Solid Organ Transplantation
Eric Jay Goldberg, M.D. • Senior Medical Director, Transplant and Immunology, ICON Clinical Research
Historical Perspective of Solid Organ Transplantation
The history of solid organ transplantation dates back to the 2nd Century B.C., where transplantation of organs was reported to have occurred in China. A more credible account of skin grafting was recorded by the Hindu surgeon Sushrata around 600 B.C.
The era of modern transplantation dates from the 19th century where corneal, arterial and venous, and ultimately solid organ transplants were attempted. French surgeon Alexis Carrel is credited as the pioneer in the suturing techniques that laid the groundwork for transplant surgery. Dr. Carrel was awarded the Nobel Prize in Physiology and Medicine in 1912 for this work. He is also credited as the first physician to identify the problem of rejection which still remains as the greatest challenge for transplant physicians today.
The early years of transplantation research focused on the technical (surgical) aspects of the transplant process. As time passed and the surgical techniques became refined, the focus changed to the biological aspects of transplantation. In the 1920s, the immune system was recognized as the major force in transplant efforts. The rejection response once referred to as the “force and power” has been the central focus of the clinical practice of transplant medicine and therefore of clinical research. In the 1940’s, Dr. Peter Medawar studied the mechanism of the immune response and in 1951, he suggested that changes that suppress the immune response could be used to treat post-transplant patients. Cortisone was the first pharmacologic used. In 1959, azathioprine was discovered and found to be more effective. But it was not until 1970, when cyclosporine was discovered, that the successful treatment of organ rejection was solidified.
Successful kidney transplantation was followed by liver, heart, and lung, gastrointestinal, pancreatic and multi-organ transplants. It was the discovery of cyclosporine that changed the field of organ transplantation from research to reality.
Today solid organ transplants are commonplace and the numbers of transplants performed is limited only by the number of donors available. Advances in transplantation have closely paralleled the development of increasingly potent and specific immunosuppressive agents, improvements in the area of organ procurement and preservation, advances in tissue typing and constant refinements in surgical technique and technology.
Table 1 lists the numbers of patients in the U.S. on waiting lists for all solid organs, broken down by specific organ. Also of interest is the substantially limited number of donors in 2008, which represents the most recent data available.
Long term graft and patient survival have replaced short-term results as the benchmark of success. The one year graft survival of a deceased kidney donor is greater than 90% at most transplant centers. However, rejection (acute and chronic) and chronic allograft dysfunction continue to be the major obstacles to long-term graft survival.
Solid Organ Transplant Clinical Trials
In recent years a number of new approaches aimed at preventing and treating both acute and chronic rejection in solid organ transplants have developed. In addition to immunosuppression research, new therapies aimed at commonly occurring infections in transplant patients are being developed and tested. Large multicenter clinical trials are the cornerstone of the ultimate clinical application of these new therapies.
The mainstay of solid organ transplant immunosuppression for the past 20 years has been the calcineurin inhibitors (cyclosporine and tacrolimus). While affording an acceptable level of success, the ongoing safety issues with this class of drugs has led to numerous attempts at modulating the immune response via alternative biological pathways.
Most recently a great deal of attention has been focused on the co-stimulation blockade of specific t-cell receptor sites as a means to control the immune response in transplant patients. Results of Phase II clinical trials utilizing these new molecules suggest that effective immunosupppression may be achievable while at the same time bypassing the well established risks of nephrotoxicity, diabetes mellitus, hypertension, and cardiovascular disease. Ongoing clinical trials will be critical in the establishment of clinical maintenance and drug regimens before this new approach to immunosuppression is accepted in clinical practice.
The other major focus of clinical trials in organ transplantation is infectious diseases. Infectious complications are a major source of morbidity and mortality in transplant recipients. Opportunistic infections such as tuberculosis, fungal and viral pathogens are a constant threat to the immunocompromised patient. New antiinfectives are constantly entering the clinical trials arena. Monitoring of infectious disease events in transplant patients in the past was often limited to passive surveillance and reporting infections as adverse events and serious adverse events. Even when a clinical trial protocol requires monitoring and reporting of infectious disease events, a simple multi-center study may have wide variations on the definition of infections and the testing performed to document those infections.
Table 2 lists the most commonly encountered pathogens in immunocompromised patients along with the recommended laboratory tests used to document these infections. Clinical trial protocols are bringing a new level of standardization in testing procedures.
Patient Safety in Organ Transplant Clinical Trials
Patient safety and welfare must always remain paramount in all clinical trials. Patients requiring organ transplants are considered among the most clinically challenging patients to treat. Most of these patients have a multitude of disease processes and are being treated with a number of medications and therapies. Drug-drug interactions are always challenging in these patients along with the very delicate balances in physiology required to keep the patient safe and feeling well along with protecting the grafted organ.
Data and Safety Monitoring Boards (DSMB) are routinely created in organ transplant clinical trials to insure patient safety. A DSMB is made up of key opinion leaders and well-respected professionals in the transplant community. They meet on a regular basis to review data and safety reports for the purpose of insuring ongoing patient safety. DSMB recommendations are immediately addressed by the sponsoring companies. Responses to safety concerns may require a modification(s) in protocol design or even termination of the study. ICON Clinical Research maintains a database in transplant medicine and surgery in order to assist sponsors in creating and maintaining DSMBs throughout the duration of the study and during the post-marketing phase.
Table 3 illustrates the decreasing incidence of acute allograft rejection rates over a recent six year period. Acute rejection rates are a major consideration in solid organ transplant studies and are often a part of the clinical trial’s endpoint analysis.
Summary
New advances in the areas of immunosuppression and infectious disease promise an increasingly bright future for the solid organ transplant recipient. Research and development, augmented by a sound well-established and safe clinical trials environment, hold the key to the brighter future.
The ICON Clinical Research transplant and immunology group offers expertise in the development and management of all aspects of organ transplant clinical trials from the earliest development to the late post-marketing environment. Excellent investigator relations and a global presence of offices and staff insure timely completion of global organ transplant clinical trials. Constant, non-compromising concern for patient safety is always the number one priority at ICON Clinical Research.