PHRM 7210 Introduction and History


Slide One:
No audio Slide Two:
Welcome to the first module of the European Pharmaceutical and Biologics Regulatory affairs
course of the Faculty of Pharmacy at the University of Georgia. My name is Seppe De Gelas and I will be your
lecturer for this first and subsequent modules covering the European Pharmaceutical regulatory
environment for both the pharmaceutical as well as biological drug products. As an introduction, I can share with you that
I am a chemist by education and started my career more than 20 years ago in clinical
trials, evolving over the year into regulatory affairs and contact with health authorities,
mainly in Europe but also abroad and include companies like Bristol Myers & Squibb, Covance,
Baxter, UCB and Lonza. Prior starting my own company and GMP laboratory
I was head of Quality Assurance, Quality Control and Regulatory Affairs at one of the major
drug substances manufacturing units in Belgium. Currently I provide extensive regulatory support
to smaller European start-up companies and larger (non-European) pharmaceutical companies
trying to establish a regulatory path forward for their innovative drug product in Europe. I live south of Brussels, Belgium with my
wife and four kids and I am active mountain biker and member of the local field hockey
team. A team which always aims to do better than
our previous season. Slide Three:
On this course I will take you through a journey on the European Regulatory Affairs landscape. It will be a journey with most probably differences
in speed and pace when it comes to content, but also there will be easy and sometimes
more challenging modules. I am aware of this I would strongly suggest
the raise your hand and catch my attention during the presentation of the different modules
if one or more items are not clear or even raise an eyebrow. I would be happy to elaborate on a specific
topic or to clarify a definition with additional examples. At the end the student should be able to understand
not only the very basics to register a medicinal product in Europe using the best possible
regulatory submission strategy, but also have a good impression of the history and legacy
of the European approval system. An inventory of about 200 definitions will
be used as a backbone in order to be sure to cover the entire spectrum of possibilities
and to use the correct terms & definitions with the regulatory framework. Slide Four:
The entire course consists of 1 + 15 modules. The first module, identified as module 0 is
the current module and entitled Introduction and History of European regulatory affairs. It will cover both the Pharmaceutical and
Biological aspects of the submission process. The next part: regulatory strategy and pre-submission
phase is divided into 6 different modules and will provide an in-dept insight in the
regulatory mechanisms and definitions. (this will be two modules), possible regulatory
options and support provided by the concerned health authorities. The fourth module will focus on patent (also
called intellectual property), data exclusivity and data protection. Module five will detail an standard drug development
process and the different expectations where the support from a regulatory expert might
be required. The last module of the regulatory strategy
& pre-submission chapter will give an extensive explanation on the art of writing a regulatory
submission dossier. Chapter two: dossier preparation & submission
will consist of two modules: module 7: dossier preparation & submission for new innovative
drug products and module 8 for generic application (in the US also known as Abbreviated New Drug
Applications or ANDA) Chapter three will be the formal approval
process in Europe. The four (4) modules of this chapter will
detail both the European wide centralised approval process as will as the national governed
application, either as standalone or via Mutual recognition procedures. A chapter will also focus on Decentralised
procedure and the next steps in the marketing authorisation process. Chapter four (4): post-approval commitments
and responsibilities will highlight an important step when reaching an agreement with the European
health authorities and will also – again – put some emphasis on the different roles
and responsibilities which are directly linked to the issuing of a marketing authorisation
to the marketing authorisation holder by the competent (health) authority. The last chapter five (5) will address life
cycle management of the drug product license in Europe and will try to identify the different
options when maintaining an approval dossier and keeping the registered details up-to-date
in a European environment. This last chapter will devote module 15 and
16 respectively to life cycle management of centralised registered drug products and life
cycle management of decentralized / MRP / National registered drug products. It is worthwhile noting that in a standard
regulatory setting the vast majority of workload and resources for the (European) staff and
team members working in a European regulatory environment consist of life cycle management
of already existing drug product applications and that only about 10% of resources are linked
to new drug product development and registration of new chemical (or even biological) entities. Slide Five:
The back bone of this European Regulatory course will be an inventory of about 200 terms
and definitions. Some of these terms and definitions have a
legal connotation, other are more of an explanatory importance in order to clear out potential
confusion. These 200 definitions have been compiled by
the different European stakeholders and are available for consultation at the EMA website. In order to make this course somehow manageable
for individuals already working part-time or even full-time in the industry or take
an assignment as student at another college, the definitions have been grouped in clusters
of ten to fifteen items. Although it is recognized that some definitions
could be clustered in a different way or even several other options, I would like to emphasize
that it is not the clustering or grouping of these definitions which is important, compared
to the actual definition of clarification itself. It is understood that several other – equally
valid – clustering are possible and even acceptable. Slide Six:
The system for regulating medicines in Europe
is unique in the world. It consists of two layers of legislations:
National (for each European Countries) versus a European (for the entire region); Both layers
will continue to exist and over the years have been streamlined to be complementary. Using both the local – national – as well
as European legislation it has allow to all type of (pharmaceutical) companies: Major
innovative companies, smaller local generic companies to obtain and maintain licenses
to keep there drug products on the markets. Slide Seven:
Prior to 1990 – please note that back then the European Union totaled only 12 countries
– each country issued independently a license for a drug product after an (extensive) review
of a local dossier ranging from a couple of pages to a room full of binders. Also the quality of review as sub-optimal
as in each country experts (pharmaceutical, non-clinical and clinical) were reviewing
the different dossiers. This lead to (too) long review cycles and
discrepancies between the different countries… Local ministry of health: evaluation of scientific
dossier + granting of marketing authorisation Consequence:
no harmonisation on approval times no harmonisation on approved indications / contra
indications / posology / adverse events no harmonisation on expertise
no harmonisation life-cycle management duplicate of work at MoH Slide Eight:
In the Early ’90 there was a paradigm shift It was the introduction of Mutual Recognition
Concept For the first time there was an agreement
that a (European) country will grant a national license based on the (scientific) evalation
of another country. Reference member state versus Concerned member
state. Consequence:
MRP is an option, not an obligation harmonisation on approval times
harmonisation on approved indications / contra indications / posology / adverse events – other
sections are still national some countries highlight their expertise
no harmonisation life-cycle management At this stage the European Union had 15 participatingCountries Slide Nine:
The basic concept of a mutual recognition was that Marketing Authorisation holder and
a Member state first come to an agreement to grant a license or marketing authorisation. The output / result of this discussion is
an assessment report. This first country is also called the reference
member state and becomes the advocate to go and defend marketing application to other
member states. These are also called concerned member states
An internal discussion between the reference member state and the concerned member states
results in a concensus and final agreement. Upon consensus each country issues a national
marketing authorisation. Slide Ten: In 1995 there is a major leap forward
With the establisment of EMEA (London, UK) + corresponding legislation at European level. The EMEA is the European Union agency for
the evaluation of medicinal products. Since 2004, it is known as the European Medicines
Agency (EMA). The EMA was set up in 1995 with funding from
the European Union and the pharmaceutical industry, as well as indirect subsidy from
member states, in an attempt to harmonise (but not replace) the work of existing national
medicine regulatory bodies. The hope was that this plan would not only
reduce the €350 million annual cost drug companies incurred by having to win separate
approvals from each member state but also that it would eliminate the protectionist
tendencies of sovereign states unwilling to approve new drugs that might compete with
those already produced by domestic drug companies. Since 1995 European commision was also granted
the (legal) authority to issue a European license for a medicinal product based on the
recommendation of the EMEA scientific committee. This European license is valid throughout
the entire European territory, regardless of the number of countries. Please note that in 1995 only these European
licenses were valid in 15 countries, when the European Union was enlarged later to 20+
countries these European licenses were automatically valid in all new countries. (important: pricing & reimboursement remains
an national authority, since directly linked to the local budget) Slide Eleven:
EM(E)A is considered as the European ministry of Health and operates as a decentralised
scientific agency (as opposed to a regulatory authority) of the European Union and its main
responsibility is the protection and promotion of public and animal health, through the evaluation
and supervision of medicines for human and veterinary use. More specifically, it coordinates the evaluation
and monitoring of centrally authorised products and national referrals, developing technical
guidance and providing scientific advice to sponsors. It is First set of rules & regulations, guidelines
Experts are selected from each country Centralised procedure is a fact & becomes
the third legal option to market a medicinal product in Europe
Other two: Individual national license
Mutual recognition procedure Slide Twelve:
In 1995 the EMA was establised and the first European license was granted to the human
medicinal product Gonal-f from Merck Serono as a biological product
One year later, 1996 the first veterinary drug product was reviewed & approved. In early 2000 the first regulation was voted. It was the Orphan Medicines regulation. IMPORTANT TO NOTE:
A directive is a European legislation which first needs to be transposed in the local
legislation of each country (and which needs to be voted, approved & signed) before it
becomes effective. A (European) Regulation is a European law
which is valid / applicable throughout Europe the moment it has been adopted by the European
parlaiment and the corresponding commission(er)=minister. Slide Thirteen:
2001: first orphan medicines are authorised and the clinical trial directive is finalised
2004: Europe expands from 15 to 25 countries (almost overnight)
This triggers a major overhaul of the european pharmaceutical legislation with an update
of directive 2004/27/EC and directive 2004/28/EC for both respectively human and veterinary
medicines 2006: Brings the first peadiatrics medicines
regulation into effect Slide Fourteen:
In 2007 both the first centrally authorised generic medicine is approved as well the first
centrally approved over the counter (OTC) medicine. 2009 brings an update & brand new pharmacovigilance
legislation, shifting the responsabilities of monitoring and reporting from the health
authorities to the marketing authorisation holders. This shift triggerd a major upgrade of the
role of european qualified person pharmacovigilance: EU QP PV Slide Fifteen:
2010 resulted in the first pediatric marketing authorisation
In the meantime Europe is enlarged to 27 countries 2011 is highlighted by the directive on falisified
medicines and the obligations by the marketing authorisation holders. In 2014 is it time for a major overhaul of
the clinical trial regulation putting better control and protection of the participants
and subjects in (European) clinical trials, setting again the gold standard for ethical
research In 2015 EMA is celebrating 20 years of european
pharmaceutical legislation. Slide Sixteen:
What will bring the future for the EMA? 2017 a Brexit was voted resulting that the
UK will formally leave the European union As a consequence the EMA as European agency
will have to leave the Canary Warf offices in London, UK
Currently about 15 cities in Europe are competing to win the public offering to host the EMA
as agency. This will be decided in fall 2017. Slide Seventeen:
In parallel to EMA a National European medicines regulatory network continues to exist. This is called the HMA=Heads of Medicines
Agency This European medicines regulatory network
is the cornerstone of EMA’s work and success. The Agency operates at the heart of the network,
coordinating and supporting interactions between over fifty national competent authorities
for both human and veterinary medicines. These national authorities supply thousands
of European experts to take part in EMA’s scientific committees, working parties and
other groups. Slide Eighteen:
For a list of national competent authorities in the EEA, see:
National competent authorities (human) National competent authorities (veterinary)
The regulatory network also includes the European Commission, whose principal role in the European
system is to take binding decisions based on the scientific recommendations delivered
by EMA. By working closely together, this network
ensures that safe, effective and high-quality medicines are authorised throughout the European
Union (EU), and that patients, healthcare professionals and citizens are provided with
adequate and consistent information about medicines.

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