Perspectives on generic substitution in NTI drugs

Perspectives on generic substitution
in NTI drugs (immunosuppressives
for transplantation)
Dr G Paget
Consultant nephrologist
Narrow therapeutic index drug
Narrow therapeutic index drug
• 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
• Such drugs require not only blood monitoring
but also relatively frequent dose adjustments
• Transplant IS drugs fall under this definition
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.
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 multisource 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
(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.
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
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???
What’s been happening
• 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 logtransformed data from a bioequivalence study that
utilizes a single dose of the test agent in healthy young,
mostly male volunteers on no other medications.
• 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.
Bioequivalence - Issues raised at ASTS
Bioequivalence - Issues raised at ASTS
“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
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
• 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
Variability with NTI
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 modified intrasubject variability = 13. 1% for Cmax and 8.8% for A UC
• Cyclosporine (Sandimmune") intrasubject variability = 23% for Cmax and 19.3% for
• 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
• 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
Factors affecting NTI drug concentration
• Drug-drug interactions - alteration of efflux pump and enzyme activity by concomitant
• Genetic Polymorphisms•
Age• Drug-food interactions
10.pdf+generic+substitution+antibodies+for+transplantation&hl=en&gl=za&pid=bl&srcid=ADGEESgLGmYLIyUoxiLwXJJqJhFVAILG2eJIcu0Fwf5yj6fM• Disease
• 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). “
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)
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.”
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… about lengthened
patent times with reduced drug costs?
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
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??

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