Open Letter to the FDA: New Drug Trials Must Be Relevant
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 combinations with older drugs in innovative immunosuppression protocols has resulted in a dramatic decrease in the rate of acute rejection from 40% to 60% to 20%, and even 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 overburden 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 mycophenolic sodium (MMF/MPS) 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 in over 70% of all kidney recipients. At discharge in 2005, 79% of kidney transplant patients were treated with tacrolimus, 15% with cyclosporine and 87% with MMF/mycophenolic acid (MPA). The FDA-approved regimen of 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 them 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 noncompliance.

The insistence of the FDA that only narrowly defined regimens are allowed in the control group in prospective randomized trials for drug registration has led to many undesirable consequences. The first is that many centers refuse to participate in these trials because they do not want to subject their patients to a regimen that they feel is inferior. A second undesirable consequence is that patients that are entered in these clinical trials are not representative of the targeted transplant population, and enrollment in these trials is being skewed in order to avoid the cyclosporine arm. Third, the reluctance of U.S. centers to enter patients in these clinical trials is shifting enrollment to patients in developing countries where clinical trials offer the opportunity of free drugs. Finally, a major problem arises when these trials are published; the results are called into question because of the type of patients being enrolled, and the new innovative regimens are compared with protocols regarded by the transplant community as outdated. Several oral small drugs and biologics are currently facing this dilemma in clinical trials.

The FDA has fulfilled its important mandate by not being swayed by opinion or emotions, and should be lauded for that. However, the trials that are used by the FDA were performed many years ago, and were not updated. Results from many clinical trials and retrospective analyses of center and registry data suggest equivalence in safety and, in some cases, superiority in efficacy of currently used regimens. 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. This will further propel the timely clinical development of new agents in transplantation. The policy needs to be changed now. The transplant community demands it, but more importantly, our transplant recipients deserve it.


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