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)

It’s (almost) all about money Societal perspective Two conflicting interests Ensure sufficient commercial motivation for originators to develop new, innovative drugs Pressure on price of drugs, contribute to lower healthcare costs 10-year data protection

The Benefit-Risk Balance Price Benefit Risk Tolerability Safety Efficacy How serious is the disease? Drug-drug interactions Convenience What is on the market already? How efficacious is it? What are the safety and tolerability issues? Special populations 4

The Benefit-Risk Balance Generics Price Benefit Risk Tolerability Safety Efficacy How serious is the disease? Drug-drug interactions Convenience What is on the market already? How efficacious is it? What are the safety and tolerability issues? Special populations 5

The Benefit-Risk Balance Generics Price Benefit Risk 90% CItest:ref for AUC0-t and Cmax 6

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

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

Generic substitution in Denmark How 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 drugs

Generic substitution in Denmark How does it work? Substance ATC code Acceptance limits for AUC and Cmax Aminophylline/ Theophylline R03DA05 R03DA04 R03DB04 R03DA54 R03DA74   90.00-111.11 % Lithium N05AN01 Thyroxine H03AA Cannot be substituted Vitamin K antagonists B01AA Antiepileptics apart from benzodiazepines N03 (But NOT N03AE) Antiarrhythmics C01B Centrally acting anorectics A08AA Tricyclic antidepressants N06AA

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

CHMP position on ciclosporin and tacrolimus generics

CHMP position on ciclosporin generics

CHMP position on tacrolimus generics

CHMP position on mycophenolate mofetil

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?

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

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

The battlefield Payers Prescribers Originator industry Generic industry Patients 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 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”

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 fatal

40 CAUSED MY NEW KIDNEY TO FAIL FERGIE’S SECOND BOOB JOB SPORT FRIDAY 30 SEPTEMBER 2011 EUROCRATS HAVE MESSED UP AGAIN EURO DRUG COMMITTEE CAUSED MY NEW KIDNEY TO FAIL PAGES OF SPORT

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?