Outdated FDA clinical trial policies harming transplant drug research, AST, ASTS presidents charge in letter

Transplant News,  April, 2008  by Jim Warren

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Clinical trials of new immunosuppressive drug regimens being conducted by transplant researchers are being seriously hampered by out-of-date approval policies of the US Food and Drug Administration (FDA), according to the heads of the nation's two major transplant societies.

Current FDA policies are discouraging many transplant centers from participating in clinical trials for new drugs, driving American patients away from enrolling in the trials, causing drug companies to seek patients outside the US for clinical trials, and is weakening clinical trial results of innovative transplant drugs, the letter's principal author Flavio Vincenti, MD, president of the American Society of Transplantation (AST) wrote. The letter, which appeared in the April American Journal of Transplantation (AJT), was also signed by Goran Klintmalm, MD, president of the American Society of Transplant Surgeons (ASTS) and Philip Halloran, MD, editor of the AJT.

The authors specifically charged FDA policy mandates the use of immunosuppressive drugs in organ transplantation clinical trials (in control arms) that are no longer the preferred regimen of drugs of transplant physicians.

"The goal of a graft lasting the life of a patient is unlikely to be achieved without further progress in novel therapeutics in transplantation," the authors wrote. "However, new drug development has been hampered by the FDA's reluctance to follow the lead of the transplant community and recognize the preferred regimens of transplant physicians and allow adoption of this regimen in control arms in clinical studies with new agents."

"Results from many clinical trials and retrospective analysis of center and registry data suggest equivalence in safety and in some cases superiority in efficacy of currently used regimens," the authors concluded. "It is time for the FDA to recognize that in order to allow meaningful and important development of new immunosuppressant agents, it is imperative to allow the use of control arms that enable the clinical and scientific community to assess the value of the investigated drug when compared to best current practice and best available data."

Here is the complete text of the letter. The letter can also be viewed on the AST Web site: www.a-s-t.org

"The past decade has witnessed a great number of new immunosuppression agents approved for use in transplantation. The use of these new drugs in different combination with older drugs in innovative immunosuppression protocols has resulted in a dramatic decrease in the rate of acute rejection from 40% - 60 % to 20% and even the low teen ranges. Since acute rejection has been a major factor associated with graft loss, this impressive achievement has resulted in increased graft and patient survival in some organ transplants. In kidney transplantation, it was similarly initially projected to result in increased long-term graft survival. However, analysis of actual graft outcome failed to show any improvement in long-term graft survival in primary renal transplant recipients. The lack of improvement in long-term outcome remains a major challenge to transplant physicians. Chronic allograft disease and graft loss overburdens an already dire graft shortage. Renal allograft failure, in fact, has emerged as the fourth most important cause of chronic kidney disease. In thoracic organ transplantation, chronic rejection continues to be a problem with no ready solution.

An analysis of the causes of graft loss and premature patient deaths with functioning grafts demonstrates the need for development of a new class of immunosuppressive agents. These new agents, whether small molecules or biologics, will have to exhibit the following characteristics: lack of nephrotoxicity and cardiovascular risk factors, selective immunosuppression without producing immunodeficiency, no malignancy and minimal side effects. The goal of a graft lasting the life of the patient is unlikely to be achieved without further progress in novel therapeutics in transplantation. However, new drug development has been hampered by the Food and Drug Administration's (FDA) reluctance to follow the lead of the transplant community and recognize the preferred regimens of transplant physicians and allow adoption of this regimen in control arms in clinical studies with new agents. The combination of tacrolimus and mycophenolate mofetil (MMF) has been adopted as a standard of care for maintenance immunosuppression in the United States as well as in most other countries as evidenced by the fact that this combination is used for over 69.8% of all kidney recipients. At discharge in 2005, 79% of kidney transplant patients were treated with tacrolimus, 15% with cyclosporine and 87% with MMF/MPA. The FDA-approved regimen cyclosporine+MMF/MPS with and without steroids is used in only 11.3 % of kidney patients at discharge. Similarly, in liver transplantation 53.4 % of discharged liver recipients are treated with tacrolimus+MMF/MPS with or without steroids. The approved regimens, cyclosporine+MMF/MPS with or without steroids are used in 3.5 % of patients and tacrolimus with or without steroids in 34% of patients. As for induction agents, there are currently none approved in liver transplantation even though 20% of all liver recipients received it in 2005. The increased use of tacrolimus has been propelled by the near consensus in the transplant community that it is a more potent immunosuppressive agent than cyclosporine, associated with better renal function, easier to dose and has less cosmetic side effects, thereby diminishing the risk of non-compliance.