Authorisation of medicinal
products: selected challenges
Rocío Salvador Roldán
Pharmaceuticals Unit/DG SANCO
This presentation only reflects the views of its author and does not necessarily reflect the opinion of the Commission
Overview
I.
High volume of procedures
Variations
Multiples
II.
Increased complexities
Generics and divergent SmPCs
Reference product:
“hybrid” application
conditional MA/exceptional circumstances
not marketed
Combination of legal basis
I.
High volume of procedures
1. Variations: state of play
Very large number of variations applications
received by EMA during 2010 (following entry
into force of new Variations Regulation):
Type IA: over 1500 applications
Type IB: over 1000 applications
Type II: almost 1000 applications
In 2010 over 750 Commission decisions were
adopted related to variations.
These figures are expected to increase in 2011
(277 Decisions have been adopted in Q1).
1. Variations: challenges
Adoption deadlines:
Some variations are critical for public health reasons
and must be implemented soonest.
Other variations are not so critical and the
implementation thereof is not urgent.
However:
Non-critical variations may be submitted as Type II
with a view to ensure earlier adoption date.
Safety warnings are often considered as Type IB.
Changes introduced through WS are often not critical
from public health standpoint and yet they must be
adopted within shortest deadlines.
1. Variations: challenges (cont.)
Effect of changes to innovator product in
generics:
General obligation for MAH (including generics) to
submit information that may affect risk-benefit or
affect the SmPC.
CA’s may also ask MAHs to submit data demonstrating
that risk-benefit remains positive.
However:
No specific deadline within which generic companies
must submit a variation application when the
marketing authorisation of the reference medicinal
product is amended.
Number of products involved may be very large: e.g.
Clopidogrel.
Confusing messages to patients when there is
different product information and possible risks to
public health.
2. Multiples: state of play
The regulatory framework:
Under the centralised procedure the general principle
is only one marketing authorisation per product;
unless public health or co-marketing.
Under Directive 2001/83, there are no specific
restrictions on the number of marketing
authorisations per company.
The note of duplicates published in 2010 aimed to
bring transparency to the cases where multiple
marketing authorisations are possible under the
centralised procedure.
Companies (particularly in the generic sector) have
expressed discontent.
2. Multiples: challenges
Public health considerations:
Risk of different information being transmitted to
consumers.
Risk of confusion due to similarity of names (e.g. in
case where excipients are different).
Increasing workload for the authorities:
Multiplication of procedures in case of variations (e.g.
clopidogrel).
Increasing number of submissions under
pharmacovigilance.
Increasing resources needed to ensure compliance
with conditions/obligations/risk management plan.
II. Increasing complexities
1. Divergent SmPCs in reference product
General rule:
In case of divergences of the SmPCs
of the reference product, MS should
follow the SmPCs as
approved/proposed by the RMS.
If disharmonisation between reference
product and generic in a CMS may
represent a risk to public health, a
referral may be triggered.
1. Divergent SmPCs in reference product
What if a generic
application
proposes SmPCs
of the global MA
not hitherto
authorised (as
such) in any MS?
Generic
Indications: A+B+C
Species: 1,2,3
MS: X
Indications: A +B
Species: 1,2
MS: Y
Indications: A
Species: 1,2,3
MS: Z
Indications: B+C
Species 1,3
1. Divergent SmPCs in reference product
Option 1:
Applicant must
provide additional
studies to “bridge”
the data.
Generic
Indications: A+B+C
Species: 1,2,3
principle of global MA?
Option 2
MS must accept such
applications
Is it a problem from a
public health
standpoint?
MS: X
Indications: A +B
Species: 1,2
MS: Y
Indications: A
Species: 1,2,3
MS: Z
Indications: B+C
Species 1,3
2. Differences introduced in generic application
A. Indications
The legislation envisages two situations:
The generic application has more indications
than the reference product:
additional studies (clinical and preclinical) must be
submitted by the generic.
The generic application has less indications
than the reference product:
An indication of the reference product under patent
protection needs not be included in the SmPCs of
generic.
2. Differences introduced in generic application
The legislation does not specifically
address the issue whether it is possible
for indication of the reference product
not be included in the SmPCs of generic
(outside of patent reasons).
Risk of disharmonisation and consequences
for public health must be considered.
In addition, for veterinary medicinal
products, the consequences in terms of
environmental risk assessment should be
carefully considered.
2. Differences introduced in generic application
B.
Strengths/Pharmaceutical Forms
SmPC is specific per strength and
pharmaceutical form.
Requiring the marketing of all
pharmaceutical forms could reduce
availability of generics.
3. “Hybrid dossier” as reference product
Should there be bioequivalence to both
the product used as reference by the
hybrid application and the hybrid
product itself?
4. Reference product authorised under
exceptional circumstances/conditional MA
The generic cannot have a different
status than the reference product.
Conditional MA requires that there is an
unmet medical need.
This criterion can hardly be met as the
reference product is on the market.
Marketing authorisation under
exceptional circumstances:
In principle, not excluded. However, generic
would have to comply with the same
obligations as the reference product.
5. Reference product not marketed
Article 10(1) provides the
possibility that the reference
medicinal product is no longer
authorised.
Public health concerns that may have
led to the withdrawal of the reference
product must be duly considered.
6. Combination of legal basis
Applications under Article 10a in exceptional
circumstances.
Results of clinical trials alone are not
considered “extensive use” and therefore do
not suffice to support an application under
Article 10a.
Is it possible to allow such submissions if the
marketing authorisation is granted under
exceptional circumstances?
Consequences for innovation if the studies relied upon
belong to a company that intends to apply for a
marketing authorisation.
Consequences in terms of public health.