Acute Myeloid 
Leukemia:  Developing 
Drugs and Biological 
Products for Treatment 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
October 2022 
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  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
and/or 
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Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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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)  
 
October 2022 
Clinical/Medical 
 
  Contains Nonbinding Recommendations 
 
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 ...................................................................14 
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 ..............................................................................................21 
4. Confirmatory Trial Procedures........................................................................................24 
IV.  REGULATORY SUBMISSIONS ............................................................................ 25 
A.  Investigational New Drug Applications ..........................................................................25 
B.  Marketing Applications ................................................................................................25 
1. Assessment of Efficacy....................................................................................................25 
2. Assessment of Safety ......................................................................................................26 
3. Clinical Pharmacology...................................................................................................27 
GLOSSARY ........................................................................................................................ 28 
APPENDICES ..................................................................................................................... 30 
Appendix 1:  Example DLT Criteria for Drugs for AML ........................................................30 
Appendix 2:  Additional Statistical Discussion .......................................................................31 
Appendix 3:  Additional Data Files for Marketing Applications for AML Drugs ......................33 
  Contains Nonbinding Recommendations 
Acute Myeloid Leukemia:  Developing Drugs and Biological 
Products for Treatment 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to assist sponsors in the clinical development of drugs and 
biological products2 for the treatment of acute myeloid leukemia (AML).  Specifically, this 
guidance addresses FDAs current thinking regarding the overall development program and 
clinical trial designs for the development of drugs to support an indication of treatment of 
AML, including indications limited to an individual phase of treatment (e.g., maintenance, 
transplantation preparative regimen, etc.).3   
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law. 
FDA guidance documents, including this guidance, should be viewed only as recommendations, 
unless specific regulatory or statutory requirements are cited.  The use of the word should in 
Agency guidance means that something is suggested or recommended, but not required. 
 
II.  BACKGROUND 
 
AML is a malignant neoplasm arising from a myeloid-lineage progenitor.  Although the disease 
is clonal, the molecular pathogenesis is highly heterogeneous.  The International Agency for 
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. 
  1  Contains Nonbinding Recommendations 
clinical, and genomic parameters, including specific genetic abnormalities.4  The median age at 
diagnosis is 68 years, but the disorder occurs in patients of all ages from neonates to the elderly.5   
For decades, the standard treatment6 for patients with AML was intensive cytotoxic 
chemotherapy for induction and consolidation with or without postremission allogeneic 
hematopoietic stem cell transplantation (HSCT), and the only intent of treatment was cure.  
Investigations of cytotoxic drugs with or without targeted drugs continue in an effort to increase 
the fraction of patients with AML who are cured.  However, many patients with AML who had 
just mild pathological or age-related organ impairment at diagnosis were considered to have too 
high a risk of life-threatening or fatal organ toxicity from such intensive therapy and therefore 
were offered only palliative treatments or no treatment at all.   
 
New classes of drugs, including drugs that target the specific pathogenetic mutations or a 
disordered epigenome, are being developed as alternatives to cytotoxic drugs for the treatment of 
AML.  In some cases, these newer approaches may extend survival without the prospect for cure, 
but extending survival may be a meaningful benefit for patients who would live for only weeks if 
left untreated.  Inducing temporary control of disease with minimal treatment burden and 
palliation of symptoms are two additional outcomes that might also be considered meaningful in 
certain circumstances (see discussion in III.B below).   
  
The expansion of treatment intent, broadening of the intended population, and development of a 
wide range of new drug classes as alternatives to cytotoxic drugs contribute substantially to the 
complexity of clinical development programs for new drugs for AML.  This guidance addresses 
these considerations and provides recommendations regarding the design and conduct of clinical 
trials and the types of supporting data that would facilitate efficient development of drugs for the 
treatment of AML.7 
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Drug Development Considerations 
 
1.  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 ICH guidance for industry E8(R1) General Considerations for Clinical Studies (April 
2022) 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. 
  2  Contains Nonbinding Recommendations 
  The Agencys expectations for the nonclinical8 programs for treatments of 
malignancies are summarized in the ICH guidances for industry S9 Nonclinical 
Evaluation for Anticancer Pharmaceuticals (March 2010) and S9 Nonclinical 
Evaluation for Anticancer Pharmaceuticals Questions and Answers (June 2018).  
These guidances apply to drugs for AML. 
 
  For cellular or gene therapy products being developed for the treatment of AML, 
sponsors should also consult the guidances for industry Preclinical Assessment of 
Investigational Cellular and Gene Therapy Products (November 2013) and Long 
Term Follow-Up after Administration of Human Gene Therapy Products (January 
2020).  
 
2.  Devices 
 
  For drugs with a specific therapeutic target, an in vitro companion diagnostic device 
(referred to as a companion diagnostic herein) may be essential for the safe and 
effective use of the drug.  Sponsors developing a targeted drug for AML should take 
into consideration the need for a companion diagnostic early in the drug development 
timeline.9  
 
  Minimal residual disease (MRD) is a biomarker of subclinical tumor burden in 
patients with AML.  In clinical development programs for new AML drugs, MRD 
assays might be used for selection of patients for participation in protocols, 
assignment of treatments by prognostic subcategories, or as a measure of efficacy.  
The guidance for industry Hematologic Malignancies: Regulatory Considerations for 
Use of Minimal Residual Disease in Development of Drug and Biological Products 
for Treatment (January 2020) provides recommendations about use of MRD and 
MRD assays in regulatory submissions for drugs or biologics, including those 
applicable to AML drugs.  
 
3.  Clinical Pharmacology 
 
  Patients with AML are commonly prescribed concomitant medication that are 
substrates, inducers, or inhibitors of cytochrome P450 (CYP) enzymes.  In particular, 
triazole antifungals are moderate to strong CYP3A inhibitors commonly prescribed to 
reduce the risk of invasive fungal infections in patients with AML.  Such drugs may 
increase the systemic exposure of new AML drugs that are metabolized by CYP3A 
and may decrease the tolerability of new AML drugs that are CYP3A substrates.  
Additional studies should be used to address this potential for harm: 
 
 
8 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible. We 
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.   
9 For guidance pertaining to companion diagnostics, see the CDRH internet page on companion diagnostics 
(https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407297.htm). 
  3  Contains Nonbinding Recommendations 
  Sponsors should conduct in vitro metabolism studies to determine if a new AML 
drug is a substrate, inhibitor, or inducer of CYP3A prior to conduct of the first-in-
human (FIH) trial.10  
 
  If an AML drug is a CYP3A substrate, sponsors should proactively incorporate 
strategies for dose modification with concomitant use of moderate and strong 
CYP3A inhibitors early in their clinical development programs.  If available, 
sponsors may leverage pharmacokinetic data (e.g., exposure-response 
relationships for safety and effectiveness, clinical drug interaction studies) from 
patients with other malignancies who have received the new drug to estimate the 
potential effect of the co-administration of the new drug with CYP3A inhibitors 
and determine an appropriate dose of the new drug with moderate or strong 
CYP3A inhibitors in patients with AML.  The development of physiologically 
based pharmacokinetic models may aid in assessing the effect of some CYP3A 
modulators on the AML drug and should be considered. 
 
  If the new AML drug is a substrate of, inhibits, or induces any major CYP 
enzyme or other metabolic enzymes in vitro, sponsors should conduct clinical 
drug interaction studies to determine appropriate mitigation strategies.  FDAs 
draft recommendations regarding such studies are described in the guidance for 
industry Clinical Drug Interaction Studies  Cytochrome P450 Enzyme- and 
Transporter-Mediated Drug Interactions and the draft guidance Drug-Drug 
Interaction Assessment for Therapeutic Proteins.11  
 
  Common supportive care medications for patients with AML, including antimicrobial 
prophylaxis (e.g., fluoroquinolones) and antiemetics (e.g., 5-HT3 receptor 
antagonists), are known to prolong the QT interval.  Sponsors should conduct an 
adequate assessment early in clinical development to assess the QT prolongation 
potential of the AML drug as described in FDA's guidance.12  If the AML drug has 
the potential to prolong the QT interval, the protocols should include appropriate 
strategies for mitigation of QT prolongation, including a list of prohibited 
concomitant medications associated with QT prolongation and/or more frequent 
monitoring of ECG and electrolytes, particularly in patients with nausea, vomiting, or 
diarrhea.  
 
  Patients with AML, especially the elderly, may have impaired hepatic or renal 
function.  Prior to enrolling patients with organ impairment on trials of treatments for 
AML, the sponsor should identify elimination pathways of the parent drug and its 
active metabolites.  If renal or hepatic elimination pathways are identified, the 
sponsor should characterize the impact of organ impairment on the pharmacokinetics 
 
10 See the Guidance for Industry In Vitro Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions Guidance for Industry (January 2020).  
11 January 2020 and August 2020, respectively. When the latter is final, the guidance will represent the FDAs 
current thinking on this topic. 
12 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs (October 2012). 
  4  Contains Nonbinding Recommendations 
of the parent drug or active metabolites early in clinical development as described in 
the FDAs guidances.13  This provides the basis of dose modifications for patients 
with organ impairment in late phase clinical studies.   
 
4.  Special Populations 
 
a.  Pediatric Patients 
 
  FDA encourages sponsors to address the pediatric population early in their clinical 
development program for drugs for the treatment of AML.  For example, adolescent 
patients should be considered for enrollment along with adults in trials for the 
treatment of AML.14 
 
  When it is not clear that dosing for pediatric patients can be derived with certainty 
from adult data, or for FIH studies in younger age groups, studies in children should 
begin with a phase 1 trial of the new drug as monotherapy.  The phase 1 monotherapy 
trial population need not be limited to patients with AML, but the acceptability of the 
recommended phase 2 dose (RP2D) should be confirmed in a small cohort of 
pediatric patients with AML before conduct of larger trials for AML in children.   
 
  Section 505B(a)(1)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
requires that certain original marketing applications  those for new active ingredients 
and for which the drug that is subject of the application is intended to treat an adult 
cancer and is directed at a molecular target that FDA determines to be substantially 
relevant to the growth or progression of a pediatric cancer  contain reports of 
molecularly targeted pediatric cancer investigations,15 unless a deferral or waiver is 
granted.  The requirement for pediatric investigations applies even if the adult cancer 
indicated does not occur in the pediatric population and even if the drug is for an 
adult indication for which orphan designation has been granted.16  Sponsors of 
molecularly targeted AML drugs should discuss the applicability of these 
requirements to their drug as early as end-of-phase 1 to allow sufficient time to 
develop a pediatric study plan, if needed.17 
 
 
 
13 See the draft guidance for industry Pharmacokinetics in Patients with Impaired Renal Function  Study Design, 
Data Analysis, and Impact on Dosing and Labeling (September 2020) (when final, this guidance will represent 
FDAs current thinking on this topic) and the guidance for industry Pharmacokinetics in Patients with Impaired 
Hepatic Function:  Study Design, Data Analysis, and Impact on Dosing and Labeling (May 2003). 
14 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). 
15 See also section 505B(a)(3) of the FD&C Act. 
16 See also section 505B(k)(2) of the FD&C Act.  For additional information, see the guidance for industry FDARA 
Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs:  Amendments to Sec. 
505B of the FD&C Act (May 2021).   
17 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).     
  5  Contains Nonbinding Recommendations 
b.  Older Adult Patients 
 
  For clinical trials of AML drugs, sponsors should enroll a population that is 
representative of the age range of patients with the disease.  It is acknowledged, 
however, that older adults with AML may have age-related comorbidities that place 
them at higher risk for adverse outcomes when treated with intensive chemotherapy.  
FDA has accepted, but does not require, use of age 75 years as an upper limit for 
inclusion in trials of intensive chemotherapy.  FDA, however, encourages use of no 
age limit for trials of nonintensive treatments for AML. 
 
  Dose reductions may be required for older patients (e.g., age 65 years and older).  
Safety, pharmacokinetic, and exposure data from older adults in early phase trials of a 
new AML drug should be used to justify the dose or dose modifications of the drug 
for older adults to be tested in later phase trials. 
 
  FDA recommends an assessment of older adults (e.g., age 65 years and older) for 
physiologic function at study baseline to assist in identifying subgroups that may be 
at risk for an adverse outcome when treated for AML.  Sponsors may consider using 
an available geriatric assessment tool or propose a new tool for use in the clinical 
trials.  A simple assessment tool evaluating single or multiple aspects of function with 
limited burden to the patient is preferred.  Sponsors are encouraged to request a 
meeting as early as possible with FDA to discuss the incorporation of an existing or a 
new assessment tool for older adult patients in AML clinical trials. 
 
c.  Patients with Organ Impairment 
 
  For late phase clinical trials of AML drugs, sponsors should enroll a population that is 
representative of patients diagnosed with AML, including those with impaired organ 
function.18  Appropriate organ impairment studies should have been conducted or the 
impact of organ impairment on the exposure of the parent drug and its active 
metabolites assessed adequately to provide appropriate dose modifications as stated in 
section III.A.3. 
 
  For drugs being developed specifically for the treatment of AML in patients with pre-
existing comorbidities that preclude use of intensive chemotherapy, FDA has 
accepted the following criteria to define the population to be included in the trials that 
will support marketing approval: 
 
  ECOG performance status > 2, 
 
  Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection 
fraction  50%, or chronic stable angina), 
 
 
18 For additional information, see the guidance for industry Cancer Clinical Trial Eligibility Criteria: Patients with 
Organ Dysfunction or Prior or Concurrent Malignancies (July 2020).   
  6  Contains Nonbinding Recommendations 
  Severe pulmonary disorder (e.g., DLCO  65% or FEV1  65%), 
 
  Creatinine clearance < 45 mL/min, and 
 
  Hepatic disorder with total bilirubin > 1.5 time the upper limit of normal. 
 
FDA will consider additional criteria if sponsors can provide data to justify their 
proposal.  
 
d.  Pregnant Women  
 
  The AML population includes a substantial proportion of young adult females.  
Pregnant women may be diagnosed with AML during the course of their pregnancy.  
The standard of care in this circumstance is to administer intensive chemotherapy 
after the first trimester.  As such, pregnant women with AML in certain 
circumstances may be considered for inclusion in AML clinical trials based on a 
thorough benefit-risk evaluation and when the trial offers the possibility of direct 
benefit to the pregnant woman and/or fetus that is unavailable outside the research 
setting. 
 
  Data from relevant nonclinical studies to support safety in pregnant patients should 
be available prior to enrolling pregnant women in AML clinical trials.  In addition, 
safety data for the drug from previous human exposure, even for indications other 
than AML, should be included in the assessment of risks.  
 
  When a pregnancy has been identified during an AML clinical trial, the risks and 
benefits of continuing versus stopping investigational treatment should be reviewed 
with the pregnant woman.  A second informed consent process reflecting additional 
benefit-risk considerations is advisable for pregnant women who choose to continue 
treatment with the investigational drug during pregnancy. 
 
  Sponsors should consider meeting with FDA early in drug development to discuss 
when and how to include pregnant women in clinical trials.  For a draft of additional 
general points to consider when pregnant women are included in clinical trials, see 
the draft guidance for industry Pregnant Women: Scientific and Ethical 
Considerations for Inclusion in Clinical Trials.19 
 
5.  Safety Reporting Considerations  
 
  Patients with AML may have adverse events due to the underlying leukemia.  
Additionally, many AML drugs are designed to be myelosuppressive and are 
expected to result in complications from the cytopenias.  Nonclinical studies and the 
analysis of class effects may also establish expected toxicities for the investigational 
drug.  Sponsors should submit a list of the anticipated serious adverse events that the 
 
19 April 2018.  When final, this guidance will represent the FDAs current thinking on this topic. 
  7  Contains Nonbinding Recommendations 
sponsor does not plan to report individually in an expedited manner to FDA.  An IND 
safety report must be submitted to FDA if an aggregate analysis indicates that the 
adverse events are occurring more frequently in the drug treatment group per 21 CFR 
312.32(c)(1)(i)(C).  Additional information can be found in the guidance for industry 
and investigators Safety Reporting Requirements for INDs and BA/BE Studies.20  
 
  Although investigators are required to report all serious adverse events to the sponsor 
immediately (312.64(b)), this requirement may be burdensome and not useful when a 
large proportion of the serious adverse events are expected at a high rate, such as 
might occur with the cytopenic complications of treatment of AML.  In such cases, 
sponsors may propose an alternative reporting arrangement for investigators in the 
protocol or in a specific waiver request to FDA, and FDA will provide comment on 
whether the alternative reporting arrangement is acceptable.  For early phase trials, 
the alternative reporting arrangement is likely to be limited to an alternative 
timeframe for the investigator to report a serious adverse event to the sponsor; not 
reporting a serious adverse event at all would be unacceptable.   
 
  Patients with AML may experience relapse while on treatment or during study 
follow-up.  AML-related events, such as relapse or death from relapse, should not be 
submitted by the sponsor as an IND safety report unless there is evidence suggesting 
a causal relationship between the investigational drug and the adverse event, such as 
an aggregate analysis showing that relapse occurred more frequently in the 
investigational treatment group.    
 
B.  Efficacy Endpoints 
 
1.  Time-to-Event Endpoints Used Commonly for AML 
 
a.  Overall Survival (OS) 
 
  OS is defined as the time from randomization to the date of death from any cause.   
 
  For patients who are alive at the data cut-off, the observations for time-to-event are 
censored at the last date of documented survival. 
 
b.  Event-Free Survival (EFS) 
 
  For studies of drugs for the treatment of AML, EFS is defined as the time from 
randomization to the date of:  
 
  Induction treatment failure (ITF), 
  
  Relapse for those who have induction treatment success (e.g., complete remission 
(CR)), or  
 
20 December 2012. 
  8  Contains Nonbinding Recommendations 
 
  Death from any cause,  
 
whichever comes first.  For patients who achieve induction treatment success and are 
alive and in remission at the data cut-off, EFS should be censored at the last 
assessment date.  See the discussion of duration of remission in section III.B.2.a. 
 
  ITF is defined as failure to achieve the initial interim efficacy endpoint within a 
prespecified period of time.  For example, for studies of intensive induction regimens 
for first-line treatment of AML, the recommended definition of ITF is failure to 
achieve morphological CR within 42 days of start of the last cycle of induction 
chemotherapy.  Because the induction period can be variable and prolonged, it raises 
ambiguities about how to define time to treatment failure.  Therefore, day 1 of 
treatment should be assigned as the event date for patients with ITF.   
 
  The credibility of the results of EFS analyses are highly dependent on the quality of 
the data.  Many of the data quality issues for EFS are similar to those encountered 
when using progression-free survival for studies of treatments for solid tumors.  For 
additional general points to consider when using such an endpoint, see the guidance 
for industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics.21 
 
c.  Relapse-Free Survival (RFS) 
 
  RFS may be acceptable as an endpoint specifically in studies of treatments for 
patients with AML in remission, such as the consolidation or maintenance phases.   
 
  For studies of drugs for the treatment of AML, RFS is defined as the time from 
randomization to the date of relapse or the date of death from any cause, whichever 
comes first.  For patients alive and in remission at the data cut-off, RFS should be 
censored at the last assessment date.   
 
d.  Statistical Considerations for Time-to-Event Endpoints 
 
  The general principles for the design and analysis of clinical trials as outlined in ICH 
E9 apply to trials of treatments for AML.  The bullets below are additional 
considerations specific to AML trials and can also be thought of as discussing 
specific attributes of the estimand concept, which is further discussed in the ICH 
guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: 
Estimands and Sensitivity Analysis in Clinical Trials.22  
 
  For time-to-event endpoints in a randomized trial for AML, the primary analysis set 
consists of all randomized subjects.  With respect to the primary analysis method, 
 
21 December 2018. 
22 May 2021.     
  9  Contains Nonbinding Recommendations 
FDA has accepted the log-rank test.  Although FDA is open to discussion about other 
methods, it is incumbent on the sponsor to provide the required justification.  
Additional summary metrics that should be reported include the estimated medians 
(where meaningful), hazard ratios, and 95% confidence intervals.  
 
  It is common for some but not all patients with AML to undergo allogeneic HSCT 
after or in conjunction with an investigational drug, which may impact EFS or RFS.  
Additionally, as more effective drugs for AML are approved, post-study treatment 
may impact OS.  As these treatments are integral to the practice of medicine, the 
primary analysis of these endpoints should be conducted without censoring for such 
treatment.23  For additional discussion about survival analyses when HSCT is a post-
study treatment, see Appendix 2.  
 
  Trials designed to cure AML often result in survival contours characterized by an 
initial drop followed by a plateau.  For additional discussion about analysis when 
there is a survival plateau, see Appendix 2.   
 
  Secondary, sensitivity and supplementary analyses of time-to-event endpoints should 
follow a prespecified statistical analysis plan.  These analyses may include the use of 
alternatively defined endpoints (e.g., alternative definition of time to ITF other than 
day 1 when using EFS), alternatively defined populations, or using alternative 
analysis methods. 
 
2.  Binary Endpoints Used Commonly for AML    
 
a.  Complete Remission (CR) 
 
  For documentation of CR, FDA has used the following definition: 
  
  Marrow blasts < 5% by morphological examination,  
  Absolute neutrophil count (ANC) > 1 Gi/L,  
  Platelet count > 100 Gi/L,  
  Absence of leukemic blasts in the peripheral blood by morphological 
examination, and  
  No evidence of extramedullary disease.   
 
  For the assessment of response for extramedullary disease, invasive testing should be 
limited only to sites involved with AML at baseline that cannot be evaluated directly 
by general physical examination, unless invasive testing is considered standard of 
care. 
 
  The protocol should provide for maximum windows of time between marrow 
sampling and peripheral blood tests used to establish CR.  Windows of 3 to 7 days 
may be justifiable.  The date of marrow sampling is assigned as the CR date.   
 
23 See the treatment policy discussion in ICH E9(R1) (ibid.).  
  10  Contains Nonbinding Recommendations 
 
  Missing data is considered failure to achieve CR.  Additional considerations may be 
needed depending on the extent of missingness, how differential it is between the 
arms when the AML study is randomized, and whether the study is open-label.  See 
section III.D.4 for a discussion of trial procedures critical to the assessment of CR 
and section IV.B.1 for the discussion of the adjudication of CR for the purpose of 
labeling. 
 
  For CR, the duration of remission (DOR) is defined as the time from CR to 
hematological relapse or death from any cause, whichever comes first.  Adequate 
follow-up is required in order to establish that the durability of CR is meaningful.    
 
  Hematological relapse is defined as marrow blasts > 5% by morphology, persistent 
reappearance of blasts in the peripheral blood by morphology, or the occurrence of 
extramedullary disease.  In general, once CR is confirmed by marrow examination, 
further follow-up for relapse may be limited initially to physical examination and 
peripheral blood tests.  The known time to relapse for the regimen in the control arm 
or from other historical data should be used when planning the frequency and 
duration of testing for relapse, but in order to determine DOR, EFS, and RFS as 
accurately as possible, the assessments would likely be performed more frequently 
than in standard practice.  When relapse is suspected on the basis of the follow-up 
physical examination or peripheral blood counts, additional testing may be performed 
to confirm the finding, but the date of relapse is set to the date of the first assessment 
that suggested relapse. 
 
b.  CR with Partial Hematological Recovery (CRh)  
 
  Use of CRh as an endpoint is applicable to drugs that are relatively nontoxic and 
nonmyelosuppressive, as might be used for palliative purposes. 
 
  For documentation of CRh, FDA has used the following definition:  
 
  Marrow blasts < 5% by morphological examination,  
 
  ANC > 0.5 Gi/L and platelet count > 50 Gi/L, but the count recovery criteria for 
CR are not met, 
 
  Absence of leukemic blasts in the peripheral blood by morphological 
examination, and  
 
  No evidence of extramedullary disease.    
 
  Since the potential utility of CR as an endpoint is similar to that of CRh in this 
setting, the actual endpoint used is CR+CRh.  Adequate follow-up is needed in order 
to establish that the durability of CR+CRh is meaningful.   
 
  11  Contains Nonbinding Recommendations 
c.  Transfusion-Independence (TI) 
 
  Durable TI as an endpoint is applicable to drugs that are relatively nontoxic and 
nonmyelosuppressive, as might be used for palliative purposes.  
 
  When durable TI is used, this endpoint should be supported by evidence showing an 
effect of the treatment on an endpoint reflecting antileukemia activity.  TI as an 
endpoint for the treatment of AML should also be distinguished from TI as used in 
the evaluation of hematopoietic growth factors (e.g., for the treatment of anemia) 
where the effect of the drug is directed at normal hematopoietic cells rather than at 
the leukemia.   
 
  TI is defined as the absence of red blood cell and platelet transfusions for a 
prespecified period of time during continued treatment.  The credibility of the data is 
dependent on the protocol specifying the minimal parameters for use of transfusions 
and documentation that the instructions were followed.  Hence, an important 
supporting analysis would include an assessment of serial measurements of 
hemoglobin and platelet counts to ensure that the observed TI was an actual treatment 
effect and not a bias in the administration of transfusions by the investigator. 
 
  TI should be assessed as a response achieved in the subgroup of patients who were 
transfusion dependent (TD) at baseline (conversion from TD to TI with treatment) 
separately from the subgroup of patients who were TI at baseline (maintenance of TI 
with treatment).  For patients with active AML, transfusion dependence at baseline is 
based on the receipt of any red blood cell or platelet transfusions within at least 28 
days prior to the start of study treatment.  Analyses of red blood cell TI and platelet 
TI separately should be used to establish consistency of the components of the TI 
endpoint. 
 
d.  Statistical Considerations for Binary Endpoints 
 
  For single-arm AML trials, the analysis set consists of all patients treated with 
investigational drug.24  If the labeling claim is limited by the target of the drug (e.g., 
AML with a FLT3 mutation for a drug that is a FLT3 inhibitor), the analysis set 
should include only those patients confirmed positive for the target using the 
proposed companion diagnostic or bridged clinical trial assay.  For binary endpoints, 
proportions and their 95% confidence interval should be reported.  
 
  For randomized AML trials, the analysis set consists of all randomized patients.  For 
binary endpoints, the primary analysis may be based on Fishers Exact test; the 
Cochran-Mantel-Haenszel test or an exact version may apply when stratification 
factors were used at randomization.  Proportions and their 95% confidence intervals 
should be reported. Any additional metrics to quantify the treatment effect, such as 
 
24 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. 
  12  Contains Nonbinding Recommendations 
the difference in proportions, ratio of proportions, or odds ratio, should be 
prespecified.  For targeted drugs, a secondary analysis should be performed where the 
analysis set is restricted to patients confirmed positive for the target. 
 
  DOR may be calculated using the Kaplan-Meier method using relapse or any-cause 
death as events.  Estimated median and range should be reported.  When the number 
of study subjects is small, or when follow-up is short, the Kaplan-Meier estimate may 
not be stable.  In this circumstance, the median and range of observed DOR may be 
reported.  Sensitivity analyses may include calculation of DOR including non-
protocol antileukemia treatment in the absence of documented relapse as an 
additional event, or calculation of DOR with censoring at HSCT.   
 
 
 
3.  Minimal Residual Disease (MRD)-Based Endpoints 
 
  For new drugs that have a demonstrated durable CR in patients with relapsed or 
refractory acute leukemia, FDA has accepted marrow MRD of less than 0.01% as 
supporting evidence of efficacy.  As technologies improve and new clinical findings 
emerge, the level of MRD needed to support an efficacy claim for AML may change. 
 
  CR as defined in section III.B.2 is the preferred timing to assess MRD as a response 
endpoint.  If assessments are made at lesser responses (e.g., marrow remission 
without count recovery), the sponsor should include data to justify the validity of the 
results to support a claim of efficacy.  
 
  The recommended analyses of MRD-based response endpoints are similar to those 
for CR discussed in section III.B.2.  When used as a binary endpoint, the denominator 
for the analysis of MRD response should be all treated patients (single-arm trial) or 
the ITT population (randomized trial), and the numerator should be all patients who 
achieved CR and the required level of MRD.  Missing data should be imputed as a 
failure. 
 
  Using MRD-based definitions to identify relapse for the purposes of determining 
DOR, EFS, or RFS can be challenging in studies of new treatments for AML, since 
that would require frequent marrow sampling.  It may be more practical to monitor 
for hematological relapse as described in section III.B.2 for the DOR, EFS, and RFS 
definitions unless there is a validated MRD assay using peripheral blood samples.  
 
  For additional information on the use of MRD as an efficacy endpoint, see the 
guidance for industry Hematologic Malignancies:  Regulatory Considerations for 
Use of Minimal Residual Disease in Development of Drug and Biological Products 
for Treatment.25  
 
 
25 January 2020. 
  13  Contains Nonbinding Recommendations 
4.  Other Potential Measures of Efficacy for AML 
 
  FDA acknowledges that as technology progresses and clinical trial data accumulate, 
alternative biomarkers or measures of efficacy may be proposed for use as endpoints 
in AML clinical trials.  When considering the use of efficacy endpoints other than 
those listed above, especially in a trial to be used to support a marketing application, 
sponsors should consult with FDA about the acceptability of the proposed novel 
endpoint prior to initiating the trial.  
 
  Key efficacy endpoints may also include well-defined and reliable patient-focused 
outcome measures.  When used as the basis of a claim of treatment of AML, such 
endpoints should be supported by data showing that the treatment also has a direct 
effect on the leukemia.  For additional information, refer to the guidance for industry 
Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Claims and the draft guidance for industry Core Patient-Reported Outcomes 
in Cancer Clinical Trials.26  
 
  Sponsors planning to use real world data27 to support an AML drug marketing 
application should consult with FDA at the time of protocol development to ensure 
that the data sources will provide the data needed to assess the treatment effect.  
Important considerations include whether the sources capture the data elements (e.g., 
marrow results, peripheral blood differentials, etc.) to derive clinically accepted 
endpoints for demonstrating efficacy, and if so, the extent of misclassification, the 
timing of assessment, and the frequency of assessment.  Sponsors should plan for 
additional discussions regarding alternative measures if the data sources do not 
capture the key elements of the clinically accepted endpoints. 
  
C.  Exploratory Trial Considerations   
 
1.  First-in-Human (FIH) Trials   
 
  Conducting an FIH trial in patients with rapidly progressing acute leukemias has 
several challenges; the doses used in the first cohorts may be subtherapeutic, and the 
assessment of toxicity may be confounded by adverse events due to the underlying 
leukemia.  Where feasible, sponsors should consider alternative designs for the FIH 
trial that would identify a pharmacologically active dose before commencing the 
dose-escalation trial in patients with AML.  For example, the sponsor may consider a 
limited window study over a short interval (days to weeks) prior to the administration 
of a standard treatment or conducting the initial dose escalation in patients with more 
slowly growing tumors (solid tumors or lymphoma).  Where applicable, sponsors 
 
26 December 2009 and June 2021, respectively. When the latter is final, the guidance will represent the FDAs 
current thinking on this topic. 
27 For additional information and guidances pertaining to real world data, see Real-World Evidence at 
https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence.  
  14  Contains Nonbinding Recommendations 
may also consider the FDAs Model Informed Drug Development (MIDD)28 pathway 
to help select the appropriate doses for efficacy and safety evaluation. 
 
  Historically, the most effective regimens for the treatment of AML have been 
combination regimens.  Nonetheless, the FIH trial should be limited to assessment of 
one drug at a time, and study of the combination should not commence until there is 
adequate information about safety and tolerability of the individual drugs.  Rare 
exceptions to this principle are described in the guidance for industry Codevelopment 
of Two or More New Investigational Drugs for Use in Combination.29 
 
  An FIH trial of a myeloablative drug to be used as a single-agent preparative regimen 
for HSCT for the treatment of patients with AML may be feasible, but prior to 
submission of the investigational new drug application (IND), sponsors should 
consult with FDA about the optimal approach for development of such drugs.  An 
FIH trial of a new drug in combination with a preparative regimen is rarely 
acceptable.30   
 
  Although many drugs developed for the treatment of AML are highly myelo-
suppressive and/or genotoxic, in select cases it may be possible to conduct the FIH 
trial in healthy volunteers.  The advantage to this approach is that the safety profile 
may be simpler to determine in the absence of confounding adverse events due to the 
underlying leukemia.  FDA recommends that sponsors request feedback on the design 
of FIH trials of new AML drugs in healthy volunteers, including the limitations in 
exposure and other restrictions needed to protect healthy volunteers participating in 
such studies.31 
 
  For AML drugs that are CYP3A substrates, sponsors should consider enrolling 
patients on azole antifungals or other CYP3A inhibitors in FIH trials to generate data 
needed to select a safe dose with these concomitant drugs (see section III.A.3).   
 
  Sponsors developing cellular or gene therapy products for the treatment of AML 
should also consult the guidances for industry Considerations for the Design of Early-
Phase Clinical Trials of Cellular and Gene Therapy Products and Long Term Follow-
Up after Administration of Human Gene Therapy Products.32  
 
2.  Exploratory Trial Population 
 
  For dose-escalation trials being conducted to determine the maximum tolerated dose 
(MTD), the eligible population is usually limited to patients who have failed all 
 
28 See the Federal Register (83 FR 16868, April 17, 2018). 
29 June 2013. 
30 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. 
31 See guidance for industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics 
in Adult Healthy Volunteers (July 2005). 
32 June 2015 and January 2020, respectively. 
  15  Contains Nonbinding Recommendations 
conventional drugs.  Patients with subtypes of AML that respond very poorly to 
conventional drugs, such as those with high-risk genetic abnormalities, might also be 
considered for such trials even without prior treatment, but if doing so, the consent 
form should clearly state the implications of foregoing conventional drugs in order to 
participate in the clinical trial.  
 
  The benefit-risk ratio for participation in a dose-escalation trial may also be 
acceptable for patients with MRD after treatment with conventional drugs for AML, 
but such protocols should include a description of the evidence that justifies the risks 
of such a study compared to the prognosis based on the level of MRD proposed for 
eligibility. 
 
  For dose-escalation trials being conducted to determine the RP2D, the eligibility 
criteria that address organ function and comorbidities should be commensurate with 
the target patient population.  For example, if developing a drug for the treatment of 
AML in patients with renal or hepatic impairment, including patients with only 
normal renal or hepatic function might conclude with a dose that is safe in patients 
with normal organ function but that is too toxic for the target population with organ 
impairment.   
 
  Multiple genetic mutations and molecular pathways have been identified as 
contributing to the pathogenesis and persistence of AML.  Nonselective new targeted 
therapies may inhibit multiple such targets.  For new drugs proposed for development 
in a population selected for a single target mutation, sponsors should consider an 
early phase trial that includes patients with and without the putative single target in 
order to confirm the need to select patients based on the presence of that target in later 
phase trials.  Including marker-negative patients might not be necessary for drugs that 
target a cell surface receptor, especially when preclinical data suggest no potential for 
a therapeutic effect in the absence of the cell surface receptor, or for drugs that show 
no activity against other AML targets in preclinical studies.    
 
3.  Dose-Escalation Trials 
 
  For dose-escalation trials, the general principles for selection of the safe starting dose 
and the frequency of administration as described elsewhere33 also apply to drugs 
being developed for the treatment of AML.  As discussed in section III.C.1, the safe 
starting dose for a study in patients with active AML may differ from the starting 
dose for a study in healthy volunteers.  The nonclinical data should also be used to 
determine the slope of the dose-toxicity curve, the anticipated therapeutic dose range, 
and the maximal exposure in order to plan the increments in dose between cohorts in 
the escalation.  For drugs that are CYP3A substrates, the selection of a safe starting 
dose should also consider the concomitant use of drugs that are CYP3A4 inhibitors 
such as azole antifungals (see section III.A.3). 
 
 
33 See ICH S9 and ICH S9 Questions and Answers.  
 
  16  Contains Nonbinding Recommendations 
  The protocol should describe the specific rule-based or model-based criteria used to 
guide the decision on whether to proceed with escalating the dose in subsequent 
cohorts.  For dose-escalation trials of conventional outpatient chemotherapy for 
patients with cancer, escalation to higher doses is generally limited by the rate of 
severe, life-threatening, or fatal events (grades 3-5) termed dose-limiting toxicities 
(DLTs), and the MTD -- as identified by the 3+3 rule -- having no more than 17% 
DLTs.  This paradigm, however, is not applicable to all types of treatments for AML.  
For example, such a rule would allow far greater toxicity than acceptable for 
continued treatment or maintenance that extends for years.  On the other hand, the 
rule would likely result in premature closure of a trial of a preparative regimen for 
HSCT, where grade 3 toxicities are common.  Hence, the criteria proposed to guide 
dose-escalation decisions should take into account the types, severities, and rates of 
toxicities accepted with standard regimens of similar intensity in the intended 
population (see Appendix 1 for examples).  The protocol should describe the data that 
support the assumptions used to develop the criteria for guiding dose-escalation.   
 
  For many cytotoxic drugs used for the treatment of AML, there is a strong dose-
response effect, and in order to achieve the highest response rate, the cited goal of the 
dose-escalation trial is to identify the MTD.  This is not necessarily true for targeted 
drugs, for which the pharmacodynamic effect may plateau at doses lower than 
maximally tolerated.  Hence, the goal of the dose-escalation trial should be to 
determine the RP2D instead.  The protocol should include a definition of the RP2D, 
and the determination of the RP2D should take into consideration the safety, 
tolerability, pharmacokinetic, pharmacodynamic, and efficacy data (see also section 
III.D.2).   
 
  Based on the design of the dose-escalation trial, participants in the initial cohorts of 
the trial may not receive optimal treatment, which may be a disadvantage for patients 
with active AML who are in need of cytoreductive treatment.  Despite the desire to 
ensure that patients with AML are treated with pharmacologically active doses of 
drug, intra-patient dose escalation based on lack of very early response may not be 
scientifically valid; a complete characterization of safety, tolerability, and efficacy at 
any dose level usually requires treatment for multiple cycles.  Intra-patient dose 
escalation may be considered in select circumstances where risks can be minimized 
objectively.  For example, if there is an established pharmacodynamic biomarker for 
safety, intra-patient dose escalation may be feasible with frequent monitoring of the 
biomarker.  Additionally, for patients who have received multiple cycles of treatment 
without evidence of cumulative toxicity or therapeutic activity, it may be beneficial to 
escalate the individual patient's dose to a higher level if that higher dose has been 
established as safe in subsequent cohorts.  The protocol should specify the criteria for 
when intra-patient dose escalation is allowed, how the new dose is assigned, any 
changes in the monitoring plan needed to accommodate the change in dose, and how 
the safety and efficacy data will be evaluated for such patients.  
 
  The planned duration of treatment should be described clearly in the protocol.  Long-
term treatment may be considered in the dose-escalation trial, typically for patients 
  17  Contains Nonbinding Recommendations 
with relapsed or refractory AML, but there should be objective criteria for when to 
discontinue treatment permanently, including high-grade toxicities.  When treatment 
in the dose-escalation trial is planned to extend beyond achievement of CR, a 
rationale should be provided for the proposed duration of treatment after remission.  
For patients who are taken off the investigational drug after achieving a CR, the 
protocol may also address retreatment in case of relapse. 
 
  Early phase trials are also the place to determine the expected time to response, 
allowing study treatment to continue in the absence of toxicity unless prespecified 
levels of disease response have not occurred within a maximum number of cycles.  
Such information will provide support for the treatment plan proposed for 
confirmatory trials designed to test for efficacy.   
 
  For early phase trials of intensive AML drugs given with curative intent, a 
maintenance phase is generally not acceptable in settings where there is no 
established benefit of maintenance; in such cases, a randomized control arm is 
recommended. 
 
  Certain toxicities of treatment, such as anemia or tumor lysis syndrome, are expected 
with almost any treatment of patients with AML.  Treatment of such usual toxicities 
is considered standard practice, and detailed instructions on the practice of medicine 
need not be included in the protocol unless a specific treatment is critical for safe use 
of the investigational drug.  Based on established class toxicities, mechanism of 
action and/or nonclinical studies, there may also be unusual drug-specific toxicities, 
such as differentiation syndrome or cytokine release syndrome.  Until treatment is 
standardized in practice, instructions for management of patients with such unusual 
drug toxicities should be included in the protocol.  
 
4.  Exploratory Expansion Cohorts 
 
  A small cohort of 6-12 subjects treated at the presumptive RP2D can be useful to 
confirm safety prior to start of additional trials.  In the absence of data from a safety 
expansion cohort, the confirmatory trial should include a very early interim safety 
analysis to corroborate safety of the RP2D.   
 
  When the new drug is being studied as an add-on and the background regimen has 
substantial toxicity (i.e., a standard intensive AML induction regimen), a randomized 
comparison may be necessary to detect even large differences in toxicity that might 
not be noticed in the single-arm setting.  
 
  Responses as defined in section III.B.2 are generally acceptable measures of activity 
that should be included in exploratory early phase clinical trials in AML.  Lesser 
responses (e.g., partial remission, shorter term transfusion-independence, etc.) may 
reflect activity of the drug, but such lesser responses should guide development of 
alternative strategies to leverage that activity (i.e., different schedules or use in 
combinations) rather than being viewed as a success.   
  18  Contains Nonbinding Recommendations 
 
  A small cohort of patients treated at the presumptive RP2D can also be used to 
provide an estimate of efficacy to support design of additional trials.  Such a cohort 
generally includes approximately 20 subjects.  Large single-arm expansion cohorts 
solely for exploratory purposes are discouraged.  Any large single-arm trial should 
have a design based on clear hypothesis testing, and the protocol should include 
justification of the sample size proposed.  
 
  Time-to-event endpoints are difficult to interpret in single-arm trials and, therefore, 
are generally not useful in assessing efficacy in exploratory early phase trials.  Data 
for such endpoints, however, should still be collected since such data could be useful 
in designing the confirmatory trials if other objective measures of efficacy support 
further development of the drug.   
 
  To ensure the safety of study participants, the expansion cohort plan should include 
stopping rules for excessive toxicity that would require pausing enrollment to 
evaluate whether the treatment plan should be modified.   
  The acceptable rate and type of toxicities will depend on the treatment setting as 
discussed for development of DLT criteria in section III.C.3.   
  For patients with AML, toxic events for stopping rules might include treatment-
related deaths, prolonged neutropenia lasting past cycle day 42 in the absence of 
disease, and high-grade nonhematological adverse reactions. 
  The protocol should describe the exact bounds for the stopping criteria, the 
statistical method used to calculate the bounds, and the basis for the clinical 
assumptions used in the calculation.  FDA recommends that the bounds be 
calculated to assure a high probability (> 60-70%) of pausing the trial at the 
lowest unacceptable toxicity rate while minimizing the probability of pausing 
(< 30%) when the toxicity rate is acceptable.  Nonstringent design parameters 
may be used to achieve these operating characteristics.  
 
D.  Confirmatory Trial Considerations 
 
1.  Confirmatory Trial Population 
 
  The protocol should use the most updated diagnostic criteria for AML or for a 
specific AML type to describe the eligible population.  Sponsors should consult with 
FDA rather than using outdated criteria solely to match a population used in support 
of a past approval. 
 
  Patients with newly diagnosed AML, patients with AML in late first relapse (e.g., 
first remission > 6 months), and patients with other relapsed or refractory AML (e.g., 
primary refractory, early first relapse, and any second or later relapse) represent three 
distinct indications.  A separate trial for each indication is recommended, but separate 
cohorts in a single trial may be used for analyses to support each indication 
independently.  In the latter circumstance, the protocol should describe clearly the 
eligibility criteria for each cohort.  HSCT is considered standard practice in the 
  19  Contains Nonbinding Recommendations 
treatment of AML, and relapse post HSCT would fall under either treatment of first 
relapse or treatment of later relapse rather than being a separate indication. 
 
  For clinical trials of a biomarker-selected AML population, the eligibility criteria 
should state clearly what assay is to be used to select patients with the cognate target, 
the tissue (blood, marrow, etc.) used for the assay, and the level of the target needed 
to meet eligibility.  
 
  For clinical trials planned to support a marketing application for the intended 
population of patients with comorbidities that preclude use of intensive induction 
chemotherapy, the eligibility criteria should include detailed parameters that describe 
the population.  See section III.A.4.c for examples of criteria for organ impairment 
that FDA has accepted to describe this subgroup of patients for AML trials.  
 
  For clinical trials being designed to support a marketing application, the eligibility 
criteria should reflect the characteristics of the general population with AML.  
Exclusion criteria should be limited to disease- or patient-related factors associated 
with a lack of benefit or an unacceptable risk of toxicity from the investigational drug 
based on data in early phase trials.34  
 
  For clinical trials of noncurative drugs for AML, the eligibility criteria should 
specifically exclude patients willing and able to receive intensive curative treatment. 
  
2.  Dose Selection and Treatment Plan 
 
  The dose and schedule of the investigational drug in the treatment regimen should be 
optimized before initiating the confirmatory trials.  Clinical pharmacokinetic data, 
pharmacodynamic data, clinical activity measures, clinical safety data, and 
nonclinical pharmacology data, should be pooled for conduct of integrated dose-
response and exposure-response analyses for activity and safety for dose 
optimization.  The results of such analysis should be included in the protocol to 
justify the dose. 
 
  For drugs planned to be administered for multiple cycles, and especially for drugs 
given long-term on an outpatient basis, tolerability should be taken into consideration 
when choosing the dose to be used in the confirmatory trial.  In general, for drugs 
planned to be given long-term or over multiple cycles, it is expected that dose 
modifications or discontinuations for adverse reactions are limited to less than 20% of 
the patients, and that at least 80% dose intensity is achieved over multiple cycles for 
at least 80% of the patients.   
 
  The protocol should include dose adjustment strategies for specific populations (e.g., 
with organ impairment or with concomitant use of moderate and strong CYP3A 
 
34 For additional discussion, see the guidance for industry Enhancing the Diversity of Clinical Trial Populations  
Eligibility Criteria, Enrollment Practices, and Trial Designs (November 2020).  
 
  20  Contains Nonbinding Recommendations 
modulators) and in response to emerging adverse events.  The experience with these 
instructions during study conduct provides the basis for dose modification 
instructions in labeling. 
 
3.  Confirmatory Trial Design   
 
a.  General Considerations for Confirmatory Trial Designs 
 
  The principles of designing trials to demonstrate efficacy for the purposes of 
supporting a marketing application are described in general guidance,35 and these 
general principles are applicable to trials for AML drugs.  The bullets below provide 
additional recommendations specific for the trials of treatments for AML. 
 
  To prevent bias in study conduct or in selection of post-study treatments, the use of 
blinded treatments where feasible is recommended for randomized trials. 
 
  The use of specific genetic targets and other prognostic factors used for eligibility or 
risk stratification should be described in detail.  For patients with relapsed or 
refractory AML, the protocol should state clearly whether these prognostic factors are 
measured at the time of diagnosis or at the time of relapse. 
 
  Because treatment for AML involves discrete stages of treatment with different goals, 
the purpose of treatment with the investigational drug should be stated clearly in the 
protocol.  Potential objectives may include remission induction alone, remission 
induction followed by consolidation, consolidation of remission alone, remission 
maintenance (after chemotherapy or transplantation), or control of complications of 
the disease in the relapsed/refractory setting.  
 
  If the clinical trial has goals in multiple stages of treatment, sequential 
randomizations may be needed.  For example, if a maintenance indication is planned 
in addition to initial treatment, patients should be rerandomized prior to maintenance 
to allow for isolation of the treatment effect of study drug(s) during maintenance. 
 
  A detailed statistical analysis plan stating the trial hypotheses, sample size, analysis 
timing, and analysis methods should be submitted before trial initiation.  The sample 
size calculation should be based on the expected efficacy in the control arm and the 
anticipated treatment effect of the investigational drug with respect to the primary 
endpoint in the planned patient population.  Estimating the outcome for the control 
arm in a molecular subgroup may be challenging for treatments of AML with new 
molecular targets that were not studied previously with standard care regimens.  
When there is little extant data to support the assumptions for the anticipated 
 
35 See the ICH guidance for industry E8(R1) General Considerations for Clinical Studies (April 2022) and E9(R1); 
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).  
  21  Contains Nonbinding Recommendations 
treatment effect, sponsors may consider an adaptive design or other novel approach.36  
In such a case, the sponsor should request feedback from FDA on the proposed 
design prior to initiating the trial.  
 
  When the design requires an active comparator, the treatment should be standard of 
care for the study population (e.g., study drug vs. 7+3).  Placebo comparators may be 
considered in add-on trials (e.g., study drug+7+3 vs. placebo+7+3) if appropriate 
treatment for the control arm.  Comparative efficacy studies of combinations that do 
not isolate the effect of the study drug (study drug+azacitidine vs. 7+3) may also be 
acceptable if the control is standard of care for the population, the activity of the 
study drug was demonstrated in other trials, and the contribution of each drug in the 
new regimen is supported by other data in the context of use. 
 
  It is common for multiple efficacy endpoints (i.e., OS, EFS, CR) to be assessed in a 
clinical trial for AML.  The statistical analysis plan should prespecify a multiple 
testing strategy for important secondary endpoints that adjusts for multiplicity 
conditioned on demonstrating a positive outcome for the primary endpoint.  Note that 
effects on secondary endpoints are generally not sufficient to support a marketing 
application in the absence of demonstration of an effect on the prespecified primary 
endpoint.  Additionally, even if an effect on a secondary endpoint is demonstrated, it 
may not be acceptable for labeling if it is not an established efficacy endpoint; for 
example, the composite of CR+CRi may not be suitable for labeling due to the 
inclusion of CRi. 
 
  In large randomized trials, an interim analysis for futility is strongly recommended to 
ensure that the benefit-risk ratio for enrolled patients continues to be favorable.  FDA 
has accepted group sequential/early stopping designs for interim analyses.  However, 
for certain endpoints, such as EFS or RFS, FDA discourages early stopping for 
efficacy based on a positive assessment at the interim analysis.  More follow-up may 
be needed to assess other important endpoints, such as duration of response and 
safety, that would be needed to determine the overall benefit-risk.  FDA is willing to 
discuss the potential pitfalls in a timely fashion when the sponsor is considering early 
study termination based on interim efficacy analysis results.  
 
  The timing of analysis of continued response (e.g., DOR, RFS, etc.) should be 
prespecified to mitigate bias in study result interpretation. 
 
b.  Treatment of AML with Curative Intent 
 
  Treatments with an expectation of a survival plateau are considered treatment with 
curative intent.  Examples include standard intensive chemotherapy as first-line 
treatment for AML. 
  
 
36 For example, see the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics 
(November 2019). 
  22  Contains Nonbinding Recommendations 
  FDA has accepted OS, EFS, and RFS as clinical endpoints that represent clinical 
benefit for traditional approval for treatments with curative intent.  
 
  AML is a heterogenous disease, and historical controls are severely limited in their 
ability to accurately parallel the intended population for the indication.  Therefore, the 
use of historical controls in AML is not appropriate for studies of treatment with 
curative intent.  Trials intended to support a marketing application for this indication 
should have a randomized control arm.  
 
c.  Treatment of AML without Curative Intent 
 
  Treatments with no expectation of a survival plateau, but where the goal is to extend 
survival or greatly improve durable CR relative to a control, are considered treatment 
without curative intent for AML.   
 
  FDA has accepted OS and EFS as clinical endpoints that represent clinical benefit for 
traditional approval for treatments without curative intent.  For studies in populations 
with a very high rate of induction treatment failure or when OS is expected to be 
short, OS may be the more practical endpoint to establish clinical benefit.  Durable 
CR may also support traditional approval depending on the disease setting and 
benefit-risk ratio. 
 
  Trials intended to support a marketing application for this indication may be 
randomized or single-arm in design, depending on the endpoint, patient population, 
and available therapy.  FDA recommends that sponsors consult with FDA on 
proposed study designs for this indication. 
 
d.  Treatment of AML with Palliative Intent 
 
  Nonintensive treatments without substantial associated toxicities administered with 
the goal of temporary disease control and minimal treatment burden are considered 
treatment with palliative intent in AML.   
 
  Durable TI may represent a direct clinical benefit resulting from the relief from the 
burdens of insufficient hematopoiesis due to active AML.  FDA has accepted durable 
CR and durable CR/CRh with TI as clinical endpoints that represent clinical benefit 
for traditional approval for treatments with palliative intent.  
 
  Trials intended to support a marketing application for this indication may be 
randomized or single-arm in design depending on the endpoint, patient population, 
and available therapy.  Best supportive care may be acceptable as a comparator in a 
randomized trial only for a patient population without available therapies.  In certain 
clinical settings, a single-arm trial may be appropriate for traditional approval if there 
are adequate historical data to support the null hypothesis.  
 
  23  Contains Nonbinding Recommendations 
4.  Confirmatory Trial Procedures 
 
  Baseline demographic and disease characteristics are used to ensure consistency of 
the benefit-risk by subgroup analyses.  The following key AML-specific information 
should be documented and collected on the case report forms: 
 
  Disease (WHO-based diagnosis37), 
 
  Disease status at enrollment (e.g., newly diagnosed, 2nd relapse, etc.),  
 
  Response status at enrollment (primary refractory vs. untreated vs. refractory 
relapse), 
 
  Duration of first remission, 
 
  Genetic profile and/or risk group at diagnosis and at enrollment (use of the most 
contemporary accepted risk stratification is recommended), 
 
  All prior treatments for AML, 
 
  Baseline functional assessments (where applicable, geriatric assessment is 
recommended), and  
 
  Relevant comorbidities (see section III.A.4.c).  
 
  Patients with AML receiving intensive chemotherapy or high-dose chemotherapy for 
transplantation are expected to have a high rate of low-grade adverse reactions.  For 
studies of drugs with well-established safety profiles, consideration should be given 
to collection of a limited amount of safety data.38  For new drugs with unclear safety 
profiles, all adverse events should be collected regardless of grade or attribution. 
 
  To ensure that data will be available for the assessment of potential interactions 
between new drugs and other drugs used commonly for patients with AML, the dates 
and doses of concomitant medications, especially antifungal medications, should be 
accurate.   
 
  To assess confounding in efficacy analyses due to subsequent post-study treatments, 
the following post-study information should be documented and collected on the case 
report forms: 
 
  At least the first post-study salvage treatment and the reasons for the treatment 
choice and 
 
37 See footnote 4.  
38 See the guidance for industry Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket 
and Postapproval Clinical Investigations (February 2016). 
  24  Contains Nonbinding Recommendations 
 
  HSCT and CAR T cell dates for patients proceeding to transplantation with an on-
study response or as a post-study salvage treatment.  
 
 
IV.  REGULATORY SUBMISSIONS 
 
A.  Investigational New Drug Applications 
 
  General requirements for INDs apply to AML.  See sections III.A and III.C for 
recommendations on submission of FIH trials in AML as the IND-initiating study.  
Sponsors may consult with from FDA through the pre-IND program.   
 
  FDA supports the use of innovative trial designs, such as master protocols, for 
efficient drug development in AML.  For IND submissions that contain innovative 
trial designs, FDA recommends consultation through the pre-IND program.  For 
additional draft recommendations, see the guidance for industry Master Protocols: 
Efficient Clinical Trial Design Strategies to Expedite Development of Oncology 
Drugs and Biologics (March 2022).  
 
  A companion diagnostic may be essential for patient selection in IND protocols for 
targeted AML drugs.  Sponsors may request a study risk determination directly from 
CDRH or in concert with the IND (see the guidance for industry Investigational In 
Vitro Diagnostics in Oncology Trials:  Streamlined Submission Process for Study 
Risk Determination 39 to determine whether an IDE is needed).  See also section 
III.A.2.   
 
B.  Marketing Applications  
 
1.  Assessment of Efficacy  
 
  Assessments of efficacy in AML clinical trials are generally based on objective 
criteria, such as neutrophil counts and marrow blast percentage.  To allow FDA to 
confirm the analyses of the treatment effect, the raw data supporting the study 
endpoints should be submitted in the marketing application. 
 
  If bone marrow pathology results exceed the character limit for a variable in an 
xpt file, a pdf of the report may be acceptable.  
 
  To assist with the adjudication of responses, the submission should include a 
summary response file (see Appendix 3) for the confirmatory study and for the 
integrated efficacy population.  
 
 
39 October 2019. 
  25  Contains Nonbinding Recommendations 
  For studies with an endpoint of TI (see section III.B.2.c), the submission should 
include a summary transfusion analysis data file (see Appendix 3) for at least the 
confirmatory study.   
 
  To assist with the assessment of response and TI, the submission should include a 
file with the dates of RBC and platelet transfusions and the number of units 
transfused. 
 
2.  Assessment of Safety 
 
  Patients with AML have a high background of adverse events due to the leukemia.  
Assessment of toxicities of the new AML drug in different disease settings (e.g., solid 
tumor patients) and in healthy volunteers is helpful in ascertaining causality of 
adverse events.  
 
  To assist with the adjudication of causality of fatal adverse events, the submission 
should include a data file with the date of death, study day of death, proximate cause 
of death (usually as reported by the investigator), and the root cause of death as 
determined by the sponsor.  The root cause is generally categorized as a direct effect 
of active AML, an adverse reaction, or an unrelated intercurrent event (such as car 
accident).  When the sponsor is considering additional categories for root cause, such 
as early death, feedback on the proposed categories should be sought at the pre-
submission meeting.  
 
  For drugs with unusual adverse reactions, such as differentiation syndrome, FDA 
encourages sponsors to meet with FDA review staff prior to submission of a new drug 
application (NDA) or biologics license application (BLA) to develop a detailed 
methodology for identifying cases, determine when additional narratives should be 
included in the submission, and to discuss the structure of the data files to be used for 
the analysis of such cases.  
 
  When the study drug is used in multiple stages of AML treatment (e.g., in 
combination with induction, in combination with consolidation, and as maintenance), 
safety and laboratory data should be assessed by treatment stage. 
 
  When a randomized trial has a comparator arm with a different duration of treatment 
(e.g., continuous oral therapy vs. a fixed duration of intensive salvage chemotherapy), 
it is important to compare toxicities between study arms for a similar duration of 
treatment.  For long-term continuous treatment with investigational drug, safety 
beyond the period of comparison should be analyzed separately and compared to 
early-period toxicities to identify unique late-onset adverse reactions. 
 
  For myelosuppressive AML drugs, an analysis should be performed to determine the 
incidence of prolonged thrombocytopenia (platelets < 50 Gi/L) or neutropenia (ANC 
< 0.5 Gi/L) past cycle day 42 in the absence of active leukemia.   
 
  26  Contains Nonbinding Recommendations 
3.  Clinical Pharmacology  
 
  If the AML drug is a CYP3A substrate, the submission should include analyses of the 
effect of concomitant drugs, including moderate and strong CYP3A inhibitors and 
inducers on the systemic exposure of parent drug and its active metabolites, on safety 
and efficacy, and whether the available safety and efficacy data support the proposed 
dose modifications for concomitant treatment with moderate and strong CYP3A 
inhibitors and inducers (see section III.A.3).  If the AML drug or its major 
metabolite(s) is an inhibitor or inducer of metabolism enzymes or transporters, the 
submission should include analyses of the effect of the parent drug and major 
metabolites on the systemic exposure of concomitant drugs that are substrates of 
metabolism pathway or transporter and have a likelihood of coadministration (e.g., 
commonly-used antibiotics, other AML drugs in the combination regimen). 
 
  For submissions specifically for indications that target the population of patients with 
comorbidities that preclude use of intensive chemotherapy for AML, the submission 
should include the results of studies on the effects of renal and hepatic impairment on 
the systemic exposure of the parent drug and its active metabolites (see section 
III.A.3).     
  27  Contains Nonbinding Recommendations 
GLOSSARY 
 
A. Terms referring to the types of AML treatment are defined as follows when used in this 
guidance 
 
Episodic treatment:  A treatment plan of multiple cycles of short-term administrations 
of intensive treatment.  A typical course of episodic first-line treatment for AML consists 
of 1-2 cycles of induction and 2-4 cycles of consolidation with or without HSCT. 
 
Continuous treatment:  Repeated cycles of treatment, usually without a drug-free 
period.  A typical course of continuous treatment of AML consists of daily dosing. 
 
B.  Terms referring to phases of AML treatment are defined as follows when used in this 
guidance 
 
Induction:  A limited course of treatment, usually intensive, with the objective of 
achieving CR. 
 
Consolidation:  A limited course of treatment, usually intensive, given after achievement 
of remission with the objective of reducing the risk of early relapse. 
 
Maintenance:  An extended but time-limited course of treatment, usually relatively 
nontoxic, given after achievement of CR with the objective of reducing the risk of relapse 
beyond the period of treatment.  When the treatment plan allows for extended therapy for 
patients without achieving CR, the course is considered continued treatment rather than 
maintenance. 
 
Continued treatment:  An extended course of treatment after induction phase with the 
objective of controlling the AML disease burden while on therapy.  Continued treatment 
may be time-limited, but it is generally administered until unacceptable toxicity or 
recurrence after a response.    
 
C.  Terms referring to intensities of AML treatment are defined as follows when used in this 
guidance 
 
Intensive therapies:  regimens expected to cause high-grade organ toxicity (including 
neurologic, pulmonary, cardiac, gastrointestinal, genitourinary, renal, hepatic, or 
cutaneous toxicities) or where the expected duration of neutropenia may approach 42 
days from the start of the treatment cycle.  Intensive regimens include 1-2 cycles of 
induction followed by consolidation with chemotherapy or HSCT.   
 
Nonintensive therapies:  lower doses of cytotoxic chemotherapy or targeted drugs with 
limited or no expected organ toxicities.  
 
  28  Contains Nonbinding Recommendations 
D. Disease status is assessed at the time of study enrollment.  Terms relevant to AML 
disease status are defined as follows when used in this guidance  
 
Primary refractory disease:  The patient did not experience CR in response to first-line 
or any subsequent induction therapy.  
 
Untreated relapse:  The patient experienced CR in response to the last prior therapy, 
then demonstrated relapse and has not yet received definitive re-induction therapy for that 
relapse.  
 
Refractory relapse:  The patient experienced disease remission in response to past 
therapy, then demonstrated relapse and was treated with definitive re-induction therapy 
but did not experience CR with this re-induction. 
 
Line of therapy:  A line of therapy is defined as the planned therapy consisting of one or 
more cycles of episodic treatment or a defined period of continuous treatment.  This may 
consist of single-agent or combination therapy as well as a planned sequence of treatment 
phases.  For example, first-line treatment of AML with induction, consolidation, and 
allogeneic HSCT is considered one line of therapy.  A line of therapy ends when the 
patient fails to achieve a response within a prespecified period (refractory) or relapses 
after achieving CR.   
  29  Contains Nonbinding Recommendations 
APPENDICES 
 
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 42  
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 ASTCT Criteria for CRS.  In the remainder of the table, grade number refers to NCI-CTCAE criteria. 
  30  Contains Nonbinding Recommendations 
Appendix 2:  Additional Statistical Discussion 
 
Postrandomization HSCT Subsequent Poststudy Treatments  
 
For AML trials, it is common for patients to receive subsequent anti-AML treatments post-
randomization, which include HSCT and/or anti-AML drugs (not to be confused with 
concomitant therapies).  As use of subsequent treatments is consistent with the practice of 
medicine, FDA recommends that the primary analysis of a time-to-event endpoint (e.g., OS, 
EFS) not censor for subsequent treatments.1  This approach implies that HSCT and/or 
subsequent anti-AML treatments are viewed as part of the as-needed AML treatment regimen 
taken after the initial study drug and that the treatment effect is the result of both the study drug 
and the subsequent anti-AML treatment.  
 
To help ensure that the treatment effect is interpretable, AML trials should be designed such that 
investigators are blinded to patients assigned treatment.  Regardless of the feasibility of blinding 
and as HSCT extends survival, rules or criteria should be clearly prespecified in the protocol 
prior to study initiation to determine how patients are to be selected for HSCT.  In addition, 
where patients are still on study, follow-up of patients should continue even after initiation of 
subsequent treatments. 
 
It has been suggested that the true treatment effect should be free from the influence of HSCT or 
subsequent treatments.2  Under this approach, the treatment effect may be interpreted as the 
difference in the endpoint between patients who initiated the investigational drug and patients 
who initiated the control treatment if HSCT and/or subsequent anti-AML treatments had not 
been available, or if available, were withheld from patients.  In settings where HSCT and/or 
subsequent treatments are integral to the practice of medicine, this approach to thinking about the 
treatment effect is currently not recommended for the primary analysis for the following reasons: 
  
  First, it may not be possible to design a clinical trial to estimate this treatment effect if 
patients are provided HSCT or subsequent treatments as needed.  This implies that this 
treatment effect can only be estimated by modeling, using causal inference methods 
developed for observational studies where the assumptions therein are difficult, if not 
impossible, to justify. 
   
  Second, the clinical relevance of such an estimand is still an open question if it can never 
be realized in practice.  
 
Plateauing Effect  
 
Trials designed to cure AML often result in survival contours characterized by an initial drop 
followed by a plateauing effect after some time point post randomization.  This is an example of 
nonproportional hazards.  While the log-rank test is somewhat robust to nonproportionality, it 
generally results in loss of power.  Furthermore, nonproportionality can cause difficulty in 
describing the treatment effect.  FDA is open to discussion about analyses based on other 
 
1 See the treatment policy discussion in ICH E9(R1).   
2 For additional reference, see the discussion on hypothetical strategies in ICH E9(R1).   
  31  Contains Nonbinding Recommendations 
approaches, such as weighted Cox regression or other weighted methods, or summarizing the 
treatment effect using restricted mean survival time (RMST) or landmark survival analysis.  
Plans that use these alternative approaches should include: 
 
  justification for what constitutes clinically meaningful difference,  
 
  justification of design parameters, such as sample size and follow-up duration, based on 
this endpoint, and  
 
  justification for the value of the threshold that will be used to calculate the RMST.     
  32  Contains Nonbinding Recommendations 
Appendix 3:  Additional Data Files for Marketing Applications for AML Drugs 
 
The following variables are recommended for custom data files to assist with endpoint 
adjudication 
 
Variables That Assist Morphological Response Assessment 
 
  Study identification number 
  Site identification number 
  Unique subject number 
  Treatment arm 
  Date of start of study drug 
  Date of last study drug 
  Study day of last study drug 
  Date of last platelet transfusion prior to CR 
  Study day of last platelet transfusion prior to CR 
  Date of last RBC transfusion prior to CR 
  Study day of last RBC transfusion prior to CR 
  Date of CR* 
  Study day of CR* 
  Date of ANC used for CR response* 
  Study day of ANC used for CR response* 
  ANC used for CR response* 
  Date of platelet count used for CR response* 
  Study day of platelet count used for CR response* 
  Platelet count used for CR response* 
  Date of marrow used for CR response* 
  Study day of marrow used for CR response* 
  Marrow blasts percentage used for CR response* 
  Date of assessment of Auer rods (yes/no) at CR response* 
  Date of assessment of extramedullary disease for CR response* 
  Study day of assessment of extramedullary disease for CR response* 
  Absence of extramedullary disease (yes/no) at CR response* 
  Date of relapse 
  Study day of relapse 
  Date of transplantation 
  Study day of transplantation 
 
* If CRh is an endpoint in the study, these measures should also be provided for CRh.   
  33  Contains Nonbinding Recommendations 
Variables That Assist the Transfusion Independence Assessment 
 
  Study identification number 
  Site identification number 
  Unique subject number 
  Treatment arm 
  Date of start of study drug 
  Date of last study drug 
  Study day of last study drug 
  RBC transfusion dependence at baseline (yes/no) 
  Platelet transfusion dependence at baseline (yes/no) 
  Transfusion dependence for either RBC or platelets at baseline (yes/no) 
  RBC transfusion independence (TI) criteria met post baseline (yes/no) 
  Platelet TI criteria met post baseline (yes/no) 
  TI criteria met for both RBC and platelet transfusions post baseline (yes/no) 
  Date of start of RBC TI 
  Study day of start of RBC TI 
  Date of end of RBC TI 
  Duration of RBC TI post baseline 
  Date of start of platelet TI 
  Study day of start of platelet TI 
  Date of end of platelet TI 
  Duration of platelet TI post baseline 
  Date of start of RBC and platelet TI 
  Study day of start of RBC and platelet TI 
  Date of end of RBC and platelet TI 
  Duration of RBC and platelet TI post baseline 
  Date of last study follow-up  
  Study day of last study follow-up  
  Status at last study follow-up (alive and TI, alive and transfusion-dependent, dead, or 
lost) 
  34