title: Clinical Trials for Immunosuppression in Transplantation: The Case for Reform and Change in Direction.
abstract: Currently trials of immunosuppression in transplantation are in decline because their objectives remain focused on improving acute rejection rates and graft survival in the first 12 months. With 1 year renal graft survival rates of greater than 90% the best that can be hoped for is noninferiority trial outcomes compared with current standard of care. Current trial design is not leading to novel therapies improving long-term outcomes and safety, and hence important unmet clinical needs in transplantation remain unanswered. Issues that need to be addressed include but are not limited to: prevention of subclinical rejection in the first year, better 5- and 10-year graft outcomes, more effective treatment for high immunological risk and sensitized (including donor-specific antibody) patients, immunosuppressive combinations that are better tolerated by patients with fewer side effects and less morbidity and mortality. In September 2015, the Transplantation Society convened a group of transplant clinical trial experts to address these problems. The aims were to substantially realign the priorities of clinical trials for renal transplant immunosuppression with the current unmet needs and to propose new designs for clinical trials for transplant immunosuppression. Moving forward, the transplant community needs to provide trial data that will identify superior treatment options for patient subgroups and allow new agents to be evaluated for efficacy and safety and achieve timely regulatory approval. Trial designs for new transplant immunosuppression must be intelligently restructured to ensure that short- and long-term clinical outcomes continue to improve.
authors.affiliation: 1 Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Sydney, NSW, Australia. 2 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. 3 Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL. 4 Division of Organ Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL. 5 Department of Renal Medicine, University of Sydney at Royal Prince Alfred Hospital, Australia. 6 The Division of Nephrology, St. Paul's Hospital, Vancouver, British Columbia, Canada. 7 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 8 Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. 9 Transplant Immunology Laboratory, University of Manitoba, Winnipeg Blood Centre, Winnipeg, Manitoba, Canada. 10 Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH. 11 Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH. 12 Department of Surgery, University of California San Francisco, San Francisco, CA. 13 Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autónoma Barcelona, Barcelona, Spain. 14 Department of Medicine, University of Cincinnati, College of Medicine, Cincinnati, OH. 15 Division of Transplantation, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD. 16 Department of Nephrology, Universitätsklinikum Charité, Humboldt University, Berlin, Germany. 17 The Comprehensive Transplant Center, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA. 18 Service de Néphrologie-Transplantation, Hôpital Necker, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris France. 19 INSERM U845, Hôpital Necker, Paris, France. 20 Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 21 Division of Transplant Surgery, University of California San Francisco, San Francisco, CA. 22 Division of Transplantation, Department of Surgery, The Johns Hopkins University, Baltimore, MD. 23 Departments of Surgery and Immunology, von Liebig Transplant Center, Mayo Clinic, Rochester, MN. 24 Transplant Surgery Division, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 25Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH. 26 Stanford University School of Medicine, Stanford, CA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: OʼConnell
authors.forename: Dirk R
authors.initials: DR
authors.lastname: Kuypers
authors.forename: Roslyn B
authors.initials: RB
authors.lastname: Mannon
authors.forename: Michael
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authors.lastname: Abecassis
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chadban
authors.forename: John S
authors.initials: JS
authors.lastname: Gill
authors.forename: Barbara
authors.initials: B
authors.lastname: Murphy
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nickerson
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Schold
authors.forename: Peter G
authors.initials: PG
authors.lastname: Stock
authors.forename: Daniel
authors.initials: D
authors.lastname: Seron
authors.forename: Rita R
authors.initials: RR
authors.lastname: Alloway
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.forename: Carmen
authors.initials: C
authors.lastname: Lefaucheur
authors.forename: Minnie
authors.initials: M
authors.lastname: Sarwall
authors.forename: Dorry L
authors.initials: DL
authors.lastname: Segev
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stegall
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Tullius
authors.forename: Germaine
authors.initials: G
authors.lastname: Wong
authors.forename: E Steve
authors.initials: ES
authors.lastname: Woodle
authors.forename: Nancy
authors.initials: N
authors.lastname: Ascher
authors.forename: Randall E
authors.initials: RE
authors.lastname: Morris
mesh_terms: D000208:Acute Disease; D002908:Chronic Disease; D002986:Clinical Trials as Topic / Q000379:methods*; D046148:Donor Selection; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000175:diagnosis / Q000523:psychology / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects*; D018579:Patient Selection; D011788:Quality of Life; D012107:Research Design / Q000639:trends; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents