1. Perspectives on generic substitution in NTI drugs (immunosuppressives for transplantation) Dr G Paget Consultant nephrologist CMJAH/Wits

2. Vs.

3. Narrow therapeutic index drug

4. FDA –narrow therapeutic range drugs as those in which small changes in dose and/or blood concentration could potentially result in clinically important changes in drug efficacy or safety Such drugs require not only blood monitoring but also relatively frequent dose adjustments Transplant IS drugs fall under this definition

5. SA Law (The MCC) Section 22 F - Medicines and Related Substances Act, No 101 of 1965 as amended (“the Medicines Act”): (1) Subject to subsections (2), (3) and (4), a pharmacist or a person licensed in terms of section 22C (1) (a) shall— (a) inform all members of the public who visit the pharmacy or any other place where dispensing takes place, as the case may be, with a prescription for dispensing, of the benefits of the substitution for a branded medicine by an interchangeable multi-source medicine, and shall, in the case of a substitution, take reasonable steps to inform the person who prescribed the medicine of such substitution; and (b) dispense an interchangeable multi-source medicine instead of the medicine prescribed by a medical practitioner, dentist, practitioner, nurse or other person registered under the Health Professions Act, 1974, unless expressly forbidden by the patient to do so.

6. SA Law (The MCC) (2) If a pharmacist is forbidden as contemplated in subsection (1) (b), that fact shall be noted by the pharmacist on the prescription. (3) When an interchangeable multi-source medicine is dispensed by a pharmacist he or she shall note the brand name or where no such brand name exists, the name of the manufacturer of that interchangeable multi- source medicine in the prescription book. (4) A pharmacist shall not sell an interchangeable multi-source medicine— (a) if the person prescribing the medicine has written in his or her own hand on the prescription the words “no substitution” next to the item prescribed; (b) if the retail price of the interchangeable multi-source medicine is higher than that of the prescribed medicine; or (c) where the product has been declared not substitutable by the council.

7. SA Law (The MCC) The MCC Policy on Non-Substitutable Medicines: the MCC states that “the interchangeable use of different brands of chemically equivalent medications …. Could under certain circumstances compromise therapeutic response and safety…” Medical Schemes Act’s regulations: Reg 8(1), “must pay in full and without co-payment for the diagnosis, treatment and care costs” of the PMBs. The PMBs are defined as follows in the PMB list (Annexure A to the Act): End stage renal disease regardless of cause: Dialysis and renal transplant where Department of Health criteria are met only

8. SA Law (The MCC) Evidence-based medicine (reg15): The conscientious, explicit and judicious use of current best evidence in making decisions about the care of beneficiaries whereby individual clinical experience is integrated with the best available external clinical evidence from systematic research. All formularies etc must be based on EBM… Impact of Consumer Protection Act???

9. What’s been happening

10. Bioequivalence A drug is deemed bioequivalent in a single dose crossover designed study if the 90% confidence interval for the ratios of the area under the curve and the Cmax between the generic test agent and the branded medication falls between 0.8 and 1.25, the so-called 80-125 rule. Generic testing is similar for both groups of drugs and requires two one-sided statistical tests using log- transformed data from a bioequivalence study that utilizes a single dose of the test agent in healthy young, mostly male volunteers on no other medications.

11. Bioequivalence FDA bioequivalence standards used to evaluate and approve generic alternatives for branded drugs do not discriminate between a drug with a wide therapeutic index and one that falls in the category of an NTI agent.

12. Bioequivalence - Issues raised at ASTS 2010

13. “Logistic regression analysis showed a highly statistically significant relationship between median MPA AUC and the occurrence of a biopsy-proven rejection (P<0.001)” - A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 1999, Jul 27;68(2):261-6

14. Bioequivalence - The FDA view Generic drugs approved by the FDA from 1996 to 2007: Average difference of Cmax and AUC between generic and brand was 4.35% and 3.56%, respectively In 98% of bioequivalence studies, the difference between brand and generic varied less than 10%; of those drugs which varied > 10%:  None were immunosuppressant drugs  None were considered narrow therapeutic index drugs  Most were drugs with intra-patient variability > 30% in Cmax and A UC  Highly variable drugs seldom meet FDA bioequivalence criteria  No excipients were identified to contribute to bioavailability differences http://docs.google.com/viewer?a=v&q=cache:CL-fBbMUc4YJ:www.utexas.edu/pharmacy/divisions/pharmaco/rounds/01-29- 10.pdf+generic+substitution+antibodies+for+transplantation&hl=en&gl=za&pid=bl&srcid=ADGEESgL-GmYLIyUoxiLwXJJqJhFVAILG2eJIcu0Fwf5yj6fM- 9HnPmAYmhb1vsyp68v3cWdb7AOQjayfFZnj7WdvauyqycruQa0KXrb3YJ5ns3XabxPKoujIvLHS1riGfZ3-Iqt51Ma&sig=AHIEtbQ0HxUnMOBvVUaHvhV7kF5uS2UxdQ

15. Bioequivalence Current evidence is insufficient that use of single patient population bioequivalence studies would demonstrate clinically significant results Transplant patients represent a heterogeneous population I. Subpopulations of poor drug absorbers 2. Large degree of pharmacokinetic variability For bioequivalence studies to reach significant statistical power with a transplant patient group, a much larger sample size would be required than with healthy individuals 1. Recruitment may be limited http://docs.google.com/viewer?a=v&q=cache:CL-fBbMUc4YJ:www.utexas.edu/pharmacy/divisions/pharmaco/rounds/01-29- 10.pdf+generic+substitution+antibodies+for+transplantation&hl=en&gl=za&pid=bl&srcid=ADGEESgL-GmYLIyUoxiLwXJJqJhFVAILG2eJIcu0Fwf5yj6fM- 9HnPmAYmhb1vsyp68v3cWdb7AOQjayfFZnj7WdvauyqycruQa0KXrb3YJ5ns3XabxPKoujIvLHS1riGfZ3- Iqt51Ma&sig=AHIEtbQ0HxUnMOBvVUaHvhV7kF5uS2UxdQ

16. Variability with NTI immunosuppressants Tacrolimus - Tacrolimus mean intrasubject variability has been reported as 12.7%-23.4% when accounting for A UC and C max in healthy individuals given two single doses of tacrolimus spaced 7 days apart Cyclosporine Cyclosporine modified intrasubject variability = 13. 1% for Cmax and 8.8% for A UC Cyclosporine (Sandimmune") intrasubject variability = 23% for Cmax and 19.3% for AUC In stable renal transplant patients maintained on controlled doses of cyclosporine, variability of cyclosporine concentrations was 26% for Co and 19% for C2 between two outpatient transplant clinic visits Sirolimus Dose-adjusted intrapatient variability of sirolimus Co levels within renal transplant patients was 42.8±16.2%31 During clinical trials, intrapatient variability of sirolimus Co levels was approximately 35% Factors affecting NTI drug concentration Drug-drug interactions - alteration of efflux pump and enzyme activity by concomitant medications Genetic Polymorphisms Age Drug-food interactions Disease http://docs.google.com/viewer?a=v&q=cache:CL- fBbMUc4YJ:www.utexas.edu/pharmacy/divisions/pharmaco/rounds/01-29- 10.pdf+generic+substitution+antibodies+for+transplantation&hl=en&gl=za&pid=bl&srcid=ADGEESgL- GmYLIyUoxiLwXJJqJhFVAILG2eJIcu0Fwf5yj6fM- 9HnPmAYmhb1vsyp68v3cWdb7AOQjayfFZnj7WdvauyqycruQa0KXrb3YJ5ns3XabxPKoujIvLHS1riGfZ3- Iqt51Ma&sig=AHIEtbQ0HxUnMOBvVUaHvhV7kF5uS2UxdQ

17. Evidence Medical literature has not been definitive with respect to efficacy of generic use – Roza A, Tomlanovich S, Merion R, et al. Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation. Transplantation. 2002;74(7):1013-1017. – similar outcomes in terms of PK only – Taber DJ, Baillie GM, Ashcraft EE, et al. Does bioequivalence between modified cyclosporine formulations translate into equal outcomes? Transplantation. 2005;80(11):1633-1635. – more rejection. “As compared to patients who received Neoral, patients who received Gengraf were significantly more likely to have an acute rejection episode (39% vs. 25%, P=0.04), more likely to have a second rejection episode (13% vs. 4%; P=0.03), or to have received an antibody preparation to treat acute rejection (19% vs. 8%; P=0.02). “

18. Evidence Kim SJ, Huh KH, Han DJ, et al. A 6-month, multicenter, single-arm pilot study to evaluate the efficacy and safety of generic tacrolimus (TacroBell)after primary renal transplantation. Transplant Proc. 2009;41(5):1671-1674 – safe at 6 months 10.6% rejection rate (Korea). The switch to generic required important dose adjustments in as many as 20% of the patients, mostly to avoid elevated levels that could culminate in potential toxicity A Post-Hoc Analysis of the Safety and Efficacy of Tacrolimus (Prograf) Versus a Generic Formulation of Tacrolimus (Tenacrine) as Primary Immunosuppressive Therapy in LRD and CAD Adults and Pediatric Renal Transplant Recipients. Mini-Oral Session 18 WMO18 – Mexico 222 patients. Approximately twice as many patients receiving the generic formulation (20.8%) developed acute rejection compared with patients receiving the nongeneric form (11.8%) (P =.080). For generic tacrolimus, there was a significant difference in mean creatinine levels at 3 and 6 months post-transplant compared with baseline and a significant difference at month 6 for creatinine clearance (P <.05). Here generic Tac levels were lower (p<0.5)

19. Evidence Immunosuppression With Generic Tacrolimus and Mycophenolate Mofetil in Renal Transplant Recipients: Preliminary Report in Chile. H. Müller, et al. Transplantation Proceedings, 40, 705–707 (2008). “generic TAC and MMF yielded effective and safe immunosuppression in terms of mortality, biopsy-proven acute rejection, and graft loss with a low incidence of adverse effects during the study period.”

20. Other issues Meier-Kriesche HU, Schold JD, Drinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4:378-383, Most studies short term – nil >1 year mean Continued research in drug development is very NB. Innovator drug companies do need to recover costs. To balance economics and justice…..how about lengthened patent times with reduced drug costs?

21. Recommendations - Drug Substitution in Transplantation: A National Kidney Foundation White Paper. American Journal of Kidney Diseases, Vol 33, No 2 (February), 1999: pp 389-397 Replicate studies to determine subject-by-formulation interactions should be required as part of the approval process for both innovator drugs and their generic equivalents Bioequivalence data in subpopulations of patients for whom, based on evidence in the literature, the drug is likely to exhibit bioavailability that differs substantially from the norm (Children, Blacks, Elderly) Education of patient is important – Recognize new/different meds. Be aware of doses/dose alterations All meds need to be easily recognizable

22. Recommendations - Drug Substitution in Transplantation: A National Kidney Foundation White Paper. American Journal of Kidney Diseases, Vol 33, No 2 (February), 1999: pp 389-397 Health care team needs to be informed timeously and effectively of substitution Drug level and organ function testing needs to be done Adverse event reporting is very important. Certain organs excluded??

23. Thankyou