Transcript Dias nummer 1

Experience with generic substitution of
narrow therapeutic index (NTI)
immunosuppressants
Jens Heisterberg, Danish Medicines Agency
Polish Presidency CHMP meeting, Warsaw, 29-30 September 2011
Immunosuppressants illustrative of
societal and clinical dilemmmas when
shifting to generics
• Expensive drugs
• Many of them NTIDs (narrow therapeutic index drugs)
• Treatment failure often fatal (rejection of vital organs)
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It’s (almost) all about money
Societal perspective
Two conflicting interests
Ensure
sufficient commercial
motivation for originators
to develop new,
innovative drugs
10-year data protection
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Pressure on
price of drugs,
contribute to lower
healthcare costs
The Benefit-Risk Balance
Price
Tolerability
Safety
Efficacy
How serious is
the disease?
Convenience
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Drug-drug
interactions
What is on the market already?
How efficacious is it? What are the
safety and tolerability issues?
Special
populations
The Benefit-Risk Balance
Generics
Price
Tolerability
Safety
Efficacy
How serious is
the disease?
Convenience
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Drug-drug
interactions
What is on the market already?
How efficacious is it? What are the
safety and tolerability issues?
Special
populations
The Benefit-Risk Balance
Generics
Price
90% CItest:ref for AUC0-t and Cmax
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Generic substitution in Denmark
Overriding principle
• Generic substitution requires that an 'automatic'
switch to another product can take place relatively
unproblematically for the vast majority of patients,
regardless of indication
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Generic substitution in Denmark
How does it work?
• By default, all approved generics can substitute
originators and other generics
– synonymous medicinal products
– same strength
– same pharmaceutical form
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Generic substitution in Denmark
How does it work?
• Exceptions where restrictions may apply
– Situations involving high risk of compliance problems
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Depot formulations
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Single dose versus multiple dose container
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Products that need to be reconstituted by patient before
use
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Tablets/capsules (soluble, effervescent, chewable,
orodispersible) or otherwise for use in the oral cavity
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Nasal sprays, inhalation products, eye drops, etc.
– Narrow therapeutic index drugs
Generic substitution in Denmark
How does it work?
ATC code
Acceptance limits
for AUC and Cmax
90.00-111.11 %
Lithium
R03DA05
R03DA04
R03DB04
R03DA54
R03DA74
N05AN01
Thyroxine
H03AA
Substance
Aminophylline/
Theophylline
Vitamin K
antagonists
Antiepileptics apart
from
benzodiazepines
Antiarrhythmics
Centrally acting
anorectics
Tricyclic
antidepressants
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90.00-111.11 %
Cannot be
substituted
B01AA
90.00-111.11 %
N03
(But NOT N03AE)
90.00-111.11 %
C01B
90.00-111.11 %
A08AA
90.00-111.11 %
N06AA
90.00-111.11 %
Handling of immunosuppressants
• Ciclosporin
– Generics first approved 2005
– Generic substitution from the beginning
– However, warning letter sent to physicians treating transplant
patients
• Tacrolimus
– Generics approved 2010
– Generic substitution from the start
• Mycophenolate mofetil
– Generics approved 2010
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– Generic substitution from the start
CHMP position on ciclosporin and
tacrolimus generics
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CHMP position on ciclosporin generics
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CHMP position on tacrolimus generics
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CHMP position on mycophenolate mofetil
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Discussion following launch of tacrolimus
and mycophenolate mofetil generics
• Shifting to generics is dangerous
• Generics are different drugs that have not been tested
on patients
• Generics should be tested in patients since
pharmacokinetics may differ from healthy subjects
• You risk losing the kidney/heart/liver/lung
• Compliance will be poor
• Patent protection more than patient protection?
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Is it dangerous to shift from originator to
generic NTI immunosuppressants without
increased monitoring?
• Probably not
• But we will never know for sure
– Rejection of transplanted organs not uncommon event
– Any (small) excess risk associated with generics will be
impossible to detect
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Should generic NTI immunosuppressants
be tested in patients?
• In theory yes
– Absorption pharmacokinetics different in transplant patients
• In practice no
– Hard to imagine how generics and originator drugs proven
bioequivalent with strict criteria in healthy subjects would be
different in patients
– Increased PK variability in patients would lead to
unrealistically(?) large BE trials
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The battlefield
Payers
Originator
industry
Prescribers
Patients
Authorities
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Generic
industry
Originator efforts before and during time
of data protection expiry
• Legal actions
– Enforcement of patents, e.g. related to manufacturing
– Preliminary injunctions
• Evergreening of product
– Development of new formulations (such as depot), routes of
administration…
• Influencing stakeholders
– Prescribing physicians (transplantation specialists)
– Patient organisations
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– National authorities
How did we conclude?
• Generic immunosupressants do not pose problems for
de novo patients
• Mycophenolate mofetil suitable for generic substitution
– Not NTI drug
– Automatic switch to copies ”unproblematic”
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How did we conclude?
• Ciclosporin and tacrolimus not suitable for generic
substitution
– NTI drugs
– Risk of switch without increased monitoring not neglible
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Likely to be small (strict (90-111%) criteria applied to
most generics)
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But difficult/impossible to assess (small excess incidence
on substantial background incidence)
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Warnings against switch in SmPCs
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Undertreatment potentially fatal
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FERGIE’S SECOND
BOOB JOB
FRIDAY 30 SEPTEMBER 2011
40
PAGES OF
SPORT
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EUROCRATS HAVE MESSED UP AGAIN
EURO DRUG COMMITTEE
CAUSED MY NEW KIDNEY
TO FAIL
Things for us to consider when assessing
generics
• Is this an NTI drug or not?
– Discussion and conclusion on NTI status of active moiety in
assessment reports for generics
– Should 90-111% criteria be applied?
• Does fulfilment of bioequivalence criteria justify full
interchangeability, including generic substitution?
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