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

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

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

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

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

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

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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