Perspectives on generic substitution in NTI drugs by hcj


									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 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
(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 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.
• 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=ADGEESgL-
• Disease                          GmYLIyUoxiLwXJJqJhFVAILG2eJIcu0Fwf5yj6fM-
• 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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