Nick Sykes, Pfizer, UK) welcomed
comments from the audience on topics as broad as an explanation of
tacit validation, Annex 6 and expiry date changes to labels, fees and
SUSAR [suspected unexpected serious adverse reaction] reporting.
SESSION 2: The FAMHP with Focus on the Patient –
Early Phase Development and Unmet Medical Needs
Reported by Angela Stokes, Director, Oncology, Global
Regulatory Affairs, Eisai Ltd.
The second session considered the FAMHP’s new business plan
which has the patient at its centre. Professor Jean-Paul Degaute,
President of Scientific Commission, FAMHP, chaired this session
and first introduced Xavier De Cuyper, CEO, FAMHP, who laid out
the vision of FAMHP from 2014 to 2020. Mr De Cuyper explained
that he was very happy with the choice of TOPRA for the symposium
because of the central role the patient plays in Belgium’s plans going
forward. The next speaker, Walter Janssens, FAMHP, discussed
strengthening clinical research in Europe and Belgium in early phase
development. Three moving fields of interest were discussed – these
being combination of products in early phase, so called novel-novel
clinical trials, good laboratory practice (GLP) and reproductive
effects estimation. Three critical points of attention at the EU level
were seen as inclusion of patients in early phase clinical trials
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Acronyms and abbreviations
CHMP – Committee for Medicinal Products for Human Use
COMP – Committee for Orphan Medicinal Products
CSR – Clinical Study Report
EAMS – Early Access to Medicines Scheme
EMA – European Medicines Agency
EPAR – European Public Assessment Report
FMD – Falsified Medicines Directive
GCP – Good Clinical Practice
GMP – Good Manufacturing Practice
HCP – Healthcare Professional
HTA – Health Technology Assessment
MAH – Marketing Authorisation Holder
MHRA – Medicines and Healthcare products Regulatory Agency
MS – Member State(s)
NCA – National Competent Authority
NICE – National Institute for Health and Care Excellence
PDCO – Paediatric Committee
PGWP – Pharmacogenomics Working Party
PIP – Paediatric Investigation Plan
PV – Pharmacovigilance
RMP – Risk Management Plan
SAWP – Scientific Advice Working Party
SEED – Shaping European Early Dialogues
VHP – Voluntary Harmonisation Procedure
(common in oncology but not in other indications); developing
specific requirements for clinical trials with advanced therapies
(ATMPs), which are often used in the personalised setting for rare
and serious diseases but where there is little experience at present;
and biomarkers, where qualification advice and health authority
opinion on efficacy may be less relevant for early phase studies).
Finally, Mr Janssens presented the FAMHP operational plan for the
coming three years, which aims to develop the concept of domains
of excellence, and which will look at accreditation of Phase I units
while maintaining short timelines and taking into account the needs
of stakeholders such as companies, contract research organisations
(CROs), academic units and patients. These same stakeholders will
also input into a steering group looking at the implementation of
regulation on clinical trials and a communication plan to provide
information to patients and volunteers will be developed.
JEAN-PAUL DEGAUTE, President of Scientific Commission, FAMHP
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Focus – Pharmaceutical Symposium
The next speakers were Greet Musch, FAMHP, and Francis Aricx,
RIZIV-INAMI (National Institute for Health and Disability Insurance),
Belgium, who both considered unmet medical needs and the need
for new legislation. Mrs Musch stated that FAMHP’s mission as part of
the EU regulatory network is “facilitating the translation of innovative
scientific advances into medicinal products meeting adequate
standards and accelerating patients’ access to promising therapies
fulfilling unmet medical needs”. She stated that there are challenges
in accelerating medicine development and patient access, not least in
balancing access with evidence, while realising that “the safest drug
that comes too late is of no benefit for the patient”. It was considered
that there was a need for implementing adaptive pathways and moving
to a more iterative process and progressive patient access schemes.
Ideas such as early temporary authorisation with a possible link to early
temporary reimbursement were considered. Francis Aricx built on the
idea of early temporary reimbursement. He explained that the CAIT-CATT
was the advice commission responsible for temporary funding for the
use of a medicine, and explained its compositions. The mission of the
CAIT-CATT is to formulate cohort propositions, advise on unmet medical
needs and advise the Co-ordination Group for Mutual Recognition and
Decentralised Procedures – Human (CMDh) on individual applications.
Mimi De Ruyck, Bayer Healthcare, Belgium, shared recent
experiences with scientific technical advice and defined
opportunities and challenges of an early dialogue between Bayer and
FAMHP-RIZIV/INAMI, and then looked at the way forward in terms of
early access to patients with an unmet medical need. The scientific
technical advice was organised by DG Pre Authorisation groups at
FAMHP at the request of industry and was an open dialogue between
the stakeholders. This open dialogue is seen as an advantage and
can give broad insight on product value (not only on price) for all
parties. Of course the discussion about product positioning starts
long before usual pricing and reimbursement procedures and
therefore some data will be lacking and there are uncertainties, and
this is seen as a challenge. So, in conclusion, early access to patients
could allow additional data generation on the use of the medicinal
product in a real-world setting much earlier than at present and this
additional data could aid the health technology assessment (HTA)
decision-makers to get a better understanding of the added value of
the product when applying for reimbursement.
Regulatory Rapporteur – Vol 11, No 12, December 2014
SESSION 3: The FAMHP with Focus on the Patient from
Two Perspectives: Falsified Medicines and Vaccines
Reported by Marta Marques, Regulatory Affairs Manager, PPD
(Pharmaceutical Products Development), Brussels, Belgium.
Mrs Greet Musch, Director General PRE Authorisation, FAMHP,
Belgium, explained that the session would cover the FAMHP’s
viewpoint on the Falsified Medicines Directive (FMD), and would
address several questions regarding the Centre of Excellence Vaccines.
Mrs Josiane Van Der Elst, Director General Inspection, FAMHP,
firstly explained that the threat of falsified medicines is a reality:
almost 9.5 million fake and illicit medicines were seized and over
9,000 websites were closed via the Pangea VII global operation
involving 111 countries. Despite the strong legal framework in EU for
manufacture, licensing, distribution and dispensing of medicines,
the risk of falsified medicines entering the European legal supply
chain is increasing as falsifications become more sophisticated. The
FMD will strengthen control by applying new measures, such as:
Manufacturing of the active substance: Previously only medicinal
products were affected by stringent GMP regulations; GMP is now
required for active pharmaceutical ingredients, particularly those
coming from third countries.
FERGUS SWEENEY, Head of Inspections and Human Medicines
Pharmacovigilance, EMA
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Focus – Pharmaceutical Symposium
anufacturing of the final product: Safety features/authentication
M
of outer packaging. The FMD has introduced an electronically
generated unique identifier for each single box of medicines by
which a product can be traced from the point of manufacture to the
pharmacy/legal selling point. Tamper-proof packaging is also in use.
Actors in the legal supply chain: The requirement to notify all
operators in the supply chain (manufacturers, importers and
distributors), including brokers, has been extended to active
pharmaceutical ingredients (APIs).
Dispensing: A common, EU-wide logo to identify legal online
pharmacies/selling points.
In the fight against falsified medicines, the patient needs to be
vigilant and empowered to:
Notify the pharmacist/doctor/authority in cases of, for example,
unexpected side effects; change in taste, smell and colour;
irregularities with packaging (eg, language errors).
Be cautious if a medicine has an unusually low price, or is
available without prescription, when generally it is only available
on prescription.
Make real-time checks when ordering medicines on the internet,
by clicking on the certified EU logo to confirm it is a legally
operating online pharmacy.
Mr Pieter Neels, Vaccine Advice, Advisory Board, NDA, then
explained why vaccines are so different from small molecules (eg,
in the structure and manufacture of the product, mode of action,
target population and clinical development strategy). Several factors
complicate vaccine development, such as very specific production
processes, unpredictable epidemics, correlation between immunogenicity and mortality/morbidity rates, which is difficult to establish
(protective titre), and complicated benefit–risk ratios. Vaccines are
difficult to evaluate and require diverse expertise in several fields
such as virology, immunology, epidemiology and risk management,
and therefore many challenges still remain. Mr Neels encouraged
regulators to continue to develop their “out of the box” thinking, thus
enabling more complex vaccines to enter the market.
Ms Nele Berthels, Clinical Assessor, FAMHP, then explained the
role and processes of the Centre of Excellence Vaccines at FAMHP,
a multidisciplinary collaboration aimed at ensuring the quality,
safety and efficacy of vaccines during clinical development and postapproval. The Centre of Excellence Vaccines offers broad expertise in
five core expert activities. Given the extraordinary benefit of vaccines
for society, it is important that this work is supported:
Scientific/regulatory advice: Upfront discussions with vaccine
developers at various stages of development, at national and
European level.
Clinical trial evaluation.
Scientific expertise: Network of in-house and external experts
closely collaborating with academia, governmental institutions,
the WHO, Superior Health Council Vaccination Group, EMA
Vaccines Working Party, PDCO, PRAC, etc.
Regulatory expertise: Rapporteurship for several vaccines;
leading the Polio Global Eradication Initiative; drafting of
guidance documents; ongoing benefit–risk assessment; GMP
inspections, etc.
P ost-licensing surveillance: An essential step, especially
for vaccines.
The final presentation was delivered by Dr Michel Stoffel, Vice
President, Global Regulatory Affairs, GSK Vaccines, Head Early
Portfolio and Europe Region. He presented an industry viewpoint
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PAOLO TOMASI, Head of Section,
Paediatric Medicines, EMA
DIRK MENTZER, PDCO Chair and
Paul-Ehrlich-Institut, Germany
on challenges in vaccine development. Consistent with previous
speakers, Dr Stoffel highlighted the benefits of the vaccination
(business model) from an individual and public health perspective,
economic and communal benefit and, finally, sustainability for the
manufacturer/developer (return on investment). Recent advances
in technology provide new opportunities for vaccine development,
yet the full development of new vaccines remains a complex, lengthy
(often >15 years), and costly process (up to US$1 billion). Challenges
that arise when developing a vaccine include unclear medical need
(eg, sporadic nature of infections), lack of epidemiological data,
competition with other products in development, expectations
from policy-makers but without advance commitment, etc. In
addition, regulatory requirements are ever-increasing and not
always harmonised between agencies. Finally, post-registration
surveillance and development (Phase IV) add to cost and complexity.
The development of many innovative vaccines is still anticipated to
be economically prohibitive, thus highlighting the need for multistakeholder reflection on the sustainability of their development.
SESSION 4: Paediatric Development
Reported by Leigh Shaw, Director, GFA.
This session was introduced and chaired by Dr Daniel Brasseur,
CHMP member, FAMHP, Belgium. Margareth Jorvid, LSM Group,
Sweden, started the presentations with an overview of the
challenges faced with filing and managing a successful paediatric
investigation plan (PIP). The presentation highlighted that a
PIP should be submitted to the EMA at the end of Phase I, and is
a binding agreement between the company and the EMA. The
PIP is therefore a living document which needs to be amended
and updated throughout development to keep it current and to
address any changes in the development plans. In order to keep
the process as smooth as possible, early dialogue with the EMA
paediatric coordinator is recommended, as is participation in
PIP pre-submission meetings. A number of challenges were
highlighted, in particular that there can be issues for companies
defining the paediatric condition as opposed to the indication, and
it was emphasised that early dialogue with the regulators is crucial.
A number of sources of information to help with the preparation,
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filing and maintenance of PIPs were highlighted, in particular
the EMA website, published opinions and decisions on previous
PIPs and the new public PIP summaries which have started to be
published this year.
Paolo Tomasi, Head of Section, Paediatric Medicines, EMA,
followed with an overview of the EMA’s role in the development of
paediatric medicines. It was noted that all of the EMA’s Scientific
Committees are involved in the development and review of
medicines for use in children, not just the Paediatric Committee
(PDCO). Statistics were presented regarding the number of PIPs,
waivers, modifications and deferrals dealt with by the EMA, and it
was clear from the statistics that the number of PIP applications
has increased over time. It was also noted that the EMA
consistently adheres to the required timelines for PIP reviews and
has made efforts to improve the PIP process. These improvements
have included the introduction of a simplified application form,
publication of new guidance, simplified opinions, and cooperation
between the EMA and regulators in the US, Japan and Canada.
The work of the PDCO and how it contributes to the development
of medicines for children was then discussed by Dirk Mentzer,
PDCO Chair and Paul-Ehrlich-Institut (PEI), Germany. It was
highlighted that the PDCO is interested in the facilitation of
the development of new medicines for children and providing
scientific input (for example in the methodologies and conduct of
studies for paediatric development).
Dr Mentzer discussed the fact that a PIP needs to relate to a
condition rather than an indication and that guidance has been
developed and published recently to provide advice to industry.
It was highlighted that there are many interactions between the
PDCO, the EMA and PIP applicants, and also between the PDCO and
various scientific committees – including the Pharmacovigilance
Risk Assessment Committee (PRAC), the Committee for Medicinal
Products for Human Use (CHMP)/Scientific Advice Working Party
(SAWP) and the Committee for Orphan Medicinal Products (COMP).
Finally it was noted that there is a lot of work ongoing by the PDCO,
including a review of the class waiver list, preparation of the tenyear status report, preparation of paediatric pharmacovigilance
(PV) guidance and reviewing the way forward to allow more early
interaction between the regulators and applicants.
The final presentation came from Florian Schmidt, Unit 5,
European Commission, who provided an update regarding
changes to the current PIP guidance and potential future changes
which may be presented in the ten-year status report. The
rationale and aims for review of the PIP guideline are to take
account of experience to date, to simplify the style and structure
of applications, and to increase flexibility and alignment with
other guidelines. The ten-year status report will be a review of
progress to date and assessment of the impact of the Paediatric
Regulation. There will be an economic analysis of the impact of
the regulation including the impact of the rewards derived from
the regulation; there will be an assessment of the public health
impact; a review of stakeholder experience; and a comparison of
the EU and US systems.
The speakers were then joined by Koenraad Norga, PDCO
Vice Chair and member of FAMHP, University Hospital, Antwerp,
Belgium, for a panel discussion and questions from the audience.
There was particular interest around changes to class waivers and
the definition of “paediatric condition”, which is clearly a hot
topic in this area.
Regulatory Rapporteur – Vol 11, No 12, December 2014
SESSION 5: Adaptive Licensing
Reported by Sarah Roberts, Vice President, Global
Regulatory Affairs, PRA Health Sciences, UK.
Professor Minne Casteels, SAWP member, FAMHP, KU Leven,
Belgium, chaired this session, with Tomas Salmonson, Chair
CHMP, and Medicinal Products Agency (MPA), Sweden firstly
presenting the perspective of a national agency. Whilst the term
“adaptive licensing” focuses on the regulatory aspects, it is more
overarching, involving multiple stakeholders to ensure success. For
a typical product there is approval at an EU level, reimbursement
at a national and regional level and adequate use must be
demonstrated at a national, regional and local level. All these
factors and stakeholders must be engaged early on in the process.
In Sweden (similar initiatives exist in other MS) the MPA coordinates
the “National Pharmaceutical Strategy” to ensure the right drug is
given to the right patient in the right way. This includes “Managed
Introductions” where national-level attempts to manage the use of
the product are made prior to its approval. This requires awareness
within the healthcare system of those products to be approved in
the foreseeable future so it can prepare for their introduction. The
presentation also highlighted the number of Quality Registries
(disease-specific) in Sweden which collaborate with other EU
registries; these are pivotal in providing data (particularly safety)
to support marketing authorisation applications and therefore
generate data of value to patients. The second part of the
presentation focused on the EMA’s adaptive licensing pilot, which
was initiated in March; early multi-stakeholder engagement is
critical to its success. In conclusion, the key factors for adaptive
licensing approaches are prospective planning, lifecycle approach,
stakeholder collaboration and using different mechanisms to
generate information.
Robert Hemmings, SAWP Chair and Unit Manager, Statistics
and Pharmacokinetics Unit, Medicines and Healthcare products
Regulatory Agency (MHRA), UK, covered the UK perspective. The UK
Life Sciences Agenda 2011 included “Regulation – Routes to Market”
in addition to communication on available flexibilities around
existing regulatory tools to support patient access to innovative
breakthrough projects. Multiple stakeholders are involved in the
MINNE CASTEELS, SAWP member, FAMHP, KU Leven, Belgium
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Focus – Pharmaceutical Symposium
FRANCESCA CERRETA, Senior Scientific Administrator, EMA
approval of a medicine for use in the UK National Health Service
(NHS). As such, the MHRA held a multi-stakeholder meeting in April
2014 and further meetings have been planned. The MHRA actively
contributes to EMA joint scientific advice meetings with the UK’s
National Institute for Health and Care Excellence (NICE) and the EMA
adaptive licensing pilot as well as plans to re-launch the joint MHRA/
NICE scientific advice procedure.
Further, the “Early Access to Medicines Scheme” (EAMS)
launched by the MHRA in April 2014 covers medicines which are still
under development but cannot yet be made available as licensed
treatments. It is a voluntary scheme and operates within the current
regulatory framework but is not a substitute for appropriate clinical
development. It is anticipated that the scheme will provide medicines
around a year prior to the final marketing authorisation. There is a
two-step process: firstly the product is given a “Promising Innovative
Medicine” (PIM) designation followed by entry into a scientific review
for an EAMS opinion. Mr Hemmings then considered the EMA’s
adaptive licensing pilot. The EMA’s Q&A document notes that the
agency is open-minded on use of the tools and flexibilities available
in the process. The sponsor decides which stakeholders are included
in the meetings but, notably, without multiple stakeholder meetings,
the true benefit of adaptive licensing may not be realised. The pilot
has focused on products with the potential for the highest learnings
for both the stakeholders and the EMA; to date, 28 submissions for
pilot participation have been received, of which nine were accepted
(six have completed safe-harbour discussions). In conclusion,
the pilot was highlighted as a great opportunity to have informal
discussions with senior regulators and other stakeholders about
the potential flexibilities and tools available to sponsors to support
clinical development.
James Anderson, Director, European Partnerships, Government
Affairs, Public Policy & Patient Advocacy, GlaxoSmithKline (GSK),
UK, provided GSK’s experience with the adaptive licensing pilot.
In general the response of industry (including GSK) was positive
to its potential. The value of collaboration and early dialogue was
highlighted, including the importance of good internal company
communications to underpin the whole process. Some case studies
demonstrated what can happen when a company is engaged with
the process and the worst-case scenario (and cost) of not following
a collaborative approach. GSK also participated in the NEWDIGS
scenario design sessions, a collaboration between academia,
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payers, regulators, patients and pharma which aims to deliver new,
better, affordable therapeutics to the right patients faster. In those
sessions, the team considered eight products (assets) at various
stages of development and proposed adaptive design features for
each asset to ensure the most appropriate tools and processes
were being employed. Data on these scenarios suggest that those
products following an adaptive approach had the potential for higher
net present values compared with products following standard
development pathways. In conclusion, adaptive licensing offers
potential benefits to sponsors as well as patients, but it is a new way
of working which challenges mind-sets. Off-label use needs to be
carefully managed alongside communicating the benefits and risks
of the approach to prescribers and patients.
A panel discussion involving the speakers, Olga Solomon, Unit
D5, European Commission, Francesca Cerreta, EMA, and Franck
Hulstaert, Federal Healthcare Knowledge Centre (KCE), Belgium HTA,
further compounded the opportunity for patient participation as
independent partners in the processes.
SESSION 6: HTA and Regulatory Development
Reported by Marcello Milano, Regulatory Intelligence Lead,
Chiesi Farmaceutici S.p.A., Italy.
João da Silva Duarte, Regulatory Intelligence & Policy Manager,
H Lundbeck A/S, France, chaired this session. The focus was on how
best to integrate regulatory strategy with HTA requirements during
drug development. This integration is crucial for market access;
challenges remain in the evidence needed to fulfil both regulatory
and HTA needs.
Francesca Cerreta, Senior Scientific Administrator, EMA,
discussed “Parallel HTA scientific advice: What is the experience so
far?” The EMA parallel scientific advice (PSA) provides a forum for
early dialogue between regulators, HTA bodies and drug developers,
where critical elements of a development plan such as the key features
of confirmatory trials are discussed. Ideally this dialogue enables a
common development track addressing the needs of regulators and
HTA bodies; normally, it helps understand project risks. In a PSA,
EMA and HTA bodies act as equal partners while maintaining their
respective roles and responsibilities. In the ongoing pilot, there have
been more than 35 procedures. The final outcome is a CHMP letter
as per the standard scientific advice process, and separate agreed
minutes with the HTA bodies. Companies should avoid seeking advice
too early or too late (ie, when the development plan can no longer
be adapted). A “best practice” guidance on PSA was issued by the
EMA this year and refinement work is now in progress. Alignment of
EMA with HTA bodies on certain methodological or clinical guidelines
seems possible to some extent and would be beneficial. Parallel
scientific/HTA qualification of surrogate endpoints/biomarkers is
a potential future development. Another area of cooperation is on
post-approval studies and registries.
Francois Meyer, Advisor to the President, International Affairs,
Haute Autorité de santé (HAS), France, then spoke on “HTA Trends:
How can EU dialogues contribute to better drug development?” The
speaker presented the EUnetHTA network of HTA agencies and its
activities for the period 2012–2015. Drug developers have three
options for early engagement of HTA bodies: at a national level
(where available), in parallel with the EMA, or multi-HTA in projects
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sponsored by the European Commission. Multi-HTA advice is based on
voluntary involvement of HTA bodies; there are no fees for companies.
The most recent, ongoing project is called “Shaping European Early
Dialogues” (SEED). SEED involves a consortium of 14 HTA partners, led
by France’s HAS, with regulators, payers and patient representatives
participating as observers. Ten early dialogues with companies are
foreseen – the first took place last May. Guidance documents and
templates are available. The company provides a briefing book with
the planned development, prospective questions and company’s
positions; the design of confirmatory trials, relative effectiveness and
economic models are commonly addressed. A face-to-face meeting
takes place firstly among HTA representatives and then with the
company. The outcome is in the form of meeting minutes reviewed
by participating HTA bodies. The SEED project will ultimately deliver a
final report to the Commission by August 2015, proposing a permanent
model for European early dialogues.
Iman Barilero, Vice President, Regulatory Development Strategy
& Policy, Lundbeck, Denmark, gave the final presentation on
“Integrating HTA and regulatory strategy: How to generate value?”
This was illustrated through a case study (nalmefene, approved
in 2012 for the treatment of alcohol dependence). Regarding use
of the European public assessment report (EPAR) content for HTA
purposes, the case study showed how information from the EPAR
was used to address HTA questions (eg, relevance of reduction of
alcohol consumption as an appropriate treatment goal, identification
of the target population, and relevance of effect size). HTA bodies
also required information beyond the EPAR (eg, further justification
of the clinical relevance of effects, other treatments available for
alcohol dependence and differentiation with nalmefene, secondary
endpoints). The outcome of nalmefene’s HTA in EU countries was
mixed: reimbursement was granted by several authorities one to
two years post-CHMP opinion but rejected by others, with arguments
including lack of acknowledgement of the treatment concept; major
price challenges are seen in countries where a comparator was
required despite the lack of clinical data in the target population.
In conclusion, the EPAR is essential but not sufficient for HTA; more
data will always be requested based on local requirements.
In the panel discussion Tapani Piha, Head of e-Health and Health
Technology Assessment Unit, DG SANCO, European Commission,
summarised the Commission’s priorities for EU cooperation in the
field of HTA. According to Mr Piha, HTA bodies benefit from working
together, but more continuity between marketing authorisations and
HTA should be pursued.
Alan Morrison, Vice President Regulatory Affairs, Amgen, UK,
presented an industry perspective on the challenges of bringing a
personalised medicine to market. The R&D model is evolving, moving
from the traditional, larger, less focused, higher risk and expensive
clinical programmes with traditional attrition rates to a model
which is leaner, more focused, with lower risk, accelerated clinical
programmes based on “pick the winner”. This new model is driven by
application of human genetics to search for new drug targets. Fuelling
this R&D renaissance is the continuing fall in genetic sequencing
costs (currently >US$3,000 per genome) and the quick determination
of how gene expression changes in response to an investigational
therapy. With scientific and technological advances, innovation has
seen a growth in the use of DNA, RNA, protein, imaging, cellular and
clinical markers which in turn have become essential components of
this innovation throughout the drug development process, of which
there are multiple industry case studies.
However, there are also challenges in bringing a personalised
medicine to market, including a lack of regulatory harmonisation
between the EU and US. In the US, a joint-approval process and
knowledge-sharing exists, yet in the EU, separate therapeutic and
diagnostic regulation means there is no umbrella agency or shared
regulatory requirement to demonstrate clinical validity versus clinical
utility. Clinical utility requirements may also become more important
for reimbursement purposes. With regulatory processes requiring
only clinical validity and not clinical utility, this puts pressure on HTA
processes. Payers have created a variety of evidence requirements to
help their assessment of cost-effectiveness of diagnostics, but often
requirements are not well defined, with significant discrepancies
in regional payer requirements. Personalised medicine is changing
the biopharmaceutical business model from early research (with
greater application of human genetics) to post-approval lifecycle
development with broader commercial portfolios and fewer
blockbuster drugs; stakeholders will also need to evolve their
processes to keep up with this evolution.
Questions and answers discussed in scientific advice for
personalised medicines were presented by Professor Dieter Deforce,
SAWP member, FAMHP, and University of Gent, Belgium. These
covered different settings for personalised medicines such as new
medicine and new test (co-development) to existing medicine and
existing test (plus all the combinations of scenarios). The EMA’s
Pharmacogenomics Working Party (PGWP), a group of European
SESSION 7: Personalised Medicines
Reported by Richard Huckle, Pope Woodhead & Associates Ltd.
This session was led by Christine Mayer-Nicolai, Merck KGaA,
Germany, chaired and introduced by Genevieve Michaux, Hunter
& Williams LLP, Belgium. Personalised medicines provide focused
treatments for targeted patient populations. However, manufacturers
are challenged with developing more complex clinical trials, which
may offer clear evidence of a drug’s efficacy in a specific patient
subgroup based on the mode of action of the drug and factoring in the
development of a suitable companion diagnostic during development.
The parallel development of drug and diagnostic poses significant
challenges – these were explored in this session.
Regulatory Rapporteur – Vol 11, No 12, December 2014
TAPANI PIHA (third from left), Head of e-Health and Health
Technology Assessment Unit, DG SANCO, European Commission
www.topra.org
Focus – Pharmaceutical Symposium
NOËL WATHION, Chief Policy Adviser, & ad interim Head of
Stakeholders and Communications, EMA
experts in pharmacogenomics, gives recommendations to the
CHMP and publishes scientific guidelines on pharmacogenomics
(and biomarkers) intended to help companies design and conduct
studies in personalised medicines. Currently there is a reflection
paper on co-development of pharmacogenomics biomarkers and
assays (ICH E16s); however, challenges still exist, notably different
regulatory authorities (medicine versus CE-marking) reviewing drugs
and diagnostics and potentially different companies developing the
medicine versus diagnostic, and timing of the diagnostic analytical
validation needed for the clinical trial. Successes include Zelboraf
(vemurafenib) for BRAF V600E mutation-positive melanomas and
its companion diagnostic (Cobas 4800 BRAF V600E mutation
test). Problems still arose such as “competition” with laboratory
developed tests and reimbursement of these much below the value
of having a targeted therapy. This raises challenges including dose
adjustment, who would conduct the studies, who would pay for the
test, and healthcare professional (HCP) training requirements. In the
case of Kalydeco (ivacaftor) for CFTR G551D mutations, the biomarker
was a known “sweat test” and mutation testing was available;
most children with cystic fibrosis have genotyping at the time of
diagnosis, so no companion diagnostic was developed (needed)
with registration trials only in patients with G551D mutations.
Adaptive licensing-type approvals may be the future, eg, conditional
approval in biomarker selected populations, followed by studies in
larger populations. For Kalydeco, this involved a post-authorisation
variation for the treatment of cystic fibrosis in patients aged ≥6 years
who have one of a number of specific gating (class III) mutations in
the CFTR gene. Regulatory input can currently be obtained via the
Innovation Task Force, HTAs, the SAWP, and PGWP.
SESSION 8: Transparency
Reported by Andrew Germain, Director Regulatory Affairs
(CMC) EU RA, Daiichi Sankyo Development Ltd.
This very topical session on transparency, chaired by Alan Hunter,
Consultant, UK, presented three viewpoints and was followed by
a panel discussion which included Professor Katelijline Denys.
This was acknowledged as a topic where everyone has a viewpoint
and expectations.
www.topra.org
Noël Wathion, Chief Policy Adviser, & ad interim Head of
Stakeholders and Communications, EMA, noted that this was the
first public communication since the EMA published the “Policy for
transparency on publication of clinical data for medicinal products
for human use”, on 2 October 2014. Mr Wathion described the
ongoing transparency initiatives starting with the 2010 EMA “Access
to Documents” policy, saying that a large step had been taken with
the current policy. The EMA’s objectives for clinical data publication
centrally are:
To enable public scrutiny – establishing trust and confidence in
the system
To enable application of new knowledge in future research, thus
increasing efficiency of medicine development (learning from
experience).
The October 2014 policy followed a long consultation process with
many stakeholders since April 2012, including a public workshop,
establishment of five EMA advisory groups and three months
of public consultation. This “mammoth” activity involved close
collaboration with stakeholders (>1,000 comments were received
from 169 stakeholders). A final targeted consultation was undertaken
in May 2014, discussed at the EMA Management Board, and adopted
into policy (unanimously) in October 2014.
Mr Wathion described the policy’s key features regarding
clinical data that is “in or out” of its scope. Notably, legacy data for
centrally authorised products (CAPs), clinical data for non-CAPs, and
individual case safety reports are out of scope. The policy has two
pillars to balance competing interests: (1) terms of use governing
access to, and use of, clinical reports; and (2) a user-friendly tool
allowing access to clinical reports.
Depending on user needs, clinical reports can either be available
onscreen for any user, or downloadable (specific to registered
identified users) for academic and non-commercial research
purposes. Common to both terms of use is that:
Trial subjects may not be re-identified
Clinical reports cannot be used to support MAA/post
authorisation procedures
A “watermark” is applied to published information
T he EMA accepts no responsibility for compliance with the
terms of use.
Mr Wathion indicated a further “mammoth” phase lies in how the
policy will be implemented; targets nonetheless are for a first phase
of clinical report publication only around Q3 2016, and individual
patient data later than this. The policy applies to any new MAA
and Article 58 application submitted as of 1 January 2015, and for
extension of indication/line extension applications as of 1 July 2015.
Richard Bergström, Director General, European Federation of
Pharmaceutical Industries and Associations (EFPIA), then provided
key data sharing considerations from EFPIA and the US industry
association, PhRMA, describing the organisations’ principles for
data sharing as: (1) safeguarding patients’ privacy; (2) respecting
the integrity of national regulatory systems; and (3) maintaining
incentives for investment in biomedical research.
Five main commitments were made by the organisations to
stakeholders:
1.
Enhancing data sharing with researchers – appreciating the
dramatic expansion of data available to researchers, with
anonymised patient level data, study level data, protocols
and complete clinical study reports (CSRs), and protecting
the public against “junk science”. Most companies expect to
Regulatory Rapporteur – Vol 11, No 12, December 2014
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Focus – Pharmaceutical Symposium
have scientific review boards (including non-employees) to
review requests for data, and the protection of patient privacy
through blocking requests where there is a reasonable chance
of re-identification.
2.
Enhancing public access to clinical study information – following
approval in the US and EU, companies expect to post CSR
synopses as a minimum, and would supplement information
posted to ClinicalTrials.gov and corresponding EU/EMA websites.
3.
Sharing results with patients who participate in clinical trials
– providing a factual summary of study results to research
participants, and ensuring summaries are non-promotional preapproval; exploring appropriate communication channels, eg,
through investigators, websites, etc.
4.
Certifying procedures for sharing clinical trial information
– where companies will certify on a public website that they
have established robust policies and procedures to implement
data sharing commitments.
5.
Reaffirming commitments to publish clinical trial results –
where results of all company-sponsored clinical trials results
should be considered for publication, irrespective of outcomes,
in the scientific literature (minimally, all Phase II trials and any
results of significant medical importance).
Mr Bergström concluded by stating we are “in the right place” and
accepted the new EMA transparency policy, but acknowledging that
much work has to be done collaboratively for practical implementation.
Finally, Marco Greco, President, European Federation of Crohn’s
and Ulcerative Colitis Associations (EFCCA), talked on the patients’
perspective for transparency in clinical trials, with two themes: (1)
how does data disclosure help the patient?; and (2) what are patient
expectations generally, particularly if they have participated in studies?
Patients are increasingly becoming active participants in their own
care, and patient involvement is a vital element in the sustainability of
European healthcare systems. In empowering patients to make fully
informed decisions, partnering with HCPs, it is pivotal that both have
ready access to relevant information. However, there is an awareness
that 50% of all clinical trials conducted have not been published, and
that positive study outcomes are perhaps twice as likely to be published.
The European Patients Forum has lobbied for all results of all clinical
trials to be published. Transparency is seen as vital for regenerating the
high trust in medical research of patients and the public.
Mr Greco indicated that there are two levels of interest – in the highlevel results of trials in simpler lay language, and access to detailed
data, both of which must be readily accessible. He concluded that
the EMA transparency policy meets patient representatives’ needs
“in general” but several questions remain, including:
How will lay summaries meet patient needs and who will control
their quality?
How will the EU Clinical Trial Regulation meet the need to have
transparent data from all trials?
How well will transparency of patient level data work?
on the impact of the PV legislation since its introduction and assessed
its current status, investigating what has gone well for PRAC and what
needs further development (eg, engagement of patients, HCPs and
the public). PRAC has overseen the investigation of drug safety while
managing benefit–risk using risk management plans (RMPs), postauthorisation safety/efficacy studies and real-time signal detection,
responding to safety and benefit–risk concerns with robust scientific
decisions to tight timelines. There has been a move from reactive to
proactive risk management while advancing transparency and realtime access to information on PRAC activities, and a move away
from binary licensing decisions, reactive PV, and overreliance on
spontaneous reports to proactive risk management activities.
With RMPs, there has been a move to strengthen methodologies
for investigating drug safety and monitoring benefit–risk in realworld populations, and prospectively planned data collection to
reduce uncertainties and manage risk throughout product lifecycles.
Benefit–risk monitoring is now being integrated throughout the
lifecycle, prioritising “important” risks, missing information requiring
further characterisation, and studies to address any safety concerns/
uncertainties, and the effectiveness of risk management tools. The
concept of the RMP is evolving to a benefit–risk management plan,
with an efficacy summary to further aid stakeholder understanding
and engagement. Recognising that the benefit–risk profile may
change throughout the lifecycle as PV data emerge, PSURs are a major
tool for updating benefit–risk, which creates opportunities to update
the label based on accumulated evidence/emerging information and
to further optimise the benefit–risk profile. There is a commitment to
collaboration; national competent authorities (NCAs), the EMA and its
Committees (PRAC, CHMP, EMA, Scientific Advisory Group (SAG), etc)
are all playing active roles in the review process, connecting benefit–
risk discussions and RMPs, with a focus on public health. There have
been major advances in transparency and stakeholder involvement,
shifting from compliance to optimisation and reactivity to proactivity.
“The impact on industry: two years with PRAC – looking back
and forward” was presented by Judith Weigel, vfa (Association of
Research-Based Pharmaceutical Companies), Germany. Dr Weigel
looked at the impact of the PV legislation on industry since its
introduction with the signal management process. The signal
management process covers all steps from detection, validation,
analysis and prioritisation, and assessment to recommending
action(s). Although logical in sequence, the wide range of information
sources available for signal detection may require some flexibility
SESSION 9: Pharmacovigilance
Reported by Richard Huckle, Pope Woodhead & Associates Ltd.
This session was led and chaired by Sarah Montagne, Bayer
HealthCare, UK. The first speaker, Almath Spooner, PRAC Co-Chair
and Health Products Regulatory Authority (HPRA), Ireland, reflected
Regulatory Rapporteur – Vol 11, No 12, December 2014
JUDITH WEIGEL, Association of
Research-Based Pharmaceutical
Companies (vfa), Germany
MARCO GRECO, President,
EFCCA, PRAC Patient
Representative Alternate
www.topra.org
Focus – Pharmaceutical Symposium
in the conduct of signal management. Since July 2014, marketing
authorisation holders (MAHs) are informed about signals the week
before the PRAC meeting. Signal monitoring implies increased
complexity and good coordination to implement risk minimisation
measures. The administrative burden on MAHs has increased with
the subsequent increase in direct HCP communication (DHPC),
assessment of signals requiring an adequate amount of time for
investigation and large number of PI [principal investigator] updates
all within a short timeframe. Dr Weigel then highlighted the challenges
with RMPs and the implementation of risk minimisation measures,
including post authorisation safety study (PASS) feasibility, the
RMP submission and different NCAs having independent comments
(even different key elements) which may in turn lead to different
educational material and approval dates. There is little experience
within industry on measuring effectiveness of the risk management
tools. Companies should bear in mind that greater collaboration and
communication with drug safety and regulatory affairs is required
along with more interaction (early meetings).
The patient perspective was presented by Marco Greco, President,
EFCCA and PRAC Patient Representative Alternate. Patient input
into PRAC is via three levels of interaction: personal (reporting
or writing, eg, of an adverse drug reaction, although this has its
limits), consulting or as a representative. Writing to PRAC usually
occurs during an ongoing procedure and may introduce a different
perspective or lead to involvement as an expert (although this is
rare). Patient consulting may occur at the agency’s request and
involves review of information or preparation of guidelines. PRAC
patients’ representatives are appointed by the European Commission
after consultation with the EU Parliament and are not only patients’
advocates with extensive experience and chairing international
patient organisations but, above all, patients, to ensure that patient
needs are taken into account. Public safety and communication on
individual medicinal products should also consider specific patient
requirements. PRAC patients’ representatives are full committee
members who also ensure clear, understandable outcomes and
related material (eg, patient cards). From 1 January 2015, patients will
have an increasing involvement in early research and development
via access to clinical trial data and a safer healthcare environment.
PARALLEL SESSION: Biosimilars
Reported by Ash Ramzan, Principal Consultant, Woodley BioReg Ltd.
With a high degree of audience participation through Q&As as
well as sharing actual experiences with biosimilars development
and registration, this session provided a fertile ground for the
presenters to discuss their interpretation (and the limitations) of
the current legislative framework. With topics as wide as analytical
development for biosimilars through to their registration and
interchangeability, this is a subject that will continue to challenge
conventional understanding of this complex group of products.
A rapidly growing interest in the area of biosimilars saw this
session well-attended by both industry and regulators. Following
a detailed insight into the current regulatory thinking regarding
biosimilars by Karen De Smet, Senior Non-Clinical Evaluator, FAMHP,
Belgium, some of the advantages, disadvantages and limitations
of the currently available technologies and data were discussed.
In particular it was noted that the EMA continues to lead the FDA in
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terms of establishing and refining frameworks for the development
and successful registration of biosimilar products. Dr De Smet
reasserted that once approved as a biosimilar, the product is treated
in its own right distinct from the reference/innovator product. This
assertion was explored and discussed in the Q&A discussions.
The session continued with some of the perceived and real
limitations of biosimilars with Cecil Nick, Vice President (Technical),
Parexel International, discussing interchangeability; the US and EU
definitions of interchangeability were examined with regard to what
is meant in real terms for patient safety and efficacy. The importance
of the mitigation of risk and balancing benefit–risk was discussed
in view of determining potency, pharmacokinetics (PK) and
immunogenicity. Using the examples of infliximab, filgrastim, and
epoetin, Mr Nick outlined the potential impact of interchangeability
on immunogenicity. The importance of using robust analytical and
biological procedures was exemplified through the changes in the
glycoprofile of rituximab to demonstrate the subtle (but measurable)
differences between biosimilar and interchangeable product
attributes. While not always necessary or possible, the use of clinical
studies to evaluate immunogenicity and interchangeability was
presented, and in particular the need for a large patient cohort for
statistical significance.
The final presenter, Janne Komi, alternate CHMP member,
Senior Medical Officer, Finnish Medicines Agency (Fimea), Finland,
continued the theme of widening the application of biosimilars by
expanding to the extrapolation of indications. Unsurprisingly, the
regulatory concerns regarding the limitations of extrapolation (age,
gender, ethnic group, concomitant diseases, organ function, etc.)
were identified as some of the considerations.
Dr Komi explained how the extent of practical comparability
evaluation through physico-chemical, biological, and additional
(non)clinical testing should be determined prospectively, based on
the prior knowledge of the reference and biosimilar molecules, as
well as the proposed change or extrapolation of indication. To aid the
development of robust extrapolation plans, the existing framework
of guidelines for extrapolation were presented, with particular
emphasis on the importance of demonstrating similarity in function,
PK, pharmacodynamics (PD), safety and efficacy in addition to
physico-chemical characteristics.
Some difficult-to-extrapolate examples of epoetins (from renal
disease to cancer) and filgrastim were contrasted against infliximab
where bioequivalence, and safety and efficacy data were successfully
used to extrapolate to rheumatoid arthritis.
The presentations during the parallel session resulted in a wide
range of in-depth questions ranging from the limitations of biosimilars
due to the complex/cell line nature of innovator products such as
multi-subunit biologics and vaccines, the effect of post-approval
changes to either the biosimilar or reference product, and the
speed with which the two “previously biosimilar” molecules would
become completely differentiated. There was audience discussion
around the effect of such changes on subsequent interchangeability
and extrapolation, with an overall feeling that while some form of
regulatory framework and guidance was helpful, it should not be
prescriptive (or restrictive) at this stage of biosimilars’ regulatory
development to ensure future challenges could be addressed.
The session closed with a general consensus that further
discussions between industry and regulators should be facilitated to
ensure the achievements are built upon and that guidance for future
developments isn’t just conceptual. Regulatory Rapporteur – Vol 11, No 12, December 2014
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