Generic immunosuppression in transplantation: current evidence and controversial issues

Abstract

The overall success of organ transplantation in the 21st century has been predicated, in part, on the use of newer, more potent, and selective immunosuppressive agents. However, the high cost of lifelong immunosuppression represents a financial burden for many patients. In the past 15 years, regulatory agencies in Europe and America have approved several generic immunosuppressants. One concern is whether the conversion between innovator and generic immunosuppressants will prove to be problematic. This manuscript aims to compare and contrast the bioequivalence requirements among regulatory authorities in the USA, Europe, and Canada, evaluate published studies of generic immunosuppressants in transplant recipients, summarize consensus statements made by transplant organizations and discuss how to engage patients in discussion regarding the choice between innovator and generic immunosuppressants.

Keywords:

• generic
• immunosuppressants
• immunosuppression
• innovator
• organ transplant

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Generic immunosuppressants have been available in the global marketplace for more than 20 years.

• Generics are only required to prove pharmaceutical equivalence and bioequivalence before approval by regulatory bodies.

• Pharmaceutical equivalence means having the same amount of the active ingredient and in similar dosage forms, be given by the same route of administration, and meet the same or similar manufacturing standards.

• Bioequivalence depicts the rate and extent to which the active ingredient reaches the systemic circulation by measuring area under the curve (AUC) and C_max of both the generic and the innovator products in healthy volunteers.

• Bioequivalence standards according to the US FDA require that the geometric mean with 90% CI for the AUC and C_max fall between 80 and 125% for all medicines.

• Both the EMA and the Canadian Health Ministry recognize that narrow therapeutic index drugs should have stricter bioequivalence ranges and require generic narrow therapeutic index products, tacrolimus, to have their AUC and C_max fall between 90 and 112% of the innovator product.

• Biosimilars are not yet available for any biopharmaceutical with a transplant indication.

• Very few well-designed clinical or pharmacokinetic studies are available regarding the use of a generic immunosuppressant in a solid organ transplant population.

• The data that are available point to the fact that generic immunosuppressants appear to be equally safe and effective compared with the innovator product, but require close monitoring when converting a patient from a brand product to a generic.

• Several transplant organizations have created consensus statements regarding generic immunosuppressants and generally support their use under controlled conditions where therapeutic drug monitoring is utilized to monitor patients’ response to a generic interchange.

• One concern that remains in the transplant community is the potential for generic-to-generic conversions at the pharmacy level that might necessitate intensified monitoring or be done without notification to the patient or prescriber.