experience with generic substitution of narrow therapeutic index (nti) immunosuppressants jens...
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Experience with generic substitution of narrow therapeutic index (NTI) immunosuppressants
Jens Heisterberg, Danish Medicines Agency
Polish Presidency CHMP meeting, Warsaw, 29-30 September 2011
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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 moneySocietal perspective
Two conflicting interests
Ensure sufficient commercial
motivation for originators to develop new, innovative drugs
Pressure onprice of drugs,
contribute to lowerhealthcare costs
10-year data protection
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The Benefit-Risk Balance
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BenefitRisk
Efficacy
Convenience
What is on the market already?How efficacious is it? What are the
safety and tolerability issues?
Tolerability
Safety
Drug-druginteractions
How serious isthe disease?
Specialpopulations
Price
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The Benefit-Risk BalanceGenerics
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BenefitRisk
Efficacy
Convenience
What is on the market already?How efficacious is it? What are the
safety and tolerability issues?
Tolerability
Safety
Drug-druginteractions
How serious isthe disease?
Specialpopulations
Price
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The Benefit-Risk BalanceGenerics
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BenefitRisk Price
90% CItest:ref for AUC0-t and Cmax
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Generic substitution in DenmarkOverriding 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 DenmarkHow 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 DenmarkHow does it work?
• Exceptions where restrictions may apply
– Situations involving high risk of compliance problems
▫ Depot formulations
▫ Single dose versus multiple dose container
▫ Products that need to be reconstituted by patient before use
▫ Tablets/capsules (soluble, effervescent, chewable, orodispersible) or otherwise for use in the oral cavity
▫ Nasal sprays, inhalation products, eye drops, etc.
– Narrow therapeutic index drugs9
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Generic substitution in DenmarkHow does it work?
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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
– Generic substitution from the start
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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?16
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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
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Originatorindustry
Genericindustry
Patients
Prescribers
Payers
Authorities
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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
– National authorities20
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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
▫ Likely to be small (strict (90-111%) criteria applied to most generics)
▫ But difficult/impossible to assess (small excess incidence on substantial background incidence)
▫ Warnings against switch in SmPCs
▫ Undertreatment potentially fatal22
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EUROCRATS HAVE MESSED
UP AGAIN
EURO DRUG COMMITTEECAUSED MY NEW KIDNEYTO FAIL
FERGIE’S SECONDBOOB JOBFRIDAY 30 SEPTEMBER 2011
40PAGES OFSPORT
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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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