week 11 part 1 Flashcards
What does EU law require?
All the medicinal product to obtain a Marketing Authorisation before they can be put on the market
In 1965, what was the first pharmaceutical Directive (65/65/EEC) triggered by?
The thalidomide catastrophe with aim to protect public health
What is necessary in order to place a medicinal product on the market?
Permission (authorisation)
What must the authorisation be granted by?
One or more member states or the European Comission for centrally authorised product (i.e. via the EMA)
What criteria must the product need to statisfy and to be submitted in a marketing authorisation application dossier?
- Quality
- Safety
- Efficacy
What are the current pharmaceutical Legislation?
- Directive 2001/83/EC
- Core legislation
- Regulation of drugs in the EU
- provides framework for regulation of medicine at national level - Regulation (EC) No 726/2004
- Establishes the EMA and sets out the centralised procedure
What does scientific advice support?
Medicine development
non-compulsory regulation
What is scientific advice?
A company developing a product comes to regulators and says give us advice on what studies to do
peculiar to the development
What happens before the first marketing authorisation?
Companies ask questions on:
- Manufacturing
- Non-clinical and clinical trials
- Risk management plans
- Ways to develop generics
- Biosimilars
What is scientific advice good for?
- Significant benefit for orphan medicine
2. Development in children
What is post MA?
Extension of indication to different age groups and stages of the disease
different conditions
+ safety aspect
What happens if a product has market authorisation?
Development of product continues and the research will continue
What is scientific advice main activity so fat?
- Scientific advice
- Protocol assistance for orphan drugs
- 2001 - 70 questions
- 2015 - over 500 questions
What does protocol assistance apply to?
orphan medicine
What did the study of positive impact of SA adherence on MAA procedure and outcome show?
If the company follows the advice given, they are more likely to get the marketing relation
What does clinical trial in human require?
Authorisation from national competent authorities
Ethical approval
What supports national decision at EU level?
Clinical trial facilitation groups
Where is clinical trials done?
National level
What is clinical trial regulation?
- New
- Not fully enforced yet
- Faciliate approval of clinical trials
What is marketing authorisation?
A license to market a medicine
Who can use a product in the market?
- Doctor
- National health service
- Very special situations
What are the 4 different routes to get marketing authorisation?
- National procedure
- Mutual Recognition procedure
- Decentralised procedure
- Centralised procedure (Via EMA)
National procedure
still possible for authorisation by a single MS
Mutual Recognition procedure + Decentralised procedure
Authorisation by several MSs
Based on assessment by Reference MS
Centralised procedure
Authorisation by European commission
Based on assessment by EMA
What is mutual recognition procedure?
European authorisation route resulting in a mutually recognised product
Mutual recognition must be used when a product is already authorised in at least one Member State on a national basis and the Marketing Authorisation Holder wishes to obtain a Marketing Authorisation (MA) for the same product in at least one other Member State
What is decentralised procedure?
DCP may be used if the product is not already authorised in any Member State, but does not want to use the centralised procedure, or the product is not eligible for the centralised procedure
What does the reference member states do?
the initial evaluation of the product and issues a draft assessment report
What does the Concerned member states do?
either agree with the RMS’s evaluation or they ask further questions/raise objections
What is found between regulation authority?
Internal market
The more licensing work
The more income you get from regulatory authority
What is a referral?
procedure used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines
What are the reasons that a referral may be started?
- Concerns over the safety of class of medicine
2. Disagreement among member states on the use of medicine
What are safety-related referrals are assessed by?
Pharmacovigilance Risk Assessment Committee (PRAC) and then either by the Committee for Medicinal Products for Human Use (CHMP) or, for nationally authorised medicines, by the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh);
What are the vast majority of product being authorised by MRP/DCP?
Generics
What are DCP being used for?
New product:
- Monoclonal antibodies
- New chemical entities
What are the pros of MR/DC procedure
- Flexibility
- Choice of RMS
- Choice of CMS - Multiple licenses
- multiple (invented) names possible
What is required in order to do marketing?
Infrastructure margin
What are the cons of MR/DC procedure?
- Complexity
- Slot rationing - Lack of 2nd primary review
What is centralised procedure used for?
Innovative products
What are the European economic area?
- Iceland
- Norway
Not Switzerland
What is identical to the European Union?
European economic area for medicine regulation
What happens when authorisation are granted in EU?
It is also validated in this country
What is common product information?
Leaflet inbox
What controls how the medicine are marketed?
Summary of product characteristics
What is illegal for the company to do?
Market product outside of summary of product characteristic
What are the features of centralised procedure?
- 1 Marketing Authorisation valid throughout EU/EEA
- 1 (invented) name
- 1 Common product information
- Identical in all official languages including Icelandic and Norwegian
- Summary of product characteristic
- User package Leaflet + Labelling
Maximum time limit
-210 days evaluation —> opinion
In 2016, how many applications were innovative product?
40 applications
- 45 for generic and biosimilars
- 24 applications for orphan medicine
Features of Centralised Procedure (CP)
- Dedicated to innovative products
- May be open to ‘‘old’’ substances in a new delivery system or in a new indication
- Products eligible are defined in the legislation
- Human and Veterinary Medicinal Products
What are examples of product that have to go to the centralised procedure, and by European Law cannot go through the National procedure?
- Recombinant DNA technology
- Controlled gene expression
- Monoclonal antibodies
- Orphan medicinal product (product for rare diseases)
- New active substance
- Advanced therapy medicinal product
What are examples of advanced therapy medicinal product?
- Gene therapy
- Cell therapy
- Tissue Engineer therapy
What is the assessment process in centralised procedure?
- A company comes and submit a market regulated dossier
- Primary evaluation and list of questions that goes back to the company
- Company answers the question and then there is a second evaluation
- There is a list of outstanding issues
- Final evaluation which leads to a decision by opinion of committee
What is clock stop?
active assessment time in the regulatory authorities stop while we wait for questions to be answered by the company
What can the total active assessment time taken out the clock stop cannot go over?
210 days
At the end you get an opinion of the CHMP which is the scientific opinion and then a number of days later you get a legal document from the European commission
Why does the company withdraw the dossier?
To prevent transparency
What happens when the marketing refuse?
there is a detailed public assessment report that explains why
Re-examination of opinion
Re-examination = ‘‘Appeal’’
15 days to request re-examination
60 days to submit grounds
CHMP 60 days to consider revision of initial opinion
No new data
Scientific advisory group may be consulted
What is the Centralised procedure (post-opinion)?
- Linguistic phase
- Draft EC decision
- Standing Committee
- Adoption of EC decision
What is the Linguistic review?
- 27 days
- Translation in all EU/EEA official languages
provided by MAH and reviewed by national competent authorities - European Commission prepares a draft decision
What is standing committee?
on Medicinal Products for Human Use gives opinion on draft decision
EC adopts the decision on granting or refusing Marketing Authorisation, which takes effect from data of notification
Outcome is published by EC and EMA (including assessment reports and clinical data)
What are the Pro’s of centralised procedure?
- Pan-EU license
- Transparency
- Predictable timeline
- Two independent primary reviews
- Dedicated EMA product Team
What are the Cons of Centralised procedure?
- Restricted access to CP
- No control over CHMP Rapp appointment
- All or nothing outcome
- Single (invented) name - single MAH
- No independent ‘‘appeal’’ body
What are there different types of marketing authorisation for?
Different types of products
Fixed dose combination - Ace inhibitor and diuretic
- Been in the market as single use component
- Very well established
- The company splits the two to find formulations
What are the requirement for generic product?
Need all the information on quality and manufacturing but not the clinical stuff
You need bioequivalence study
What does the manufacturing methods have?
Profound impact on the molecule
What is biosimilar?
Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal product, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical test or clinical trials relating to these conditions must be provided
Medicinal product shall be subject to medical prescription where they:
- are likely to present a danger either directly or indirectly, even when used correctly, if utilized without medical supervision
- Are frequently and to a very wide extent used incorrectly, and as a result are likely to present a direct or indirect danger to human health
- Contain substances or preparations, the activity and or adverse reactions of which require further investigation
- Are normally prescribed by a doctor to be administered parenterally
What is organ designation?
∇ Is a legislation about a millennium
∇ Tries to stimulate companies to produce medicine for rare diseases
∇ It gives the company a monopoly for 10 years what’s on the market
∇ COMP: Committee on orphan on medicinal product – assess the product in development are eligible to be called an orphan medicine
What are orphan designation criteria?
- Prevalence
- Seriousness of condition
- Comparison to available treatment
Prevalence of orphan designation criteria
Rare condition affecting not more than 5 in 10,000 person in the EU
Unlikely that the medicine would generate sufficient returns to justify investment
Seriousness of condition
Life threatening and/or chronically debilitating condition
Comparison to available treatment
No satisfactory methods exist
or significant benefit vs. existing method
What are the types of marketing authorisation?
- Normal MA
- Conditional MA
- MA under exceptional circumstances
What is Accelerated assessment?
For product of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation
Request to be submitted and agreed in advance of submitting the MA application
Maximum active time is 150 days
What happens to a product not marketed in EU for 3 consecutive year peiod
Lose their authorisation
