Transcript EU Marketing Authorisation Procedures Registration Dossier

National Drug Quality
Assurance
• Regulated introduction of new drugs
• National Drug QA laboratory
• Inspection of the drug supply chain
(GMP)
• Organised recall if quality defects
1
Regulated introduction of
new drugs
WHO: 3 levels
•„Registration”: assessment of
submitted dossier + certain own
tests
•„Authorisation” on the basis of
foreign registration + WHO
Certification Scheme
•„Notification” (simple listing)
2
Notification
• In the less developed countries: only
„to know, what is on the market”
• If drugs imorted in ahigher quantity
or donated: their data (name, API,
origin, etc.) must be notified (e.g.
MoH)
• MoH has/issues the actual list
3
Authorisation
• Moderately developed countries:
select countries the drug
authorisation of which is recognised,
publish it + WHO Certificate from
these countries’ authorities needed
• No (or minimal) local assessment,
data put into the Register
4
Registration
• Submission of formal dossiers (quality,
safety, efficacy, both animal and human
studies) requested
• (at least some parts of the) dossier
assessed locally (e.g. quality,
bioequivalence), some own tests (e.g.
physico-chemical and chemical quality
control, in vitro dissolution)
• Suitable also for registration of locally
manufactured drugs
5
Further on, we speak about full
Drug Registration
(Bee careful, the EU and WHO/USA
English may differ!)
I use registration = marketing
authorisation
6
Why is it important?
The pharmacist always
should speak about
medicines. It were a pity
not to know how they
are assessed and
authorised...
7
Moreover...
There are always inventors
Natural products in fashion
Physicians’ or pharmacists’
new combinations
The patient heard something (Internet!)
8
Medicine (assessment for)
registration =
= very complex
(and
interesting!) in
nature, it is
better to know
it!
9
Medicine registration =
marketing authorisation (EU
terminology)
Medicine Act: only
authorised
medicines may be
used
Marketing
authorisation: the
most frequent one
10
Other kinds of authorisation?
• Individual import or compassionate
use (rare diseases, to a named patient or
to a hospital)
• Donation (to hospital, pharmacist’s
supervision advisable!)
• Clinical trial samples
11
Medicine registration
Legal side (both the
regulatory authority and
the Firm are concerned)
Pharmaceutical/medical (professional)
side (assessment: suitable to be
medicine or not?)
12
Registration?
• Product
categorisation is it
medicine?
• Professional side is
it suitable to be
medicine?
• Legal side civil
service step with
consequences
13
Professional side
Assessment of the
documentation
(sample) submitted
• Quality
(substances and
preparation)
• Relative safety
• Efficacy
(risk/benefit)
14
Registration: professional side
• Application — Assessment of
• Quality and its guarantee (Manufacture and
?
process validation, Quality Specification and
method validation, Pharmaceutical development)
• Safety (animal and clinical toxicology)
• Efficacy (experimental and clinical
pharmacology)
• Authorisation with info material
15
Before detailing the drug
registration:
• Intellectual Property rights (IP):
Patent protection
• Data exclusivity
16
Patent protection
• After synthesis (etc.), new
innovations (e.g. drug entities) may
be patented
• As a rule, 20 years
• („Bolar provision” permits the same
drug development, clinical trials,
registration underpatent protection,
but not marketing!)
17
Data exclusivity, 1
• Generic route of registration: patent
expired, other manufacturer may
produce similar drug with the same
API
• No animal experiments and human
clinical trials performed, only the
„equivalence” to the innovator
product proven…
18
Data exclusivity, 2
• …as if it said „I do not know what is
in the innovator’s pre-clinical and
clinical dossier submitted, however,
for I Have proven the equivalence,
take as I had submitted the same
dossiers”
• =reference to the innovator’s data
19
Data exclusivity, 3
• DE is to forbid the regulatory
authorities to accept any reference to
the innovator’s data for a specified
period of time after the registration
(10 years in the EU at present, from
the first registration in any of the
member states)
20
PP and DE
• Patent: 20 years from filing the
patent protection request (the drug
still in early development phase)
• DE: 10 years from the first
registration!
21
Patent/DE issues during
registration
• As a rule, DRAs are not empowered to
clarify patent/DE issues when new drug
applications are submitted (however, in
Canada, the MA is on hold and issued only
after patent issues are checked)
• Moreover, it would require enormous
resources
• Advisable solution: Applicant’s
declaration required that IP/DE rules
were clarified and no violation found
22
Doha declaration
• November 2001
• Permits development and export of a
generic product, still under PP in the
country of manufacture, to
developing countries
• as a rule, the brand patent holder’s
(BPH) consent needed
• BPH is given also royalty
23
Doha arrengement
• e.g. Canada, European Union signed
• Labelling that would hinder re-export
• e.g. HIV/AIDS medicines concerned
24
The art of medicine
registration and assessment
Documentation
Expert Reports
25
In drug assessment
• Work interdisciplinary
• Everything must be evaluated from
every angle!
• (A fulsih exampleon the next slide)
26
„Everything must be evaluated form every
angle”!
Do you like
this girl?
See it upside down. Do you
still like her?
27
Common Technical
Document
• An ICH Guideline
• International Conference on
Harmonisation of technical requirements
for registration of pharmaceuticals for
human use: EU, USA, Japan - DRA and
Industry
• „Soft law”
28
CTD
M1
Regional
administrative info
Quality
M2
Not part of
CTD
Nonclinical
overview
Clinical
overview
Nonclinical
summary
Clinical
summary
overall
summary
M3
M4
M5
Quality
Nonclinical study
reports
Clinical study
reports
CTD
29
Structure and terms
Structure for all parts:
• Introduction
• Overview: short description
• Overall summary:
 written
 tabulated
• Original study/trial reports
E
X
P
E
R
T
R
E
P
O
R
T
S
30
Expert reports
• EU phylosophy: an evaluated
documentation should be submitted
for authorisation
• DRA review: comparison of the
review done by the Company expert
with that done by the regulatory one
• Never „to try to find out” why
something was (not) done
31
Quality Overall Summary
• 40 pages + tables, figures
• Evaluates the quality module,
emphasising critical key parameters,
justifies when guidelines are not
followed, reference to other modules
(e.g. toxicological qualification of
impurities)
32
Quality module, 1
DRUG SUBSTANCE (API)
• General info (nomenclature, structure,
general properties)
• Manufacture (flow diagram, catalysators,
solvents, temp., yields, etc.)
• QC of starting materials (standards and
justification of the grade)
• Critical steps (identification and control)
33
Structure elucidation of new
APIs – see the 3D structure!
paroxetin
SO2NH 2
Cl
furosemid
HOOC
NH-CH2
O
34
Structure elicidation of new APIs
paroxetin
SO2NH 2
Cl
furosemid
HOOC
NH-CH2
O
35
3D structure
• Elucidation (abs. and rel.) – but not enough!
• Assessment: other structure also present
impurity characterisation
• Racemate or one single? (issue, PK, PD)
corporate decision: reveal it – hide it until PP
expires? citalopram – escitalopram
• Stereochem. stability
– If rapid interconversion: in vivo also possible
metabolism
– If slow interconversion: take it into consideration
at PD and PK for the other form may have
different action or at the toxicity studies (3
months + peri- és postnatal, minimum in 1 dose),
36
as well as at planning human clinical trials
Physical structure
• Particle size (issue: dosage-form,
significance?)
– Dissolution, bioavailability? (PK) Coated tablets
under electron– During the processing?
microscope
– Stability?
– Content Uniformity (API-content in dosageform units)?
– appearance?
37
Quality module, 2
DRUG SUBSTANCE
• Process validation (plans, limits, operational
parameters, etc.)
• Manufacturing process development
(description, discussion, changes)
• Characterisation (impurities, reference to their
toxicity, specification, test methods and validation,
batch analyses, reference standards)
38
„Impurity rule”, ICH
• Unknown impurity should be noted:
max. daily dose 1 g: 0.1%; 1 g: 0.05%
• Impurity should be identified:
max. daily dose 1 mg: 1%; 1-10 mg: 0,5%; 10 mg2 g: 0.2%; 2 g: 0.1%
• Impusity must be toxicologically
characterised:
max. daily dose 1 mg: 1%; 1-100 mg: 0.5%; 100
mg-2 g: 0.2%; 2 g: 0.15%
genotox. (in vitro mutagen. + kromoszóma-aberráció),
egyszeri dózis, ismételt dózis 1-3 hó
39
Quality evaluation
Drug analysis!
Toxic degradation products, 1)
• Acetilsalicylic acid (everobody knows?)
• cefalosporins
• oxitetracyclin
• PAS
• Fat emulsions...
40
Tetracyclin and its one toxic
degradation product
H3C OH
HO
CH3
N-CH3
O HO O O
H
tetracyklin
H3C
CH3
N-CH3
OH
OH
CONH2
CONH2
HO
OH O O O
H
epi-anhidro-tetracyclin
Renal complaints, tubular
necrosis, reverzible Fanconisyndrome
41
Quality evaluation
2) Anaphylactoid reactions of
degradation products
• corticosteroids
• penicillins
The ampicillin story
Studies in a Swiss hospital pharmacy
42
Corticosteroid-protein interaction
CH2-OH
C=O
cortikosteroid
HC=O
ox.
C=O
H2N
H2N
CH-
arginin-reziduum
of human
proteins
The new modified protein is taken as
„foreign” by the human immune system and
antibody formation starts
43
The ampicillin-story
• Hungary, the early 80’s. The Paediatric Clinic
(Budapest) notifies the regulatory authority:
after administration of the (Bulgarian)
Ampicillin injection there was a temperature
elevation in children. It never occurred
formerly when British Ampicillin injection
was used
• ?
• HPLC-analyses, withdrawal from the market.
International debate (won!), etc.
• What happened?
44
Amino-penicillin decomposition
product as eliciting antigen
• Beta-lactam of one penisicllin molecule reacts the
amino group on the side chain of an other
penicillin molecule, the beta-lactam of which
reacts another side chain amino group, etc.
• oligomers (n = 4-8) formed this way)
-CO-NH-, i.e. peptide!
• (With which bonds)
• These are still small molecules for antibody
formation, however, may react with existing
penicillin antibodies giving rise to clinical
manifestation of an anaphylactoid reaction (no
clinical manifestation would occur in case of
intect penicillin!)
• One of the symptom of the anaphlactoid reaction
is: fever!
45
Swiss hospital pharmacy study
• Comparison of penicillin infusion
treatment
• Two groups
– Penicillin injection into a large volume (1 litre)
infusion solution („inject the patient only
once”), preparation the day before, stored in
refrigerator
– Penicillin injection as bolus or in rapid infusion
• Significantly more hyeprsensitivity
reactions in the first group!
46
Solvent residues, ICH
3 solvent classes:
1. To be avoided! benzene, chloro-ethanes…
2. To be limited chloro-methanes, methanol,
ethylene glycol, acetonitrile…
3. Less toxic
• Limits everywhere, depending on the
single and daily dose, but there are also
absolute limits such as for acetonitrile 410
ppm
47
Solvent residues, examples
• Benzene (class 1!) e.g. may be sideproduct of a Grignard-reaction (Ph-Mghalogenide, hydrolysis of its excess)
• The API is mesylate and the dosage-form
has ethanol residues: ethyl mesylate is
formed later (mutagenic)!
(Methanesulfonate = mesulyte)
• In an application: loss on drying of an
API”: 99.2% ethanol, 0.1% water. What can
be the remaining part? Wasis absolute
ethanol, the benzene is possible?
48
Quality module, 3
DRUG SUBSTANCE
• Container and closure system (choice
of primary packaging, quality, dimensions,
description of secondary)
• Stability (pre-approval forced degradation:
types of studies, their justification; post-approval
study plans, data and evaluation)
49
Quality module, 4
DRUG PRODUCT
• Description and composition (all
constituents, their functions and qualities)
• Pharmaceutical development
(compatibility of API with excipients, rationale,
formulation development, manufacturing process
development, container and closure,
microbiological attributes, if appropriate)
50
Just a word: are the excipients
„inactive” regarding therapy,
and safe?
The CJD story
51
Terms
• Creutzfeld-Jacob Disease = CJD =
fatal neurodegenerative condition.
Patients develop a rapidly
progressive dementia associated
with multifocal neurologic signs
• Sporadic CJD = sCJD, 1-2 cases per
million people per year. Its cause is
unknown.
(continued)
52
Terms (continued)
• Variant CJD = vCJD = caused by
prion (see BSE!) or iatrogenic way by
contaminated human pituitaryderived growth hormone,
gonadotropin, corneal transplants,
etc.
• The casual link between vCJD and
BSE is based on epidemiological,
biochemical and transmission
(animal) studies
(continued)
53
Terms (continued)
• Bovine Spongiform Encephalopathy = BSE.
Identified first in British cattle. Attacks the
brain of the animal. The disease originated
from the use of feed supplements contained
meat contaminated with a TSE agent
(mammalian derived protein)
• TSE = Transmissible Spongiform
Encephalopathy = BSE, scrapie (in sheeps,
goats)
(continued)
54
Risk
• Human blood products
exclusion criteria for donation:
- CJD
- transfusion
- pituitary gland hormon therapy
• Vaccines produced in animals
• Bovine, etc. derived materials used
in drug production
55
Measures to minimise risk to
humans from vaccines produced
in animals
• Selection of source countries: GBR
Geographic BSE Risk (World
Organization for Animal Health)
• Use of well-monitored herds
56
Measures to minimise risk to
humans from excipients from
animal sources
• Lactose from milk – appeared to be
less/non infectious
• Gelatin (!) from bovine bone, skin…
(Animal, human) Tissue infecticity
categories
57
High-infectivity tissues
High-infectivity tissues
brain, spinal cord, retina, pituitary
gland…
Lower-infectivity tissues
lymph nodes, large intestine, lung,
perhaps blood
Tissues with no detected infectivity
placenta fluids, bone, skin, milk
58
Gelatin
• Skin gelatin: less dangerous than
bone gelatin
• Bone gelatin: brain, spinal cord must
be excluded from source bone!
• Alkaline hydrolysis better than acidic
treatment alone
• Also: source country and noninfected herd selection, certification
(gelatin deliveries should be followed
back to the source)
59
Quality module, 5
DRUG PRODUCT
• Manufacture (each steps, batch formula,
process and IPC description, critical steps and
their control, process validation, excipient control
and its validation)
• Product control (specifications, justification,
test methods, validation batch analyses,
reference standards)
• Container and closure system
60
Importance of dosage-form
characteristics (such as
dissolution)
• …and the presentation of the
dosage-form development in the
application dossier
• The nitroglycerol sublingual tablet
story in Hungary
61
Nitroglycerol 0.5 mg sublingual
tablets
• Angina pectoris attack
– treatment
– prevention (according to the personal
experience, to be used before/starting
the provocation of the attack)
• Adjuvant therapy of acute asthma
cardiale in urgent cases
• In acute myocardial infarct…
62
angina pectoris and nitroglycerol…
63
Nitroglycerol 0.5 mg
sublingual tablets
• Hungary, early 80’s: the nitroglycerol
API production temporarily blocked
• The Ministry of Health, to avoid
shortages, imported „similar” tablets
without prior checks or registration
(that time it was possible)
• They appeared to be not „similar”!
64
The NG story
• The most of the complaints received
to the „Soviet” tablet. There were two
kinds of complaints
– No therapeutic action
– Too rapid and strong action
• The API content was in order
• The regulatory authority developed a
special dissolution test (small
volume dissolution media + HPLC)
65
NG 0.5 mg sublingual tablets
100
80
Dissolv- 60
ed %
Soviet
Polish
Hungarian
Roman
40
20
Soviet
5
4
3
2
Roman
1
0
0
time (min)
Well, which of the is
„good”?
66
The question was wrong!
• Any of them can be „good”!
• But you can toke take any according to
the another’s instructions!
• Hungarian tablets: „when you feel the
attack is coming, place one tablet under
your tongue. When the signs of the attack
are over, take the remaining part of the
tablet out of your mouth”
67
NG 0.5 mg sublingual tablets
• The Soviet one was a „pastille”, it
disintegrated completely at once in the
mouth by releasing all the NG. Then
– If the patient swallowed it: the absorption
from the stomach is slower = „no action”
– If not, all the active principle absorbed
from under the tongue at once: „too strong
action”
• Remember to one of the former class
hours: „Drug = product + information”!
68
Quality module, 6
DRUG PRODUCT
• Stability (pre-approval forced degradation:
types of studies, their justification; post-approval
study plans, data and evaluation)
• Literature references
69
Nonclinical overview
• 30 pages. Critical evaluation.
Comments on GLP status.
Association with quality module
(impurity pharmacology and
toxicology)
• The structure follows that of the
nonclinical written summaries
70
Nonclinical written
summary, 1
GENERAL GUIDANCE
• Age- and gender-related effects should be
discussed
• Animal exposure discussed in relation to
that in humans
• Species sequence (mouse-rat-hamster-rabbitdog-primates-other)
• Route of administration sequence oraliv-im-ip-sc-inhal-topical)
71
Nonclinical written summary, 2
PHARMACOLOGY
•
•
•
•
•
•
Primary pharmacodynamics
Secondary pharmacodinamics
Safety pharmacology
Pharmacodynamic drug interactions
Discussion, conclusions
Tables, Figures
72
Pharmacology evaluation
Experimental
pharmacology on
animals
• What is the action?
the pain test story
73
Hot plate test
• Hot-plate test: rat placed on a plate, itis
warmed, the time (or temperature) when
the rat licks its legs or jumps (indicating
the warmth of the plate has been
recognised) is recorded
• The better is the pain-killing effect the
later (at a higher temperature) is the
record
74
The hot plate test story
• Hungarian inventor: new substance,
with a morphine-like pain-killing
result
• Authority assessor: dose too close
to LD50
• Assessment: the rat became sick
with the high dose, if so: recognised
the warmth later, but it is not a painkilling effect!
75
The hot plate test story
• Pharmacology results can not be
evaluated without taking the
toxicology data into account!
• In general: all different data needed
for the final evaluation!
76
Nonclinical written summary, 3
PHARMACOKINETICS
•
•
•
•
•
•
•
Methods of analysis
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetic drug interactions
Discussion, Tables, Figures
77
Nonclinical written summary, 4
TOXICOLOGY
• Rationale for the programme
• Single-dose tox., Repeat-dose tox. (various
from 1 to 9 months), Genotox.,
Carcinogenecity, Reproductive tox., Studies
in juvenile animals, others (e.g.
dependence).
• Discussion, Tables, Figures
78
Other nonclinical part
• Nonclinical tabulated summaries
• Nonclinical study reports
79
Clinical overview
• 30 pages. Critical evaluation.
Comments on GCP status.
Association with safety module
(toxic symptoms, interactions)
• The structure follows that of the
nonclinical written summaries
80
Clinical written summary, 1
• 50 to 400 pages
BIOPHARMACEUTIC studies
• Development, in vitro-in vivo, dissolution
to develop bioavailability, anal. methods
• Summary of individual studies,
comparison accross studies (possible
effect of food…)
81
Clinical written summary, 2
CLINICAL PHARMACOLOGY
• Human PK, PD, in vitro studies on
human cells (dose-response,
metabolism, dosage-ranging, single and
repeated-dose PK, population PK)
• Immunogenecity (for proteins, e.g.
vaccines)
• Clinical microbiology (if relevant)
82
Clinical written summary, 3
CLINICAL EFFICACY
• The programme of controlled (and any
other) studies, design, comparative
efficacy, long-term efficacy
• Individual studies, comparison of
results across studies (population,
baseline characteristics, drop-outs, etc.)
83
Clinical written summary, 4
CLINICAL SAFETY
• Extent of exposure to the drug (population,
concomitant illness, etc.)
• Adverse events (common, serious, deaths, by
organ and syndrome)
• Clinical Lab evaluations
• Special groups and situations (ethnic,
alcohol-food, pregnancy and lactation, overdose,
abuse, withdrawal, driving
84
Clinical written summary, 5
CLINICAL SAFETY
• Post-marketing data (ADR reporting if it
does exist in the country. Spontaneous
or mandatory reporting)
85
Proof for safe use of a drug
• I.e. acceptable therapeutic
effect/health risk ratio
• How it was established: we speak
about different „levels of proof”
86
Levels of proof:
I. Meta-analysis of randomised, controlled
clinical trials
Ib. At least one randomised, controlled
clinical trial
IIa. At least one controlled, non/randomised
clinical trial
IIb. At least one open clinical trial
III. Documented data on individual
treatments, evaluated by scientific
methods
IV. Expert/regulatory Committees published
standpoint on the basis of evaluated
literature data
87
Terms used
• Meta-analysis: statistical method to „pool”
data generated in different clinical trials
• „Randomised”, „controlled”, „open”: see
the lecture on clinical trials
• Level I. gives the highest, level IV. the
lowest acceptable proof
• As a rule, minimum level Ib. is needed for
the registration of a new drug in the
Developed World. Herbal drugs: see later
88
Complete application (new
medicine)
• (ten)thousands of
pages
• hundredMios of
USD
89
Application types
Not only „completely
new”:
• Registered in
another country
• Line-extension
• Generic
90
Line extension
• New strength,
dosage-form...
• It is advisable to
use the template of
the complete
application and
explain what is
missing and why
91
Generics
“it shall not be required to provide
results of toxicological and
pharmacological tests and/or clinical
trials if it is demonstrated that the
product is essentially similar to a
medicinal product authorised in the
Member State concerned…”
92
Generics
• PP and DE expired
• Equivalence proven instead of pharmacotoxicology and CTs: bio-, farmacodynamic,
clinical, evidence, in vitro
• cheaper!
C
time
93
„Pharmaceutical
equivalence”
• identical API
• comparable (administration) dosageform
• strength?
only the same strength
two 50 mg tablets = one 100 mg tablet
½ 100 mg tablet = one 50 mg tablet?
94
Bioequivalence
• Equivalence established by
pharmacokinetic (PK) method
• After administration of two
(pharmaceutically equivalent) drug
products: comparison of blood level –
time curves
• Area under curve (AUC), the maximum
concentration (cmax)and the time
belonging to cmax (tmax) are compared, the
maximu permitted differences specified
95
Pharmacodinamic equivalence
• Not only blood level could be
measured for comparison in some
cases, but e.g. blood pressure, body
temperature…
• Rarely used
96
Equivalence by comparative
clinical trials
• When no blood level or
pharmacodynamic data could be
measured
• E.g. comparing the two
pharmaceutically equivalent drugs
by treating 100-100 patients
97
Equivalence based on
„evidence”
• E.g. two aqueous i.v. injections are,
by definition, bioequivalent (shot into
the vein: the drug is there!)
• Also, as a rule, oral aqueous
solutions
98
Equivalence established by in
vitro data
• Limited value! (Can the LADME be
modelled by L exclusively?)
• Can be used e.g. for oral immediate
release dosage-forms with an API
that is highly soluble and permeable
(see the Biopharmaceutical
Classification System, BCS)
99
Medicine assessment
• surely multidisciplinary business
• experts writing the summaries must
emphasise the logics of the product
development, preclinical study and CT
strategy
100