Graft-versus-Host Diseases: 
Developing Drugs, 
Biological Products, and 
Certain Devices for 
Prevention or Treatment 
Guidance for Industry 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit electronic comments to https://www.regulations.gov. Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852. All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Robert Le at 240-402-8320, 
(CBER) Office of Communication, Outreach and Development at 800-835-4709 or 240-402-
8010, or (CDRH) Regulatory, Policy and Combination Products Staff at 
cdrhproductjurisdiction@fda.hhs.gov.   
  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
September 2023 
Clinical/Medical 
   
Graft-versus-Host Diseases: 
Developing Drugs, 
Biological Products, and 
Certain Devices for 
Prevention or Treatment 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information   Office of Communication, Outreach and Development  
Center for Drug Evaluation and Research  Center for Biologics Evaluation and Research 
Food and Drug Administration   Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor   10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002   Silver Spring, MD 20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431- Phone: 800-835-4709 or 240-402-8010 
6353  Email: ocod@fda.hhs.gov 
Email: druginfo@fda.hhs.gov    https://www.fda.gov/vaccines-blood-biologics/guidance-
https://www.fda.gov/drugs/guidance-compliance-regulatory- compliance-regulatory-information-biologics/biologics-
information/guidances-drugs  guidances     
and/or 
 
Office of Policy 
Center for Devices and Radiological Health 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 66, Room 5431 
Silver Spring, MD 20993-0002 
Email: CDRH-Guidance@fda.hhs.gov 
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
September 2023 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAMS ..................................................................................... 3 
A. General Drug Development Considerations ................................................................................ 3 
1. Nonclinical Considerations ............................................................................................................. 3 
2. Biomarker and Diagnostic Device Considerations ......................................................................... 3 
3. Clinical Pharmacology Considerations ........................................................................................... 4 
4. First-in-Human Trials ...................................................................................................................... 5 
5. Early Phase Trials and Dose Optimization ..................................................................................... 6 
6. Drug Combinations .......................................................................................................................... 8 
7. Organ-Specific Systemic Therapies ................................................................................................. 8 
8. Organ-Specific Topical Therapies ................................................................................................... 9 
B. Prevention of GVHD...................................................................................................................... 9 
1. Efficacy Endpoints ........................................................................................................................... 9 
2. Exploratory Trial Considerations .................................................................................................. 10 
3. Pivotal Trial Considerations.......................................................................................................... 12 
C. Treatment of Acute GVHD ......................................................................................................... 15 
1. Efficacy Endpoints ......................................................................................................................... 15 
2. Exploratory Trial Considerations .................................................................................................. 16 
3. Pivotal Trial Considerations.......................................................................................................... 17 
D. Treatment of Chronic GVHD ..................................................................................................... 21 
1.  Efficacy Endpoints ......................................................................................................................... 21 
2.  Exploratory Trial Considerations .................................................................................................. 23 
3.  Pivotal Trial Considerations.......................................................................................................... 24 
IV.  MARKETING APPLICATIONS .................................................................................. 28 
A.    Assessment of Efficacy ............................................................................................................ 28 
B.    Assessment of Safety................................................................................................................ 31 
APPENDICES ............................................................................................................................. 32 
Appendix 1. Example Estimand for Prevention of Graft-versus-Host Disease (GVHD) ........... 32 
Appendix 2. Example Estimand for Treatment of Steroid-Refractory Acute GVHD (aGVHD) 33 
Appendix 3. Example Estimand for Duration of Complete Response (CR) ................................ 34 
Appendix 4. Example Estimand for the First-Line Treatment of Chronic GVHD (cGVHD) ... 35 
Appendix 5. Glossary of Terminology in This Guidance............................................................... 36 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Graft-versus-Host Diseases: Developing Drugs, Biological Products, 
2  and Certain Devices for Prevention or Treatment 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
8  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  The purpose of this guidance is to assist sponsors in the clinical development of drugs,  
18  biological products, therapeutic devices, and cell processing devices2 for the prevention or 
19  treatment of acute graft-versus-host disease (aGVHD) or chronic graft-vs-host disease (cGVHD) 
20  after allogeneic hematopoietic stem cell transplantation (HSCT).3 Specifically, this guidance 
21  addresses FDAs current thinking regarding the overall clinical development program and 
22  critical design elements for early and late phase trials for the intended populations.  
23   
24  This guidance is not intended to provide advice on the technical aspects of therapeutic or       
25  cell-processing devices. For feedback on the technical aspects of these devices, sponsors 
26  should request a presubmission meeting from the appropriate Center.4   
27   
28  This guidance focuses on clinical trial design, statistical analysis, or other issues specific to 
29  aGVHD or cGVHD, and it does not contain a discussion of the general principles regarding 
30  statistical analysis, clinical trial design, or drug development. Those general topics are addressed 
31  in other guidances for industry, including E9 Statistical Principles for Clinical Trials (September 
 
1 This guidance has been prepared by the Division of Hematological Malignancies 1 in the Center for Drug 
Evaluation and Research (CDER) in cooperation with the Oncology Center of Excellence (OCE), the Center for 
Biologics Research and Evaluation (CBER), and the Center for Devices and Radiological Health (CDRH) at the 
Food and Drug Administration.  
 
2 For the purposes of this guidance, references to drugs include both human drug products and biological drug 
products regulated by CDER and CBER, unless otherwise specified. 
 
3 GVHD may also arise in other settings, such as after blood transfusions or after solid organ transplantation.  
GVHD in settings other than allogeneic HSCT are outside the scope of this guidance. For example, blood irradiators 
identified by product code MOT are outside the scope of this guidance.   
 
4 See the guidance for industry and FDA staff Requests for Feedback and Meetings for Medical Device Submissions: 
The Q-Submission Program (June 2023). We update guidances periodically. For the most recent version of a 
guidance, check the FDA guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
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Draft  Not for Implementation 
32  1998), E10 Choice of Control Group and Related Issues in Clinical Trials (May 2001), and draft 
33  guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
34  Biological Products (December 2019), respectively.5 Lastly, this guidance addresses only those 
35  clinical pharmacology issues that would require specific consideration for drugs intended to 
36  prevent or treat aGVHD or cGVHD.  
37   
38  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
39  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
40  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
41  the word should in Agency guidances means that something is suggested or recommended, but 
42  not required. 
43   
44   
45  II.  BACKGROUND 
46   
47  Acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD) are 
48  clinical syndromes that may arise after HSCT as a result of immunocompetent donor cells 
49  recognizing and reacting to disparity with major or minor histocompatibility antigens on 
50  recipient tissues. aGVHD has an acute onset and rapidly progressive course manifested as an 
51  inflammatory skin rash, elevated bilirubin, and enteritis with nausea and diarrhea; it generally 
52  occurs early after transplantation. cGVHD is marked by a more protracted course with chronic 
53  inflammation and/or fibrosis primarily affecting the skin, liver, lungs, and mucosal surfaces; it 
54  generally occurs months after transplantation.   
55   
56  The classical approach to prevention of GVHD involves pharmacological or physical methods 
57  to deplete alloreactive T cells in the immediate peritransplant setting with or without additional 
58  drugs to prevent activation of naive T cells. Should aGVHD or cGVHD occur despite these 
59  measures, treatment has depended largely on drugs that impair T cells. Major complications of 
60  such profound immunosuppression include serious infections and loss of immunological control 
61  of the underlying malignancy. Further basic science investigations have elucidated the molecular 
62  mechanisms behind the clinical manifestations of aGVHD and cGVHD, including cytokines, the 
63  innate immune system, and components of the adaptive immune system other than T cells. These 
64  scientific advances have provided opportunities for development of biomarkers to identify the 
65  specific immune dysfunction present in an individual patient and for development of drugs to 
66  modulate the immune system with precision rather than to just suppress the immune system 
67  broadly.  
68   
69  FDA has previously discussed the challenges with clinical trial design and endpoints for 
70  prevention of GVHD and for treatment of aGVHD in a public workshop6 and has worked with 
 
5 When final, this guidance will represent the FDAs current thinking on this topic.  
 
6 Workshop on Clinical Trial Endpoints for Acute Graft-vs-Host Disease after Allogeneic Hematopoietic Stem Cell 
Transplantation held on May 19, 2009, in conjunction with the National Heart, Lung, and Blood Institute (NHLBI), 
National Cancer Institute (NCI), Center for International Blood and Marrow Transplant Research (CIBMTR), 
American Society for Blood and Marrow Transplantation (ASBMT), and National Institute of Allergy and 
Infectious Diseases (NIAID). 
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71  stakeholders regarding clinical trial design and endpoints for treatment of cGVHD.7 Given the 
72  complexity of the clinical manifestation of aGVHD and cGVHD and the potential for a paradigm 
73  shift in the management of GVHD, FDA is providing this guidance with recommendations 
74  regarding the design and conduct of clinical trials and the types of supporting data that could 
75  facilitate efficient development of drugs and/or certain devices for the prevention or treatment of 
76  aGVHD or cGVHD.   
77   
78   
79  III.  DEVELOPMENT PROGRAMS 
80   
81  A.  General Drug Development Considerations 
82   
83  1.  Nonclinical Considerations 
84   
85    As aGVHD and cGVHD are serious and life-threatening diseases, the 
86  recommendations for nonclinical programs described in the guidances for industry S9 
87  Nonclinical Evaluation for Anticancer Pharmaceuticals (March 2010), S9 
88  Nonclinical Evaluation for Anticancer Pharmaceuticals  Questions and Answers 
89  (March 2010), and Severely Debilitating or Life-Threatening Hematologic Disorders: 
90  Nonclinical Development of Pharmaceuticals (March 2019) are generally applicable. 
91   
92    For cellular or gene therapy products being developed for prevention or treatment of 
93  GVHD, also refer to the guidances for industry, Preclinical Assessment of 
94  Investigational Cellular and Gene Therapy Products (November 2013) and Long 
95  Term Follow-Up After Administration of Human Gene Therapy Products (January 
96  2020). 
97   
98  2.  Biomarker and Diagnostic Device Considerations 
99   
100    Sponsors intending to use a GVHD biomarker for regulatory purposes, including as 
101  an efficacy endpoint, may obtain feedback from FDA on the clinical validity and 
102  analytical validity of the proposed biomarker by requesting a Type C meeting.8 
103  Sponsor may also obtain feedback from FDA through the formal drug development 
104  tool (DDT) qualification process.9  
105   
106   
 
7 Martin, PJ, SJ Lee, D Przepiorka, MM Horowitz, J Koreth, GB Vogelsang, I Walker, PA Carpenter, LM Griffith, 
G Akpek, M Mohty, D Wolff, SZ Pavletic, and CS Cutler, 2015, National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical 
Trial Design Working Group Report, Biol Blood Marrow Transplant, 21(8):1343-1359.  
 
8 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (September 2023). When final, this guidance will represent the FDAs current thinking on this topic. 
 
9 For additional information on the DDT qualification process, see the DDT Qualification Programs web page at 
www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/default.htm and 
the guidance for industry and FDA staff Qualification Process for Drug Development Tools (November 2020). 
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107    For drugs developed in a population selected on the basis of a biomarker of disease 
108  activity, an in vitro companion diagnostic device (referred to as a "companion 
109  diagnostic" herein) may be needed. A companion diagnostic is an in vitro diagnostic 
110  device (IVD) that provides information that is essential for the safe and effective 
111  use of the drug.10 IVDs used in clinical trials of a drug will generally be considered 
112  investigational devices, subject to applicable regulations,11 unless employed for an 
113  intended use for which the device is already cleared or approved. Drug sponsors of 
114  trials that utilize IVDs may request a study risk determination directly from Center 
115  for Devices and Radiological Health (CDRH) or the Center for Biologics Evaluation 
116  and Research (CBER) as appropriate, or in concert with the Investigational New Drug 
117  application (IND),12,13 to determine whether an Investigational Device Exemption 
118  (IDE) is needed for the proposed trial to proceed under the IND. Sponsors may also 
119  consult CDRH or CBER as appropriate through a presubmission to obtain advice on 
120  codevelopment of a companion diagnostic with a therapeutic product.14 
121   
122  3.  Clinical Pharmacology Considerations 
123   
124    Patients with GVHD are commonly prescribed concomitant medications, such as 
125  antifungal agents or other immunosuppressants, that are substrates, inducers, or 
126  inhibitors of cytochrome P450 (CYP) enzymes, other metabolizing enzymes, or 
127  transporters.   
128   
129    Sponsors should conduct in vitro metabolism studies to determine if a new 
130  GVHD drug is a substrate, inhibitor, or inducer of CYP3A or transporters (e.g., 
131  P-glycoprotein [P-gp], organic anion-transporting polypeptide [OATP]) prior to 
132  conducting the first clinical trial in patients with GVHD in order to better inform 
133  dose selection in the presence and absence of these agents.15   
134   
135    Sponsors should assess the in vitro ability of new GVHD drugs to act as a 
136  substrate or as a perpetrator of other metabolizing enzymes or transporters early 
137  in clinical development and to incorporate strategies for dose modifications in 
 
10 See the guidance for industry and FDA staff In Vitro Companion Diagnostic Devices (August 2014). 
 
11 See 21 CFR 812, 21 CFR 50, and 21 CFR 56 for applicable regulations. 
 
12 See the guidance for industry and FDA staff Requests for Feedback and Meetings for Medical Device 
Submissions: The Q-Submission Program (June 2023).  
 
13 See the guidance for industry Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission 
Process for Study Risk Determination (October 2019).  
 
14 See the draft guidance for industry and FDA staff Principles for Codevelopment of an In Vitro Companion 
Diagnostic Device with a Therapeutic Product (July 2016). When final, this guidance will represent the FDAs 
current thinking on this topic. 
 
15 See the guidance for industry In Vitro Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions (January 2020). 
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138  clinical trials as warranted if interactions are expected. Additional clinical      
139  drug-drug interactions trials may be needed based on the in vitro results. 
140   
141    Patients with GVHD may have organ impairment due to concurrent medications 
142  that affect renal or hepatic function (e.g., calcineurin inhibitors and high-dose 
143  chemotherapy, respectively) or due to liver involvement by GVHD. Sponsors should 
144  identify elimination pathways of the parent drug and its active metabolites early in 
145  drug development, and if renal or hepatic elimination pathways are identified, the 
146  sponsor should characterize the impact of organ impairment on the pharmacokinetics 
147  (PK) of the parent drug and active metabolites.16 The impact of GVHD liver 
148  involvement on the PK of the parent drug or active metabolites should also be 
149  evaluated (e.g., population PK analysis).17 Dose modifications for renal or hepatic 
150  impairment and for GVHD liver involvement should be included in late phase clinical 
151  trials.  
152   
153    Although patients are presumed to be immunocompromised after HSCT, antibody 
154  responses may still occur. For biological products, the sponsor should characterize the 
155  development of anti-drug antibodies to the new GVHD drug.18 
156   
157  4.  First-in-Human Trials 
158   
159    The purpose of the first-in-human (FIH) trial is to identify the recommended phase 2 
160  dose (RP2D) or the range of doses of a new investigational drug to be taken further 
161  into clinical development based on PK and pharmacodynamic (PD) data, clinical 
162  activity measures, clinical safety data, and tolerability. For additional information on 
163  FIH trials by GVHD indication, see Sections III.B.2, III.C.2, and III.D.2 
164   
165    An accurate characterization of the new investigational drug may be limited when the 
166  study population has a high background rate of adverse events or when there are 
167  concurrent medications (e.g., preparative regimen, other immunosuppressive drugs, 
168  supportive care drugs, etc.) that may affect the PK, PD, or clinical activity. An FIH 
169  trial in healthy volunteers may be an alternative in select cases. 
170   
171    For the FIH trial, a single-ascending dose (SAD) study, and potentially a 
172  subsequent multiple-ascending dose (MAD) study, in healthy volunteers may be 
173  considered for drugs that are immunomodulatory, immunosuppressive, or that 
174  stimulate tissue repair, depending on the mechanism of action, expected 
 
16 See the draft guidance for industry Pharmacokinetics in Patients with Impaired Renal Function  Study Design, 
Data Analysis, and Impact on Dosing and Labeling (September 2020; when final, this guidance will represent 
FDAs current thinking on this topic) and the guidance for industry Pharmacokinetics in Patients with Impaired 
Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling (May 2003). 
 
17 Ibid.  
 
18 See the guidances for industry Immunogenicity Testing of Therapeutic Protein Products  Developing and 
Validating Assays for Anti-Drug Antibody Detection (February 2019) and Immunogenicity Assessment for 
Therapeutic Protein Products (August 2014). 
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175  biological effect, and anticipated exposure duration. FDA recommends that 
176  sponsors request feedback on the design of FIH trials of new GVHD drugs in 
177  healthy volunteers, including the limitations in exposure and other restrictions 
178  needed to protect the study participants. 
179   
180    Note that due to differences in the constitution of the immune system in healthy 
181  volunteers, patients after allogeneic HSCT, and patients with aGVHD or with 
182  cGVHD, it is likely that an FIH trial in healthy volunteers will provide only a 
183  range of doses suitable for further study in patients with GVHD rather than a 
184  RP2D. Nonetheless, narrowing the dose range in this way may accelerate 
185  development in the intended population. 
186   
187  5.  Early Phase Trials and Dose Optimization 
188   
189    Sponsors should consider that lymphocyte homeostasis in patients after HSCT, 
190  especially those with active aGVHD or cGVHD, may differ from that in healthy 
191  volunteers or patients with other immunological disorders. As such, when selecting 
192  the starting dose for the clinical trial, the RP2D cannot be assumed to be the same in 
193  all populations.   
194   
195    Since the treatment objective is to prevent GVHD or to ameliorate the signs and 
196  symptoms of active aGVHD or cGVHD, substantial toxicity from the study agent 
197  should be avoided and escalation to the maximal tolerated dose (MTD) may not be 
198  warranted if adequate pharmacological activity occurs at a lower dose. The criteria to 
199  be used for selecting the RP2D should be contemplated when designing the dose 
200  escalation rules. Ideally, dose escalation would be guided by a target drug level or 
201  biomarker rather than toxicity alone. Monitoring for dose-limiting toxicities (DLTs) 
202  is still needed in case the MTD is reached before the optimal biological dose (OBD) 
203  is found.    
204   
205    In the absence of an in vitro correlate with efficacy for use as a pharmacodynamic 
206  biomarker in the dose escalation rules, the dose-escalation trial for prevention or 
207  treatment of GVHD may benefit from a control arm or may need larger cohorts than 
208  used in a typical dose-escalation design (e.g., 3+3 design) in order to generate 
209  sufficient data to select an OBD.  
210    
211    If choosing to expand or back-fill cohorts in the dose-escalation trial, include the 
212  criteria to be used to select the dose levels to be expanded.   
213   
214    Dose optimization may also be pursued using randomization between doses. For 
215  such studies, the cohorts should be large enough to generate sufficient data for 
216  exposure-response analyses and need not be designed for formal statistical 
217  comparisons of arms for efficacy.   
218   
219    Large single-arm expansion cohorts solely for exploratory purposes are 
220  discouraged. Any large single-arm trial should have a design based on clear 
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221  hypothesis testing, and the protocol should include justification of the sample size 
222  proposed. 
223   
224    The dose and schedule of investigational new GVHD drugs should be optimized in 
225  the early phase trials before initiating the pivotal trials.  
226   
227    Clinical PK and PD data, clinical activity measures, clinical safety data, and 
228  nonclinical pharmacology data should be used to conduct integrated               
229  dose-response and exposure-response analyses for activity and safety for dose 
230  optimization.   
231   
232    Sponsors should evaluate clinical data over a range of dosages and in a sufficient 
233  number of patients with adequate duration of follow up to characterize the dose- 
234  and exposure-response relationships for efficacy, safety, and PD markers to 
235  support the optimal dosage(s) for further clinical development. 
236   
237    Dose-escalation trials with small cohorts may provide information to warrant 
238  further dose exploration in dose-expansion cohorts (e.g., exploration of a 
239  minimum of 2 dose levels with at least 20 participants per dose level) and/or in a 
240  randomized dosage-finding trial to generate the additional data needed for dose 
241  optimization. These trials need not be powered to demonstrate significant 
242  differences in efficacy by dose.   
243   
244    For drugs intended for administration for multiple cycles, and especially for drugs 
245  given long-term on an outpatient basis, tolerability should be taken into 
246  consideration when choosing the dose to be used in the pivotal trial. In general, 
247  for drugs intended for long-term administration or over multiple cycles, it is 
248  expected that dose modifications or discontinuations for adverse reactions are 
249  limited (e.g., at least 80% dose intensity is achieved over multiple cycles for at 
250  least 80% of the patients). 
251   
252    If long-term treatment in the early phase trial is anticipated, the sponsor should 
253  provide early study stopping criteria to ensure that accrual does not continue when 
254  there is evidence of unacceptable late toxicity. The study protocol should specify 
255  the criteria for excess toxicity, the actual bounds for stopping, the basis for the 
256  assumptions used in the calculation, and the software/program used to calculate 
257  the bounds. The assumptions for the bounds should be based on a toxicity rate that is 
258  generally observed for the study population. 
259   
260    In addition to dose, these early phase trials may also be used to assess other aspects of 
261  the treatment regimen, such as the optimal duration of therapy. 
262   
263    If a therapeutic drug monitoring (TDM) device is needed for safe use of a drug, 
264  codevelopment of the TDM device should begin as early as possible in the clinical 
265  development timeline. 
266   
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267    For additional information on early phase trials by GVHD indication, see Sections 
268  III.B.2, III.C.2, and III.D.2. 
269   
270  6.  Drug Combinations 
271   
272    For testing a new drug as an add-on to an existing drug or standard drug combination 
273  for prevention or treatment of GVHD, the submission should include justification for 
274  the add-on strategy, including but not limited to a discussion of whether the drugs' 
275  mechanisms of action are complementary or potentially antagonistic, whether the 
276  patients in the trial were selected based on a specific immune dysfunction targeted by 
277  the new drug, whether the combination poses additional risks due to an increase in the 
278  degree of immunosuppression, and dosage optimization for the combination.  
279   
280    Protocols for treatment of aGVHD or cGVHD should include instructions on whether 
281  GVHD prophylaxis should be continued when the new drug for treatment is started 
282  and whether prior drugs used for treatment of either aGVHD or cGVHD should be 
283  stopped or continued. In general, in the absence of a scientific rationale, drugs that 
284  failed as prior treatment of aGVHD or cGVHD should be discontinued, and the 
285  patients should be receiving the fewest number of immunosuppressive therapies 
286  concurrently.  
287   
288  7.  Organ-Specific Systemic Therapies 
289   
290    Organ-specific therapies have systemic exposure and mechanistically target the 
291  initiating event, effector mechanism, or tissue regeneration solely in a single organ 
292  (e.g., the small intestine) or in multiple related organs (e.g., the GI tract).   
293   
294    Due to their limited functionality, organ-specific systemic therapies are likely to be 
295  developed in combinations with other drugs in order to assure success in aGVHD or 
296  cGVHD which affect multi-organs. See Section III.A.4 for caveats regarding 
297  combinations of drugs for prevention or treatment of GVHD. 
298   
299    The clinical trial designs discussed in Sections III.B, III.C, and III.D apply to 
300  development of systemically-administered organ-specific therapies. Note, however, 
301  that even when an organ-specific claim is being sought, the assessment of any    
302  organ-specific benefit should be in addition to a GVHD-free survival (GFS), rather 
303  than in lieu of it. For example, in a clinical trial of a treatment to prevent lower GI 
304  aGVHD, GFS should be tested as an efficacy endpoint as well as lower GI     
305  aGVHD-free survival. Whether demonstration of an organ-specific effect in the 
306  absence of impact on the overall GVHD outcome would be sufficient to support a 
307  marketing application will be a review issue. Additional evidence of benefit, such as 
308  patient-reported outcomes, may be needed to conclude that the benefit-risk is 
309  favorable. 
310   
311   
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312  8.  Organ-Specific Topical Therapies 
313   
314    The objective of topical palliative therapies is to provide local symptomatic relief 
315  without systemic drug exposure. This guidance does not address clinical trial design 
316  for topical palliative treatments for aGVHD or cGVHD that are intended to purely 
317  provide symptomatic relief and are not disease-modifying. For advice on developing 
318  a topical palliative treatment specifically for aGVHD or cGVHD, sponsors should 
319  contact the relevant FDA review Division (e.g., Division of Ophthalmology for 
320  topical treatments of ocular GVHD). 
321   
322  B.  Prevention of GVHD 
323   
324  1.  Efficacy Endpoints  
325   
326  a.  GVHD-Free Survival (GFS) 
327   
328    GFS is the time from date of HSCT to date of onset of a GVHD event or death from 
329  any cause (see examples below). For this endpoint, GVHD should be diagnosed and 
330  graded or scored using valid criteria.19 The GVHD event depends on the indication 
331  being sought. The following are examples:  
332   
333    Grades 2-4 aGVHD GFS: From date of HSCT to first occurrence of Grades 2-4 
334  aGVHD with follow-up through 180 days post HSCT or death 
335   
336    Grades 3-4 aGVHD GFS: From date of HSCT to first occurrence of Grades 3-4 
337  aGVHD with follow-up through 180 days post HSCT or death 
338   
339    Moderate-to-severe cGVHD GFS: From date of HSCT to first occurrence of 
340  moderate-to-severe cGVHD with follow-up through 24 months post HSCT or 
341  death 
342   
343    Acute and chronic GVHD GFS: From date of HSCT to first occurrence of Grades 
344  2-4 aGVHD or moderate-to-severe cGVHD with follow-up through 24 months 
345  post HSCT or death 
346   
 
19 For examples of diagnostic and staging or scoring criteria that FDA has accepted in marketing applications, see 
Harris, AC, R Young, S Devine, WJ Hogan, F Ayuk, U Bunworasate, C Chanswangphuwana, YA Efebera, E 
Holler, M Litzow, R Ordemann, M Qayed, AS Renteria, R Reshef, M Wolfl, YB Chen, S Goldstein, M Jagasia, F 
Locatelli, S Mielke, D Porter, T Schechter, Z Shekhovtsova, JL Ferrara, and JE Levine, 2016, International, 
Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount 
Sinai Acute GVHD International Consortium, Biol Blood Marrow Transplant, 22(1):4-10; and Lee, SJ, D Wolff, C 
Kitko, J Koreth, Y Inamoto, M Jagasia, J Pidala, A Olivieri, PJ Martin, D Przepiorka, I Pusic, F Dignan, SA 
Mitchell, A Lawitschka, D Jacobsohn, AM Hall, ME Flowers, KR Schultz, G Vogelsang, and S Pavletic, 2015, 
Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response 
Criteria Working Group Report, Biol Blood Marrow Transplant, 21(6):984-999. 
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347    See Appendix 1 for an example estimand for Grades 2-4 aGVHD GFS. 
348  Supplementary analyses may include using the hypothetical strategy (censoring) at 
349  the time of graft rejection or relapse. 
350   
351    The planned interval between assessments should be as short as possible in order to 
352  ensure that the metric is reliable. For example, monitoring for aGVHD may require 
353  assessments weekly through Day 100 and every 4 weeks through Day 180, and 
354  monitoring for cGVHD may require assessments at least every 4 weeks. The protocol 
355  should specify that the study visit activities should encompass events in the 
356  intervening period since the last visit. Optimally, an unscheduled visit should be used 
357  to collect data on events occurring between scheduled visits. 
358   
359    To prevent bias in study conduct, the use of blinded treatments where feasible is 
360  recommended for randomized trials that assess GFS.   
361   
362    The credibility of the GFS endpoint is highly dependent on the completeness of the 
363  data, and efforts should be made to minimize missing data. The statistical analysis 
364  plan (SAP) should include a plan for addressing missing data.   
365   
366    For evaluation of GFS, the primary analysis set consists of all patients who received 
367  the allograft. With respect to the primary hypothesis testing method, FDA has 
368  accepted the log-rank test. Additional summary metrics that should be reported 
369  include the hazard ratio and 95% confidence interval. 
370   
371  b.  Overall Survival (OS) 
372   
373    OS is defined as the time from randomization to death from any cause. For evaluation 
374  of OS, the primary analysis set consists of all randomized subjects. With respect to 
375  the primary hypothesis testing method, FDA has accepted the log-rank test. 
376  Additional summary metrics that should be reported include the hazard ratio and 95% 
377  confidence interval.   
378   
379    We recommend including a supplementary analysis of OS using OS defined as the 
380  time from the date of HSCT (instead of the date of randomization) to death from any 
381  cause. 
382   
383  2.  Exploratory Trial Considerations   
384   
385  a.  Initial Dose-Escalation Trials 
386   
387    An FIH trial of a new investigational drug for prevention of GVHD is rarely 
388  acceptable. An example of an exception could be for a cell therapy unsuitable for 
389  study in a less complex population and where there is no scientific justification for 
390  study of the cell therapy outside of the HSCT setting. See additional information in 
391  Section III.A.4. 
392   
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393    See Section III.B.3 for caveats regarding patient-related and transplant-related factors 
394  to consider when designing an exploratory trial for GVHD prophylaxis. These factors 
395  may affect the observed adverse effects at any given dose level, so for single-arm 
396  dose-escalation trials in particular, substantial heterogeneity in these factors may 
397  preclude conclusions about dose-related toxicity.   
398   
399    For the initial dose-escalation trial: 
400   
401    The patient population should be commensurate with the risk. In general, patients 
402  with a good prognosis using standard-of-care (SOC) transplantation procedures 
403  (e.g., acute leukemia in first remission or a lower-risk myelodysplastic syndrome 
404  with a human leukocyte antigen [HLA]-identical sibling donor) would not be 
405  appropriate for inclusion when preliminary evidence of efficacy has not yet been 
406  established or there is a known serious risk with the investigational drug.   
407   
408    The observation period for DLTs should be at least 28 days. For drugs with a 
409  known or expected delayed onset of adverse events or with a prolonged half-life, 
410  a longer observation period may be needed. For regimens that begin prior to 
411  transplantation and extend for several months, the DLT observation period should 
412  include the period of peak regimen-related toxicity (from start of therapy through 
413  Transplant Day 28) and at least an additional 28 days after that period (total 56 
414  days).  
415   
416    As GVHD prophylaxis is supportive care, the target regimen should have little 
417  moderate toxicity and no severe toxicity. Anticipated adverse reactions may be 
418  informed by nonclinical studies, the FIH study in healthy volunteers, and trials in 
419  other diseases. However, given that the toxicities of the investigational drug may 
420  overlap with those of the preparative regimen, or that the investigational drug may 
421  exacerbate toxicities of the preparative regimen, attribution may not be possible.  
422  Therefore, the assessment of DLTs should reflect the need to not increase the risk 
423  of known toxicities in transplant recipients. The sponsor should identify the 
424  incidence of such toxicities with the background preparative regimen and plan the 
425  doseescalation rule based on that incidence. For example, the 3+3                  
426  dose-escalation rule may still apply if the DLT criteria are defined as Common 
427  Terminology Criteria for Adverse Events (CTCAE) Grade 45 organ toxicities on 
428  Transplant Days 0-28. 
429   
430  b.  Dose Optimization and Signal Verification 
431   
432    For trials used for dose selection and efficacy signal verification: 
433   
434    Due to the impact of many concurrent factors on the occurrence of GVHD and on 
435  survival after transplantation (see Section III.B.3), and due to the uncertainty 
436  regarding the natural history of GVHD in populations expected to be included in 
437  pre-emption trials, historical control data may not be suitable to support design of 
438  a single-arm GVHD prevention trial, especially if small treatment effects are 
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439  being tested. Consequently, prevention trials beyond the initial dose-escalation 
440  phase should generally include a randomized control arm. Adaptive phase 2-3 
441  studies may also be considered.20 In certain circumstances, randomization among 
442  a wide range of doses would also be acceptable.  
443   
444    See Section III.A.5 for additional considerations for dose optimization. 
445   
446    As randomized exploratory trials are generally too small and too short in duration for 
447  comparative analyses of a time-to-event efficacy endpoint like GFS, one might 
448  instead use a short-term binary measure of activity, such as alive without prior Grades 
449  2-4 acute GVHD on Transplant Day 100. The incidence of Grades 2-4 acute GVHD 
450  calculated by the cumulative incidence function is generally less credible due to 
451  inconsistent rates of competing risks. We consider that such endpoints are exploratory 
452  only and would not be suitable as the basis for efficacy in a marketing application.   
453   
454    Early nonrelapse mortality (NRM) (e.g., prior to 100 days after HSCT) is used 
455  commonly in the study stopping rule for safety issues in clinical trials for GVHD, but 
456  this metric alone is not sufficient for safety monitoring when there is still uncertainty 
457  in the safety profile. Additional potential safety outcomes to monitor would include 
458  adverse reactions as defined in the DLT criteria, graft failure, and specific infections. 
459  Stopping bounds should be based on the known incidence of these events using the 
460  SOC or the same treatment plan without the investigational drug in the same patient 
461  population. It is also important to consider monitoring the need for dose reductions or 
462  withdrawals due to adverse reactions; for example, a rate of dose reduction or 
463  withdrawal greater than 20% may indicate that the dose is too toxic. 
464    
465  3.  Pivotal Trial Considerations 
466   
467  a.  Indications and Intended Populations 
468   
469    GVHD prevention trials include studies of prophylaxis and studies of pre-emptive 
470  therapy. 
471     
472    GVHD prophylaxis for HLA-identical related donor HSCT and for matched 
473  unrelated donor or other alternative donor HSCT are considered separate 
474  indications. Marketing applications seeking both indications should include a trial 
475  designed to generate data sufficient to test efficacy in each indication individually 
476  or separate trials for each indication.  
477   
478    Pre-emptive therapy for a selected population with subclinical but no active 
479  GVHD and pre-emptive therapy to prevent worsening of GVHD from a lower 
480  severity to a higher severity are considered separate indications. 
481   
 
20 See the guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics (December 2019).  
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482  b.  Establishing Clinical Benefit 
483   
484    GFS is the clinical endpoint that represents clinical benefit for traditional approval for 
485  drugs or devices for prevention of GVHD. OS may be used as the primary endpoint, 
486  but as there are multiple potential root causes of death after HSCT, OS itself may not 
487  be sufficient to establish a treatment effect with regard to prevention of GVHD, so if 
488  OS is chosen as the primary endpoint in the pivotal trial to support a marketing 
489  application for prevention of GVHD, analysis of GFS should still be planned.   
490   
491  c.  Pivotal Trial Design 
492   
493    Pivotal trials to support a marketing application for prevention of GVHD should be 
494  randomized controlled trials. Although such trials generally seek to demonstrate 
495  superiority of the arm with the new investigational arm, noninferiority trials may be 
496  considered for populations where the expected GFS is high with SOC regimens, 
497  especially if the new investigational drug is expected to improve safety or 
498  compliance. 
499   
500    The first pivotal trial for a new GVHD indication should be designed to isolate the 
501  treatment effect of the investigational drug.   
502   
503    Add-on designs and head-to-head comparisons are both appropriate for this 
504  setting (see Appendix 5 Glossary for trial design definitions). 
505   
506    For add-on designs, the protocol should use a specific base regimen rather than 
507  allowing investigator's choice. For example, because the effectiveness differs for 
508  different calcineurin inhibitors (CNI), a study of Drug A plus investigator's choice 
509  of CNI versus investigator's choice of CNI alone would not be adequate to isolate 
510  the treatment effect of Drug A. Instead, the specific CNI to be used should be 
511  identified in the protocol.  
512   
513    Comparative effectiveness trial designs may be suitable for supplementary indications 
514  if the contribution of the drug to the treatment effect was established in a prior trial.  
515   
516  d.  Patient and Transplant-Related Factors 
517   
518    Critical patient-related factors that may impact the risk of GVHD or the survival 
519  component of the efficacy endpoint (GFS) should be taken into consideration when 
520  determining the eligibility criteria for the trial that will support a marketing 
521  application.  
522   
523    The eligible population should have sufficient expected survival to allow an 
524  adequate follow-up for assessment of GVHD. A good prognosis subgroup (e.g., 
525  acute leukemia in first remission) would have the least potential for refractory 
526  leukemia or early relapse confounding the assessment of GFS. 
527   
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528    Pediatric patients are known to have a lower risk of GVHD than adults. If a 
529  clinical trial includes both adult and pediatric patients, randomization should be 
530  stratified by age group.   
531   
532    Critical transplant-related factors that may impact the risk of GVHD or the survival 
533  component of the efficacy endpoint (GFS) should be taken into consideration when 
534  determining the treatment plan for the trial that will support a marketing application.  
535   
536    The stem cell source may affect the risk of GFS. If the clinical trial allows use of 
537  either peripheral blood or marrow stem cells, this should be taken into account at 
538  randomization or at analysis.   
539   
540    The preparative regimen may affect the risk of relapse and the survival 
541  component of GFS. The use of long-acting biologics (such as antithymocyte 
542  globulin or anti-CD20 monoclonal antibodies) may affect the risk of GVHD. 
543  Ideally, the trial should include a single preparative regimen. If regimens of 
544  differing intensity are used, or if the preparative regimen includes a biologic that 
545  interacts with the infused stem cells, this should be justified, and there should be a 
546  plan to account for this at randomization or at analysis.  
547   
548  e.  Treatment Plan 
549   
550    The instructions for the complete GVHD prevention strategy should be detailed in the 
551  protocol.  
552   
553    See Sections III.A.4 and III.B.2 for information regarding optimization of the 
554  GVHD prevention strategy prior to conduct of the trial that will support a 
555  marketing application.   
556   
557    When using an SOC base regimen, the dose, administration schedule, and dose 
558  modifications for the drugs in the SOC regimen should be included in the protocol 
559  to reduce the chance that assessment of the treatment effect of the investigational 
560  drug is not confounded by clinical site-specific differences in use of the SOC 
561  regimen. 
562   
563    Differences in handling early treatment of aGVHD may affect subsequent 
564  occurrence of high grade aGVHD or onset of cGVHD. Include in the protocol the 
565  minimum recommended first-line treatment for aGVHD that may occur, so that 
566  differences in efficacy measures between treatment arms are not inadvertently 
567  impacted by differences in early aGVHD treatment.   
568   
569    Include in the protocol the recommended schedule of discontinuation or tapering 
570  for the investigational drug and for any SOC drugs in the regimen. 
571   
572   
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573  f.  Marketing Applications 
574   
575    See Section IV for special data collection considerations for the pivotal trial. 
576   
577  C.  Treatment of Acute GVHD 
578   
579  1.  Efficacy Endpoints 
580   
581  a.  Response 
582   
583    For documentation of response to treatment of aGVHD, FDA has accepted the 
584  definitions below with the response assessment conducted following 4 weeks of 
585  therapy (e.g., at the Day-29 visit) and using valid staging criteria for aGVHD.21  
586   
587    Complete Response (CR): Stage 0 in all organs (skin, liver, and GI tract) and no 
588  intervening additional therapy  
589   
590    Partial Response (PR): Improvement of at least 1 stage in 1 or more organs 
591  without progression in other organs, and no intervening additional therapy 
592   
593    Very Good Partial Response (VGPR): Improvement by at least one stage in one 
594  or more organs and 
595   
596    Skin: No rash or bullae, and residual erythema limited to <25% of the body 
597  surface, and 
598   
599    Liver: Total serum bilirubin concentration <2 mg/dL or <25 % of baseline at 
600  enrollment, and 
601   
602    Gut: Tolerating food or enteral feeding, predominantly formed stools, no overt 
603  gastrointestinal bleeding or abdominal cramping, no more than occasional 
604  nausea or vomiting, and 
605   
606    No intervening additional therapy 
607   
608    See Appendix 2 for an example estimand for treatment of aGVHD. 
609   
610    A minimum of 180 days of follow-up is required to establish durability of responses. 
611  The planned interval between assessments should be no less frequently than weekly 
612  for the first 8 weeks and at least monthly thereafter through Study Day 180. The 
613  protocol should specify that the study visit activities should encompass events in the 
614  intervening period since the last visit.  
615   
 
21 See footnote 19.  
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616    There are two measures of durability of the response as defined below. Both measures 
617  of durability of response are of interest for the evaluation of clinical benefit. 
618   
619    Duration of response (DOR) is defined as the time from the Day 28 response to 
620  the day of progression,22 new systemic therapy for aGVHD,23 or death from any 
621  cause, whichever occurs first. See Appendix 3 for an example estimand for 
622  duration of CR. 
623   
624    An additional measure of durability that considers the natural history of aGVHD, 
625  which may flare and resolve without additional systemic treatment, is defined as 
626  the time from the Day 28 response to the day of new systemic therapy for 
627  aGVHD or death from any cause, whichever occurs first.  
628   
629    For the evaluation of response in randomized trials, the analysis set consists of all 
630  randomized patients. In single-arm trials, the analysis set is all patients who received 
631  any dose of study drug. The proportions of subjects achieving response and 95% 
632  confidence intervals should be reported. For a randomized trial, the primary analysis 
633  should use the difference in proportions to quantify the treatment effect.  
634   
635    For the adjudication of response at Study Day 28, missing data is considered a failure. 
636  For the adjudication of DOR, the SAP should include a plan for addressing missing 
637  data.  
638   
639  b.  Overall Survival (OS) 
640   
641    See Section III.B.1.b. for the definition of OS.  
642   
643  2.  Exploratory Trial Considerations 
644   
645  a.  Initial Dose-Escalation Trials 
646   
647    Conducting an FIH trial in patients with active aGVHD, a life-threatening disease, 
648  is discouraged; the doses used in the first cohorts may be subtherapeutic, and the 
649  assessment of toxicity may be confounded by adverse events due to the underlying 
650  GVHD or concomitant medications. If the product characteristics preclude study in an 
651  alternative population (see Section III.A.4), sponsors should consider a SAD window 
652  study in patients with aGVHD to identify a pharmacologically-active dose before 
653  commencing a MAD trial in this population.  
654   
655    See Section III.C.3 for caveats regarding disease-related and treatment-related factors 
656  to consider when designing an exploratory trial for treatment of aGVHD.  
 
22 Progression is defined as worsening by one stage from nadir in any organ without improvement in other organs in 
comparison with the prior response. 
 
23 For the purposes of assessing DOR, new systemic therapy is defined as any new systemic treatment for aGVHD 
or an increase in the dose of corticosteroids to methylprednisolone equivalent (MPE) 2 mg/kg (10%) or more. 
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657    The patient population should be commensurate with the risk.  
658   
659    The benefit-risk assessment of a new drug that has a moderate degree of adverse 
660  events without preliminary evidence of activity for aGVHD may not be 
661  appropriate to study in patients with the least severe aGVHD who have a 
662  high response rate with topical therapy or first-line systemic corticosteroids alone. 
663   
664    Until the safety profile of the drug is better known, enrollment into early phase 
665  exploratory studies should be limited to patients who have achieved                
666  post-transplant neutrophil recovery.  
667   
668    Dose escalation decision rules should take into consideration the need to minimize 
669  Grade 2 organ toxicities and avoiding any Grade 3 or higher toxicities.   
670   
671    Trials to treat aGVHD would be expected to have a limited duration of treatment. 
672  Sponsors should specify the duration of treatment (e.g., to time of resolution of 
673  aGVHD) in the protocol. When treatment in the dose-escalation trial is planned 
674  to extend beyond Day 28, a rationale should be provided for the proposed duration of 
675  treatment. For patients who are taken off the investigational drug after achieving a 
676  CR, the protocol may also address retreatment in case of recurrence of aGVHD. 
677   
678  b.  Dose Optimization and Signal Verification 
679   
680    Response is the appropriate efficacy endpoint in exploratory trials of aGVHD 
681  treatments. For additional information, see Section III.C.3.  
682   
683    The effects of the study drug in patients on steroids alone and in those on steroids 
684  plus a CNI or another systemic immunosuppressant medication should be tested. 
685   
686    See Section III.A.5 for additional considerations for dose optimization. 
687   
688  3.  Pivotal Trial Considerations 
689   
690  a.  Indications and Intended Populations 
691   
692    First-line therapy for aGVHD, therapy for steroid-refractory aGVHD (SR-aGVHD), 
693  and therapy for patients who have failed a prespecified number of lines of therapy 
694  represent three distinct indications. A separate trial for each indication is 
695  recommended, but prespecified analyses in separate cohorts in a single trial may also 
696  be used to support each indication independently. If sponsors intend to pursue 
697  multiple indications on the basis of one trial (e.g., treatment of SR-aGVHD and 
698  treatment of aGVHD failing two or more therapies), ensure that the protocol clearly 
699  describes the eligibility criteria for each cohort and that the trial design is adequate to 
700  provide evidence of effectiveness for each indication. Include the following in 
701  consideration of the intended population: 
702   
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703    For studies of first-line therapy for aGVHD, patients should not have been treated 
704  with 1 mg/kg methylprednisolone equivalents (MPE) for more than 72 hours 
705  prior to start of study drug.  
706   
707    FDA considers the following criteria to be acceptable to define SR-aGVHD: 
708   
709    progressed after 3 days of treatment with MPE >2 mg/kg/day, 
710   
711    did not improve after 7 days of treatment with MPE >2 mg/kg/day, 
712   
713    progressed to a new organ after treatment with MPE >1 mg/kg/day for 
714  isolated skin and/or upper GI GVHD, or  
715   
716    recurred during or after a steroid taper. 
717   
718    At the present time, there are no standardized criteria for refractory to or failing a 
719  prior therapy. Protocols for patients failing a prespecified number of lines of 
720  therapy should include justification for how failure is defined.  
721   
722  b.  Establishing Clinical Benefit 
723   
724    Response endpoints have been used for traditional approval for treatments of 
725  aGVHD. 
726   
727    OR (defined as CR+PR) following 4 weeks of therapy is a clinical endpoint 
728  accepted by FDA for traditional approval.  
729   
730    For the purposes of demonstrating superiority, improvements in more 
731  conservative endpoints may be considered. VGPR, a subset of PR with very 
732  limited residual manifestation of disease, may be used in place of PR (e.g., the 
733  endpoint would be CR + VGPR). Additionally, CR alone may be used as the 
734  primary endpoint.  
735   
736    As there are multiple potential root causes of death after HSCT, OS itself may not 
737  be sufficient to establish a treatment effect with regard to treatment of aGVHD, so 
738  if OS is chosen as the primary endpoint in the pivotal trial to support a marketing 
739  application for aGVHD treatment, analysis of response should still be planned. 
740   
741  c.  Pivotal Trial Design 
742   
743    The first pivotal trial of a new indication for treatment of aGVHD should be designed 
744  to isolate the treatment effect of the investigational drug. 
745   
746    Pivotal trials to support a marketing application for first-line treatment of aGVHD 
747  should be randomized controlled trials.   
748   
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749    Add-on designs and head-to-head comparisons are both appropriate (see 
750  Appendix 5 Glossary for definitions). 
751   
752    Although such trials generally seek to demonstrate superiority of the arm with the 
753  new investigational drug, noninferiority trials may be considered for populations 
754  where the expected response is high with SOC regimens, especially if the new 
755  investigational drug is expected to improve safety or compliance.  
756   
757    To prevent bias in study conduct, the use of blinded treatments, where feasible, is 
758  recommended for randomized trials.  
759   
760    Enrollment on randomized trials should be stratified by factors associated with the 
761  likelihood of response, including a measure of aGVHD severity and patient age.  
762   
763    For investigational drugs intended for use in second or later lines of therapy when a 
764  highly effective SOC therapy is available, the sponsor should conduct a randomized 
765  controlled trial to support a marketing application. 
766   
767    In some cases, such as when the intended population has refractory disease and there 
768  are no available therapies, a marketing application might be supported by positive 
769  results from a single-arm trial. The sample size of the trial would need to be sufficient 
770  to show a meaningful clinical benefit and exclude an overall response rate (ORR) that 
771  is not meaningful for the intended population.  
772   
773  d.  Patient-Related Factors 
774   
775    Critical patient-related factors that may impact treatment response should be taken 
776  into consideration when determining the eligibility criteria, study design, and efficacy 
777  analyses.  
778   
779    Patients may have active disease at screening that may then improve due to 
780  changes in steroid dosing prior to start of study drug. Ensure that the protocol has 
781  an assessment of aGVHD on the day that the investigational drug is started. 
782  Include in the SAP how to handle patients who are responding to steroids or other 
783  pretreatment on the day that the investigational drug is started. 
784   
785    Pediatric patients may have response profiles that differ from adults. If a clinical 
786  trial includes both adult and pediatric patients, randomization should be stratified 
787  by age group. For conducting clinical investigations in pediatric populations, also 
788  refer to the draft guidance for industry, sponsors, and IRBs Ethical 
789  Considerations for Clinical Investigations of Medical Products Involving 
790  Children (September 2022)24 and guidance for industry, E11 (R1) Addendum: 
791  Clinical Investigation of Medicinal Products in the Pediatric Population       
792  (April 2018). 
 
24 When final, this guidance will represent the FDAs current thinking on this topic. 
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793    Baseline disease severity is a prognostic factor for aGVHD.  
794   
795    Provide objective criteria for categorizing aGVHD severity. Include the data 
796  or references to support the validity of the criteria. 
797   
798    If the eligible population is heterogeneous with regard to aGVHD severity, 
799  randomization should be stratified by a valid clinical or biomarker-based 
800  severity categorization.   
801   
802    The wide array of drugs and methods used to prevent GVHD or treat aGVHD may 
803  results in a heterogeneity in specific aspects of immune dysfunction in patients 
804  presenting for treatment of aGVHD, especially for those with recurrent or refractory 
805  disease. The protocol should address how prior and concurrent GVHD drugs are 
806  taken into account when assessing efficacy outcomes. 
807   
808  e.  Treatment Plan 
809   
810    The treatment plan should be detailed in the protocol.  
811   
812    See Sections III.A.4 and III.B.2 for information regarding optimization of the 
813  regimen for treatment of aGVHD prior to conduct of a trial to support a marketing 
814  application. 
815   
816    In all cases, in order to ensure that the treatment effect of the investigational drug 
817  can be assessed in the trial, consider carefully what immunosuppressive drugs can 
818  be continued from the prestudy period to the on-study period. In general, drugs 
819  for long-term prophylaxis, such as CNIs, can be continued in the absence of a 
820  pharmacological contraindication (see Section III.A.5), but continued use of 
821  other treatments of aGVHD would need to be justified. 
822    
823    The protocol should include a plan for tapering immunosuppression, including 
824  steroids, any other drugs being continued for the treatment of aGVHD, and the 
825  drugs used for GVHD prophylaxis. The protocol should also specify the order in 
826  which drugs are to be tapered. The experience with these immunosuppression 
827  tapering instructions will provide the basis for standardized instructions in 
828  labeling.  
829   
830    We recommend that information be collected for the first aGVHD treatment 
831  administered after completion of study drug administration.  
832   
833    Consider providing for retreatment with the investigational drug in patients who 
834  respond initially and then have recurrence of aGVHD.   
835   
836  f.  Marketing Applications 
837   
838    See Section IV for special data collection considerations for the pivotal trial. 
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839  D.  Treatment of Chronic GVHD 
840   
841  1.   Efficacy Endpoints 
842   
843  a.  Response 
844   
845    For documentation of response to treatment of cGVHD, FDA has accepted the 
846  definitions below with the response assessments conducted serially through 6 months 
847  of therapy (e.g., up to and including the Week 25 visit) and using valid staging 
848  criteria for cGVHD.25  
849   
850    Complete Response (CR): Has no clinically active disease as defined by the 
851  organ-level complete response criteria in all organs,26 and no intervening new 
852  therapy since start on study treatment.27 
853   
854    Partial Response (PR): Meets organ-level partial response criteria in one or more 
855  organs without progression28 in any other organ in comparison to study baseline, 
856  and no intervening new therapy from study baseline.29 
857   
858    See Appendix 4 for an example estimand for treatment of cGVHD. 
859   
860    A minimum of 1 year of follow-up is required to establish durability of responses. 
861  The planned interval between assessments should be no less frequently than every 
862  2-3 weeks for the first 6 months and at least every 3 months thereafter through 
863  completion of 1 year of follow-up. The protocol should specify that the study visit 
864  activities should encompass events in the intervening period since the last visit.   
865   
866    There are two measures of durability of the response as defined below. Both measures 
867  of durability of response are of interest for the evaluation of clinical benefit. 
868   
 
25 See footnote 19.  
 
26 Note that the overall response definition uses only the organ-level criteria and does not include the Global Score 
criteria. Additionally, for CR, the organ-level criteria should be met without regard to previous organ involvement 
(i.e., in order to exclude involvement of new organs, the response assessment requires data in all organs rather than 
just those involved at study baseline). PR can be excluded with partial data if there is progression from study 
baseline in any organ. 
 
27 For the purposes of assessing response and durability of response, new systemic therapy is defined as any new 
systemic treatment for cGVHD or an increase in the dose of corticosteroids to prednisolone equivalent (PE) 1 mg/kg 
(10%) or more. 
 
28 See footnote 26.  
 
29 See footnote 27.  
21 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
869    Duration of response (DOR) is defined as the time from the date of first response 
870  to the date of progression,30 new systemic therapy for cGVHD,31 or death from 
871  any cause, whichever occurs first.   
872   
873    An additional measure of durability that considers the natural history of cGVHD, 
874  which may flare and resolve without additional systemic treatment, is defined as 
875  the time from the date of first response to the date of new systemic therapy for 
876  cGVHD or death from any cause, whichever occurs first.  
877   
878    For the evaluation of response in randomized trials, the analysis set consists of all 
879  randomized patients. In single-arm trials, the analysis set is all patients who received 
880  any dose of study drug. The proportions of subjects achieving response and 95% 
881  confidence intervals should be reported. For the primary analysis in a randomized 
882  trial, difference in proportions should be used to quantify the treatment effect.  
883   
884    The credibility of the endpoints is dependent on the completeness of the data, and 
885  efforts should be made to minimize missing data. For adjudication of response and for 
886  adjudication of DOR, the SAP should include a plan for addressing missing data. 
887   
888  b.  Overall Survival (OS) 
889   
890    See Section III.B.1.b. for the definition of OS. 
891   
892  c.  Patient-Reported Outcomes (PRO) 
893    
894    PROs based on the symptoms of active cGVHD or residual effects of cGVHD may 
895  also be considered as the basis for an efficacy claim.  
896   
897    The PRO tool should be validated for the context of use32 and be age-appropriate.  
898  Examples of contexts of use include treatment of multisystem cGVHD agnostic of 
899  line of therapy, treatment of chronic ocular sicca due to irreversible lacrimal gland 
900  damage, etc. 
901   
902    The PRO measure or concept of interest proposed to denote clinical benefit (e.g., 
903  change in symptom burden) should be well-defined and reliable. Given the 
904  heterogeneity in organ involvement by cGVHD, careful consideration should be 
905  given to whether the concept of interest is organ-specific or total score derived from 
906  multiple organs. Additionally, adequate follow-up is required to establish that the 
907  durability of the observed benefit is clinically meaningful. We recommend that 
 
30 For assessment of DOR, progression from nadir in an organ is defined as worsening according to the organ-level 
criteria from best prior organ status independent of changes in any other organ. 
 
31 See footnote 27.  
 
32 For additional information, see the guidance for industry Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims (December 2009).    
22 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
908  sponsors submit the PRO development package and proposed statistical analysis 
909  plan to FDA for feedback prior to use of the PRO in a trial to support a marketing 
910  application.        
911     
912  d.  Other Potential Measures of Efficacy  
913   
914    FDA acknowledges that the ultimate goal for treatment of cGVHD is to promote 
915  restoration of tolerance, and as such, efficacy endpoints that reflect complete 
916  resolution of clinical disease that is durable in the absence of systemic therapy would 
917  be of interest. When considering the use of efficacy endpoints other than those listed 
918  above, especially in a trial to be used to support a marketing application, sponsors 
919  should obtain feedback from FDA about the acceptability of the proposed novel 
920  endpoint prior to initiating the trial.  
921   
922  2.   Exploratory Trial Considerations 
923   
924  a.  Initial Dose-Escalation Trials 
925    
926    Conducting an FIH trial in patients with active cGVHD may be challenging due to 
927  the confounding by adverse events due to the underlying GVHD or concomitant 
928  medications. Additionally, the benefit-risk may not be favorable for conduct of such 
929  a trial in patients with newly diagnosed cGVHD where there is an established SOC, 
930  and it would not be acceptable to conduct an FIH study as a combination with SOC. 
931  See Section III.A.4 for additional information.  
932   
933    See Section III.D.3 for caveats regarding disease-related and treatment-related factors 
934  to consider when designing an exploratory trial for treatment of cGVHD.   
935   
936    The patient population should be commensurate with the risk. The benefit-risk 
937  assessment of a new drug that has a moderate degree of adverse events without 
938  preliminary evidence of activity for cGVHD may not be appropriate to study in 
939  patients with mild cGVHD who have a high response rate with topical therapy or 
940  first-line systemic corticosteroids alone. 
941   
942    Dose escalation decision rules should take into consideration the need to minimize 
943  Grade 2 organ toxicities and avoiding any Grade 3 or higher toxicities.   
944   
945    Intra-patient dose escalation may be considered in select circumstances where risks 
946  can be minimized objectively. Additionally, for patients who have received multiple 
947  cycles of treatment without evidence of cumulative toxicity or therapeutic activity, it 
948  may be beneficial to escalate the individual patient's dose to a higher level if that 
949  higher dose has been established as safe in subsequent cohorts. The protocol should 
950  specify the criteria for when intra-patient dose escalation is allowed, how the new 
951  dose is assigned, any changes in the monitoring plan needed to accommodate the 
952  change in dose, and how the safety and efficacy data will be evaluated for such 
953  patients. 
23 
  Contains Nonbinding Recommendations 
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954    The planned duration of treatment should be described clearly in the protocol.   
955   
956    Long-term treatment may be considered in the dose-escalation trial, but when 
957  treatment is planned to extend beyond achievement of CR, a rationale should be 
958  provided for the proposed duration of treatment after response, and there should 
959  be objective criteria for when to discontinue treatment permanently.     
960   
961    For patients who are taken off the investigational drug after achieving a CR, the 
962  protocol may also address retreatment in case of recurrence of cGVHD. 
963   
964    Early phase trials are also the place to determine the expected time to response, 
965  allowing study treatment to continue in the absence of toxicity unless prespecified 
966  levels of disease response have not occurred within a maximum number of cycles.  
967  Such information will provide support for the treatment plan proposed for pivotal 
968  trials designed to test for efficacy. 
969   
970  b.  Dose Optimization and Signal Verification 
971   
972    Response is the appropriate efficacy endpoint in exploratory trials of cGVHD 
973  treatments. For additional information, see Section III.D.3.  
974   
975    The effects of study drug in patients on steroids alone and in those on steroids plus a 
976  CNI or another systemic immunosuppressant medication should be tested. 
977   
978    See Section III.A.5 for additional considerations for dose optimization. 
979   
980  3.   Pivotal Trial Considerations 
981   
982  a.  Indications and Intended Populations 
983   
984    First-line therapy for cGVHD, therapy for steroid-refractory cGVHD (SR-cGVHD), 
985  and therapy for patients who have failed a prespecified number of lines of therapy 
986  represent three distinct indications. A separate trial for each indication is 
987  recommended, but prespecified analyses of separate cohorts in a single trial may also 
988  be used to support each indication independently. If sponsors intend to pursue 
989  multiple indications on the basis of one trial (e.g., treatment of SR-GVHD and 
990  treatment of cGVHD failing two or more therapies), ensure that the protocol clearly 
991  describes the eligibility criteria for each cohort and that the trial design is adequate to 
992  provide evidence of effectiveness for each indication.  
993   
994    Include the following in consideration of the intended population: 
995   
996    For studies of first-line therapy for cGVHD, patients should not have been treated 
997  with 1 mg/kg prednisone equivalents (PE) for more than 72 hours prior to start 
998  of study drug.  
999   
24 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1000    FDA considers the following criteria to be acceptable to define cGVHD that 
1001  failed steroids: 
1002   
1003    Manifestations progress despite the use of >1 mg/kg/day PE for at least 
1004  1 week,  
1005   
1006    Manifestations persist without improvement despite treatment with 
1007  >0.5 mg/kg/day or 1 mg/kg every other day for at least 4 weeks, 
1008   
1009    Recurrence after a CR, or 
1010   
1011    Progression after a PR. 
1012   
1013    At the present time, there are no standardized criteria for refractory to or failing 
1014  a prior therapy with other drugs. Protocols for patients failing a prespecified 
1015  number of lines of therapy should include justification for how failure is defined.  
1016  If the intended population is one failing treatment with a specific drug, the 
1017  submission should include data to support the criteria used to define "failure" 
1018  for that drug.  
1019   
1020    Patients with active cGVHD who are steroid-intolerant may not have the same 
1021  response profile as those who are actually refractory to or recurrent after steroids 
1022  or other treatments. Patients with steroid intolerance as the only treatment failure 
1023  should be excluded in a study for treatment of steroid-refractory cGVHD.  
1024   
1025    Patients with steroid-dependent cGVHD, i.e., those who recur during steroid taper 
1026  and respond with an increase in steroid dose, would not be evaluable for response 
1027  to a new treatment if the cGVHD resolved with the increased dose of steroids. 
1028  Patients with steroid-dependent cGVHD should not be included in cGVHD 
1029  treatment trials.   
1030   
1031  b.  Establishing Clinical Benefit 
1032   
1033    OR (defined as CR+PR) at any time within the first 6 months of treatment is a clinical 
1034  endpoint accepted by FDA for traditional approval with supporting data on a 
1035  clinically meaningful measure of durability.  
1036   
1037    For the purposes of demonstrating superiority, improvements in more conservative 
1038  endpoints, such as CR alone, may be considered.  
1039   
1040    As there are multiple potential root causes of death after HSCT, OS itself may not be 
1041  sufficient to establish a treatment effect with regard to treatment of cGVHD, so if OS 
1042  is chosen as the primary endpoint in a trial to support a marketing application for 
1043  cGVHD treatment, analysis of response should still be planned. A randomized trial is 
1044  required to assess OS.   
1045   
25 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1046    As cGVHD is a chronic symptomatic disorder, a PRO endpoint may also be 
1047  considered. When used as the basis of a claim for a systemic treatment of active 
1048  cGVHD, the PRO endpoint should be supported by data showing that the treatment 
1049  also has a direct effect on the clinical manifestations of cGVHD. A randomized trial 
1050  is required to support indication for symptomatic improvement.  
1051   
1052    There is currently no established endpoint to support a claim of "steroid-sparing" in 
1053  the treatment of cGVHD. Sponsors who plan to pursue such a claim should seek input 
1054  from FDA early in clinical development.    
1055   
1056  c.  Pivotal Trial Design 
1057   
1058    The first pivotal trial for a new indication for treatment of cGVHD should be 
1059  designed to isolate the treatment effect of the investigational drug. 
1060   
1061    Pivotal trials to support a marketing application for first-line treatment of cGVHD 
1062  should be randomized controlled trials.   
1063   
1064    Add-on designs and head-to-head comparisons are both appropriate (see 
1065  Appendix 5 Glossary for definitions). 
1066   
1067    Although such trials generally seek to demonstrate superiority of the arm with the 
1068  new investigational arm, noninferiority trials may be considered for populations 
1069  where the expected response is high with SOC regimens, especially if the new 
1070  investigational drug improves safety or compliance.  
1071   
1072    To prevent bias in study conduct, the use of blinded treatments where feasible or 
1073  blinded assessors is recommended for randomized trials. For studies with a PRO 
1074  endpoint, the use of blinded treatments is essential for the credibility of the PRO 
1075  results.  
1076   
1077    In second or later lines of therapy when a highly effective SOC therapy is available, a 
1078  randomized trial should be used to support the marketing application. 
1079   
1080    In some cases, such as when the intended population has refractory disease and there 
1081  are no available therapies, a marketing application might be supported by positive 
1082  results from a single-arm trial. The sample size of the trial would need to be sufficient 
1083  to show a meaningful clinical benefit and exclude an ORR that is not meaningful for 
1084  the intended population.  
1085   
1086  d.  Patient-Related Factors 
1087   
1088    Critical patient-related factors that may impact treatment response, OS, or PROs 
1089  should be taken into consideration when determining the eligibility criteria, study 
1090  design, and efficacy analyses.  
1091   
26 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1092    Patients may have active disease at screening that may then improve due to 
1093  changes in steroid dosing prior to start of study drug. Ensure that the protocol has 
1094  an assessment of cGVHD on the day that the investigational drug is started. 
1095  Include in the SAP how to handle patients who are responding to steroids or other 
1096  pretreatment on the day that the investigational drug is started. 
1097   
1098    Pediatric patients may have response profiles that differ from adults. If a clinical 
1099  trial includes both adult and pediatric patients, randomization should be stratified 
1100  by age group.   
1101   
1102    Studies of new systemic cGVHD treatments generally include patients with 
1103  moderate or severe disease.  
1104   
1105    Within the severe category, justification should be provided for the criteria 
1106  used to exclude patients with fibrosing manifestations considered irreversible, 
1107  such as advanced bronchiolitis obliterans, who would not be expected to 
1108  respond to anti-inflammatory drugs. 
1109   
1110    If the eligible population is heterogeneous with regard to cGVHD severity, 
1111  randomization should be stratified by a valid clinical or biomarker-based 
1112  severity classification.   
1113    
1114    Subcategories of cGVHD (e.g., classic, overlap, etc.) may be associated with 
1115  prognosis. If eligibility criteria include all subcategories, the potential impact of 
1116  these subcategories on efficacy outcomes should be addressed either at 
1117  randomization or in the efficacy analysis.  
1118   
1119    The wide array of drugs and methods used to prevent GVHD, treat aGVHD, and 
1120  treat cGVHD may result in a heterogeneity in specific aspects of immune 
1121  dysfunction in patients presenting for treatment of cGVHD, especially for those 
1122  with recurrent or refractory disease. The protocol should address how prior and 
1123  concurrent GVHD drugs are taken into account when assessing efficacy 
1124  outcomes. 
1125   
1126    It is acknowledged that cGVHD may occur after HSCT independent of the risk of 
1127  relapse of the underlying malignancy, so clinical trials of new drugs for cGVHD 
1128  should not exclude patients based on the risk of relapse. However, since relapse 
1129  may occur during the expected 1-year follow-up for patients in cGVHD treatment 
1130  trials, the statistical analysis plan should address the potential impact of fatal 
1131  relapse on the OS endpoint in trials using OS as an endpoint. 
1132   
1133    For trials that include a PRO endpoint, consideration should be given to the 
1134  minimum burden of symptoms required for eligibility to allow detection of a 
1135  response to treatment.    
1136   
27 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1137  e.  Treatment Plan 
1138   
1139    The treatment plan should be detailed in the protocol.  
1140   
1141    See Sections III.A.4 for information regarding optimization of the dose and 
1142  administration schedule for new cGVHD drugs prior to conduct of the trial that 
1143  will support a marketing application. 
1144   
1145    To ensure that the treatment effect of the investigational drug can be assessed in 
1146  the trial, which immunosuppressive drugs can be continued from the prestudy 
1147  period to the on-study period must be considered carefully. In general, drugs for 
1148  long-term prophylaxis, such as CNIs, can be continued in the absence of a 
1149  pharmacological contraindication (see Section III.A.5), but continued use of other 
1150  treatments of cGVHD would need to be justified. A rationale should be provided 
1151  as to how the impact of the heterogeneity in background therapy will be 
1152  controlled in the assessment of the efficacy endpoint.  
1153   
1154    The protocol should include a plan for tapering immunosuppression, including 
1155  steroids, any other drugs being continued for the treatment of cGVHD, and the 
1156  drugs used for GVHD prophylaxis. The protocol should also specify the order in 
1157  which drugs are to be tapered. The experience with these immunosuppression 
1158  tapering instructions will provide the basis for standardized instructions in 
1159  labeling.  
1160   
1161    We recommend that information be collected for the first cGVHD treatment 
1162  administered after completion of study drug administration.  
1163   
1164    Consider providing instructions for retreatment of patients who respond initially 
1165  and then have recurrence of cGVHD.   
1166   
1167  f.  Marketing Applications 
1168   
1169    See Section IV for special data collection considerations for the pivotal trial. 
1170   
1171   
1172  IV.  MARKETING APPLICATIONS 
1173   
1174  A.   Assessment of Efficacy 
1175   
1176    Assessments of efficacy in GVHD clinical trials are generally based on objective 
1177  criteria. However, collection of only the investigator-determined GVHD stage or only 
1178  the investigator-determined response is not sufficient to document efficacy. Case 
1179  Report Forms (CRFs) should be designed to collect the raw data for efficacy 
1180  assessments in order to allow independent adjudication. Ensure that the protocol 
1181  stipulates an appropriate window for the primary efficacy assessment and that 
1182  missing data are minimized.   
28 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1183    To assist with FDA's review of responses, the raw data supporting the study 
1184  endpoints should be submitted in the marketing application.  
1185   
1186    For GVHD prevention trials, the raw data file should include all variables needed 
1187  to assess for aGVHD and cGVHD (listed in the next two bullets) at each 
1188  prespecified study visit and at unscheduled visits for new onset of aGVHD or 
1189  cGVHD or for a change in grade or score, respectively.  
1190   
1191    For treatment of aGVHD trials, the raw data file should include all variables 
1192  needed to apply the proposed staging system. For example, for standardized 
1193  staging of aGVHD,33 the following would be needed at each study visit: total 
1194  bilirubin, diarrheal stool output episodes or volume, presence of grossly bloody 
1195  stool, severe abdominal pain, skin rash percentage, presence of erythroderma with 
1196  bullae or desquamation, presence of persistent nausea, vomiting or anorexia, and 
1197  additional explanatory comments.   
1198   
1199    For treatment of cGVHD trials, the raw data file should include all variables 
1200  needed to apply the proposed scoring system. For example, for use of the 2014 
1201  National Institutes of Health (NIH) Consensus Criteria34 for cGVHD response, 
1202  the following would be needed at each study visit: skin score (0-3), eye score    
1203  (0-3), modified OMRS (0-12), esophagus score (0-3), UGI score (0-3), LGI score 
1204  (0-3), lung score (0-3), FEV-1 (% predicted), joint score (0-3), P-ROM for each 
1205  joint (4-7), total bilirubin, ALT, alkaline phosphatase, and additional explanatory 
1206  comments for each.   
1207   
1208    Sponsors are encouraged to develop an algorithmic approach using the raw data for 
1209  independent assessment of efficacy. If such an algorithmic approach is used, the 
1210  submission should include well-commented programs to replicate the output using 
1211  only the submitted datasets and a detailed description of the algorithm, including a 
1212  pseudocode.  
1213   
1214    To allow FDA to confirm the analyses of the treatment effect, the submission should 
1215  include an efficacy summary file with all enrolled patients for the pivotal study and 
1216  for the integrated efficacy population. 
1217   
 
33 Harris, AC, R Young, S Devine, WJ Hogan, F Ayuk, U Bunworasate, C Chanswangphuwana, YA Efebera, E 
Holler, M Litzow, R Ordemann, M Qayed, AS Renteria, R Reshef, M Wolfl, YB Chen, S Goldstein, M Jagasia, F 
Locatelli, S Mielke, D Porter, T Schechter, Z Shekhovtsova, JL Ferrara, and JE Levine, 2016, International, 
Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount 
Sinai Acute GVHD International Consortium, Biol Blood Marrow Transplant, 22(1):4-10.  
 
34 Lee, SJ, D Wolff, C Kitko, J Koreth, Y Inamoto, M Jagasia, J Pidala, A Olivieri, PJ Martin, D Przepiorka, I Pusic, 
F Dignan, SA Mitchell, A Lawitschka, D Jacobsohn, AM Hall, ME Flowers, KR Schultz, G Vogelsang, and S 
Pavletic, 2015, Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health 
Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 
Response Criteria Working Group Report, Biol Blood Marrow Transplant, 21(6):984-999. 
29 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1218    For GVHD prevention trials, the summary file should include variables such as: 
1219  date of randomization (if applicable), treatment start date, transplantation date, 
1220  date of onset of grades 2-4 aGVHD, date of onset of grades 3-4 aGVHD, date of 
1221  onset of cGVHD, data of onset of moderate-to-severe cGVHD, date of first new 
1222  systemic therapy for aGVHD or cGVHD, date of relapse, date of first new 
1223  systemic therapy for treatment of relapse, date of death, date of last GVHD 
1224  assessment.   
1225   
1226    For treatment of aGVHD trials, the summary file should include variables such 
1227  as: date of randomization (if applicable), treatment start date, Day-28 date,     
1228  Day-28 response, date of first new systemic therapy, date of first organ 
1229  progression from nadir after Day 28, date of death, date of last aGVHD 
1230  assessment. 
1231   
1232    For treatment of cGVHD trials, the summary file should include variables such 
1233  as: date of randomization (if applicable), treatment start date, date of first 
1234  response, first response, date of best response, best response, date of first new 
1235  systemic therapy, date of first organ progression from nadir, date of death, date of 
1236  last cGVHD assessment.  
1237     
1238    Baseline demographic and disease characteristics are used to ensure consistency of 
1239  the benefit-risk assessment in subgroup analyses. The following key information 
1240  should be documented, collected on the CRFs, and submitted in the datasets 
1241  supporting a marketing application: 
1242   
1243    Transplant information: Preparative regimen intensity, stem cell type, degree of 
1244  patient-donor histocompatibility 
1245   
1246    GVHD prevention used: Prophylaxis regimen and/or graft manipulation to 
1247  prevent GVHD. 
1248   
1249    GVHD treatments: All prior treatments of aGVHD and cGVHD. If collected as 
1250  part of the Concomitant Medications data file, include a variable to identify the 
1251  line of therapy.    
1252   
1253    Regarding the on-study concomitant medications, include a variable for corticosteroid 
1254  dose as MPE for aGVHD treatment trials and as PE for cGVHD treatment trials.  
1255   
1256    Measurement of biomarkers and submission of the assay results are encouraged. See 
1257  also Section III.A.2. 
1258   
30 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1259    Sponsors planning to use real world data35 to support a GVHD drug marketing 
1260  application should consult with FDA at the time of protocol development to ensure 
1261  that the data sources will provide the data needed to assess the treatment effect. 
1262  Important considerations include whether the sources capture the individual data 
1263  elements needed to derive clinically accepted endpoints for demonstrating efficacy, 
1264  and if so, the extent of misclassification, the timing and the frequency of assessment. 
1265  Sponsors should plan for additional discussions regarding alternative measures if the 
1266  data sources do not capture the key elements of the clinically accepted endpoints. 
1267   
1268  B.   Assessment of Safety 
1269   
1270    To assist with the adjudication of causality of fatal adverse events, the submission 
1271  should include a data file with the date of death, study day of death, proximate cause 
1272  of death (usually as reported by the investigator), and the root cause of death as 
1273  determined by the sponsor. The root cause is generally categorized as a direct effect 
1274  of the primary disease, an adverse drug reaction, or an unrelated intercurrent event 
1275  (such as a car accident). Given the complexity of determining the root cause of death 
1276  after allogeneic transplantation, we recommend that the analysis plan prespecify the 
1277  details of a standardized approach36 that will be applied to determining the root cause 
1278  of death. 
1279   
1280    As most drugs for treatment or prevention of GVHD have immunosuppressive 
1281  properties, the submission should include a detailed analysis of infections. 
1282   
1283    In addition to the adverse reactions due to class effects, the following           
1284  transplant-related events should be considered in the analysis of adverse events of 
1285  special interest: graft failure, relapse, post-transplantation lymphoproliferative 
1286  disease, bleeding, nonrelapse mortality, overall survival.   
1287   
1288    Plan to collect all-grade adverse events through at least 5 half-lives or 28 days 
1289  (whichever is longer) from the last dose of study drug unless you have data that 
1290  the biological effect extends beyond that period. For the longer-term follow-up, 
1291  collection of related serious adverse events, relapse, and survival data are 
1292  recommended. 
1293   
1294   
1295   
1296   
1297   
 
35 For additional information and guidances pertaining to real world data, see Real-World Evidence at 
https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence.  
  
36 See an example as published in Copelan, E, JT Casper, SL Carter, JA van Burik, D Hurd, AM Mendizabal, JE 
Wagner, S Yanovich, and NA Kernan, 2007, A Scheme for Defining Cause of Death and Its Application in the T 
Cell Depletion Trial, Biol Blood Marrow Transplant, 13:1469-1476.  
31 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1298  APPENDICES 
1299   
1300  Appendix 1. Example Estimand for Prevention of Graft-versus-Host Disease (GVHD) 
1301   
1302  Clinical Question: Does the addition of the investigational drug product to a standard GVHD 
1303  prophylaxis regimen improve acute GVHD (aGVHD) GVHD-free survival (GFS)?  
1304   
 Estimand Attribute    Example  
 Population     12 years old  
  AML, MDS, or ALL in CR1 or CR2 
  Planned for allogeneic HSCT with a matched unrelated donor  
 Treatment     Standard GVHD prophylaxis 
  Randomized study drug (investigational product or blinded placebo) 
through day + X post-HSCT  
 Endpoint(s)     Grades 2-4 aGVHD-free survival from HSCT through Day + 180 
post-HSCT 
  Event 1: Death 
  Event 2: Grade 2-4 aGVHD  
M  issing data plan is needed in the SAP 
 Intercurrent Event    Strategy    Description  
  Discontinuation of    Treatment Policy    Discontinuation of assigned treatment 
assigned treatment before  before Day 180 visit is documented. Data 
Day 180   on the main outcome are continued to be 
  collected.  
  Occurrence of graft failure    Treatment Policy    Occurrence of graft failure before Day 180 
visit is documented. Data on the main 
outcome are continued to be collected.  
  Use of a nonprotocol new    Treatment Policy    Use of a new systemic therapy before 
systemic GVHD therapy  Day180 visit is documented. Data on the 
before Day 180 without  main outcome are continued to be 
the occurrence of GVHD  collected.   
  Use of a nonprotocol new    Treatment Policy    Use of a new systemic therapy before 
systemic GVHD therapy  Day180 visit is documented. Data on the 
before Day 180 for  main outcome are continued to be 
treatment of cGVHD  collected. 
  Use of a nonprotocol new    Composite    Occurrence of aGVHD is considered an 
systemic GVHD therapy  event. 
before Day 180 for 
treatment of aGVHD 
  Death prior to onset of    Composite    Death prior to Day 180 is considered an 
GVHD before Day 180  event. 
  Relapse of primary    Treatment Policy     Relapse of primary malignancy is 
malignancy   documented. Data on the main outcome are 
continued to be collected. 
 Population-level summary    Hazard ratio (95% CI) for the randomized population 
1305  Abbreviations: ALL - acute lymphoblastic leukemia, AML - acute myeloid leukemia, CR1 - first complete response, 
1306  CR2 - second complete response, HSCT - hematopoietic stem cell transplantation, MDS - myelodysplastic 
1307  syndromes, SAP - statistical analysis plan, SOC - standard-of-care. 
32 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1308  Appendix 2. Example Estimand for Treatment of Steroid-Refractory Acute GVHD 
1309  (aGVHD) 
1310   
1311  Clinical Question: Does treatment with the investigational drug result in a Day-28 complete response 
1312  (CR) + partial response (PR) rate that is at least x% without the need for additional treatments in patients 
1313  with steroid-refractory aGVHD? 
1314   
Estimand Attribute  Example 
Population    12 years old 
  Grade 2-4 aGVHD at baseline 
  Steroid-refractory: 
  Progressed after 3 days of treatment with 2 mg/kg MPE 
  No improvement after 7 days of treatment with 2 mg/kg MPE 
  Progressed to a new organ after treatment with 1 mg/kg MPE 
for skin or UGI aGVHD  
  Progressed from nadir during or after a steroid taper 
  No other prior aGVHD treatment 
Treatment    Investigational drug through Week X 
  Continue steroid at current dose   
  Uniform steroid taper schedule 
  Continue GVHD prophylaxis 
Endpoint(s)    Day-28 overall response 
  Success includes 
  CR or PR by prespecified criteria at Day 28 visit 
  Alive at Day 28 visit 
  No new systemic therapy before Day 28 visit 
Missing data at baseline or on Day 28 assessment is considered a    
non-response 
Intercurrent Event  Strategy  Description 
  Discontinuation of    Treatment Policy    Discontinuation of assigned treatment 
assigned treatment  before Day 28 visit is documented. Data 
before the Day 28 visit  on the main outcome are continued to 
be collected. 
  Use of a new systemic    Composite    Use of a new systemic therapy before 
therapy before Day 28  Day 28 visit is considered a              
(includes 2 mg/kg  non-response. 
MPE)   
  Death prior to the Day    Composite    Death prior to Day 28 visit is 
28 visit  considered a non-response. 
  Relapsed of primary    Treatment Policy    Relapsed of primary malignancy is 
malignancy  documented. Data on the main outcome 
are continued to be collected. 
Population-level summary  Proportion (95% CI) of patients with CR or PR at the Day 28 visit 
among those who received at least one dose of the investigational drug 
1315  Abbreviations: MPE - methylprednisolone equivalents, UGI - upper gastrointestinal.  
1316   
1317     
33 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1318  Appendix 3. Example Estimand for Duration of Complete Response (CR) 
1319   
1320  Clinical Question: What is the duration of CR in patients with steroid-refractory acute GVHD (aGVHD) 
1321  who achieve Day-28 CR without the need for additional therapies when treated with the investigational 
1322  drug?  
1323   
Estimand Attribute  FDA Recommendation 
Population    Treated with Investigational Drug for steroid-refractory aGVHD 
  CR at the Day-28 visit   
Treatment    Investigational drug through Week X 
  Uniform steroid taper schedule 
  Continue GVHD prophylaxis 
Endpoint(s)    Duration of CR, defined as time from CR at Day-28 visit to 
whichever occurs first: 
  Recurrence of aGVHD in any organ   
  Initiation of new systemic therapy for aGVHD 
  Death from any cause 
Missing data plan needed in SAP 
Intercurrent Event  Strategy  Description 
  Death from any cause    Composite    Death is considered an event; document 
after achieving CR on  the date of death. 
Day 28 
 
  Use of new systemic    Composite    Use of a new systemic therapy for 
therapy for aGVHD  aGVHD after achieving CR on Day 28 
after achieving CR on  is considered an event; document date of 
Day 28  new systemic therapy. 
 
  Use of new systemic    Treatment Policy    Document relapse and continue to collect 
therapy for cGVHD  data on the main outcome. 
after achieving CR on 
Day 28 
 
  aGVHD recurrence     Composite    aGVHD recurrence is considered an 
event; document date of recurrence. 
  Relapse of primary    Treatment Policy    Document relapse and continue to collect 
malignancy  data on the main outcome. 
 
  Use of topical therapy    Treatment policy    Document new therapy and continue to 
for aGVHD  collect data on the main outcome.  
 
Population-level summary  Median (95% CI) by Kaplan-Meier and range of duration of CR 
1324  Abbreviation: SAP - statistical analysis plan.  
1325   
1326   
1327     
34 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1328  Appendix 4. Example Estimand for the First-Line Treatment of Chronic GVHD 
1329  (cGVHD) 
1330   
1331  Clinical Question: Does the investigational drug in combination with corticosteroids improve the 
1332  complete response (CR) rate through the Week 25 visit in patients with new onset cGVHD of moderate to 
1333  severe intensity without the need for additional new therapy prior to response (CR)? 
1334   
Estimand Attribute  FDA Recommendation 
Population     12 years old 
  Moderate to severe new onset cGVHD   
  No more than x days on PE 1 mg/kg for treatment of cGVHD 
Treatment    Placebo vs investigational drug x dose/schedule 
  Steroids uniform at PE 1 mg/kg/day 
  Uniform steroid taper schedule  
  May continue CNI or sirolimus prophylaxis 
  May continue topical therapies 
Endpoint    CR achieved by Week 25 visit.  
  Success includes 
  CR by Week 25 visit 
  No new systemic therapy before CR  
  No death prior to Week 25 visit 
Missing data at baseline or by Week 25 assessment is a non-response 
Intercurrent Event  Strategy  Description 
  Discontinuation of    Treatment Policy    Discontinuation of assigned treatment by 
assigned treatment by  Week 25 visit is documented. Data on 
Week 25 visit  the main outcome are continued to be 
  collected. 
 
  Use of a new systemic    Composite    Use of a new systemic therapy by Week 
therapy prior to response  25 visit is considered a non-response. 
by Week 25 visit 
 
  Death prior to response    Composite    Death prior to Week 25 visit is 
by Week 25 visit   considered a non-response. 
 
  Relapse of primary    Treatment Policy    Relapse of primary malignancy is 
malignancy  documented. Data on the main outcome 
are continued to be collected. 
Population-level summary  Difference (95% CI) between two treatment groups in proportion of 
randomized patients meeting the endpoint by Week 25 visit  
1335  Abbreviations: CNI - calcineurin inhibitor, PE - prednisone equivalents.  
1336     
35 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1337  Appendix 5. Glossary of Terminology in This Guidance 
1338   
1339  A. Terms referring to the types of interventions for management of GVHD 
1340    
1341  Pre-emptive: Use of the drug for to prevent established subclinical GVHD from becoming 
1342  clinically overt, or use of the drug to prevent worsening of GVHD from a lower severity to a 
1343  higher severity. 
1344   
1345  Prophylaxis: Use of the drug for the prevention of GVHD from occurring. 
1346   
1347  Treatment: Use of the drug for amelioration of signs and symptoms of clinically-overt GVHD.  
1348   
1349  B. Terms referring to clinical trial designs  
1350   
1351  Add-on: An add-on study is a placebo-controlled trial of a new agent conducted in people also 
1352  receiving standard treatment (e.g., new drug plus standard vs. placebo plus standard). The 
1353  objective is to determine the treatment effect of the new drug relative to placebo when combined 
1354  with a standard therapy.  
1355   
1356  Comparative effectiveness: A comparative effectiveness study compares two active 
1357  interventions without necessarily isolating the treatment effect of an individual drug (e.g., 
1358  combination chemotherapy vs. radiation, or combination regimen 1 vs. combination regimen 2).  
1359  The objective is to determine which intervention provides the superior outcome.  
1360   
1361  Exploratory: Early phase trials designed to obtain data for the initial characterization of safety 
1362  of a drug, preliminary evidence of efficacy, and/or dose optimization. 
1363   
1364  Head-to-head: A head-to-head study is a clinical trial of two therapies that are compared against 
1365  each other either alone or in combination with a standard treatment (e.g., new drug vs. old drug, 
1366  or new drug plus standard vs. old drug plus standard). The objective is to determine the treatment 
1367  effect of the new drug relative to an old drug. 
1368   
1369  Pivotal: Adequate and well-controlled trial designed to provide data that establishes the safety 
1370  and effectiveness of a drug as the basis of approval of a marketing application. 
1371   
1372  C. Additional terms used in the guidance 
1373   
1374  Line of therapy: A line of therapy is defined as the planned therapy consisting of one or more 
1375  cycles of episodic treatment or a defined period of continuous treatment. This may consist of 
1376  single-agent or combination therapy as well as a planned sequence of treatment phases. A line of 
1377  therapy ends when the patient fails to achieve a response within a prespecified period 
1378  (refractory), progresses after achieving a PR, or relapses after achieving CR. 
36