Transcript EU Marketing Authorisation Procedures Registration Dossier

Prescription (legal) status
Categories vary
country by country
• NP („OTC”)
• POM
• Subcategories
Prescription
1
EU Directive
Main categories
• NP
• POM
renewable/non-renewable
prescriptions
 special medical prescr.
 restricted medical prescr., reserved
for use in spec. areas
2
EU Directive
A medicinal product is NP, if it does
not meet the criteria of POM
(Very important!)
(In many countries just the opposite is
applied)
3
EU Directive
When POM?
• danger, even used correctly, if
without medical supervision
• frequently used incorrectly
presenting danger
• APIs with activity/ADRs still be
studied
• parenterals
4
EU Directive
POM, sub-category specialist’s
prescription
• narcotic/psychotropic substance
• if used incorrectly, abuse/misuse
• novel active principle, precautionary
5
EU Directive
POM, sub-category restricted use
• can be used in hospitals only
• can be diagnosed in hospitals only
• specialist’s supervision (e.g. ADRs)
6
EU Directive
(SUB)CATEGORIZATION
• Taking into account single and max.
daily doses, strength, dosage-form,
pack unit
• Annually updated published list of
POM (sub)categories
7
EU Guideline
Goal:
To help MAHs when applying to
change the classification
(i.e., to harmonize the swithches!)
• POM/NP criteria
• switch application criteria
8
Guideline NP or POM?
Direct danger: even if used correctly
• Toxicity
• Serious and existing less serious
ADRs
• Interactions with commonly used
drugs
9
Guideline NP or POM?
Indirect danger:
• Masking conditions that would
require medical attention. NP: timelimit must be set
• Wider use increase resistance,
particularly in general population
10
Guideline NP or POM?
Risk and consequences of incorrect
use
• If used according to indications (too
many contra-indications,
precautions, warnings, etc. May lead
to incorrect use
• If the opposite: off-label or longer
use
11
Guideline NP or POM?
Self-assessment/diagnosis
• Symptoms can be correctly assessed
by patients (may vary country by
country!)
• Natural course of disease, duration
or re-occurrence of symptoms may
be self-assessed
• Contraindications, etc. can be
understood by the consumer
12
Guideline NP or POM?
• The way patient info is written
• „If not POM, must be less
dangerous”
• Layman’s terms used?
• Explanation of use?
• Explanation when should not be
used?
13
Good question - who is
„Patient”?
14
Summarising the legal status
Ailment Treatm. ADR Dr’s diagn. Med.Att. Status
Minor
Major
Major
Major
Major
1if
any
single
long
long
any
NS
NS
NS
S
any
none
yes
yes
yes
yes
no
NP
no
NP/POM
rare NP/POM
rare NP1/POM
yes NP2/POM
the patient can be informed…
2the
smallest pack size
15
In case of rigid systems...
The NP/POM choice may cease to
exist!
Rigid systems:
• Drugs are officially classified either
NP or POM (NP may be prescribed
but not vice versa!)
• If NP no reimbursement
16
Professional switches?
• It must be realised: this is a semipolitical matter!
• If no consensus between
reimbursement-policy makers and
DRAs, affordability problems may
occur!
17
The second issue:
OTC distribution channels in the
country
and/or
18
The third issue:
Patients, their perception to
medication, knowledge on drugs, etc.
(Average patient does not exist!)
19
Back to the registration:
Accompanying sheets
• SmPC (Summary of
Product
Characteristics = Data
Sheet) for
Medi
cine
professionals
• PIL for patients
• Label
• (Assessment
Report written by
the DRA)
20
Issuance of the MA
STAMP
• Civil Service
authoritative text
(what is contained
is binding!)
• The
Accompanying
Sheets annexed
21
Actual marketing (in many
countries)?
Pricing and
reimbursement
negotiations!
• MA: risk/benefit
• Pricing,
reimbursement:
cost/benefit
22
MA withdrawn (deletion
from the Register)
• Applies to „the product”!
• Who may initiate:
• MAH - without specifying any reason
(!)
• Medical Boards, DRA - with good
reason (risk/benefit)
• Civil Service authoritative decision
23
Withdrawal/Recall from the
market
• It applies to a given batch of the
medicine!
• Decided by the DRA, MAH may initiate it
• In Hungary: DRA informs by telefax the
Nat. Publ. Health Serv., and central
health-care organs
• Then “info-cascade” in the counties
24
European Union
• The present marketing authorisation
rules and procedures
25
Certain EU terms
• Sources of law:
 Regulation
 Directive
• Brussels: Commission, DGs
DG Enterprise, DG SANCO
• London: European Medicines
Agency (EMA)
26
EMA
• Established in 1995
• Both 2 DGs pharmacists until now
• Task: centralised MA procedure,
ADR monitoring, guidance, appeal
procedures
• Committees (one per member state)
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EMA Committees
• C’ttee of Human Medicinal Prodcts CHMP
• C’ttee of Veterinary Medicinal Products
CVMP
• C’ttee of Orphan Medicinal Products
COMP
• Herbal Medicinal Products C’ttee HMPC
• Pediatric Committee PDCO
• C’ttee of Advanced Therapy Medicinal
Products CAT
28
MA procedures in the EU
Procedures
• Centralised CP
• Decentralised DP
• Mutual recognition
MRP
• National
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Centralised MA procedure
• Mandatory: biotech substances, HIV/AIDS,
cancer, diabetes, neurodegenerative
diseases, orphan drugs (5:100,000),
somatic cell- and tissue therapy medicinal
products
• Possible:
 new active substances
“high-tech products”
 new, “important” indication
30
 blood products
Centralised procedure
• One single application to EMA
• CHMP-assessment (2 rapporteurs from MSs)
• 210 days dead-line, then EMA issues
Accompanying Sheets (SmPC, PIL) and
Assessment Report in all languages
• MSs: 15-day possibility for „serious risk to public
health” appeal
• Then signature by the Commission in Brussels:
MA valid for the whole EU
• If negative: banned for the whole EU!
31
Decentralised procedure
• Possible: any product for which CP
is not mandatory
• “Referens MS (DRA)”, RMS where
the first application is submitted
(“lead market”) and
• Concerned MS (DRA) CMS where to
submit later
32
Decentralised procedure
• Application dossiers sent to RMS and
CMSs, validation
• RMS: preliminary MA issued (time-frame!),
Accompanying Sheets and Assessment
Report (also in English)
• Discussion with to CMSs = final MA =
national MAs in RMS and CMSs
• Opposing opinions: appeal (see CP)
• Any changes: similar procedure
33
Mutual recognition
• (When the MA has already been issued in
one MS)
• The Firm requests an AR (in English) from
the national competent authority (it is the
RMS then)
• It, together with the full documentation
submitted to CMSs asking a „recognition”
of the AR (time-frames!)
• Opposing opinions: appeal (see CP, the
decision is binding)
• Any changes: similar procedure
34
EU registration collaborations
• Many Working Groups and
Committees under EMEA and
Commission
• EMEA CHMP Q, S, E, Herbal
Medicines, Pharmacovigilance,
Heads of Agencies, etc. Working
Parties
• Commission Pharmaceutical
Committee
35
Back to the general regulatory
affairs concerning registered
drugs on the market
36
Post-marketing surveillance
• GMP (manufacturers), GDP
(wholesalers), GCP (CT sites), GLP
(safety study laboratories)
• Drug Adverse effect monitoring
(Pharmacovigilance)
• Mandatory Quality defect reporting
national system
37
Pharmacovigilance
Doctors and Marketing Authorisation Holders
must report (to the DRA)
• serious
• unexpected (not listed in the information for
professionals)
side effects (=adverse drug reactions, ADRs),
level of seriousness, time-frames may be
specified in the law
38
A little story: what happens to
these ADR reports?
• ADR Data Banks at national, regional (e.g.
European Union) and global (e.g. WHO ADR
Monitoring Centre in Uppsala, Sweden)
• All ADR data put into the Banks
• From time-to-time, professionals review similar
data
• If the connection between taking a drug and the
ADR is possible: it is called a signal and national
ADR centres, professional societies, etc.
signalised: monitor this ADRs of this drug strictly
• If the connection becomes proven (many cases!):
it comes to the information material of the drug
39
A signal generation story (WHO
Uppsala Monitoring Centre)
•
•
•
•
Spontaneous reports ot the Data Bank
Data „mining” with softwares
Signal generation review
If causality probable: signal message to
the National Monitoring Centres
• If proven later: part of the information
material of that drug
40
Signal to the hydroalcoholic
extract of a medicinal plant:
Teucrium chamaedrys
41
Signal generation example 1
• Teucrium chamaedrys: the hydroalcoholic
(alcohol-water) extracts of the herb are
extremely bitter. It is frequent component of
reductant (anti-obesity) tees
• There were more than 20 data on hepatic
adverse reactions (jaundice, hepatitis) in the
WHO database
• In cases when the patients, after recovery,
drank the tee again, the same symptoms were
recurring very quickly (in 2 days, the note at
the registration was: rarely possible!)
42
Signal generation example 2
• How to start the review?
• If the quick recurrence is true, that would mean
an immunological mechanism
• Literature search: can liver damage be caused
via immunological mechanism?
• Answer: yes!
• Literature search: the main components of the
plant are diterpenoids and fenyl-ethanoid
glycosides, they are free radical scavengers
43
Signal generation example 3
• But these are small molecules, too small for an
immune response. Could they modify human
proteins by binding on them? (E.g. an
alkylating mechanism)?
• Literature search:
– the tsructure of the plant components: there is no
alkílating agent among them
– but, if free radical scavengers, they perhaps will be
metabolised via oxidation
• Literature search: what could be oxidised
metabolites of these components? There is a
furane ring on the side chain of one of the
triterpenoids (the tecurin-A)
44
Signal generation example 4
• Literature search: the oxidative
metabolism of the furane ring is:
CYP450
O
O
O
• Irodalmazás: this epoxid can alkylate the
human epoxid hydrolase enzyme, the
resulting modified protein is „foreign”,
there will be antibody formation against
it…
45
Signal generation example 5
• But the extracts of the plant are widely used in various products
as amarum. If this is the basis of the adverse effect, why is it so
rare?
• The place of oxidative metabolisms is the liver. Perhaps is there
something in the liver to react with the epoxide, other that the
mentioned enzyme?
• Literature search: the epoxidesaz epoxidok prefer reaction with
„soft” (according to the Pearson classification) nucleofils
• Is there such compound in the liver? Yes! The
γ-L-glutamyl-L-cysteinil-glycin (glutathion)
-HN-CH-CO-NHCH2-SH
46
Signal generation example 6
• Now we already know why only the antiobesity tees caused the (relatively high
number of the) adverse effects
• Glutathion: extreme diurnal changes in
the organism! When fasting, its level
goes almost to zero! And people whi take
anti-obesity tees are fasting…
• The signal is ready!
WHO Signal, March 2006, pp. 8-17
47
National mandatory quality
defect reporting system
• Wholesalers, marketing authorisation
holders must report to the DRA drug
quality defects, pharmacies even
suspected ones
• Prerequisite: at least organoleptic
checking of incoming drugs
mandatory
48
You may say that no quality
defect can never be identified
by organoleptic checking – is it
true?
49
„the same”
tablets in the
same package
unit
50
„the same” coated tablets
51
One ointment, if check the
inside…
52
the same ointment
53
Drug assessment for
registration:
multidisciplinary
business!
54
There is still a big mistake!
• In certain Universities it is presumed
that assessment of medicines can be
taught by simply teaching chemistry,
analysis, technology, pharmacology,
some clinical sciences, etc.
• That is not true!
55
Big mistake!
Medicine evaluation means the
recognition of the links between data
generated under different scientific
disciplines
56
Big mistake!
• E.g. if a medicine (registration
application) is evaluated by
chemists, analysts, pharmacists,
pharmaco-logists/toxicologists and
clinicians separately, this a wrong
evaluation!
• It is also the message of the EU
Directive!
57
Examples to indicate the spirit
of interdisciplinary medicine
evaluation
Naturally, this topic can not be covered
in a few minutes. However, it may be
indicated by a few examples
58
Penicillin powder for injection in
vials
• Quality Dossier: water content not more
than 2.5 % — what shall I check during
evaluation of this medicine?
• As a requirement per se : may be
acceptable
• The anal. method (not Karl Fischer) seems
to be O.K.
• However, a good assessor tends to be
anxious to check:
59
Penicillin powder for injection in vials
- topics to check
The main decomposition route is hydrolysis
• Water content in the samples for stability
studies (much less than 2.5 %?)
• Water content in clinical trial samples (the
same question, for the sensitisation
potential of decomposition products,
chiefly the penicillin-polymers is higher)
60
Penicillin powder for injection in vials,
2
• By the way, is there any data in the clinical
trial reports about the time between
reconstitution of the injection solution and
the administration (hydrolysis! Was it required
to use the solutions within a specified time?)
• Was the decomposition rate after
reconstitution determined? And its
temperature dependence?) (If not, can I
evaluate the clinical safety at all?)
61
Penicillin powder for injection in vials,
3
• Is there anything in the SmPC about
the quick use after reconstitution?
• Is this issue addressed when the
possibility of administration after
mixing with a slow infusion is
discussed from the medical point of
view?
62
Next example: CYP450
metabolism, 2
• Is the interaction issue reflected in
the clinical trial plans? (was the
concomitant medication studied, or was it
“carefully avoided”? Oxydator-phenotype
classification of trial subjects? Patient
exposure high enough?)
63
Next example: CYP450
metabolism, 3
• Does the SmPC and the PIL reflect
the significance of the issue and the
clinical data?
• By the way, let us go back to the chemical
part and check whether the whole
issue was reflected in the purity
(related substances qualification)
part
64
CYP450 metabolism… 4
Cl
CH3–CH2-O
NH-C-CH3
NH-C-CH3
O
O
fenacetin
intermedierproduct:
p-chloro-acetanilid
65
CYP450 metabolism, 5
OH
Cl
CH3–CH2-O
CH3–CH-O
CH3–CH2-O
NH-C-CH3
NH-C-CH3
NH-C-CH3
O
O
O
fenacetin
intermedierproduct: p-chloroacetanilid
N-C-CH3
HO
O
fenacetin CYP450
metabolism
66
How to facilitate the
multidisciplinary drug
assessment
Electronic submissions!
67
Importance of electronic submissions
• Huge paper submissions
vs. a few CD - handling, archiving,
etc...
this is true. PLUS:
• EU procedures: more fast-track
recognition than assessment!
68
Paper
submission:
330,000
pages per
application
69
Electronic submissions for
registration
Past:
Present/future:
70
Electronic applications
1000 - 3000 hyperlinks connect the
related text parts of chemical pharmaceutical - preclinical - clinical SmPC/PIL etc.


71
Electronic dossier assessment:
navigation, 1
METABOLISM: Expert Report:
SmPC: expiry date/
CYP450 interaction possibilities
spec. Storage
 Preclin. Dossier?
 Ch/Ph Expert Report
 Clin. Expert Report?
Ch/Ph Dossier,
 Clin. Dossier, CT Protocol
Stability results,
design?
statistical CI
 CT results
 SmPC?
72
Electronic dossier as-sesment:
navigation, 2
Ch/Ph Dossier: Impurity Profile 
Ch/Ph Expert Report
Tox. Expert Report (discussed?)
Tox. Dossier (same profile?)
Clin. Dossier (same profile?)
73
The Essence of Hyperlinking
“If Regulatory Affairs comprise an art of recognising
interdisciplinary relations when reviewing dossiers,
hyperlinks may be taken as ‘Materialization’ of
these interdisciplinary relations” TLP, 1998
(Quoted in: Witzel et al.: Damos Experience Report,
Lorenz GmbH, Frankfurt, 1998)
74
Different hyperlinking needs:
review structure
External or internal
assessors?
C’ttee/Peer review?
Rapporteurs?
Or concrete Q/A’s to/from experts?
Quality assessment connected to laboratory
analyses?
REVIEW SOFTWARE INTRANET?
75
Different hyperlinking needs:
DRA structure
Highly specialised review
units (e.g., Quality, GMP,
Toxicology, Pharmacology,
Clinical, SPC/PIL,
Registration sections)
or
more concentrated expertise (such as Qua-lity, GMP,
Biomedical and Registration)?
76
The next registration issue
We are living in a World where the human
beings are the same everywhere!
Why do not we collaborate in drug
registration?
77
Drug registration: an
international business
• It became as international as the drug
development
• Apart from the European Union where
the system of Community medicine
registration exists, there are many
related international collaborations
78
Content
• Why collaboration?
• Why regional collaboration?
• Which collaboration technique to be
chosen?
79
Content
• Why collaboration?
• Why regional collaboration?
• Which collaboration technique to be
chosen?
80
“Every State is responsible
for its public health issues” why collaboration?
81
Fact:
Drug development became
an international business
82
Medicine development is a
global business...
83
To answer this challenge, DRAs
should also go beyond frontiers (They
are doing so!)
• GMP, GLP, GCP inspections over the
globe? Or information sharing (e.g. WHO
Certification Scheme…)recognition? (If you do not
require such data, this is recognition without information! )
• Information on foreign drug/CT approvals/rejections (Are you not interest-ed?)
• PhV (Are you satisfied with your country’s reports, if any,
alone?)
84
Next argument
• Is Q-S-E assessment based on
science? YES
• Is science international? YES
• Then?
85
Next argument
• Drugs are for patients to cure diseases
• Are patients and diseases different in
different countries?
• ICH assessment: mostly not, in a few
per cent yes
• Exaggerated! Pharmacogenetic and
pharmacokinetic differences in the
same population
86
Concrete example (Drug Y)
• No pharmacokinetic differences
between Caucasian, Japanese and
Black races
• Combined effects of gender, age
smoking within the same race: the
Creatinine Clearence in young smoking
males 3 times higher than that in elderly
non-smoking females
B.K. Malhotra, 2001
87
Further argument
• If new medicines of proven high efficacy
appear, is there a public health interest
to make them available as soon as
possible?
• It were very difficult to answer “no”!
• But let us discuss it in more detail, it is a
hot topic!
88
Thus, all DRAs benefit the
international collaboration when
registering drugs...
…by using/taking into account
• literature data
• foreign DRA decisions (e.g. WHO channel)
• foreign registration and GMP certificates (e.g.
WHO Certification Scheme…)
• foreign PhV data
in a non-structured way!
89
Entering into collaboration
The national DRA will have
access to these and even
more data/information in a
structured way!
90
Content
• Why collaboration?
• Why regional collaboration?
• Which collaboration technique to be
chosen?
91
Why regional
collaboration,1
Sometimes: all DRAs did it
before!
See countries before splitting
into new States
92
Why regional collaboration,
2
Many do exist successfully!
1999 Geneva WHO/CIOMS Meeting on
Regional Harmonisation: many
identified
• Latin America (at least 2)
• Africa
• Middle East
• South-East Asia...
93
Changing drug selection, medical
practice...
…problems not experienced elsewhere
• Hungarian example: the antipyretic
aminophenazone shifted to paracetamol,
resulting in a “few” deaths due to
intoxication
• the same rapid action expected by
patients/parents
• high alcohol consumption in Hungary
94
Benefits of a regional
collaboration
Apart from the psychological
factor, should every country
repeat evaluations (QC
analyses, CTs, etc.) done in
another country?
95
Regional collaborationcounter-arguments
“We are more clever
(knowledgeable, professional, etc.)
than those in another countries”
(No comment!)
96
Regional collaborationcounter-arguments
(The psychological factor)
The Hungarian ice-hockey team
example
(Who would be the leader?)
97
Regional collaboration counter-arguments
Too many collaborations!
• Financing
• Time
(However - see benefits - the more the
DRA can afford it the more benefits,
also saving resources, are gained!
See CADREAC, PERF...)
98
Content
• Why collaboration?
• Why regional collaboration?
• Which collaboration
technique to be chosen?
99
Collaboration techniques,
examples, evaluation
• Supranational as EU. General. “Forced”
collaboration, limited sovereignty, i.e.
Community Procedures, etc. It would be
more than premature for SEE.
• Global technical, see ICH. Surely not a
SEE goal
100
Collaboration techniques,
examples, evaluation (cont’d)
• Mandatory special such as former EFTA
Conventions like PIC (GMP), or OECD
(GLP), or Eu.Pharm. Mandatory
recognition in special areas. Not worthwile and may not be acceptable
101
Collaboration techniques,
examples, evaluation (cont’d)
• Not mandatory but information and
expertise-sharing such as EFTA Schemes
(e.g. Pharmaceutical Evaluation Report
Scheme, PER). Shared info on registered
medicines and the results of the evaluation,
arguments for acceptance-rejection,
common guidelines, etc. Consider it!
102
How to build up a regional
collaboration, 1
• Common meetings. Will needed
• Agreement between DRAs, it
communicated to industry
• Start with info sharing on
drugs registered/refused, reason
 CTs authorised refused, reason
 Laws/regulations/guidelines issued
 Implementation experiences, problems
Still nothing mandatory
103
How to build up a regional
collaboration, 2
If it works:
• Extension to collaborative development
of
technical guidelines
 procedural guidance
104
How to build up a regional
collaboration, 3
If it works, extension to
• Common drug evaluation
 personnel changes, study tours
 participation in each other’s drug
evaluation
 joint inspection teams
Still nothing is mandatory!
105
How to build up a regional
collaboration, 4
If it works, possible extension to
• Mutual recognition” (in the EU meaning) of
marketing authorisation, inspections
still retaining the ultimate national
responsibility for decision!
STEPWISE APPROACH, EXISTING
FORMS, NO LEGAL OBLIGATION, IT
WOULD BE WORTH OF TRYING!
106
Hungarian international drug
registration collaborations
• European Pharmacopoeia
• Pharmaceutical Inspection Cooperation
Scheme (PIC-S)
• OECD GLP Working Party...
• WHO International Pharmacopoeia,
guidelines…
• European Union…
107
Exam topic
108
Registration of drugs
• Different kinds of drug authorisations for use: the 3 levels
according to WHO
• Medicine use possibilities, other than registered ones
• Registration as product characterisation plus legal and
professional sides
• The 3 main elements of the professional side
• Characterisation of the content of an application (CTD)
• The flow of the registration process of a new drug
• The CJD issue
• Prescription statuses, their reason, switches between these
statuses
• Accompanying info for professionals and patients
• Deletion from the register versus batch recall
109
Registration of generics and the
European Union marketing
authorisation routes
• Description of the application types (from fill
application to generics)
• Patent protection and data exclusivity
• Doha declaration
• What is a generic drug. Ho9w to establish
equivalence
• Discuss the EU Community procedures (3) in
short
• The European Medicines Agency
• International (global and regional) registration
collaborations
110
Levels of proof for the use of
drugs
• List the levels of proof and their
order
• Explain the clinical terminology
111