PRINCIPLES OFDRUG DEVELOPMENTIN TRANSPLANTATIONAND AUTOIMMUNITY

Ronald Lieberman, M.D.

Asoke Mukherjee, Ph.D.Center for Drug Evaluation and Research

Food and Drug AdministrationRockville, Maryland, U.S.A.

CHAPMAN & HALLI©P An International Thomson Publishing Company _ _ , T / —

R.G. LANDES COMPANYNew York • Albany • Bonn * Boston • Cincinnati • Detroit • London • Madrid • Melbourne •Mexico City • Pacific Grove • Paris • San Francisco • Singapore • Tokyo • Toronto • Washington A I T r - r i kj

=CONTENTS ^ — = —Section A

BASIC SCIENCE AND CLINICAL DEVELOPMENT

Part I: Basic Principles and Essential Concepts

1. Transplantation Immunology 3Yolonda L. Colson and Suzanne T. lids tadMolecular Basis of Alloreactivity: Transplantation Antigens 3Clinical Aspects of Histocompatibility: Tissue Typing 5Basic Components of the Immune System 6Accessory Antigen-Presenting Cells: Macrophages, Monocytes and Dendritic Cells 7,T-Lymphocytes: The Antigen-Specific Cells in Rejection 8B-Lymphocytes 13Natural Killer (NK) Cell 14Cytokines: The Soluble Immune Cell Regulators 14Regulation of the Cytokine Response 17Cellular Basis of Graft Rejection 18Future Direction in Prevention of Rejection 18

2. Host Mechanisms of Acute and Chronic Allograft Rejection 21Christof Schmid, Uwe W. Heemann, Haruhito Azuma and Nicholas L. TilneyAcute Allograft Rejection 21Chronic Allograft Rejection 25Conclusion 27

r3. Pathophysiology of Xenograft Rejection 31\J Soheyla Saadi, Nathan S. Ihrcke and Jeffey L Platt

Introduction 31Clinical and Pathologic Outcomes of Xenotransplantation 31Mechanisms of Immunorecognition Leading to Hyperacute Xenograft Rejection ..: 34Pathogenesis of Xenograft Rejection 35Pathophysiology of Hyperacute Xenograft Rejection 37Pathophysiology of Acute Vascular Rejection 40Pathophysiology of Accommodation 41

4/ Graft-Versus-Host Disease After Bone Marrow Transplantation 471/ Richard A. Nash and Rainer Storb

Introduction 47Historical Perspective 47Acute GVHD 48Chronic GVHD 52Summary 54

5/ Transplant Tolerance Induction: Basic Concepts and Therapeutic Approaches 59Judith M. Thomas and Kathryn M. VerbanacTransplant Tolerance: The Mission 59Immune Mechanisms Implicated in Tolerance 60Factors That Influence Transplant Tolerance Induction 61Strategies for Leading Transplant Tolerance from the Lab to the Bedside 63Summary 71

6. Pathogenesis of Autoimmune Disease 81Robert I. Fox andArgyrios N. TheofilopoulosIntroduction 81General Issues 82Tolerance 82Apoptosis and Autoimmunity 84Genetic Factors That Influence Autoimmune Responses 85Environmental Factors That May Induce Autoimmunity 87Summary 88

7. Immunosuppressive Agents, Immunodeficiency States and Malignancy 93Israel PennCancers in Organ Transplant Recipients 93Incidence of Posttransplant Cancers 93Age and Sex of Patients with Cancers 93Time of Appearance of Tumors 94Common Types of Posttransplant Malignancies 94Cancers in Naturally-Occurring Immunodeficiency Disorders 98Cancers in the Acquired Immunodeficiency Syndrome (AIDS) 99Possible Causes of Tumors in Immunosuppressed Patients 100

Part II: New Drug and Biologic Product Development

8. Overview of Therapeutic Agents 105

,8.1. Classification and Mechanism of Action of Therapeutic Agents1 / Used in Transplantation 107v Ronald Lieberman

Historical Perspective of Anti-Rejection Drug Development 107Classification of Drug and Biological Agents 108Rational Combinations and Developmental Strategies 112Unmet Therapeutic Needs 114Multiple Actions and Therapeutic Implications 114Perspective 114

8.2. Classification and Mechanism of Action of Therapeutic AgentsUsed in Autoimmune Disease 117Robert I. FoxIntroduction 117Rapid-Acting Anti-Inflammatory Drugs 118Slow-Acting Anti-Rheumatic Drugs (SAARDs) 122Biologic Modifiers 127Oral Tolerance for Immune Suppression 128Summary 128

Mechanisms of Action of Cyclosporine A and Tacrolimus (FK506):Immunosuppression Through Immunophilin-Dependent Inhibitionof Calcineurin Function 133Francis J. DumontIntroduction 133

Chemical Structures 133Suppression of T Cell Activation 134Inhibition of Lymphokine Gene Transcription 135Effects on Other Ca2+-Dependent Activation Events 137Cellular Binding Proteins: Immunophilins 138Inhibition of the PPIase Activity of Immunophilins Does Not Mediate

Immunosuppression 139Gain of Function Model 140Interaction of the Immunophilin-Drug Complexes with Calcineurin 140Calcineurin Inhibition as the Central Mechanism for Suppression of T Cell Activation

by CsA and FK506 141Structure of the Immunophilin-Drug Complexes 142Mechanisms ofToxicity 145Conclusion 147

10/ Tacrolimus (FK506) 157

10.1. Discovery, Immunopharmacology and Rationale for the Developmentof Tacrolimus: A Novel Immunosuppressant of Microbial Origin 159Toshio GotoIntroduction 159Discovery of Tacrolimus 159Chemistry of Tacrolimus 160Early Predinical Immunopharmacology 161

10.2. Tacrolimus for Experimental Organ Transplantation 165Satoru Todo and Noriko MuraseIntroduction 165FK506 for Experimental Organ Allotransplantation 165FK506 for Experimental Xenotransplantation 167

10.3. The Influence of Tacrolimus on Experimental Autoimmune Disease 171Angus W. Thomson, Noriko Murase, Michael A. Nalesnik and Thomas E. StarzlIntroduction 171Mode of Action of Tacrolimus 172Effects of Tacrolimus on Immune Reactivity 173Toxicity of Tacrolimus in Experimental Animals 173Influence of Tacrolimus in Autoimmune Disease Models 173Combined T and B Cell Directed Therapy of Spontaneous Autoimmune Disease

Using Tacrolimus and Low Dose Cydophosphamide 178

10.4. Tacrolimus in Solid Organ Transplantation 183JohnJ. Fung, Satoro Todo and Thomas £. StarzlPreclinical Development 183Clinical Trials 183Dosing of FK506 187Monitoring FK506 188Toxicity 188Conclusions 189

10.5. Tacrolimus Immunoprophyiaxis and Rescue Therapyin Liver Transplantation 191Marwan S. Abouljoudand Goran B. KlintmalmIntroduction 191U.S. FK506/CsA Multicenter Trial 191European Multicenter FK506 Trial 194FK506 Rescue Therapy in Liver Transplantation 194Recommended Dosing Strategy 195

10.6. The European Multicenter Liver Trial—Tacrolimus Versus Cydosporine 199Paul McMaster and Peter FA. BerryIntroduction 199Methods 199Results 200Discussion 202Conclusions 203

10.7. Tacrolimus-Based Immunosuppression for the Preventionof Acute GVHD After Marrow Transplantation 205Richard A. Nash and Rainer StorbIntroduction 205Preclinical Investigations 206Clinical Studies in Marrow Transplantation 207

10.8. Tacrolimus and Therapy of Human Autoimmune Disorders 211Patricia B. Carroll, Angus W. Thomson, Jerry McCauley, Kareem Abu-Elmagd,

Horacio R. Rilo, William Irish, John McMichael, David H. Van ThielandThomas E. Starzl

Introduction 211Rationale for the Use of Tacrolimus in Autoimmune Diseases 211Comparative Biological and Pharmacological Properties of Tacrolimus and CsA 212Influence of Tacrolimus on Experimental Autoimmune Diseases 213Early Clinical Experience with Tacrolimus at the University

of Pittsburgh Medical Center 213Side Effects of Tacrolimus in Humans 217An Intelligent Dosing System for Individualizing Tacrolimus Therapy

in Autoimmune Disease 218Prospects for Drug Combination Therapies 219Conclusions 219

11. The Cyclosporines: New Uses, New Analogs and New Formulations 221

11.1. Twenty Years of Continuing Research on Cyclosporines:Can Cyclosporine Be Improved? 223Gilles Feutren and Jean F. Borel

11.2. Cyclosporine: Therapeutic Use in Autoimmune Disease 225Beat von GraffenriedProblems of Clinical Testing in Autoimmune Diseases 225Therapeutic Efficacy 226

Adverse Events 230Implications of Pharmacokinetic Properties for Therapy and the Role

of Pharmacological Monitoring 231Optimal Use of CsA in Autoimmune Diseases 232Perspectives for the Future 233

(il.3JThe Immunopharmacological Profile of Cyclosporine G 239\ /Peter C. Hiestand

In Vitro Activities 240In Vivo Activities .-. 242Discussion 245

11.4. Experimental and Clinical Experience with Cyclosporine G' in Kidney Transplantation 249

Daniel Salomon, Bruce Kaplan, Horst Schran, June Mason, Helen Torley,Carol Bainbridge and Gilles Feutren

Summary 249Introduction 250Experimental Studies 250Clinical Studies 253Conclusions 256

11.5. Improved Oral Absorption of Cyclosporine by Using Neoral™,A Microemulsion Formulation 259Armin Meinzer, Edgar A. Mueller, DetlefNiese, Gerry Choc, Robert Wong,

Jacky Vonderscher, Miguel Bernabeu and Gilles FeutrenBarriers to Optimal Absorption of Oral Cyclosporine 259Cyclosporine Microemulsion: An Improved Oral Formulation 260Efficacy and Tolerability of Neoral 264

12. Sirolimus (Rapamycin, Rapamune™) 269

(12.1.JSirolimus: A New Immunosuppressive Agent—A Historical Perspective and Immunosuppressive Profile 271Suren N. SehgalIntroduction 271Producing Organism 272Production and Isolation 272Physicochemical Properties and Chemistry 272Biosynthesis of Sirolimus 273Antifungal Activity 273Protection Against Systemic Candidiasis 274Antitumor Activity 274In Vitro Immunological Properties 274Interactions Between CsA, Sirolimus andFK506 275Mechanism of Action 275Target of Sirolimus: FKBP Complex 278Conclusion 278

12.2. Sirolimus Pharmacokinetics and Therapeutic Monitoringin Animal Models of Transplantation 283Randall W. YatscoffBlood Distribution of RAPA 283Measurement of RAPA 285Pharmacokinetics 285Therapeutic Range Determinations 286Summary and Conclusions 287

12.3. Sirolimus: Side Effect Profile in Animal Studies 289John F. Dijoseph and Suren N. Sehgal

\1A. Effects of Sirolimus on Allognaft and Xenograft Survivalin Animal Models of Transplantation 295Stanislaw M. StepkowskiIntroduction 295Evaluation of the Immunosuppressive Effects of RAPA on Organ Allograft

' Survival in Rodents 295Evaluation of the Immunosuppressive Effects of RAPA on Organ Allograft

Survival in Other Species 296Effect of RAPA in Combination with CsA and/or Brequinar (BQR)

on Allograft Survival 297Mechanism of RAPA Immunosuppression 299Effect of RAPA on Xenograft Survival 300Conclusions 300

12.5. Effect of Rapamycin in Animal Models of Arthritisand Other Autoimmune Diseases 303Richard P. Carlson and Suren N. SehgalIntroduction 303Spontaneous Autoimmune Models 303Antigen-Induced Autoimmune Models 304Conclusion 307

13. Leflunomide—A New Direction in Immunosuppression 309

13.1. Discovery, Rationale and Developmental History of Leflunomide 311James W. Williams

(13.2.\ln Vitro Pharmacology and Mechanism of Action of Leflunomide 313^ SAnita S-F Chong and James W. Williams

Effects on Mediator Release of Inflammatory Cells 313Effects on Cell Proliferation 313Effects on Stimulation of T-Lymphocytes 314Leflunomide as aTyrosine Kinase Inhibitor 314

13.3\ln Vivo Pharmacology and Toxicology of Leflunomide in Animals 317JJames W. Williams and Fei Xiao

13.4. Leflunomide in Animal Models of Rheumatic Diseasesand Other Autoimmune Disorders 319James W. WilliamsInhibition of Experimental Arthritis 319Other Non-Arthritic Autoimmune Diseases 320

13.5. Leflunomide in Animal Models of Allograftand Xenograft Transplantation 321James W. Williams and Fei XiaoEffects on Allotransplantation 321Effects on Chronic Rejection 328Effects on Bone Marrow Transplantation 329Effects.on Xenotransplantation 329Summary of In Vivo Studies in Animal Models 329Summary and Conclusion 330

14. Mycophenolate Mofetil (MMF) 333

14.1. Discovery and Rationale for the Development of Mycophenolate Mofetil.. 335Thomas R. Matthews

14.2. In Vitro Pharmacology and Mechanism of Action of MMF 339Thomas R. MatthewsInhibition of Lymphocyte Proliferation 339Cytokine Production 339Antibody Formation In Vitro • 339Inhibition of Fucose and Mannose Transfer to Glycoproteins 340

14.3. Effects of MMF in Animal Models of Acuteand Chronic Transplant Rejection 343Thomas R. MatthewsLymphocyte-Selective, Reversible Cytostatic Effects 343Inhibition of Cell-Mediated Immune Response to Allogeneic Cells 343Inhibition of Antibody Formation 343Prevention of Allograft Rejection 343Prevention of Chronic Rejection 344

14.4. Human Pharmacokinetics of MMF 347Thomas R. Matthews

14.5. Clinical Development Strategy in Organ Transplantationand Rheumatoid Arthritis (RA) 349Roberts. Kauffman and Ronald GoldblumOrgan Transplantation 349Rheumatoid Arthritis 350

14.6. Clinical Studies of MMF in Transplantation 351Robert S. KauffmanKidney Transplantation 351Cardiac Transplantation 353Liver Transplantation 353Phase III Trials 353

14.7. Clinical Studies of MMF in RA 355Ronald GoldblumConclusion 356

15. Mizoribine 359Scott A. Gruber and Stephen E. Hughes

! Introduction and Rationale 359In Vitro Mechanism of Action 359Drug Assay 361Pharmacokinetics/Metabolism in Animals 362Pharmacology/Toxicology in Animals 362In Vivo Effects in Animal Models of Transplantation and Autoimmunity 363Clinical Pharmacokinetics 364Use in Clinical Transplantation 364Future Role in Organ Transplantation 365

16. Brequinar Sodium 369Donald V. CramerIntroduction: Rationale and Mechanism of Action 369Preclinical Evaluation of Immunosuppressive Activity 370Pharmacokinetic Properties in Patients 371The Use of Brequinar Sodium in Clinical Trials 372

Summary 372

17. Gusperimus (15-Deoxyspergualin) 375

17.1. Discovery, Rationale and Clinical Status of 15-Deoxyspergualin (DSG) 377Hiroshi AmemiyaHistorical Background 377Mechanism of Action 377Experimental Studies 379Clinical Use .' 379Actualities in Japan 381Future Clinical Application 381

17.2. In Vitro Pharmacology, Mechanism of Actionand Preclinical Pharmacokinetics and Toxicology of DSG 383Mark A. TepperIntroduction 383In Vitro Studies 384Biochemical Mechanism of Action of DSG 385Pharmacokinetics and Toxicology 385

17.3. Experience with DSG in Experimental Models of Transplantation 389Dixon B. KaufmanNeovascularized Allotransplant Models 389Immediately Vascularized Allotransplant Models 391Xenotransplantation and Antihumoral Immunity 392

17.4. DSG: Clinical Strategies and Recent Clinical Experiencein Transplantation 397PaulF. Gores and Susan L. KelleyTreatment of Ongoing Allograft Rejection Episodes 397Prevention of Antibody Response to Immunogenic Protein-Based Therapeutics 398Suppression of the Humoral Response in Sensitized Patients 398Prevention of Macrophage Mediated Damage

of Non-Immediately Vascularized Grafts 399

18. Monoclonal Antibodies Against T Cell and Novel Cell Surface Determinants 403

18.1. Monoclonal Antibodies for the Prevention and Treatment of Rejectionin Solid Organ Transplantation 405John S. Thompson and James F. BurdickIntroduction 405Reported Phase II and III Studies 406What's Ahead? 409

18.2. Anti-ICAM-1 Monoclonal Antibody:Discovery, Rationale and Clinical Development 415Robert Rothlein and Judith R JaegerAbstract 415Introduction 415In Vitro Pharmacology and Mechanism of Action 416In Vivo Effects in Animal Models 416Clinical Development 417Summary and Conclusions 419

19. Pharmacologic and Biologic Purging of Bone Marrow 423

19.1. Cydophosphamide Analogs in Pharmacological Purgingof Autologous Bone Marow for Transplantation 425Anthony J. MurgoIntroduction 4254-Hydroperoxycydophosphamide 426Mafosfamide 429Conclusion 432

19.2. Biologically Processed Bone Marrow 437Stephen D. LitwinBone Marrow 437Why is Regulation of Bone Marrow Processing Complicated? 438Characterization of Processed Bone Marrow 438The Conundrum of Bone Marrow Purging 440Selection of Progenitor Cells 441Perspectives 441

Section BSCIENTIFIC, REGULATORY

AND PHARMACOECONOMIC ASPECTS

Part III: Managing the Drug Development Process

20. The Incentives of the Orphan Drug Actand Immunosuppressive Drug Development 445Marlene E. Haffher and John V. KelseyThe Orphan Drug Act 446

! The Office of Orphan Products Development 446Protocol Assistance 446Exclusivity 446Tax Credits 447Orphan Designation 447Grants Program 449The OPD Program and Transplantation and Autoimmune Disorders 449AIDS and the Orphan Products Program 449Biotechnology Patent Issue 450Conclusion 450

21.y Preclinical Pharmacokinetics—Pharmacodynamics and its Applicationto the Clinical Development of Tacrolimus (FK506) in Organ Transplantationand Autoimmunity: A Review of Regulatory Research 453Asoke Mukherjee and Ronald LiebermanIntroduction 453In Vitro Activity 454In Vivo Activity 456Pharmacology and Toxicity of FK506 458Pharmacokinetic, Toxicokinetic and Pharmacodynamic Correlations 461Future Development 465Summary and Conclusion 466

22. Pnarmacokinetics and Immunopharmacodynamic MonitoringImmunosuppressant Agents 471

22.1. New Immunosuppressant Drug Clinical Trials: The Need for SpecificConcentration Measurement of Parent Drug and Metabolitesin the Evaluation of Concentration-Effect Relationshipsand in Therapeutic Drug Monitoring (TDM) 473Leslie M. Shaw and Gerard F. CooneyIntroduction 473Cyclosporine A-Based IS Protocols and the Evolution of TDM Strategy 474The Need for Specific Methods for the Measurement of Parent Drug

and Metabolites in TDM and RCCCT 474New Immunosuppressive Drugs 475Implications for TDM 480

22.2. Pharmacokinetics, Metabolism and Therapeutic Drug Monitoringof the Macrolide Immunosuppressants Tacrolimus (FK506)and Sirolimus (Rapamycin) 483Uwe Christians and Karl-Friedrich SewingIntroduction 483Tacrolimus and Rapamycin Metabolites 485Cytochrome P450 and Drug Interactions 491Therapeutic Drug Monitoring 493Pharmacokinetics 497Conclusions 498

22.3. Immunophilin Receptors for Immunosuppressive Drugs:j Their Use in Therapeutic Drug Monitoring 507

Steven J. SoldinIntroduction 507Historical Perspectives 507Immunophilins 508Possible Mechanisms of Action of CsA, FK506 and RAPA 508Studies on Minor Immunophilins (14 kDa and 52 kDa) 508Receptor Assays 509Summary and Future Studies 509

23. Histopathologic Diagnosis of Allograft Rejection 513

23.1. Hepatic Allograft Rejection 515Russell H. WiesnerHyperacute Rejection 515Cellular Rejection 516Ductopenic Rejection 516Incidence and Timing 517Histologic Grading of Cellular Rejection 518Histologic Findings in the Clinical Setting of Biochemical Dysfunction 519Conclusion 519

23.2. Histopathologic Diagnosis of Kidney Transplant Rejection 521Sharda G. SabnisIntroduction 521Preservation Injury 521"Imminent" Rejection 522Hyperacute Rejection 522Acute Rejection 523Chronic Rejection 524Cyclosporine Toxicity 526Recurrent and De Novo Diseases 527Banff Classification 527

23.3. Rejection of the Cardiac Allograft: Current Morphologic Criteriafor Diagnosis and Classification 529Gerald J. Berry and Margaret E. BillinghamIntroduction 529Acute Cellular Rejection 529

Classification and Grading of Acute Cellular Rejection 530Morphologic Mimics of Acute Cellular Rejection 533Hyperacute Allograft Rejection 535Acute Vascular ("Humoral") Rejection 535Graft Coronary Disease 536Future Developments 536

23.4. Pulmonary Allograft Rejection: Histopathologic Manifestations 539Gerald J. BerryThe Transplant Recipient: Methods of Postoperative Surveillance 539Acute Lung Rejection 540Chronic Lung Rejection 543Future Directions in Lung Transplantation 545

24. Chronic Rejection and New Drug Development 547

24.1. Chronic Allograft Rejection—Definitionand Clinical Laboratory Correlates 549Arthur J. MatasDefinition 549Clinical Correlates 550Nonimmunologic Mechanisms 551Laboratory Correlates 552Treatment 552Hypotheses 552Conclusion 553

24.2. Intermediate Efficacy End-Points for Chronic Kidney Allograft Rejection:Implications of Protocol Core Biopsy for Early Registrationof New Agents 557Pekka Hdyry, Serdar Yilmaz, Eero Taskinen and Helena IsoniemiIntroduction 557Histopathology and Differential Diagnosis 558Histological Changes of Chronic Allograft Rejection are Frequently Present

in Renal Allografts with Normal Function 559Predictive Value of Early Histological Changes of Chronic Rejection

for Long-Term Clinical Outcome of the Allograft 559Conclusions and Recommendations 560

25. Infections Associated with Solid Organ Transplantation 565Marian G. Michaels and Michael GreenPretransplant Factors Within the Host 565Donor Associated Risk Factors 566Intraoperative Risk Factors 566Posttransplant Risk Factors 566Small Bowel Transplantation 567Xenotransplantation 567

26. The Nephrotoxicity of Immunosuppressant Agents in Modern Transplantation.. 571Jerry McCauleyIntroduction 571Cyclosporine A 571Tacrolimus (FK506) 574Rapamycin 575Methotrexate 575Other Immunosuppressants with Minimal Nephrotoxicity 575Summary and Conclusions 576

27. Clinical Trials of New Agents in Organ Transplantation 579

27.1. Practical Issues for the Design and Analysis of Clinical Trials' in Organ Transplantation: A Regulatory Commentary 581

David Hoberman and Ronald LiebermanIntroduction 581Study Questions and Endpoints 581Study Designs 582Statistical Considerations for Design and Analysis 584Conclusion and Future Directions 588

27.2. Methods of Survival Analysis for the Assessment of Clinical Outcomein Organ Transplantation 591Robert D. GordonThe Life Table Method 592Kaplan-Meier (Product-Limit) Analysis 595Measurement of Error and Statistical Comparisons 596The Cox Regression Model 598

27-3. Quantitative Approaches for the Evaluationof New Immunosuppressive Agents 605Barry D. KahanIntroduction 605Evaluation of Clinical Utility of New Immunosuppressive Agents 605Concentration/Controlled Cyclosporine Regimens 606Combination Drug Methodology 607Prospectus 612

27.4. An Artificial Intelligence Modeling System (AIMS) for Tacrolimusand Cyclosporine A: Application in Concentration ControlledClinical Trials and Cost Effective Drug Monitoring 615John McMichael, Ronald Lieberman, Hector Ramos, Mario Magnone,

Jerry McCauley and Howard DoyleIntroduction 615Declarative vs Procedural Languages 616Using AI to Solve a Medical Problem 616Model Development 616Validation of the Models 617Physician vs Computer 618AIMS Guided Concentration Controlled Trials 619Implications for Cost Effective Drug Evaluation and Patient Management 620

28. FDA Postmarketing Surveillance 623

28.1. The New FDA MedWatch Programand Postmarketing Drug Surveillance 625Dianne L. KennedyMedWatch 625What to Report 627How to Report 628

28.2. Postlicensure Surveillance of Biological Product Safety 629Robert P. WiseIntroduction 629

, The FDA Spontaneous Reporting System (SRS) 630OKT3 Reports to FDA 630Increased Frequency Reports 631Conclusion 632

28.3. Posttransplant Development of Lymphoproliferative Disordersand Other Malignancies Following Orthodone OKT3 Therapy 633Dominique Bertin, Thomas Haverty, Marilyn Sanders, Debbie Daniel, Jean O 'Connor,

Sharon Spence, Kathryn Starzer-Farrell, Patricia Treichler and Shu-Chen WuIntroduction 633Clinical Studies 634Postmarketing Survey 635Survey Design 635Reporting Rate 636Survey Results 636Conclusions 639

Appendix 1: Federal Regulation of Donation, Distribution, Reimbursementand Technology Assessment for Organ Transplantation 643

Part AHistorical Perspective on the National Organ Transplant Act 643

Jerold MandeOverview of Federal Regulation of Organ Transplantation 647

Judith B. BraslowThe United Network for Organ Sharing (UNOS) 649

RuudAF. KromOrgan Procurement Organizations 651

Gwen MayesThe National Marrow Donor Program 653

Craig W. S. Howe

PartBOverview of Federal Reimbursement and Technology Assessment

for Organ Transplantation 655Peter Rheinstein

Federal Reimbursement of Organ Transplantation: Role of HCFA 656Sam Shekar

Technology Assessment of Organ Transplantation: Role of the AHCPR 659Tom Holohan

Technology Assessment: Role of NIH 666John Ferguson

Appendix 2: Compliance Monitoring of Immunosuppressive Agents 669A Legislative Chronology of Issues Related to Immunosuppressant Drugs

From 1972-1993 669Charles L. Plante

Understanding Issues in Transplant Recipient Noncompliance 671Patti DeLone

Noncompliance in Organ Transplant Recipients 673Mary A. Swanson and Robert T. Schweizer

' Use of Contracts to Increase Compliance of Transplant Recipients 675Ginger Caldwell

Part IV: Future Directions in Drug and Biological Development

29. Therapeutic Strategies of the Future 681

29.1. Immunosuppression and the Bidirectional Paradigm of TransplantationImmunology 683Thomas E. Starzl and Anthony J. Demetris

29.2. The Role of Hematologic Growth Factors and Cytokinesin Solid Organ Transplantation 689Preston F. Foster, Deepak Mital, Howard N. Sankary, Lawrence P. McChesney,

JoAnn Marcon, Kent Kociss and James W. WilliamsIntroduction 689Amelioration of Side Effects of Immunosuppressive and Anti-Infective Agents 690TNF 690Adhesion Molecules 690G-CSF Induction of Increased Circulating Levels of Soluble IL-2 Receptor 691Other Examples of Growth Factor and Cytokine Administration in

Solid Organ Transplantation 691Summary 692

29.3. SCR1, a Novel Complement Inhibitor: Development and PotentialApplications for Treating Hyperacute Rejection of Transplanted Organs... 695James L. Levin, Henry C. Marsh, Jr. andAlR. RudolphThe Complement System 695Human Complement Receptor Type 1 696Soluble Complement Receptor Type 1 697Transplantation 698Clinical Development 699

29.4. Xenotransplantation and Transgenic Pigs:A Solution to the Problem of Organ Shortage in Transplantation? 703David White

29.5. Evolutionary Limits to Xenogeneic Transplantation 707Claus R. HammerEvolutionary Factors 707Anatomical Differences 707Physiological Characteristics 708Xenogeneic Natural Antibodies (XNA) 710Summary 711

29.6. Current Status of Transplantation of Fetal Pancreatic Tissue 715DebraA. Hullett and Hans W. SollingerIntroduction 715Clinical Transplantation of Human Fetal Pancreas (HFP) 715The Potential of HFP 715The Disadvantages of HFP 716Solutions 717Summary 717

29.7. Fetal Neural Transplants for Parkinson's Disease 719CurtR. Freed, RobertE. Breeze, NeilL. Rosenberg, Christopher F. OBrien

and Stuart A. SchneckIntroduction 719History and Characterization of Parkinson's Disease 719Neural Transplants as Treatment for Advanced Parkinson's Disease 720Need for Immunosuppression 720Patient Assessment 720Patient Selection 720Surgical Strategy 720Outcome of Fetal Neural Implants 721

29.8. Oral Tolerization Approaches for Autoimmune Disorders 723Howard L. Weiner, David E. Trentham, Robert B. Nussenblatt and David A. HaflerMechanisms of Oral Tolerance 723Bystander Suppression 724Treatment of Organ Specific Autoimmune Diseases in Animals 724Treatment of Autoimmune Diseases in Humans 725Future Directions 727

30. Structure Based Design of New Therapeutic Agents: Biophysical Analysisof FKBP12 Complexed with Immunosuppressants and De Novo DesignofaNovelFKBP12Ligand 729DavidM. Armistead andMatthew W. HardingBiochemical Function of Immunophilin Proteins 729Structure Determination of FKBP12 and the FKBP12-FK506 Complex 732Specific FKBP12 Residues Are Essential for Binding Calcineurin 733De Novo Design of a Novel PPIase Inhibitor and Its FBBP12-Complex Structure 735

31. Novel Uses of Immunosuppressive Agents:Modulation of Multiple Drug Resistance (MDR) in Cancer 739

31.1. Immunosuppressive Agents as Modulators of MDR in Cancer—Preclinical Studies 741Adorjan AszalosGeneral Considerations 741Studies on the Mechanism of Action of P-Glycoprotein Blockers 742Action of Cyclosporine A and Its Analogs on MDR Cells 744Effect of FK506 and Rapamycin on MDR Cells 745In Vivo Animal Experiments 745

31.2. Modulation of MDR Gene Expression in Patients with Cancerby Immunosuppressive Agents 749Lorraine A. Cazenave

32. Pharmacoeconomic Aspects of New Drug Development and Transplantation 755

32.1. Economic Evaluation of Pharmaceuticals:From Cost-Efficacy to Cost-Effectiveness 757Bernie OBrienIntroduction 757Rationale for Economic Evaluation 757Distinguishing Features of Economic Evaluations 758Cost-Efficacy vs Cost-Effectiveness 760Summary 761

32.2. Regulatory Guidelines for Pharmaceutical Drug Economic Analysis:Canadian View 763Mitchell A. H. LevineWhat is the Validity of the Evidence? 764Appropriate Choice of Comparative Product 764Sufficient Duration of Followup 764Relevant Clinical Outcomes 764Generalizable Results 764

32.3. Evaluation and Promotion of Cost-Effectiveness and Quality of Life:FDA Commentary 767Russell Fleischer, Louis Morris and Janet L. RosePharmacoeconomics 767Quality of Life 769Conclusion 769

32.4. Economic Issues in Transplantation: Procedures and Drugs 771Roger W. Evans

32.5. The National Minority Organ/Tissue Transplant Education Program(MOTTEP): A Cost Effective Model for Community Empowerment 777Clive 0. Callender and David E. RivadeneiraAbstract 777Introduction 778Materials and Methods 778Results 779Summary and Conclusion 780

Index 781