Retrospective Analysis on the Impact of Generic Immunosuppressants on Acute Rejection and Long Term Graft Survivals (U01)
Background: Survival after solid organ transplantation has increased substantially due in part to the broad clinical use of immunosuppressants. Immunosuppressive regimens typically include a combination of a calcineurin inhibitor (tacrolimus or cyclosporine), an antiproliferative agent (mycophenolate mofetil, mycophenolate sodium, or azathioprine), and corticosteroids. Proliferation signal inhibitors, e.g., sirolimus, may also be used either in combination with a calcineurin inhibitor or antiproliferative agent, or as a replacement for one. Availability of generic versions for these immunosuppressants allows for reduced drug costs that translate to increased drug access and significant cost savings for both insurers and patients. Maintenance of the immunosuppressive balance is critical for allograft patency, minimization of adverse effects, and ultimately long-term survival of solid organ transplant recipients. The question whether the brand to generic switch or switch among multiple generic products may introduce clinically relevant changes in drug exposure and thus affect acute rejection, adverse events, and long term graft survival remains debated in transplant community. To address transplant communityÂ’s concern, FDA funded research studies to compare the pharmacokinetics (PK) of approved generic tacrolimus capsules to Prograf (brand product) in stable liver and kidney adult transplant patients with moderate and high immunological risk. However, the impact of introduction of generic immunosuppressants on long term graft survival was never systematically evaluated. These clinical outcome studies are critically needed to confirm the therapeutic equivalence of generic immunosuppressants with the brand product, thereby increasing transplant community confidence on the use of generic immunosuppressants. Objectives: The objective of this study is to conduct a retrospective analysis about the impact of generic immunosuppressants on short term acute rejection and long term patient graft survival since the introduction of generic immunosuppressants. The outcome of this study will help respond to public concerns regarding the interchangeability of generic immunosuppressants and improve review practices of generic immunosuppressants if necessary. The retrospective analysis will also aid in the design of prospective studies to investigate generic substitution for immunosuppressants. Detailed Descriptions: The model drugs to be studied should include at least cyclosporine, tacrolimus, mycophenolate mofetil, and mycophenolate sodium. The project may include the following: 1. Conduct a multi-center retrospective analysis of kidney, heart, liver transplant recipients using any model drug listed above. Data including demographic, immunosuppressive medications (drug, brand/generic, single/multiple generic), dosage level and adjustment, transplant organ function, acute rejection, renal/liver biopsy results and others should be collected from clinical databases, electronic medical records or other relevant databases. 2. Evaluate patient adherence to their immunosuppressant therapy 3. Perform acute rejection and long-term survival analysis (e.g., 1, 3, 5 or 10-year survival) of patients taking brand immunosuppresants only, generic immunosuppressants only, or both brand and generic immunosuppressants. Further subgroup analysis in children, adults, and African Americans is recommended. 4. Analyze other factors such as donor-, transplant-, and patient-related risk factors which may potentially affect long-term survival of patients.
Office: Food and Drug Administration
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