1. Experience with generic substitution of narrow therapeutic index (NTI) immunosuppressants
Jens Heisterberg, Danish Medicines Agency Polish Presidency CHMP meeting, Warsaw, 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

4. 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

5. 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

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

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
ATC code
Acceptance limits for AUC and Cmax
Aminophylline/ Theophylline
R03DA05 R03DA04 R03DB04 R03DA54 R03DA74 %
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

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

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 Payers Prescribers Originator industry
Generic industry
Patients
Authorities

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

24. 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

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 % criteria be applied?
Does fulfilment of bioequivalence criteria justify full interchangeability, including generic substitution?