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Introduction Generic medications offer the advantage of providing equivalent therapeutic efficacy at a lower cost to the patient, the health-care system and society. Although generic pharmaceuticals have been in use for many years, generic substitution remains a topic of heated debate among health-care professionals, members of the pharmaceutical industry, patients/consumers and society. The patent for cyclosporine expired in 1995 in the US and generic formulations of cyclosporine were available during the late 1990's. Since the US has the largest experience of generic cyclosporine use (very limited experience in Europe) particular weight must be attached to the US experience and the FDA's opinion / comments. Approved cyclosporine formulations can be found on http://www.fda.gov/cder/ob/default.htm (medications that state cyclosporin as an active ingredient). Novartis (formerly Sandoz) has played an important role in the emerging world of organ transplantation. Cyclosporine was developed during the late 1970's and from the early 80's it significantly altered the prognosis for patients in the final stages of organ failure. This has given Novartis a unique position within the community of transplantation and recently they celebrated the success of their partnership with this clinical community via a special supplement in Transplantation Proceedings 36 (Suppl 2S), 2004. IVAX Response to the Novartis-sponsored consensus report (.pdf) A meeting of 14 transplant and pharmacokinetic specialists from Europe and North America was convened in November 2001 to evaluate scientific and clinical data regarding the use of different formulations of cyclosporine A (CsA). The consensus conference was sponsored by an unrestricted educational grant from Novartis Pharma AG, Basel, Switzerland. During the meeting, seven consensus statements were agreed upon. IVAX addresses these seven statements below which are included in the dossier for approval, focusing on the available data for Equoral, as well as the data for Sandimmun Neoral/Sandimmun, and other expert opinions.
IVAX Response: Systemic bio-availability in healthy volunteers and in transplant patients following oral drug administration has been shown to be equivalent for Equoral and Sandimmun Neoral, as judged by standard pharmacokinetic measures. This data has led the FDA to conclude that Cyclosporine IVAX is both bio-equivalent and therapeutically equivalent to Sandimmun Neoral.
IVAX Response: The pharmacokinetics of Equoral has been compared to those of Sandimmun Neoral in renal transplant patients, as well as healthy volunteers. Bioequivalence was demonstrated in all sub-groups investigated. The question of standard bioequivalence studies and their relevance in the transplant population has been repeatedly challenged. These objections are based primarily upon Sandimmun and Sandimmun Neoral, two drugs that have been proven to be non-bioequivalent to each other. IVAX notes that the Department of Biopharmaceutical Science at the University of California, USA, conducted an independent review of the US FDA guidelines and concluded that the present FDA bioequivalence guidelines were adequate for generic cyclosporine formulations. The authors concluded that from a regulatory, practical and statistical perspective, further bioequivalence assessment beyond that required by the FDA was unnecessary.
IVAX Response: In all studies carried out by IVAX, in fed and fasted volunteers and renal transplant patients, bioequivalence has been confirmed. Preliminary sub-group analyses of different races of renal transplant patients suggest similar PK profiles for cyclosporine and Sandimmun Neoral. In the US, generic cyclosporine has been used since the 1990's. There have been less successful generics with variability in concentration, and SangCyA was withdrawn. Note that despite this negative prior experience, the FDA found Equoral to be bio and therapeutically equivalent to Sandimmun Neoral. The American Society of Transplantation discussed immunosuppressive drugs and the use of generic immunosuppressants and concluded that there is strong support for the use of generic alternatives. This meeting was not sponsored by the pharmaceutical industry. The results were published in The American Journal of Transplantation 2003 (.pdf)
IVAX Response: The Collaborative Transplant Study referred to was a retrospective, open-label, unbalanced treatment group study, and interpretation of data from this study must be viewed with caution. The study was not specifically designed to assess outcomes with generic cyclosporins versus Neoral. The majority of patients were switched from Sandimmun to Sandimmun Neoral. As repeatedly discussed above, these products are not bio-equivalent, hence this data is not relevant to the IVAX product. The remaining 397 (2.3%) patients were treated with unspecified generic cyclosporines, limiting interpretation of data from this relatively small sub-group. Concerns regarding the substitutability of cyclosporines were also expressed in a meta-analysis by Shah et al. (also referred to in the consensus report). Once again, however, this analysis compares two non-bioequivalent formulations of cyclosporine (Sandimmun and Sandimmun Neoral), hence these findings are of no relevance to Equoral. In conclusion none of the published data regarding adverse short- and long-term clinical outcomes with differing CsA formulations is relevant to IVAX cyclosporine. Pharmacokinetic studies with Equoral has shown that Equoral is bio-equivalent and will provide the same plasma concentration as Sandimmun Neoral, both at specific time points and in total AUC, and therefore, outcomes similar to those for Sandimmun Neoral are anticipated.
IVAX Response: Since Equoral is bio-equivalent to Sandimmun Neoral, it is very likely that C2 monitoring with Equoral will have the same outcome as C2 monitoring with Sandimmun Neoral (see graph below - Switchability of Neoral and Equoral According to Food and Drug Administration Rules and Regulations M. A. Masri et al.pdf). Another problem with C2 monitoring is that it is not considered as standard procedure in many transplant centres in many countries.  Mean cyclosporine concentrations in 70 stable renal transplant recipients
IVAX response: Equoral has been shown to be bio-equivalent to Sandimmun Neoral in patients. Therefore an increased incidence of graft rejection and toxicity versus Sandimmun Neoral is not anticipated. Thus, it will be the drug cost that determines total health-care cost, and it is anticipated that IVAX`s cyclosporine will be substantially more cost-effective than Sandimmun Neoral.
IVAX response: Cyclosporine IVAX has been approved in 10 EU and 20 non-EU countries Successful switches of substantial proportions of patients in 4 of these countries has to date been achieved without the need for intensive peri-switch pharmacokinetic monitoring, which supports observations regarding the bioequivalence of IVAX`s product as previously described. References:
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