Acute Myeloid 
Leukemia:  Developing 
Drugs and Biological 
Products for 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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Donna Przepiorka at 301-796-5358 
or Donna.Przepiorka@fda.hhs.gov, or (CBER) Office of Communication, Outreach and 
Development at 800-835-4709 or 240-402-8010.  
 
 
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) 
 
August 2020 
Clinical/Medical 
 
   
Acute Myeloid 
Leukemia:  Developing 
Drugs and Biological 
Products for Treatment 
 
Guidance for Industry 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
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and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances     
 
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)  
 
August 2020 
Clinical/Medical 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  General Drug Development Considerations ................................................................................ 2 
1. Nonclinical ....................................................................................................................................... 2 
2. Devices ............................................................................................................................................. 3 
3. Clinical Pharmacology .................................................................................................................... 3 
4. Special Populations ......................................................................................................................... 5 
5. Safety Reporting Considerations ..................................................................................................... 7 
B.  Efficacy Endpoints ......................................................................................................................... 8 
1. Time-to-Event Endpoints Used Commonly for AML ....................................................................... 8 
2. Binary Endpoints Used Commonly for AML ................................................................................. 10 
3. Minimal Residual Disease (MRD)-Based Endpoints ..................................................................... 13 
4. Other Potential Measures of Efficacy for AML ............................................................................. 13 
C.  Exploratory Trial Considerations .............................................................................................. 14 
1. First-in-Human (FIH) Trials ......................................................................................................... 14 
2. Exploratory Trial Population ........................................................................................................ 15 
3. Dose-Escalation Trials .................................................................................................................. 16 
4. Exploratory Expansion Cohorts .................................................................................................... 18 
D.  Confirmatory Trial Considerations ........................................................................................... 19 
1. Confirmatory Trial Population ...................................................................................................... 19 
2. Dose Selection and Treatment Plan ............................................................................................... 20 
3. Confirmatory Trial Design ............................................................................................................ 20 
4. Confirmatory Trial Procedures ..................................................................................................... 23 
IV.  REGULATORY SUBMISSIONS.................................................................................. 24 
A.  Investigational New Drug Applications ..................................................................................... 24 
B.  Marketing Applications ............................................................................................................... 25 
1. Assessment of Efficacy ................................................................................................................... 25 
2. Assessment of Safety ...................................................................................................................... 25 
3. Clinical Pharmacology .................................................................................................................. 26 
GLOSSARY................................................................................................................................. 27 
APPENDICES ............................................................................................................................. 29 
Appendix 1:  Example DLT Criteria for Drugs for AML ................................................................ 29 
Appendix 2:  Additional Statistical Discussion .................................................................................. 30 
Appendix 3:  Additional Data Files for Marketing Applications for AML Drugs ......................... 32 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Acute Myeloid Leukemia:  Developing Drugs and Biological 
2  Products for 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 and 
18  biological products2 for the treatment of acute myeloid leukemia (AML).  Specifically, this 
19  guidance addresses FDAs current thinking regarding the overall development program and 
20  clinical trial designs for the development of drugs to support an indication of treatment of 
21  AML, including indications limited to an individual phase of treatment (e.g., maintenance, 
22  transplantation preparative regimen, etc.).3   
23   
24  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
25  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
26  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
27  the word should in Agency guidances means that something is suggested or recommended, but 
28  not required.  
29   
30   
31  II.  BACKGROUND 
32   
33  AML is a malignant neoplasm arising from a myeloid-lineage progenitor.  Although the disease 
34  is clonal, the molecular pathogenesis is highly heterogeneous.  The International Agency for 
35  Research on Cancer classifies AML and related neoplasms on the basis of morphological, 
                                                 
1 This guidance has been prepared by the Oncology Center of Excellence, the Center for Drug Evaluation and 
Research, and the Center for Biologics Evaluation and Research in consultation with the Center for Devices and 
Radiological Health at the Food and Drug Administration. 
2 For the purposes of this guidance, references to drugs include drugs approved under section 505 of the Federal 
Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 355) and biological products licensed under section 351 
of the Public Health Service Act (42 U.S.C. 262). 
3 In addition to consulting guidances, sponsors are encouraged to contact the appropriate review division to discuss 
specific issues that arise during the development of drugs for the treatment of AML. 
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Draft  Not for Implementation 
36  clinical, and genomic parameters, including specific genetic abnormalities.4  The median age at 
37  diagnosis is 68 years, but the disorder occurs in patients of all ages from neonates to the elderly.5   
38  For decades, the standard treatment6 for patients with AML was intensive cytotoxic 
39  chemotherapy for induction and consolidation with or without postremission allogeneic 
40  hematopoietic stem cell transplantation (HSCT), and the only intent of treatment was cure.  
41  Investigations of cytotoxic drugs with or without targeted drugs continue in an effort to increase 
42  the fraction of patients with AML who are cured.  However, many patients with AML who had 
43  just mild pathological or age-related organ impairment at diagnosis were considered to have too 
44  high a risk of life-threatening or fatal organ toxicity from such intensive therapy and therefore 
45  were offered only palliative treatments or no treatment at all.   
46   
47  New classes of drugs, including drugs that target the specific pathogenetic mutations or a 
48  disordered epigenome, are being developed as alternatives to cytotoxic drugs for the treatment of 
49  AML.  In some cases, these newer approaches may extend survival without the prospect for cure, 
50  but extending survival may be a meaningful benefit for patients who would live for only weeks if 
51  left untreated.  Inducing temporary control of disease with minimal treatment burden and 
52  palliation of symptoms are two additional outcomes that might also be considered meaningful in 
53  certain circumstances (see discussion in III.B below).   
54    
55  The expansion of treatment intent, broadening of the intended population, and development of a 
56  wide range of new drug classes as alternatives to cytotoxic drugs contribute substantially to the 
57  complexity of clinical development programs for new drugs for AML.  This guidance addresses 
58  these considerations and provides recommendations regarding the design and conduct of clinical 
59  trials and the types of supporting data that would facilitate efficient development of drugs for the 
60  treatment of AML.7 
61   
62   
63  III.  DEVELOPMENT PROGRAM 
64   
65  A.  General Drug Development Considerations 
66   
67  1.  Nonclinical 
68   
69    The Agencys expectations for the nonclinical programs for treatments of 
70  malignancies are summarized in the ICH guidances for industry S9 Nonclinical 
                                                 
4 For examples, see Swerdlow SH, Campo E, Harris NL, et al (eds), WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues, 2017.  Consult www.iarc.fr for resources with the latest diagnostic criteria 
for AML classification (accessed July 16, 2020).  
5 National Cancer Institute SEER Stat Fact Sheets:  Acute myeloid leukemia.  Available from: 
http://seer.cancer.gov/statfacts/html/amyl.html (accessed July 16, 2020). 
6 See the Glossary for definitions of the AML treatment and disease-related terms used in this guidance. 
7 This guidance does not contain discussion of the general issues of statistical analysis or clinical trial design.  Those 
topics are addressed in the draft ICH guidance for industry E8(R1) General Considerations for Clinical Studies 
(May 2019; when final, this guidance will represent the FDAs current thinking on this topic) and the ICH guidances 
for industry E9 Statistical Principles for Clinical Trials (September 1998) and E10 Choice of Control Group and 
Related Issues in Clinical Trials (May 2001).  For the most recent version of a guidance, check the FDA guidance 
web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
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Draft  Not for Implementation 
71  Evaluation for Anticancer Pharmaceuticals (March 2010) and S9 Nonclinical 
72  Evaluation for Anticancer Pharmaceuticals Questions and Answers (June 2018).  
73  These guidances apply to drugs for AML. 
74   
75    For cellular or gene therapy products being developed for the treatment of AML, 
76  sponsors should also consult the guidances for industry Preclinical Assessment of 
77  Investigational Cellular and Gene Therapy Products (November 2013) and Long 
78  Term Follow-Up after Administration of Human Gene Therapy Products (January 
79  2020).  
80   
81  2.  Devices 
82   
83    For drugs with a specific therapeutic target, an in vitro companion diagnostic device 
84  (referred to as a companion diagnostic herein) may be essential for the safe and 
85  effective use of the drug.  Sponsors developing a targeted drug for AML should take 
86  into consideration the need for a companion diagnostic early in the drug development 
87  timeline.8  
88   
89    Minimal residual disease (MRD) is a biomarker of subclinical tumor burden in 
90  patients with AML.  In clinical development programs for new AML drugs, MRD 
91  assays might be used for selection of patients for participation in protocols, 
92  assignment of treatments by prognostic subcategories, or as a measure of efficacy.  
93  The guidance for industry Hematologic Malignancies: Regulatory Considerations for 
94  Use of Minimal Residual Disease in Development of Drug and Biological Products 
95  for Treatment (January 2020) provides recommendations about use of MRD and 
96  MRD assays in regulatory submissions for drugs or biologics, including those 
97  applicable to AML drugs.  
98   
99  3.  Clinical Pharmacology 
100   
101    Patients with AML are commonly prescribed concomitant medication that are 
102  substrates, inducers, or inhibitors of cytochrome P450 (CYP) enzymes.  In particular, 
103  triazole antifungals are moderate to strong CYP3A inhibitors commonly prescribed to 
104  reduce the risk of invasive fungal infections in patients with AML.  Such drugs may 
105  increase the systemic exposure of new AML drugs that are metabolized by CYP3A 
106  and may decrease the tolerability of new AML drugs that are CYP3A substrates.  
107  Additional studies should be used to address this potential for harm: 
108   
109    Sponsors should conduct in vitro metabolism studies to determine if a new AML 
110  drug is a substrate, inhibitor, or inducer of CYP3A prior to conduct of the first-in-
111  human (FIH) trial.9  
112   
                                                 
8 For guidance pertaining to companion diagnostics, see the CDRH internet page on companion diagnostics 
(https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407297.htm). 
9 See the draft guidance for industry In Vitro Metabolism- and Transporter- Mediated Drug-Drug Interaction 
Studies (October 2017).  When final, this guidance will represent the FDAs current thinking on this topic. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
113    If an AML drug is a CYP3A substrate, sponsors should proactively incorporate 
114  strategies for dose modification with concomitant use of moderate and strong 
115  CYP3A inhibitors early in their clinical development programs.  If available, 
116  sponsors may leverage pharmacokinetic data (e.g., exposure-response 
117  relationships for safety and effectiveness, clinical drug interaction studies) from 
118  patients with other malignancies who have received the new drug to estimate the 
119  potential effect of the co-administration of the new drug with CYP3A inhibitors 
120  and determine an appropriate dose of the new drug with moderate or strong 
121  CYP3A inhibitors in patients with AML.  The development of physiologically 
122  based pharmacokinetic models may aid in assessing the effect of some CYP3A 
123  modulators on the AML drug and should be considered. 
124   
125    If the new AML drug is a substrate of, inhibits, or induces any major CYP 
126  enzyme or other metabolic enzymes in vitro, sponsors should conduct clinical 
127  drug interaction studies to determine appropriate mitigation strategies.  FDAs 
128  draft recommendations regarding such studies are described in the draft guidance 
129  for industry Clinical Drug Interaction Studies  Study Design, Data Analysis and 
130  Clinical Implications.10  
131   
132    Common supportive care medications for patients with AML, including antimicrobial 
133  prophylaxis (e.g., fluoroquinolones) and antiemetics (e.g., 5-HT3 receptor 
134  antagonists), are known to prolong the QT interval.  Sponsors should conduct an 
135  adequate assessment early in clinical development to assess the QT prolongation 
136  potential of the AML drug as described in FDA's guidance.11  If the AML drug has 
137  the potential to prolong the QT interval, the protocols should include appropriate 
138  strategies for mitigation of QT prolongation, including a list of prohibited 
139  concomitant medications associated with QT prolongation and/or more frequent 
140  monitoring of ECG and electrolytes, particularly in patients with nausea, vomiting, or 
141  diarrhea.  
142   
143    Patients with AML, especially the elderly, may have impaired hepatic or renal 
144  function.  Prior to enrolling patients with organ impairment on trials of treatments for 
145  AML, the sponsor should identify elimination pathways of the parent drug and its 
146  active metabolites.  If renal or hepatic elimination pathways are identified, the 
147  sponsor should characterize the impact of organ impairment on the pharmacokinetics 
148  of the parent drug or active metabolites early in clinical development as described in 
149  the FDAs guidances.12  This provides the basis of dose modifications for patients 
150  with organ impairment in late phase clinical studies.   
151   
                                                 
10 October 2017.  When final, this guidance will represent the FDAs current thinking on this topic. 
11 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs (October 2005). 
12 See the draft guidance for industry Pharmacokinetics in Patients with Impaired Renal Function  Study Design, 
Data Analysis, and Impact on Dosing and Labeling (March 2010) (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). 
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152  4.  Special Populations 
153   
154  a.  Pediatric Patients 
155   
156    FDA encourages sponsors to address the pediatric population early in their clinical 
157  development program for drugs for the treatment of AML.  For example, adolescent 
158  patients should be considered for enrollment along with adults in trials for the 
159  treatment of AML.13 
160   
161    When it is not clear that dosing for pediatric patients can be derived with certainty 
162  from adult data, or for FIH studies in younger age groups, studies in children should 
163  begin with a phase 1 trial of the new drug as monotherapy.  The phase 1 monotherapy 
164  trial population need not be limited to patients with AML, but the acceptability of the 
165  recommended phase 2 dose (RP2D) should be confirmed in a small cohort of 
166  pediatric patients with AML before conduct of larger trials for AML in children.   
167   
168    Section 505B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) requires that 
169  certain marketing applications, those for certain drugs that are directed at a molecular 
170  target that FDA determines to be substantially relevant to the growth or progression 
171  of a pediatric cancer, contain reports of molecularly targeted pediatric cancer 
172  investigations, unless a deferral or waiver is granted.  The requirement for pediatric 
173  investigations applies even if the drug is for an indication for which orphan 
174  designation has been granted.14  Sponsors of molecularly-targeted AML drugs should 
175  discuss the applicability of these requirements to their drug as early as end-of-phase 1 
176  to allow sufficient time to develop a pediatric study plan, if needed.15 
177   
178  b.  Older Adult Patients 
179   
180    For clinical trials of AML drugs, sponsors should enroll a population that is 
181  representative of the age range of patients with the disease.  It is acknowledged, 
182  however, that older adults with AML may have age-related comorbidities that place 
183  them at higher risk for adverse outcomes when treated with intensive chemotherapy.  
184  FDA has accepted, but does not require, use of age 75 years as an upper limit for 
185  inclusion in trials of intensive chemotherapy.  FDA, however, encourages use of no 
186  age limit for trials of nonintensive treatments for AML. 
187   
188    Dose reductions may be required for older patients (e.g., age 65 years and older).  
189  Safety, pharmacokinetic, and exposure data from older adults in early phase trials of a 
                                                 
13 See the guidance for industry Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical 
Trials (March 2019) and the guidance for industry and IRBs Cancer Clinical Trial Eligibility Criteria: Minimum 
Age Considerations for Inclusion of Pediatric Patients (July 2020). 
14 For additional information, see the draft guidance for industry FDARA Implementation Guidance for Pediatric 
Studies of Molecularly Targeted Oncology Drugs:  Amendments to Sec. 505B of the FD&C Act (December 2019).  
When final, this guidance will represent the FDAs current thinking on this topic.  
15 For additional information see the guidance for industry Pediatric Study Plans: Content of and Process for 
Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans (July 2020).     
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190  new AML drug should be used to justify the dose or dose modifications of the drug 
191  for older adults to be tested in later phase trials. 
192   
193    FDA recommends an assessment of older adults (e.g., age 65 years and older) for 
194  physiologic function at study baseline to assist in identifying subgroups that may be 
195  at risk for an adverse outcome when treated for AML.  Sponsors may consider using 
196  an available geriatric assessment tool or propose a new tool for use in the clinical 
197  trials.  A simple assessment tool evaluating single or multiple aspects of function with 
198  limited burden to the patient is preferred.  Sponsors are encouraged to request a 
199  meeting as early as possible with FDA to discuss the incorporation of an existing or a 
200  new assessment tool for older adult patients in AML clinical trials. 
201   
202  c.  Patients with Organ Impairment 
203   
204    For late phase clinical trials of AML drugs, sponsors should enroll a population that is 
205  representative of patients diagnosed with AML, including those with impaired organ 
206  function.16  Appropriate organ impairment studies should have been conducted or the 
207  impact of organ impairment on the exposure of the parent drug and its active 
208  metabolites assessed adequately to provide appropriate dose modifications as stated in 
209  section III.A.3. 
210   
211    For drugs being developed specifically for the treatment of AML in patients with pre-
212  existing comorbidities that preclude use of intensive chemotherapy, FDA has 
213  accepted the following criteria to define the population to be included in the trials that 
214  will support marketing approval: 
215   
216    ECOG performance status > 2, 
217   
218    Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection 
219  fraction  50%, or chronic stable angina), 
220   
221    Severe pulmonary disorder (e.g., DLCO  65% or FEV1  65%), 
222   
223    Creatinine clearance < 45 mL/min, and 
224   
225    Hepatic disorder with total bilirubin > 1.5 time the upper limit of normal. 
226   
227  FDA will consider additional criteria if sponsors can provide data to justify their 
228  proposal.  
229   
                                                 
16 For additional information, see the guidance for industry Cancer Clinical Trial Eligibility Criteria: Patients with 
Organ Dysfunction or Prior or Concurrent Malignancies (July 2020).   
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230  d.  Pregnant Patients  
231   
232    The AML population includes a substantial proportion of young adult females.  
233  Pregnant women may be diagnosed with AML during the course of their pregnancy.  
234  The standard of care in this circumstance is to administer intensive chemotherapy 
235  after the first trimester.  As such, pregnant women with AML in certain 
236  circumstances may be considered for inclusion in AML clinical trials based on a 
237  thorough benefit-risk evaluation and when the trial offers the possibility of direct 
238  benefit to the woman and/or fetus that is unavailable outside the research setting. 
239   
240    Data from relevant nonclinical studies to support safety in pregnant patients should be 
241  available prior to enrolling pregnant women in AML clinical trials.  In addition, 
242  safety data for the drug from previous human exposure, even for indications other 
243  than AML, should be included in the assessment of risks.  
244   
245    When a pregnancy has been identified during an AML clinical trial, the risks and 
246  benefits of continuing versus stopping investigational treatment should be reviewed 
247  with the pregnant woman.  A second informed consent process reflecting additional 
248  benefit-risk considerations is advisable for women who choose to continue treatment 
249  with the investigational drug during pregnancy. 
250   
251    Sponsors should consider meeting with FDA early in drug development to discuss 
252  when and how to include pregnant women in clinical trials.  For a draft of additional 
253  general points to consider when pregnant women are included in clinical trials, see 
254  the draft guidance for industry Pregnant Women: Scientific and Ethical 
255  Considerations for Inclusion in Clinical Trials.17 
256   
257  5.  Safety Reporting Considerations  
258   
259    Patients with AML may have adverse events due to the underlying leukemia.  
260  Additionally, many AML drugs are designed to be myelosuppressive and are 
261  expected to result in complications from the cytopenias.  Nonclinical studies and the 
262  analysis of class effects may also establish expected toxicities for the investigational 
263  drug.  Sponsors should submit a list of the anticipated serious adverse events that the 
264  sponsor does not plan to report individually in an expedited manner to FDA.  An IND 
265  safety report must be submitted to FDA if an aggregate analysis indicates that the 
266  adverse events are occurring more frequently in the drug treatment group per 21 CFR 
267  312.32(c)(1)(i)(C).  Additional information can be found in the guidance for industry 
268  and investigators Safety Reporting Requirements for INDs and BA/BE Studies 
269  (December 2012).  
270   
271    Although investigators are required to report all serious adverse events to the sponsor 
272  immediately (312.64(b)), this requirement may be burdensome and not useful when a 
273  large proportion of the serious adverse events are expected at a high rate, such as 
                                                 
17 April 2018.  When final, this guidance will represent the FDAs current thinking on this topic. 
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274  might occur with the cytopenic complications of treatment of AML.  Sponsors may 
275  propose an alternative reporting arrangement for investigators in the protocol or in a 
276  specific waiver request to FDA, and FDA will provide comment on whether the 
277  alternative reporting arrangement is acceptable.  For early phase trials, the alternative 
278  reporting arrangement is likely to be limited to an alternative timeframe for the 
279  investigator to report a serious adverse event to the sponsor; not reporting a serious 
280  adverse event at all would be unacceptable.   
281   
282    Patients with AML may experience relapse while on treatment or during study 
283  follow-up.  AML-related events, such as relapse or death from relapse, should not be 
284  submitted by the sponsor as an IND safety report unless there is evidence suggesting 
285  a causal relationship between the investigational drug and the adverse event, such as 
286  an aggregate analysis showing that relapse occurred more frequently in the 
287  investigational treatment group.    
288   
289  B.  Efficacy Endpoints 
290   
291  1.  Time-to-Event Endpoints Used Commonly for AML 
292   
293  a.  Overall Survival (OS) 
294   
295    OS is defined as the time from randomization to the date of death from any cause.   
296   
297    For patients who are alive at the data cut-off, the observations for time-to-event are 
298  censored at the last date of documented survival. 
299   
300  b.  Event-Free Survival (EFS) 
301   
302    For studies of drugs for the treatment of AML, EFS is defined as the time from 
303  randomization to the date of:  
304   
305    Induction treatment failure (ITF), 
306    
307    Relapse for those who have induction treatment success (e.g., complete remission 
308  (CR)), or  
309   
310    Death from any cause,  
311   
312  whichever comes first.  For patients who achieve induction treatment success and are 
313  alive and in remission at the data cut-off, EFS should be censored at the last 
314  assessment date.  See the discussion of duration of remission in section III.B.2.a. 
315   
316    ITF is defined as failure to achieve the initial interim efficacy endpoint within a 
317  prespecified period of time.  For example, for studies of intensive induction regimens 
318  for first-line treatment of AML, the recommended definition of ITF is failure to 
319  achieve morphological CR within 42 days of start of the last cycle of induction 
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320  chemotherapy.  Because the induction period can be variable and prolonged, it raises 
321  ambiguities about how to define time to treatment failure.  Therefore, day 1 of 
322  treatment should be assigned as the event date for patients with ITF.   
323   
324    The credibility of the results of EFS analyses are highly dependent on the quality of 
325  the data.  Many of the data quality issues for EFS are similar to those encountered 
326  when using progression-free survival for studies of treatments for solid tumors.  For 
327  additional general points to consider when using such an endpoint, see the guidance 
328  for industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
329  (December 2018). 
330   
331  c.  Relapse-Free Survival (RFS) 
332   
333    RFS may be acceptable as an endpoint specifically in studies of treatments for 
334  patients with AML in remission, such as the consolidation or maintenance phases.   
335   
336    For studies of drugs for the treatment of AML, RFS is defined as the time from 
337  randomization to the date of relapse or the date of death from any cause, whichever 
338  comes first.  For patients alive and in remission at the data cut-off, RFS should be 
339  censored at the last assessment date.   
340   
341  d.  Statistical Considerations for Time-to-Event Endpoints 
342   
343    The general principles for the design and analysis of clinical trials as outlined in ICH 
344  E9 apply to trials of treatments for AML.  The bullets below are additional 
345  considerations specific to AML trials and can also be thought of as discussing 
346  specific attributes of the estimand concept, which is further discussed in the draft ICH 
347  guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: 
348  Estimands and Sensitivity Analysis in Clinical Trials.18  
349   
350    For time-to-event endpoints in a randomized trial for AML, the primary analysis set 
351  consists of all randomized subjects.  With respect to the primary analysis method, 
352  FDA has accepted the log-rank test.  Although FDA is open to discussion about other 
353  methods, it is incumbent on the sponsor to provide the required justification.  
354  Additional summary metrics that should be reported include the estimated medians 
355  (where meaningful), hazard ratios, and 95% confidence intervals.  
356   
357    It is common for some but not all patients with AML to undergo allogeneic HSCT 
358  after or in conjunction with an investigational drug, which may impact EFS or RFS.  
359  Additionally, as more effective drugs for AML are approved, post-study treatment 
360  may impact OS.  As these treatments are integral to the practice of medicine, the 
361  primary analysis of these endpoints should be conducted without censoring for such 
                                                 
18 June 2017.  When final, this guidance will represent the FDAs current thinking on this topic.   
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362  treatment.19  For additional discussion about survival analyses when HSCT is a post-
363  study treatment, see Appendix 2.  
364   
365    Trials designed to cure AML often result in survival contours characterized by an 
366  initial drop followed by a plateau.  For additional discussion about analysis when 
367  there is a survival plateau, see Appendix 2.   
368   
369    Secondary and sensitivity analyses of time-to-event endpoints should follow a 
370  prespecified statistical analysis plan.  These analyses may include the use of 
371  alternatively-defined endpoints (e.g., alternative definition of time to ITF other than 
372  day 1 when using EFS), alternatively-defined populations, or using alternative 
373  analysis methods. 
374   
375  2.  Binary Endpoints Used Commonly for AML    
376   
377  a.  Complete Remission (CR) 
378   
379    For documentation of CR, FDA has used the following definition: 
380    
381    Marrow blasts < 5% by morphological examination,  
382    Absolute neutrophil count (ANC) > 1 Gi/L,  
383    Platelet count > 100 Gi/L,  
384    Absence of leukemic blasts in the peripheral blood by morphological 
385  examination, and  
386    No evidence of extramedullary disease.   
387   
388    The protocol should provide for maximum windows of time between marrow 
389  sampling and peripheral blood tests used to establish CR.  For the response 
390  assessment of extramedullary disease, invasive testing should be limited only to sites 
391  involved with AML at baseline that cannot be evaluated directly by general physical 
392  examination, unless invasive testing is considered standard of care.  The date of 
393  marrow sampling is assigned as the CR date.  Missing data is considered failure to 
394  achieve CR.  Additional considerations may be needed depending on the extent of 
395  missingness, how differential it is between the arms when the AML study is 
396  randomized, and whether the study is open-label.  See section III.D.4 for a 
397  discussion of trial procedures critical to the assessment of CR and section IV.B.1 for 
398  the discussion of the adjudication of CR for the purpose of labeling. 
399   
400    For CR, the duration of remission (DOR) is defined as the time from CR to 
401  hematological relapse or death from any cause, whichever comes first.  Adequate 
402  follow-up is required in order to establish that the durability of CR is meaningful.    
403   
                                                 
19 See the draft treatment policy discussion in the draft ICH E9(R1).  When final, this guidance will represent the 
FDAs current thinking on this topic.  
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404    Hematological relapse is defined as marrow blasts > 5% by morphology, persistent 
405  reappearance of blasts in the peripheral blood by morphology, or the occurrence of 
406  extramedullary disease.  In general, once CR is confirmed by marrow examination, 
407  further follow-up for relapse may be limited initially to physical examination and 
408  peripheral blood tests.  The known time to relapse for the regimen in the control arm 
409  or from other historical data should be used when planning the frequency and 
410  duration of testing for relapse, but in order to determine DOR, EFS, and RFS as 
411  accurately as possible, the assessments would likely be performed more frequently 
412  than in standard practice.  When relapse is suspected on the basis of the follow-up 
413  physical examination or peripheral blood counts, additional testing may be performed 
414  to confirm the finding, but the date of relapse is set to the date of the first test that 
415  suggests relapse. 
416   
417  b.  CR with Partial Hematological Recovery (CRh)  
418   
419    Use of CRh as an endpoint is applicable to drugs that are relatively nontoxic and 
420  nonmyelosuppressive, as might be used for palliative purposes. 
421   
422    For documentation of CRh, FDA has used the following definition:  
423   
424    Marrow blasts < 5% by morphological examination,  
425   
426    ANC > 0.5 Gi/L and platelet count > 50 Gi/L, but the count recovery criteria for 
427  CR are not met, 
428   
429    Absence of leukemic blasts in the peripheral blood by morphological 
430  examination, and  
431   
432    No evidence of extramedullary disease.    
433   
434    Since the potential utility of CR as an endpoint is similar to that of CRh in this 
435  setting, the actual endpoint used is CR+CRh.  Adequate follow-up is needed in order 
436  to establish that the durability of CR+CRh is meaningful.   
437   
438  c.  Transfusion-Independence (TI) 
439   
440    Durable TI as an endpoint is applicable to drugs that are relatively nontoxic and 
441  nonmyelosuppressive, as might be used for palliative purposes.  
442   
443    When durable TI is used, this endpoint should be supported by evidence showing an 
444  effect of the treatment on an endpoint reflecting antileukemia activity.  TI as an 
445  endpoint for the treatment of AML should also be distinguished from TI as used in 
446  the evaluation of hematopoietic growth factors (e.g., for the treatment of anemia) 
447  where the effect of the drug is directed at normal hematopoietic cells rather than at 
448  the leukemia.   
449   
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450    TI is defined as the absence of red blood cell and platelet transfusions for a 
451  prespecified period of time during continued treatment.  The credibility of the data is 
452  dependent on the protocol specifying the minimal parameters for use of transfusions 
453  and documentation that the instructions were followed.  Hence, an important 
454  supporting analysis would include an assessment of serial measurements of 
455  hemoglobin and platelet counts to ensure that the observed TI was an actual treatment 
456  effect and not a bias in the administration of transfusions by the investigator. 
457   
458    TI should be assessed as a response achieved in the subgroup of patients who were 
459  transfusion dependent (TD) at baseline (conversion from TD to TI with treatment) 
460  separately from the subgroup of patients who were TI at baseline (maintenance of TI 
461  with treatment).  For patients with active AML, transfusion dependence at baseline is 
462  based on the receipt of any red blood cell or platelet transfusions within at least 28 
463  days prior to the start of study treatment.  Analyses of red blood cell TI and platelet 
464  TI separately should be used to establish consistency of the components of the TI 
465  endpoint. 
466   
467  d.  Statistical Considerations for Binary Endpoints 
468   
469    For single-arm AML trials, the analysis set consists of all patients treated with 
470  investigational drug.20  If the labeling claim is limited by the target of the drug (e.g., 
471  AML with a FLT3 mutation for a drug that is a FLT3 inhibitor), the analysis set 
472  should include only those patients confirmed positive for the target using the 
473  proposed companion diagnostic or bridged clinical trial assay.  For binary endpoints, 
474  proportions and their 95% confidence interval should be reported.  
475   
476    For randomized AML trials, the analysis set consists of all randomized patients.  For 
477  binary endpoints, the primary analysis may be based on Fishers Exact test; the 
478  Cochran-Mantel-Haenszel test may apply when stratification factors were used at 
479  randomization.  Proportions and their 95% confidence intervals should be reported. 
480  Any additional metrics to quantify the treatment effect, such as the difference in 
481  proportions, ratio of proportions or odds ratio, should be prespecified.  For targeted 
482  drugs, a secondary analysis should be performed where the analysis set is restricted to 
483  patients confirmed positive for the target. 
484   
485    DOR may be calculated using the Kaplan-Meier method using relapse or any-cause 
486  death as events.  Estimated median and range should be reported.  When the number 
487  of study subjects is small, or when follow-up is short, the Kaplan-Meier estimate may 
488  not be stable.  In this circumstance, the observed median and range of observed DOR 
489  may be reported.  Sensitivity analyses may include calculation of DOR including 
490  nonprotocol antileukemia treatment in the absence of documented relapse as an 
491  additional event, or calculation of DOR with censoring at HSCT.   
492   
                                                 
20 In cases of personalized products with the potential for a high rate of manufacturing failure, additional efficacy 
analyses based on enrolled patients may be needed even in a single-arm trial in order to assess the impact of 
manufacturing failure on the efficacy endpoint. 
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493  3.  Minimal Residual Disease (MRD)-Based Endpoints 
494   
495    For new drugs that have a demonstrated durable CR in patients with relapsed or 
496  refractory acute leukemia, FDA has accepted marrow MRD of less than 0.01% as 
497  supporting evidence of efficacy.  As technologies improve and new clinical findings 
498  emerge, the level of MRD needed to support an efficacy claim for AML may change. 
499   
500    CR as defined in section III.B.2 is the preferred timing to assess MRD as a response 
501  endpoint.  If assessments are made at CR without count recovery (CRi), or at lesser 
502  responses, to support a claim of efficacy, the sponsor should include data to justify 
503  the validity of the plan.  The recommended analyses of MRD-based response 
504  endpoints are similar to those for CR discussed in section III.B.2.  When used as a 
505  binary endpoint, the denominator for the analysis of MRD response should be all 
506  treated patients (single-arm trial) or the ITT population (randomized trial), and the 
507  numerator should be all patients who achieved CR and the required level of MRD.  
508  Missing data should be imputed as a failure. 
509   
510    Using MRD-based definitions to identify relapse for the purposes of determining 
511  DOR, EFS, or RFS can be challenging in studies of new treatments for AML, since 
512  that would require frequent marrow sampling.  It may be more practical to monitor 
513  for hematological relapse as described in section III.B.2 for the DOR, EFS, and RFS 
514  definitions unless there is a validated MRD assay using peripheral blood samples.  
515   
516    For additional information on the use of MRD as an efficacy endpoint, see the 
517  guidance for industry Hematologic Malignancies:  Regulatory Considerations for 
518  Use of Minimal Residual Disease in Development of Drug and Biological Products 
519  for Treatment.  
520   
521  4.  Other Potential Measures of Efficacy for AML 
522   
523    FDA acknowledges that as technology progresses and clinical trial data accumulate, 
524  alternative biomarkers or measures of efficacy may be proposed for use as endpoints 
525  in AML clinical trials.  When considering the use of efficacy endpoints other than 
526  those listed above, especially in a trial to be used to support a marketing application, 
527  sponsors should obtain advice from FDA about the acceptability of the proposed 
528  novel endpoint prior to initiating the trial.  
529   
530    Key efficacy endpoints may also include well-defined and reliable patient-focused 
531  outcome measures.  When used as the basis of a claim of treatment of AML, such 
532  endpoints should be supported by data showing that the treatment also has a direct 
533  effect on the leukemia.  For additional information, refer to the guidance for industry 
534  Patient-Reported Outcome Measures: Use in Medical Product Development to 
535  Support Claims (December 2009).  
536   
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537    Sponsors planning to use real world data21 to support an AML drug marketing 
538  application should obtain advice from FDA at the time of protocol development to 
539  ensure that the data sources will provide the data needed to assess the treatment 
540  effect.  Important considerations include whether the sources capture the data 
541  elements (e.g., marrow results, peripheral blood differentials, etc.) to derive clinically 
542  accepted endpoints for demonstrating efficacy, and if so, the extent of 
543  misclassification, the timing of assessment, and the frequency of assessment.  
544  Sponsors should plan for additional discussions regarding alternative measures if the 
545  data sources do not capture the key elements of the clinically accepted endpoints. 
546    
547  C.  Exploratory Trial Considerations   
548   
549  1.  First-in-Human (FIH) Trials   
550   
551    Conducting an FIH trial in patients with rapidly progressing acute leukemias has 
552  several challenges; the doses used in the first cohorts may be subtherapeutic, and the 
553  assessment of toxicity may be confounded by adverse events due to the underlying 
554  leukemia.  Where feasible, sponsors should consider alternative designs for the FIH 
555  trial that would identify a pharmacologically-active dose before commencing the 
556  dose-escalation trial in patients with AML.  For example, the sponsor may consider a 
557  limited window study over a short interval (days to weeks) prior to the administration 
558  of a standard treatment or conducting the initial dose escalation in patients with more 
559  slowly growing tumors (solid tumors or lymphoma).  Where applicable, sponsors 
560  may also consider the FDAs Model Informed Drug Development (MIDD)22 pathway 
561  to help select the appropriate doses for efficacy and safety evaluation. 
562   
563    Historically, the most effective regimens for the treatment of AML have been 
564  combination regimens.  Nonetheless, the FIH trial should be limited to assessment of 
565  one drug at a time, and study of the combination should not commence until there is 
566  adequate information about safety and tolerability of the individual drugs.  Rare 
567  exceptions to this principle are described in the guidance for industry Codevelopment 
568  of Two or More New Investigational Drugs for Use in Combination (June 2013). 
569   
570    An FIH trial of a myeloablative drug to be used as a single-agent preparative regimen 
571  for HSCT for the treatment of patients with AML may be feasible, but prior to 
572  submission of the investigational new drug application (IND), sponsors should obtain 
573  advice from FDA about the optimal approach for development of such drugs.  An 
574  FIH trial of a new drug in combination with a preparative regimen is rarely 
575  acceptable.23   
                                                 
21 For additional information, see Framework for FDAs Real-World Evidence Program at 
https://www.fda.gov/media/120060/download and the draft guidance for industry Submitting Documents Using 
Real-World Data and Real-World Evidence to FDA for Drugs and Biologics (May 2019).  When final, this guidance 
will represent the FDAs current thinking on this topic. 
22 See the Federal Register (83 FR 16868, April 17, 2018). 
23 An example of an exception would be for a cell therapy where there is no scientific justification for study of the 
cell therapy in the absence of a prespecified standard preparative regimen.  
 
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576   
577    Although many drugs developed for the treatment of AML are highly 
578  myelosuppressive and/or genotoxic, in select cases it may be possible to conduct the 
579  FIH trial in healthy volunteers.  The advantage to this approach is that the safety 
580  profile may be simpler to determine in the absence of confounding adverse events due 
581  to the underlying leukemia.  FDA recommends that sponsors request feedback on the 
582  design of FIH trials of new AML drugs in healthy volunteers, including the 
583  limitations in exposure and other restrictions needed to protect healthy volunteers 
584  participating in such studies.24 
585   
586    For AML drugs that are CYP3A substrates, sponsors should consider enrolling 
587  patients on azole antifungals or other CYP3A inhibitors in FIH trials to generate data 
588  needed to select a safe dose with these concomitant drugs (see section III.A.3).   
589   
590    Sponsors developing cellular or gene therapy products for the treatment of AML 
591  should also consult the guidance for industry Considerations for the Design of Early-
592  Phase Clinical Trials of Cellular and Gene Therapy Products (June 2015) and the 
593  guidance for industry Long Term Follow-Up after Administration of Human Gene 
594  Therapy Products.  
595   
596  2.  Exploratory Trial Population 
597   
598    For dose-escalation trials being conducted to determine the maximum tolerated dose 
599  (MTD), the eligible population is usually limited to patients who have failed all 
600  conventional drugs.  Patients with subtypes of AML that respond very poorly to 
601  conventional drugs, such as those with high-risk genetic abnormalities, might also be 
602  considered for such trials even without prior treatment, but if doing so, the consent 
603  form should clearly state the implications of foregoing conventional drugs in order to 
604  participate in the clinical trial.  
605   
606    The benefit-risk ratio for participation in a dose-escalation trial may also be 
607  acceptable for patients with MRD after treatment with conventional drugs for AML, 
608  but such protocols should include a description of the evidence that justifies the risks 
609  of such a study compared to the prognosis based on the level of MRD proposed for 
610  eligibility. 
611   
612    For dose-escalation trials being conducted to determine the RP2D, the eligibility 
613  criteria that address organ function and comorbidities should be commensurate with 
614  the target patient population.  For example, if developing a drug for the treatment of 
615  AML in patients with renal or hepatic impairment, including patients with only 
616  normal renal or hepatic function might conclude with a dose that is safe in patients 
617  with normal organ function but that is too toxic for the target population with organ 
618  impairment.   
                                                 
24 See also the guidance for industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers (July 2005). 
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619   
620    Multiple genetic mutations and molecular pathways have been identified as 
621  contributing to the pathogenesis and persistence of AML.  For new drugs proposed to 
622  target these mutations or pathways, the clinical development program should have an 
623  early phase trial that includes patients with and without the putative target in order to 
624  assess the need in later phase trials to select patients based on the presence of the 
625  target.  Including marker-negative patients might not be necessary for drugs that 
626  target a cell surface receptor, especially when preclinical data suggest no potential for 
627  a therapeutic effect in the absence of the cell surface receptor.    
628   
629  3.  Dose-Escalation Trials 
630   
631    For dose-escalation trials, the general principles for selection of the safe starting dose 
632  and the frequency of administration as described elsewhere25 also apply to drugs 
633  being developed for the treatment of AML.  As discussed in section III.C.1, the safe 
634  starting dose for a study in patients with active AML may differ from the starting 
635  dose for a study in healthy volunteers.  The nonclinical data should also be used to 
636  determine the slope of the dose-toxicity curve, the anticipated therapeutic dose range, 
637  and the maximal exposure in order to plan the increments in dose between cohorts in 
638  the escalation.  For drugs that are CYP3A substrates, the selection of a safe starting 
639  dose should also consider the concomitant use of drugs that are CYP3A4 inhibitors 
640  such as azole antifungals (see section III.A.3). 
641   
642    The protocol should describe the specific rule-based or model-based criteria used to 
643  guide the decision on whether to proceed with escalating the dose in subsequent 
644  cohorts.  For dose-escalation trials of conventional outpatient chemotherapy for 
645  patients with cancer, escalation to higher doses is generally limited by the rate of 
646  severe, life-threatening, or fatal events (grades 3-5) termed dose-limiting toxicities 
647  (DLTs), and the MTD as identified by the 3+3 rule has no more that 17% DLTs.  This 
648  paradigm, however, is not applicable to all types of treatments for AML.  For 
649  example, such a rule would allow far greater toxicity than acceptable for continued 
650  treatment or maintenance that extends for years.  On the other hand, the rule would 
651  likely result in premature closure of a trial of a preparative regimen for HSCT, where 
652  grade 3 toxicities are common.  Hence, the criteria proposed to guide dose-escalation 
653  decisions should take into account the types, severities, and rates of toxicities 
654  accepted with standard regimens of similar intensity in the intended population (see 
655  Appendix 1 for examples).  The protocol should describe the data that support the 
656  assumptions used to develop the criteria for guiding dose-escalation.   
657   
658    For many cytotoxic drugs used for the treatment of AML, there is a strong dose-
659  response effect, and in order to achieve the highest response rate, the cited goal of the 
660  dose-escalation trial is to identify the MTD.  This is not necessarily true for targeted 
661  drugs, for which the pharmacodynamic effect may plateau at doses lower than 
662  maximally-tolerated.  Hence, the goal of the dose-escalation trial should be to 
                                                 
25 See ICH S9 and ICH S9 Questions and Answers.  
 
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663  determine the RP2D instead.  The protocol should include a definition of the RP2D, 
664  and the determination of the RP2D should take into consideration the safety, 
665  tolerability, pharmacokinetic, pharmacodynamic, and efficacy data (see also section 
666  III.D.2).   
667   
668    Based on the design of the dose-escalation trial, participants in the initial cohorts of 
669  the trial may not receive optimal treatment, which may be a disadvantage for patients 
670  with active AML who are in need of cytoreductive treatment.  Despite the desire to 
671  ensure that patients with AML are treated with pharmacologically-active doses of 
672  drug, intra-patient dose-escalation based on lack of very early response may not be 
673  scientifically valid; a complete characterization of safety, tolerability, and efficacy at 
674  any dose level usually requires treatment for multiple cycles.  Intra-patient dose-
675  escalation may be considered in select circumstances where risks can be minimized 
676  objectively.  For example, if there is an established pharmacodynamic biomarker for 
677  safety, intra-patient dose escalation may be feasible with frequent monitoring of the 
678  biomarker.  Additionally, for patients who have received multiple cycles of treatment 
679  without evidence of cumulative toxicity or therapeutic activity, it may be beneficial to 
680  escalate the individual patient's dose to a higher level if that higher dose has been 
681  established as safe in subsequent cohorts.  The protocol should specify the criteria for 
682  when intra-patient dose escalation is allowed, how the new dose is assigned, any 
683  changes in the monitoring plan needed to accommodate the change in dose, and how 
684  the safety and efficacy data will be evaluated for such patients.  
685   
686    The planned duration of treatment should be described clearly in the protocol.  Long-
687  term treatment may be considered in the dose-escalation trial, typically for patients 
688  with relapsed or refractory AML, but there should be objective criteria for when to 
689  discontinue treatment permanently, including high-grade toxicities.  When treatment 
690  in the dose-escalation trial is planned to extend beyond achievement of CR, a 
691  rationale should be provided for the proposed duration of treatment after remission.  
692  For patients who are taken off the investigational drug after achieving a CR, the 
693  protocol may also address retreatment in case of relapse. 
694   
695    Early phase trials are also the place to determine the expected time to response, 
696  allowing study treatment to continue in the absence of toxicity unless prespecified 
697  levels of disease response have not occurred within a maximum number of cycles.  
698  Such information will provide support for the treatment plan proposed for 
699  confirmatory trials designed to test for efficacy.   
700   
701    For early phase trials of intensive AML drugs given with curative intent, a 
702  maintenance phase is generally not acceptable in settings where there is no 
703  established benefit of maintenance; in such cases, a randomized control arm is 
704  recommended. 
705   
706    Certain toxicities of treatment, such as anemia or tumor lysis syndrome, are expected 
707  with almost any treatment of patients with AML.  Treatment of such usual toxicities 
708  is considered standard practice, and detailed instructions on the practice of medicine 
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709  need not be included in the protocol unless a specific treatment is critical for safe use 
710  of the investigational drug.  Based on established class toxicities, mechanism of 
711  action and/or nonclinical studies, there may also be unusual drug-specific toxicities, 
712  such as differentiation syndrome or cytokine release syndrome.  Until treatment is 
713  standardized in practice, instructions for management of patients with such unusual 
714  drug toxicities should be included in the protocol.  
715   
716  4.  Exploratory Expansion Cohorts 
717   
718    A small cohort of 6-12 subjects treated at the presumptive RP2D can be useful to 
719  confirm safety prior to start of additional trials.  In the absence of data from a safety 
720  expansion cohort, the confirmatory trial should include a very early interim safety 
721  analysis to corroborate safety of the RP2D.   
722   
723    When the new drug is being studied as an add-on and the background regimen has 
724  substantial toxicity (i.e., a standard intensive AML induction regimen), a randomized 
725  comparison may be necessary to detect even large differences in toxicity that might 
726  not be noticed in the single-arm setting.  
727   
728    Responses as defined in section III.B.2 are generally acceptable measures of activity 
729  that should be included in exploratory early phase clinical trials in AML.  Lesser 
730  responses (e.g., partial remission, shorter term transfusion-independence, etc.) may 
731  reflect activity of the drug, but such lesser responses should guide development to 
732  alternative strategies to leverage that activity (i.e., different schedules or use in 
733  combinations) rather than being viewed as a success.   
734   
735    A small cohort of patients treated at the presumptive RP2D can also be used to 
736  provide an estimate of efficacy to support design of additional trials.  Such a cohort 
737  generally includes approximately 20 subjects.  Large single-arm expansion cohorts 
738  solely for exploratory purposes are discouraged.  Any large single-arm trial should 
739  have a design based on clear hypothesis testing, and the protocol should include 
740  justification of the sample size proposed.  
741   
742    Time-to-event endpoints are difficult to interpret in single-arm trials and, therefore, 
743  are generally not useful in assessing efficacy in exploratory early phase trials.  Data 
744  for such endpoints, however, should still be collected, since such data could be useful 
745  in designing the confirmatory trials if other objective measures of efficacy support 
746  further development of the drug.   
747   
748    To ensure the safety of study participants, the expansion cohort plan should include 
749  stopping rules for excessive toxicity that would require pausing enrollment to 
750  evaluate whether the treatment plan should be modified.  The acceptable rate and type 
751  of toxicities will depend on the treatment setting as discussed for development of 
752  DLT criteria in section III.C.3.  The protocol should describe the exact bounds for the 
753  stopping criteria, the statistical method used to calculate the bounds, and the basis for 
754  the clinical assumptions used in the calculation.  FDA recommends that the bounds be 
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755  calculated using nonstringent parameters (i.e., 70% power or 80% posterior 
756  probability), so that the trial can be paused at the earliest sign of excessive toxicity.  
757  For patients with active AML, toxic events for stopping rules might include 
758  treatment-related deaths, prolonged neutropenia lasting past cycle day 42 in the 
759  absence of disease, and high-grade nonhematological adverse reactions. 
760   
761  D.  Confirmatory Trial Considerations 
762   
763  1.  Confirmatory Trial Population 
764   
765    The protocol should use the most updated diagnostic criteria for AML or for a 
766  specific AML type to describe the eligible population.  Sponsors should seek advice 
767  from FDA rather than using outdated criteria solely to match a population used in 
768  support of a past approval. 
769   
770    Patients with newly-diagnosed AML, patients with AML in late first relapse (e.g., 
771  first remission > 6 months), and patients with other relapsed or refractory AML (e.g., 
772  primary refractory, early first relapse, and any second or later relapse) represent three 
773  distinct indications.  A separate trial for each indication is recommended, but separate 
774  cohorts in a single trial may be used for analyses to support each indication 
775  independently.  In the latter circumstance, the protocol should describe clearly the 
776  eligibility criteria for each cohort.  HSCT is considered standard practice in the 
777  treatment of AML, and relapse post HSCT would fall under either treatment of first 
778  relapse or treatment of later relapse rather than being a separate indication. 
779   
780    For clinical trials of a biomarker-selected AML population, the eligibility criteria 
781  should state clearly what assay is to be used to select patients with the cognate target, 
782  the tissue (blood, marrow, etc.) used for the assay, and the level of the target needed 
783  to meet eligibility.  
784   
785    For clinical trials planned to support a marketing application for the intended 
786  population of patients with comorbidities that preclude use of intensive induction 
787  chemotherapy, the eligibility criteria should include detailed parameters that describe 
788  the population.  See section III.A.4.c for examples of criteria for organ impairment 
789  that FDA has accepted to describe this subgroup of patients for AML trials.  
790   
791    For clinical trials being designed to support a marketing application, the eligibility 
792  criteria should reflect the characteristics of the general population with AML.  
793  Exclusion criteria should be limited to disease- or patient-related factors associated 
794  with a lack of benefit or an unacceptable risk of toxicity from the investigational drug 
795  based on data in early phase trials.26  
796   
                                                 
26 For additional discussion, see the draft guidance for industry Enhancing the Diversity of Clinical Trial 
Populations  Eligibility Criteria, Enrollment Practices, and Trial Designs (June 2019).  When final, this guidance 
will represent the FDAs current thinking on this topic. 
 
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797    For clinical trials of noncurative drugs for AML, the eligibility criteria should 
798  specifically exclude patients willing and able to receive intensive curative treatment. 
799    
800  2.  Dose Selection and Treatment Plan 
801   
802    The dose and schedule of the investigational drug in the treatment regimen should be 
803  optimized before initiating the confirmatory trials.  Clinical pharmacokinetic data, 
804  pharmacodynamic data, clinical activity measures, clinical safety data, and 
805  nonclinical pharmacology data, should be pooled for conduct of integrated dose-
806  response and exposure-response analyses for activity and safety for dose 
807  optimization.  The results of such analysis should be included in the protocol to 
808  justify the dose. 
809   
810    For drugs planned to be administered for multiple cycles, and especially for drugs 
811  given long-term on an outpatient basis, tolerability should be taken into consideration 
812  when choosing the dose to be used in the confirmatory trial.  In general, for drugs 
813  planned to be given long-term or over multiple cycles, it is expected that dose 
814  modifications or discontinuations for adverse reactions are limited to less than 20% of 
815  the patients, and that at least 80% dose intensity is achieved over multiple cycles for 
816  at least 80% of the patients.   
817   
818    The protocol should include dose adjustment strategies for specific populations (e.g., 
819  with organ impairment or with concomitant use of moderate and strong CYP3A 
820  modulators) and in response to emerging adverse events.  The experience with these 
821  instructions during study conduct provides the basis for dose modification 
822  instructions in labeling. 
823   
824  3.  Confirmatory Trial Design   
825   
826  a.  General Considerations for Confirmatory Trial Designs 
827   
828    The principles of designing trials to demonstrate efficacy for the purposes of 
829  supporting a marketing application are described in general guidance,27 and these 
830  general principles are applicable to trials for AML drugs.  The bullets below provide 
831  additional advice specific for the trials of treatments for AML. 
832   
833    To prevent bias in study conduct or in selection of poststudy treatments, the use of 
834  blinded treatments where feasible is recommended for randomized trials. 
835   
836    The use of specific genetic targets and other prognostic factors used for eligibility or 
837  risk stratification should be described in detail.  For patients with relapsed or 
                                                 
27 See the draft ICH E8(R1) and E9(R1) (when final these guidances will represent the FDAs current thinking on 
these topics); the ICH guidances for industry E9 and E10; and the draft guidance for industry Demonstrating 
Substantial Evidence of Effectiveness for Human Drug and Biological Products (December 2019) (when final, this 
guidance will represent the FDAs current thinking on this topic).  
  20  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
838  refractory AML, the protocol should state clearly whether these prognostic factors are 
839  measured at the time of diagnosis or at the time of relapse. 
840   
841    Because treatment for AML involves discrete stages of treatment with different goals, 
842  the purpose of treatment with the investigational drug should be stated clearly in the 
843  protocol.  Potential objectives may include remission induction alone, remission 
844  induction followed by consolidation, consolidation of remission alone, remission 
845  maintenance (after chemotherapy or transplantation), or control of complications of 
846  the disease in the relapsed/refractory setting.  
847   
848    If the clinical trial has goals in multiple stages of treatment, sequential 
849  randomizations may be needed.  For example, if a maintenance indication is planned 
850  in addition to initial treatment, patients should be rerandomized prior to maintenance 
851  to allow for isolation of the treatment effect of study drug(s) during maintenance. 
852   
853    A detailed statistical analysis plan stating the trial hypotheses, sample size, analysis 
854  timing, and analysis methods should be submitted before trial initiation.  The sample 
855  size calculation should be based on the expected efficacy in the control arm and the 
856  anticipated treatment effect of the investigational drug with respect to the primary 
857  endpoint in the planned patient population.  Estimating the outcome for the control 
858  arm in a molecular subgroup may be challenging for treatments of AML with new 
859  molecular targets that were not studied previously with standard care regimens.  
860  When there is little extant data to support the assumptions for the anticipated 
861  treatment effect, sponsors may consider an adaptive design or other novel approach.28  
862  In such a case, the sponsor should request feedback from FDA on the proposed 
863  design prior to initiating the trial.  
864   
865    When the design requires an active comparator, the treatment should be standard of 
866  care for the study population (e.g., study drug vs. 7+3).  Placebo comparators may be 
867  considered in add-on trials (e.g., study drug+7+3 vs. placebo+7+3) if appropriate 
868  treatment for the control arm.  Comparative efficacy studies of combinations that do 
869  not isolate the effect of the study drug (study drug+azacitidine vs. 7+3) may also be 
870  acceptable if the control is standard of care for the population, the activity of the 
871  study drug was demonstrated in other trials, and the contribution of each drug in the 
872  new regimen is supported by other data in the context of use. 
873   
874    It is common for multiple efficacy endpoints (i.e., OS, EFS, CR) to be assessed in a 
875  clinical trial for AML.  The statistical analysis plan should prespecify a multiple 
876  testing strategy for important secondary endpoints that adjusts for multiplicity 
877  conditioned on demonstrating a positive outcome for the primary endpoint.  Note that 
878  effects on secondary endpoints are generally not sufficient to support a marketing 
879  application in the absence of demonstration of an effect on the prespecified primary 
880  endpoint.  Additionally, even if an effect on a secondary endpoint is demonstrated, it 
881  may not be acceptable for labeling if it is not an established efficacy endpoint; for 
                                                 
28 For example, see the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics 
(November  2019). 
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Draft  Not for Implementation 
882  example, the composite of CR+CRi may not be suitable for labeling due to the 
883  inclusion of CRi. 
884   
885    In large randomized trials, an interim analysis for futility is strongly recommended to 
886  ensure that the benefit-risk ratio for enrolled patients continues to be favorable.  FDA 
887  has accepted group sequential/early stopping designs for interim analyses.  However, 
888  for certain endpoints, such as EFS or RFS, FDA discourages early stopping for 
889  efficacy based on a positive assessment at the interim analysis.  More follow-up may 
890  be needed to assess other important endpoints, such as duration of response and 
891  safety, that would be needed to determine the overall benefit-risk.  FDA is willing to 
892  discuss the potential pitfalls in a timely fashion when the sponsor is considering early 
893  study termination based on interim efficacy analysis results.  
894   
895    The timing of analysis of continued response (e.g., DOR, RFS, etc.) should be 
896  prespecified to mitigate bias in study result interpretation. 
897   
898  b.  Treatment of AML with Curative Intent 
899   
900    Treatments with an expectation of a survival plateau are considered treatment with 
901  curative intent.  Examples include standard intensive chemotherapy as first-line 
902  treatment for AML. 
903    
904    FDA has accepted OS, EFS, and RFS as clinical endpoints that represent clinical 
905  benefit for traditional approval for treatments with curative intent.  
906   
907    AML is a heterogenous disease, and historical controls are severely limited in their 
908  ability to accurately parallel the intended population for the indication.  Therefore, the 
909  use of historical controls in AML is not appropriate for studies of treatment with 
910  curative intent.  Trials intended to support a marketing application for this indication 
911  should have a randomized control arm.  
912   
913  c.  Treatment of AML without Curative Intent 
914   
915    Treatments with no expectation of a survival plateau, but where the goal is to extend 
916  survival or greatly improve durable CR relative to a control, are considered treatment 
917  without curative intent for AML.   
918   
919    FDA has accepted OS and EFS as clinical endpoints that represent clinical benefit for 
920  traditional approval for treatments without curative intent.  For studies in populations 
921  with a very high rate of induction treatment failure or when OS is expected to be 
922  short, OS may be the more practical endpoint to establish clinical benefit.  Durable 
923  CR may also support traditional approval depending on the disease setting and 
924  benefit-risk ratio. 
925   
926    Trials intended to support a marketing application for this indication may be 
927  randomized or single-arm in design, depending on the endpoint, patient population, 
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Draft  Not for Implementation 
928  and available therapy.  FDA recommends that sponsors request advice from FDA on 
929  proposed study designs for this indication. 
930   
931  d.  Treatment of AML with Palliative Intent 
932   
933    Nonintensive treatments without substantial associated toxicities administered with 
934  the goal of temporary disease control and minimal treatment burden are considered 
935  treatment with palliative intent in AML.   
936   
937    Durable TI may represent a direct clinical benefit resulting from the relief from the 
938  burdens of insufficient hematopoiesis due to active AML.  FDA has accepted durable 
939  CR and durable CR/CRh with TI as clinical endpoints that represent clinical benefit 
940  for traditional approval for treatments with palliative intent.  
941   
942    Trials intended to support a marketing application for this indication may be 
943  randomized or single-arm in design depending on the endpoint, patient population, 
944  and available therapy.  Best supportive care may be acceptable as a comparator in a 
945  randomized trial only for a patient population without available therapies.  In certain 
946  clinical settings, a single-arm trial may be appropriate for traditional approval if there 
947  are adequate historical data to support the null hypothesis.  
948   
949  4.  Confirmatory Trial Procedures 
950   
951    Baseline demographic and disease characteristics are used to ensure consistency of 
952  the benefit-risk by subgroup analyses.  The following key AML-specific information 
953  should be documented and collected on the case report forms: 
954   
955    Disease (WHO-based diagnosis29), 
956   
957    Disease status at enrollment (e.g., newly-diagnosed, 2nd relapse, etc.),  
958   
959    Response status at enrollment (primary refractory vs. untreated vs. refractory 
960  relapse), 
961   
962    Duration of first remission, 
963   
964    Genetic profile and/or risk group at diagnosis and at enrollment (use of the most 
965  contemporary accepted risk stratification is recommended), 
966   
967    All prior treatments for AML, 
968   
969    Baseline functional assessments (where applicable, geriatric assessment is 
970  recommended), and  
971   
                                                 
29 See footnote 4.  
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972    Relevant comorbidities (see section III.A.4.c).  
973   
974    Patients with AML receiving intensive chemotherapy or high-dose chemotherapy for 
975  transplantation are expected to have a high rate of low-grade adverse reactions.  For 
976  studies of drugs with well-established safety profiles, consideration should be given 
977  to collection of a limited amount of safety data.30  For new drugs with unclear safety 
978  profiles, all adverse events should be collected regardless of grade or attribution. 
979   
980    To ensure that data will be available for the assessment of potential interactions 
981  between new drugs and other drugs used commonly for patients with AML, the dates 
982  and doses of concomitant medications, especially antifungal medications, should be 
983  accurate.   
984   
985    To assess confounding in efficacy analyses due to subsequent post-study treatments, 
986  the following post-study information should be documented and collected on the case 
987  report forms: 
988   
989    At least the first post-study salvage treatment and the reasons for the treatment 
990  choice and 
991   
992    HSCT and CAR T cell dates for patients proceeding to transplantation with an on-
993  study response or as a post-study salvage treatment.  
994   
995   
996  IV.  REGULATORY SUBMISSIONS 
997   
998  A.  Investigational New Drug Applications 
999   
1000    General requirements for INDs apply to AML.  See sections III.A and III.C for 
1001  recommendations on submission of FIH trials in AML as the IND-initiating study.  
1002  Sponsors may request advice from FDA through the pre-IND program.   
1003   
1004    FDA supports the use of innovative trial designs, such as master protocols, for 
1005  efficient drug development in AML.  For IND submissions that contain innovative 
1006  trial designs, FDA recommends consultation through the pre-IND program.  For 
1007  additional draft recommendations, see the draft guidance for industry Master 
1008  Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of 
1009  Oncology Drugs and Biologics.31  
1010   
1011    A companion diagnostic may be essential for patient selection in IND protocols for 
1012  targeted AML drugs.  Sponsors may request a study risk determination directly from 
1013  CDRH or in concert with the IND (see the guidance for industry Investigational In 
                                                 
30 See the guidance for industry Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket 
and Postapproval Clinical Investigations (February 2016). 
31 September 2018.  When final, this guidance will represent the FDAs current thinking on this topic. 
  24  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1014  Vitro Diagnostics in Oncology Trials:  Streamlined Submission Process for Study 
1015  Risk Determination (October 2019) to determine whether an IDE is needed).  See also 
1016  section III.A.2.   
1017   
1018  B.  Marketing Applications  
1019   
1020  1.  Assessment of Efficacy  
1021   
1022    Assessments of efficacy in AML clinical trials are generally based on objective 
1023  criteria, such as neutrophil counts and marrow blast percentage.  To allow FDA to 
1024  confirm the analyses of the treatment effect, the raw data supporting the study 
1025  endpoints should be submitted in the marketing application. 
1026   
1027    If bone marrow pathology results exceed the character limit for a variable in an 
1028  xpt file, a pdf of the report may be acceptable.  
1029   
1030    To assist with the adjudication of responses, the submission should include a 
1031  summary response file (see Appendix 3) for the confirmatory study and for the 
1032  integrated efficacy population.  
1033   
1034    For studies with an endpoint of TI (see section III.B.2.c), the submission should 
1035  include a summary transfusion analysis data file (see Appendix 3) for at least the 
1036  confirmatory study.   
1037   
1038    To assist with the assessment of response and TI, the submission should include a 
1039  file with the dates of RBC and platelet transfusions and the number of units 
1040  transfused. 
1041   
1042  2.  Assessment of Safety 
1043   
1044    Patients with AML have a high background of adverse events due to the leukemia.  
1045  Assessment of toxicities of the new AML drug in different disease settings (e.g., solid 
1046  tumor patients) and in healthy volunteers is helpful in ascertaining causality of 
1047  adverse events.  
1048   
1049    To assist with the adjudication of causality of fatal adverse events, the submission 
1050  should include a data file with the date of death, study day of death, proximate cause 
1051  of death (usually as reported by the investigator), and the root cause of death as 
1052  determined by the sponsor.  The root cause is generally categorized as a direct effect 
1053  of active AML, an adverse reaction, or an unrelated intercurrent event (such as car 
1054  accident).  When the sponsor is considering additional categories for root cause, such 
1055  as early death, feedback on the proposed categories should be sought at the 
1056  presubmission meeting.  
1057   
1058    For drugs with unusual adverse reactions, such as differentiation syndrome, FDA 
1059  encourages sponsors to meet with FDA review staff prior to submission of a new drug 
  25  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1060  application (NDA) or biologics license application (BLA) to develop a detailed 
1061  methodology for identifying cases, determine when additional narratives should be 
1062  included in the submission, and to discuss the structure of the data files to be used for 
1063  the analysis of such cases.  
1064   
1065    When the study drug is used in multiple stages of AML treatment (e.g., in 
1066  combination with induction, in combination with consolidation, and as maintenance), 
1067  safety and laboratory data should be assessed by treatment stage. 
1068   
1069    When a randomized trial has a comparator arm with a different duration of treatment 
1070  (e.g., continuous oral therapy vs. a fixed duration of intensive salvage chemotherapy), 
1071  it is important to compare toxicities between study arms for a similar duration of 
1072  treatment.  For long-term continuous treatment with investigational drug, safety 
1073  beyond the period of comparison should be analyzed separately and compared to 
1074  early-period toxicities to identify unique late-onset adverse reactions. 
1075   
1076    For myelosuppressive AML drugs, an analysis should be performed to determine the 
1077  incidence of prolonged thrombocytopenia (platelets < 50 Gi/L) or neutropenia (ANC 
1078  < 0.5 Gi/L) past cycle day 42 in the absence of active leukemia.   
1079   
1080  3.  Clinical Pharmacology  
1081   
1082    If the AML drug is a CYP3A substrate, the submission should include analyses of the 
1083  effect of concomitant drugs, including moderate and strong CYP3A inhibitors and 
1084  inducers on the systemic exposure of parent drug and its active metabolites, on safety 
1085  and efficacy, and whether the available safety and efficacy data support the proposed 
1086  dose modifications for concomitant treatment with moderate and strong CYP3A 
1087  inhibitors and inducers (see section III.A.3).  If the AML drug or its major 
1088  metabolite(s) is an inhibitor or inducer of metabolism enzymes or transporters, the 
1089  submission should include analyses of the effect of the parent drug and major 
1090  metabolites on the systemic exposure of concomitant drugs that are substrates of 
1091  metabolism pathway or transporter and have a likelihood of coadministration (e.g., 
1092  commonly-used antibiotics, other AML drugs in the combination regimen). 
1093   
1094  For submissions specifically for indications that target the population of patients with 
1095  comorbidities that preclude use of intensive chemotherapy for AML, the submission should 
1096  include the results of studies on the effects of renal and hepatic impairment on the systemic 
1097  exposure of the parent drug and its active metabolites (see section III.A.3).     
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Draft  Not for Implementation 
1098  GLOSSARY 
1099   
1100  A.  Terms referring to the types of AML treatment are defined as follows when used in this 
1101  guidance 
1102   
1103  Episodic treatment:  A treatment plan of multiple cycles of short-term administrations of 
1104  intensive treatment.  A typical course of episodic first-line treatment for AML consists of 1-2 
1105  cycles of induction and 2-4 cycles of consolidation with or without HSCT. 
1106   
1107  Continuous treatment:  Repeated cycles of treatment, usually without a drug-free period.  A 
1108  typical course of continuous treatment of AML consists of daily dosing. 
1109   
1110  B.  Terms referring to phases of AML treatment are defined as follows when used in this 
1111  guidance 
1112   
1113  Induction:  A limited course of treatment, usually intensive, with the objective of achieving 
1114  CR. 
1115   
1116  Consolidation:  A limited course of treatment, usually intensive, given after achievement of 
1117  remission with the objective of reducing the risk of early relapse. 
1118   
1119  Maintenance:  An extended but time-limited course of treatment, usually relatively 
1120  nontoxic, given after achievement of CR with the objective of reducing the risk of relapse 
1121  beyond the period of treatment.  When the treatment plan allows for extended therapy for 
1122  patients without achieving CR, the course is considered continued treatment rather than 
1123  maintenance. 
1124   
1125  Continued treatment:  An extended course of treatment after induction phase with the 
1126  objective of controlling the AML disease burden while on therapy.  Continued treatment may 
1127  be time-limited, but it is generally administered until unacceptable toxicity or recurrence 
1128  after a response.    
1129   
1130  C.  Terms referring to intensities of AML treatment are defined as follows when used in this 
1131  guidance 
1132   
1133  Intensive therapies:  regimens expected to cause high-grade organ toxicity (including 
1134  neurologic, pulmonary, cardiac, gastrointestinal, genitourinary, renal, hepatic, or cutaneous 
1135  toxicities) or where the expected duration of neutropenia may approach 42 days from the 
1136  start of the treatment cycle.  Intensive regimens include 1-2 cycles of induction followed by 
1137  consolidation with chemotherapy or HSCT.   
1138   
1139  Nonintensive therapies:  lower doses of cytotoxic chemotherapy or targeted drugs with 
1140  limited or no expected organ toxicities.  
1141   
  27  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1142  D.  Disease status is assessed at the time of study enrollment.  Terms relevant to AML 
1143  disease status are defined as follows when used in this guidance  
1144   
1145  Primary refractory disease:  The patient did not experience CR in response to first-line or 
1146  any subsequent induction therapy.  
1147   
1148  Untreated relapse:  The patient experienced CR in response to the last prior therapy, then 
1149  demonstrated relapse and has not yet received definitive re-induction therapy for that relapse.  
1150   
1151  Refractory relapse:  The patient experienced disease remission in response to past therapy, 
1152  then demonstrated relapse and was treated with definitive re-induction therapy but did not 
1153  experience CR with this re-induction. 
1154   
1155  Line of therapy:  A line of therapy is defined as the planned therapy consisting of one or 
1156  more cycles of episodic treatment or a defined period of continuous treatment.  This may 
1157  consist of single-agent or combination therapy as well as a planned sequence of treatment 
1158  phases.  For example, first-line treatment of AML with induction, consolidation, and 
1159  allogeneic HSCT is considered one line of therapy.  A line of therapy ends when the patient 
1160  fails to achieve a response within a prespecified period (refractory) or relapses after 
1161  achieving CR.   
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1162  APPENDICES 
1163   
1164  Appendix 1:  Example DLT Criteria for Drugs for AML 
Setting  Hematological SAR Criteriaa  Nonhematological SAR Criteria 
Healthy Volunteer Study  Any grade > 2  Any grade > 2 
Continuous Long-Term  Any grade > 3 ANC or PLTS  Any grade 3 lasting > 72 hours 
Treatment (e.g.,  lasting more than 7 days 
Any grade > 4 
maintenance, extended 
treatments like imatinib)  Hy's law cases 
Any AR that leads to dose reduction or 
withdrawal 
Short-Term Episodic  Any grade > 4 ANC or PLTS  Any grade 3 (with exceptions) b 
Outpatient Therapy (e.g.,  lasting more than 7 days 
Any grade > 4 
CHOP-like) 
Hy's law cases 
Any AR that leads to dose reduction or 
withdrawal 
Episodic Reduced Intensity  Any grade > 4 ANC or PLTS  Any grade 3 (with exceptions) b 
(e.g., azacitidine)  lasting past cycle day 28  
Any grade > 4 
Hy's law cases 
Any AR that leads to dose reduction or 
withdrawal 
Episodic Intensive  Any grade > 4 ANC or PLTS  Grade > 4 organ toxicityc 
Chemotherapy with  lasting past cycle day 42  
Hy's law cases 
Curative Intent (e.g., 7+3 - 
based) 
CAR T Cells   Any grade > 4 ANC or PLTS  Grade > 3d CRS (with exceptions)b 
lasting past day 42, or marrow 
Grade 3 neurotoxicity (with exceptions)b 
cellularity < 5% at day 42 
Grade 4 neurotoxicity 
Other grade > 3 toxicity to vital organs 
(with exceptions)b,c 
Myeloablative Preparative  No ANC recovery to > 0.5  Grade > 4 organ toxicityc 
Regimen (e.g., high-dose  Gi/L by day 21 (PBSC), 28 
busulfan)  (marrow), or 42 (UCBT) 
Abbreviations: ANC - absolute neutrophil count, AR  adverse reaction, CAR - chimeric antigen receptor, CRS - cytokine 
release syndrome, PBSC - peripheral blood stem cells, PLTS - platelet count, SAR - suspected adverse reaction, and UCBT - 
umbilical cord blood transplantation. 
 
a Not applicable in the presence of active leukemia.  Patients with active leukemia are not evaluable for a hematological DLT. 
b May exclude grade 3 toxicities that resolve within a prespecified time frame (e.g., 72 hours). 
c Adverse reactions involving neurologic, pulmonary, cardiac, gastrointestinal, genitourinary, renal, hepatic, or cutaneous   
  systems. 
d Refers to Lee Criteria for CRS.  In the remainder of the table, grade number refers to NCI-CTCAE criteria. 
1165 
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Draft  Not for Implementation 
1166  Appendix 2:  Additional Statistical Discussion 
1167   
1168  Postrandomization HSCT Subsequent Poststudy Treatments  
1169   
1170  For AML trials, it is common for patients to receive subsequent anti-AML treatments post-
1171  randomization, which include HSCT and/or anti-AML drugs (not to be confused with 
1172  concomitant therapies).  As use of subsequent treatments is consistent with the practice of 
1173  medicine, FDA recommends that the primary analysis of a time-to-event endpoint (e.g., OS, 
1174  EFS) not censor for subsequent treatments.1  This approach implies that HSCT and/or 
1175  subsequent anti-AML treatments are viewed as part of the as-needed AML treatment regimen 
1176  taken after the initial study drug and that the treatment effect is the result of both the study drug 
1177  and the subsequent anti-AML treatment.  
1178   
1179  To help ensure that the treatment effect is interpretable, AML trials should be designed such that 
1180  investigators are blinded to patients assigned treatment.  Regardless of the feasibility of blinding 
1181  and as HSCT extends survival, rules or criteria should be clearly prespecified in the protocol 
1182  prior to study initiation to determine how patients are to be selected for HSCT.  In addition, 
1183  where patients are still on study, follow-up of patients should continue even after initiation of 
1184  subsequent treatments. 
1185   
1186  It has been suggested that the true treatment effect should be free from the influence of HSCT or 
1187  subsequent treatments.2  Under this approach, the treatment effect may be interpreted as the 
1188  difference in the endpoint between patients who initiated the investigational drug and patients 
1189  who initiated the control treatment if HSCT and/or subsequent anti-AML treatments had not 
1190  been available, or if available, were withheld from patients.  In settings where HSCT and/or 
1191  subsequent treatments are integral to the practice of medicine, this approach to thinking about the 
1192  treatment effect is currently not recommended for the primary analysis for the following reasons: 
1193    
1194    First, it may not be possible to design a clinical trial to estimate this treatment effect if 
1195  patients are provided HSCT or subsequent treatments as needed.  This implies that this 
1196  treatment effect can only be estimated by modeling, using causal inference methods 
1197  developed for observational studies where the assumptions therein are difficult, if not 
1198  impossible, to justify. 
1199     
1200    Second, the clinical relevance of such an estimand is still an open question if it can never 
1201  be realized in practice.  
1202   
1203  Plateauing Effect  
1204   
1205  Trials designed to cure AML often result in survival contours characterized by an initial drop 
1206  followed by a plateauing effect after some time point post randomization.  This is an example of 
1207  nonproportional hazards.  While the log-rank test is somewhat robust to nonproportionality, it 
                                                 
1 See the draft treatment policy discussion in the draft ICH E9(R1).  When final, this guidance will represent the 
FDAs current thinking on this topic. 
2 For additional reference, see discussion on hypothetical strategies in draft ICH E9(R1).  When final, this guidance 
will represent the FDAs current thinking on this topic. 
  30  Contains Nonbinding Recommendations 
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1208  generally results in loss of power.  Furthermore, nonproportionality can cause difficulty in 
1209  describing the treatment effect.  FDA is open to discussion about analyses based on other 
1210  approaches, such as weighted Cox regression or other weighted methods, or summarizing the 
1211  treatment effect using restricted mean survival time (RMST) or landmark survival analysis.  
1212  Plans that use these alternative approaches should include: 
1213   
1214    justification for what constitutes clinically meaningful difference,  
1215   
1216    justification of design parameters, such as sample size and follow-up duration, based on 
1217  this endpoint, and  
1218   
1219    justification for the value of the threshold that will be used to calculate the RMST.     
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1220  Appendix 3:  Additional Data Files for Marketing Applications for AML Drugs 
1221   
1222  The following variables are recommended for custom data files to assist with endpoint 
1223  adjudication 
1224   
1225  Variables That Assist Morphological Response Assessment 
1226   
1227    Study identification number 
1228    Site identification number 
1229    Unique subject number 
1230    Treatment arm 
1231    Date of start of study drug 
1232    Date of last study drug 
1233    Study day of last study drug 
1234    Date of last platelet transfusion 
1235    Study day of last platelet transfusion 
1236    Date of last RBC transfusion 
1237    Study day of last RBC transfusion 
1238    Date of CR* 
1239    Study day of CR* 
1240    Date of ANC used for CR response* 
1241    Study day of ANC used for CR response* 
1242    ANC used for CR response* 
1243    Date of platelet count used for CR response* 
1244    Study day of platelet count used for CR response* 
1245    Platelet count used for CR response* 
1246    Date of marrow used for CR response* 
1247    Study day of marrow used for CR response* 
1248    Marrow blasts percentage used for CR response* 
1249    Date of assessment of Auer rods (yes/no) at CR response* 
1250    Date of assessment of extramedullary disease for CR response* 
1251    Study day of assessment of extramedullary disease for CR response* 
1252    Absence of extramedullary disease (yes/no) at CR response* 
1253    Date of relapse 
1254    Study day of relapse 
1255    Date of transplantation 
1256    Study day of transplantation 
1257   
1258  * If CRh is an endpoint in the study, these measures should also be provided for CRh.   
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1259  Variables That Assist the Transfusion Independence Assessment 
1260   
1261    Study identification number 
1262    Site identification number 
1263    Unique subject number 
1264    Treatment arm 
1265    Date of start of study drug 
1266    Date of last study drug 
1267    Study day of last study drug 
1268    RBC transfusion dependence at baseline (yes/no) 
1269    Platelet transfusion dependence at baseline (yes/no) 
1270    Transfusion dependence for either RBC or platelets at baseline (yes/no) 
1271    RBC transfusion independence (TI) criteria met post baseline (yes/no) 
1272    Platelet TI criteria met post baseline (yes/no) 
1273    TI criteria met for both RBC and platelet transfusions post baseline (yes/no) 
1274    Date of start of RBC TI 
1275    Study day of start of RBC TI 
1276    Date of end of RBC TI 
1277    Duration of RBC TI post baseline 
1278    Date of start of platelet TI 
1279    Study day of start of platelet TI 
1280    Date of end of platelet TI 
1281    Duration of platelet TI post baseline 
1282    Date of start of RBC and platelet TI 
1283    Study day of start of RBC and platelet TI 
1284    Date of end of RBC and platelet TI 
1285    Duration of RBC and platelet TI post baseline 
1286    Date of last contact 
1287    Study day of last contact 
1288    Status at last contact (alive and TI, alive and transfusion-dependent, dead, or lost) 
  33