AST Member Awarded FDA Grants to Study Immunosuppression

In 2008 and 2009, the first generic mycophenolate mofetil and tacrolimus formulations were introduced for use in transplantation. This was met with significant concern by the transplant community regarding the safety, efficacy, and switchability of these new formulations in transplantation. The most concern centered around the use of the narrow therapeutic index drug tacrolimus. To address public concerns regarding the use of generic products, new legislation and regulations have recently been implemented, 1) The Generic Drug User Fee Amendments of 2012, and 2) Tacrolimus Scaled Average Bioequivalence Testing Guidelines. The Generic Drug User Fee Amendments of 2012 (GDUFA) is designed to speed access to safe and effective generic drugs to the public and reduce costs to industry. The law requires industry to pay user fees to supplement the costs of reviewing generic drug applications and inspecting facilities. GDUFA enables the FDA to assess user fees to support critical and measurable enhancements to the FDAs generic drugs program. This guidance is intended to provide updated answers to common questions regarding the use of generic drugs. Funding from GDUFA has become available for 2 projects related to immunosuppression described below.

In April 2012, the FDA posted RFA-FD-12-021 entitled “Pharmacokinetic Studies of Tacrolimus in Transplant Patients” and was awarded to Rita R. Alloway, PharmD, Uwe Christians, MD, PhD; and Alexander Vinks, PharmD, PhD. This study will compare healthy volunteer bioequivalence data, manufacturing processes and excipients of all FDA approved generic tacrolimus formulations to identify the generic formulation most likely to result in the highest tacrolimus concentrations (Generic Hi) and lowest tacrolimus concentration (Generic Lo) for comparison to Prograf (Brand). Once the formulations are identified, several lots of Generic Hi, Generic Lo and Brand will undergo dissolution and content uniformity testing to further identify the specific lot that is most disparate from the Brand. Once the final product lots are selected, 36 kidney and 36 liver stable transplant recipients will be sequentially randomized into a fully replicated 6-period crossover study where each patient receives the Generic Hi, Generic Lo and Brand formulation for two one-week pharmacokinetic periods each. At the end of each week, 15 tacrolimus levels will be assessed to construct the tacrolimus pharmacokinetic time concentration curve for the tacrolimus formulation used during that study period. The pharmacokinetic information will be used to compare intra-product variability (ie Brand vs Brand, Generic Hi vs Generic Hi, Generic Lo vs Generic Lo) and inter-product variability (ie Generic Hi vs Generic Lo, Generic Hi vs Brand, and Generic Lo vs Brand). Adherence, safety and efficacy measures will be performed as well as many other pharmacokinetic analyses. (NCT01889758)

In August 2013, the FDA posted solicitation 13-223-SOL-00102 entitled, ‘Evaluation of Clinical and Safety Outcomes Associated with Conversion from Brand-Name to Generic Tacrolimus Products in High Risk Transplant Recipients.” The contract was also awarded to the research group lead by Dr. Alloway at the University of Cincinnati. This contract consists of a retrospective and prospective study in high risk transplant recipients. In the retrospective study, transplant recipients will be assessed one year prior and one year post conversion to generic tacrolimus. All dose and levels in the pre and post conversion year will be assessed for variability. Predictors of tacrolimus variability will be assessed such as formulation, age, race, gender, presence of steroids, presence of diabetes, markers of sensitization, type and number of transplants. Safety and outcome variables for analysis will include but not limited to incidence of rejection, hospital admission, changes in renal function, changes in transplanted organ function. The prospective study is a comparison of the relative bioavailability and steady-state pharmacokinetics of 6 tacrolimus formulations (all commercially available generic and brand tacrolimus formulations) in a prospective, 6-way cross-over study including CYP3A5 expressors (n=30) and non-expressor (n=30) transplant patients. Six tacrolimus formulations will be tested and each patient will receive each formulation once. The pharmacokinetic evaluation will incorporate limited sampling strategies with a focus on fully characterizing the Cmax out to hour 4 post dose. Subsequent PK sampling and trough blood concentrations will be monitored on a daily basis using dried blood spots that the study subjects will collect by themselves at home. The daily monitoring of levels will allow us to specifically address whether the need of additional monitoring upon formulation conversion is necessary. Adherence will be monitored using test diaries, pill counts and MEMS caps. Average bioequivalence metrics and analysis of variance as appropriate and intra-individual variability of the formulations will be compared. This study design comparing all tacrolimus formulations in CYP3A5 expressors and non-expressors was based upon preliminary data which may suggest CYP3A5 expressors may exhibit greater variability in Cmax than non-expressors. In addition, this design will allow us to assess any formulation differences in this enriched transplant population for pharmacokinetic variability and subsequently at risk transplant populations. (NCT-submitted)

The results of these studies should address public concerns regarding the use of generic tacrolimus formulations in transplant recipients and provide the transplant clinician and recipients with objective data to address their concerns. Enrollment into both trials should begin within the next 3 months.

The Office of Generic Drugs convenes a public hearing annually to engage industry and stakeholders to develop an annual list of regulatory science initiatives for review. Read the full list of the 2014 GDUFA funding priorities here.