Experience with generic substitution of narrow therapeutic index (NTI) immunosuppressants Jens Heisterberg, Danish Medicines Agency Polish Presidency CHMP meeting, Warsaw, 29-30 September 2011

2 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)

3 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 Tolerability Safety Efficacy How serious is the disease?

Convenience What is on the market already?

How efficacious is it? What are the safety and tolerability issues?

Drug-drug interactions Special populations Price

The Benefit-Risk Balance Generics Tolerability Safety Efficacy How serious is the disease?

Convenience What is on the market already?

How efficacious is it? What are the safety and tolerability issues?

Drug-drug interactions Special populations Price

The Benefit-Risk Balance Generics 90% CI test:ref for AUC 0-t and C max Price

7 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

8 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

9 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

10 Generic substitution in Denmark How does it work?

Substance

Aminophylline/ Theophylline Lithium Thyroxine

ATC code

R03DA05 R03DA04 R03DB04 R03DA54 R03DA74 N05AN01 H03AA Vitamin K antagonists Antiepileptics apart from benzodiazepines Antiarrhythmics Centrally acting anorectics Tricyclic antidepressants B01AA N03 (But NOT N03AE) C01B A08AA N06AA

Acceptance limits for AUC and C max

90.00-111.11 % 90.00-111.11 % Cannot be substituted 90.00-111.11 % 90.00-111.11 % 90.00-111.11 % 90.00-111.11 % 90.00-111.11 %

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 – Generic substitution from the start

12 CHMP position on ciclosporin and tacrolimus generics

13 CHMP position on ciclosporin generics

14 CHMP position on tacrolimus generics

15 CHMP position on mycophenolate mofetil

16 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?

17 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

18 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

19 The battlefield Originator industry Payers Prescribers Patients Authorities Generic industry

20 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

21 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”

22 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

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FERGIE’S SECOND BOOB JOB

FRIDAY 30 SEPTEMBER 2011

40 PAGES OF

SPORT EUROCRATS HAVE MESSED UP AGAIN EURO DRUG COMMITTEE CAUSED MY NEW KIDNEY TO FAIL

25 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?