Expansion Cohorts: Use in 
First-in-Human Clinical 
Trials to Expedite 
Development of Oncology 
Drugs and Biologics 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Oncology Center of Excellence (OCE) 
 
March 2022 
Procedural 
   
Expansion Cohorts: Use in 
First-in-Human Clinical 
Trials to Expedite 
Development of Oncology 
Drugs and Biologics 
Guidance for Industry 
 
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Food and Drug Administration 
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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 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Oncology Center of Excellence (OCE) 
 
March 2022 
Procedural 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  FIH MULTIPLE EXPANSION COHORT TRIAL DEFINITION AND 
POTENTIAL OPPORTUNITIES AND CHALLENGES ............................................ 3 
A.  Definition ........................................................................................................................................ 3 
B.  Potential Opportunities and Challenges ...................................................................................... 3 
IV.  DRUG PRODUCT AND SUBJECT CONSIDERATIONS .......................................... 4 
V.  CONSIDERATIONS BASED ON COHORT OBJECTIVES ...................................... 4 
A.  Assessing Safety of Recommended Phase 2 Dose ........................................................................ 5 
B.  Evaluating Preliminary Antitumor Activity ................................................................................ 5 
C.  Evaluating Specific PK and Pharmacodynamic Aspects ........................................................... 6 
D.  Further Dose/Schedule Exploration ............................................................................................. 6 
E.  Biomarker Development ............................................................................................................... 7 
F.  Evaluating Drug Product Changes ............................................................................................... 7 
G.  Evaluating More Than One Therapeutic Drug ........................................................................... 8 
H.  Evaluating PK, Tolerability, and Initial Evidence of Activity in the Pediatric Population .... 9 
VI.  STATISTICAL CONSIDERATIONS .......................................................................... 10 
VII.  SAFETY CONSIDERATIONS ..................................................................................... 10 
A.  Safety Monitoring and Reporting Plans .................................................................................... 10 
B.  Independent Data Monitoring Committee ................................................................................ 11 
C.  IRB/Independent Ethics Committee .......................................................................................... 12 
D.  Informed Consent Document ...................................................................................................... 13 
VIII.  PROTOCOL CONTENT ............................................................................................... 14 
A.  Initial Protocol .............................................................................................................................. 14 
B.  Protocol Amendments ................................................................................................................. 15 
C.  Communications and Interactions With FDA ........................................................................... 15 
 
  Contains Nonbinding Recommendations 
Expansion Cohorts:  Use in First-in-Human Clinical Trials to 
Expedite Development of Oncology Drugs and Biologics 
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 provide advice to sponsors regarding the design and conduct 
of first-in-human (FIH) clinical trials intended to efficiently expedite the clinical development of 
oncology drugs, including biological products, through multiple expansion cohort trial designs.2 
These are trial designs that employ multiple, concurrently accruing subject cohorts, where 
individual cohorts assess different aspects of the safety, pharmacokinetics, and antitumor activity 
of the drug product.  
 
This guidance provides FDAs current thinking regarding (1) characteristics of drug products 
best suited for consideration for development under a multiple expansion cohort trial; (2) 
information to include in investigational new drug applications (INDs) to support the use of 
individual cohorts; (3) when to interact with FDA on planning and conduct of multiple expansion 
cohort trials; and (4) safeguards to protect subjects enrolled in FIH expansion cohort trials. 
 
This guidance does not address all issues relating to clinical trial design, statistical analysis, or 
the biomarker development process. Those topics are addressed in other guidances including the 
International Council for Harmonisation (ICH) guidances for industry E9 Statistical Principles 
for Clinical Trials (September 1998) and E10 Choice of Control Group and Related Issues in 
 
1 This guidance has been prepared by the Office of Oncologic Diseases in the Center for Drug Evaluation and 
Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at  the Food and 
Drug Administration. 
 
2 For the purposes of this guidance, all references to drugs or drug products include both human drugs and biological 
drug products regulated by CDER and CBER unless otherwise specified. 
1  Contains Nonbinding Recommendations 
Clinical Trials (May 2001) as well as the guidance for industry and FDA staff In Vitro 
Companion Diagnostic Devices (August 2014).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.  
FDAs guidance documents should be viewed only as recommendations, unless specific 
regulatory or statutory requirements are cited.  The use of the word should in Agency guidances 
means that something is suggested or recommended, but not required. 
 
 
II.  BACKGROUND 
 
Phase 1 clinical trials are designed to determine the metabolism and pharmacologic actions of an 
investigational drug in humans, the side effects associated with increasing doses, and, when 
conducted in patients rather than healthy subjects, to gain early evidence of effectiveness.4 The 
primary rationale for conducting phase 1 studies is to obtain sufficient information about the 
drugs pharmacokinetic (PK) and pharmacologic effects to permit the design of subsequent well-
controlled, scientifically valid phase 2 studies. The number of subjects included in phase 1 trials 
is anticipated to be 20 to 80 subjects. 
 
FIH multiple expansion cohort trials are intended to expedite development by seamlessly 
proceeding from initial determination of a tolerated dose to assessments that are more typical of 
phase 2 trials (i.e., to estimate antitumor activity) within individual expansion cohorts. In 
general, these expansion cohorts will be initiated before the analysis of the metabolism and 
pharmacokinetics of the investigational drug and with limited safety assessment. Therefore, it is 
critical to ensure close and prompt monitoring for toxicity in expanded cohorts, given that such 
trials have enrolled between a few hundred to more than 1,000 subjects.5, 6 
 
Because of the rapid enrollment and evolving nature of the information obtained in these trials, 
large numbers of subjects are exposed to drugs with unknown efficacy and minimally 
characterized toxicity profiles. To limit the number of subjects that could be exposed to 
unacceptable safety risks or an ineffective drug, sponsors should establish an infrastructure to 
streamline trial logistics, facilitate data collection (see section VII., Safety Considerations), and 
incorporate plans to rapidly assess emerging data in real time and to disseminate interim results 
to investigators, institutional review boards (IRBs), and regulators. 
 
 
 
 
3 We update guidances periodically. 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.  
 
4 21 CFR 312.21(a)(1) and (2). 
 
5 See, for example, KEYNOTE-001 study design at https://clinicaltrials.gov/ct2/show/NCT01295827. 
 
6 See, for example, JAVELIN study design at https://clinicaltrials.gov/show/NCT01772004.  
2  Contains Nonbinding Recommendations 
III.  FIH MULTIPLE EXPANSION COHORT TRIAL DEFINITION AND 
POTENTIAL OPPORTUNITIES AND CHALLENGES 
 
A.  Definition 
 
For the purpose of this guidance, an FIH multiple expansion cohort trial is an FIH trial with a 
single protocol with an initial dose-escalation phase followed by three or more additional subject 
cohorts with cohort-specific objectives. The objectives of these expansion cohorts can include 
assessment of antitumor activity in a disease-specific setting, assessment of a dose with 
acceptable safety in specific populations (e.g., pediatric or elderly subjects, subjects with organ 
impairment, subjects with specific tumor types), evaluation of alternative doses or schedules, 
establishment of dose and schedule for the investigational drug administered with another 
oncology drug, or evaluation of the predictive value of a potential biomarker. In general, 
comparison of activity between cohorts is not planned except when a prespecified randomization 
and analysis plan are part of the protocol design. 
 
B.  Potential Opportunities and Challenges 
 
The principal advantage of conducting FIH multiple expansion cohort trials is efficiency in drug 
development by gaining earlier evidence on whether a drug may be effective across a range of 
diseases and populations. 
 
FIH multiple expansion cohort trials pose several challenges and risks, including the following: 
 
  The need to disseminate new safety information to investigators, IRBs, and regulators as 
soon as possible. FDA and investigators must be updated with new serious and 
unexpected safety information as soon as possible but no later than 15 calendar days after 
the sponsor determines that the information should be reported,7,8,9 so that they can 
provide the necessary oversight for protection of human subjects and so that investigators 
can ensure that subjects can provide adequate informed consent. 
 
  Exposing a large number of subjects across multiple, simultaneously accruing cohorts to 
potentially suboptimal or toxic doses of an investigational drug. 
 
  Exposing more subjects to the potential risks of the investigational drug than required to 
achieve the cohorts objectives. 
 
  Possible misinterpretation of preliminary trial results and unplanned analyses that can 
lead to delays in clinical development (e.g., selection of dosage regimens or biomarker-
 
7 See, for example, 21 CFR 312.32(c)(1).  
 
8 21 CFR 312.55. In turn, investigators must promptly notify an IRB of all unanticipated problems involving risks to 
human subject per 21 CFR 312.53(c)(vii), among other obligations. 
 
9 See 21 C.F.R. 312.50. 
3  Contains Nonbinding Recommendations 
selected populations based on an apparent large effect that is a chance occurrence or 
reflects a response in a subpopulation that is not representative of the general population). 
 
 
IV.  DRUG PRODUCT AND SUBJECT CONSIDERATIONS 
 
Given the potential for increased risks to subjects posed by these trial designs (see section III., 
FIH Multiple Expansion Cohort Trial Design Definition and Potential Opportunities and 
Challenges), clinical trials with FIH multiple expansion cohorts should be limited to 
investigational drug products for indications and subjects populations in which the potential risks 
are not unreasonable in the context of the disease for which the drug is being studied. The patient 
population should therefore be limited to subjects with serious oncologic diseases for which no 
satisfactory alternative therapies are available. Sponsors should provide a strong rationale for use 
of an expansion cohort trial. As drug product development progresses the drug products 
potential to provide an advance over available therapy should continue to be examined as one 
measure of determining whether the potential benefits of using an expansion cohort continue to 
outweigh the potential for the increased risks to subjects.10 
 
Drug product formulations containing drug substances with material attributes that allow for 
relatively straightforward bridging between early drug product formulations and marketing 
formulations (e.g., biopharmaceuticals classification system Class 1 designation, nonliposomal 
injections, immediate release oral drug products) may be more appropriate for multiple 
expansion cohort trials. For more complex drug products and drug substances, FDA encourages 
discussion early in the formulation and manufacturing development to address anticipated 
challenges in bridging between earlier formulations and the appropriateness for inclusion of the 
drug product in multiple expansion cohort trials. 
 
Examples of characteristics of investigational drug products that are not suitable for study in 
clinical trials with multiple expansion cohorts because of increased risks of drug-related toxicity 
include those drug products with steep toxicity indices and large inter- and intra-patient 
variability (i.e., coefficient of variability greater than or equal to 100 percent) in 
pharmacokinetics unless there is adequate data to determine a recommended phase 2 dose. 
 
 
V.  CONSIDERATIONS BASED ON COHORT OBJECTIVES 
 
Sponsors of FIH multiple expansion cohort trials should provide the scientific rationale for 
studying each proposed cohort. A sponsor should carefully design key elements for each cohort, 
including specific endpoints, eligibility, monitoring plan, and statistical considerations to justify 
the sample size in light of the available safety information and should include adjustments for 
Type I error when a prespecified randomization and analysis are part of the design and more than 
one comparison between cohorts is planned.11 This information, as well as the information 
 
10 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014). 
 
11 See the draft guidance for industry Multiple Endpoints in Clinical Trials (January 2017). When final, this 
guidance will represent the FDAs current thinking on this topic.   
4  Contains Nonbinding Recommendations 
described in section VI., Statistical Considerations, should be included in all new FIH clinical 
trial protocols and subsequent protocol amendments adding one or more expansion cohorts. 
 
A.  Assessing Safety of Recommended Phase 2 Dose 
 
Expansion cohorts can be intended to further evaluate safety beyond the initial dose-escalation 
portion of a trial. These studies should be supported by detailed information on available safety 
and PK data from the dose-escalation phase and a summary of safety data from other expansion 
cohorts, if available. In situations when there is a narrow therapeutic index and dose-limiting 
toxicities have been observed in the dose escalation phase that may be fatal or result in serious 
morbidity, FDA strongly recommends that expansion be delayed until sufficient data are 
available to determine the recommended phase 2 dose to help ensure subjects safety. 
 
B.  Evaluating Preliminary Antitumor Activity 
 
Information to support expansion cohorts assessing disease-specific cohort antitumor activity 
should include the following: 
 
 
  A scientific rationale for inclusion of each population within a cohort based on proposed 
mechanism of action of the drug, any antitumor activity data and data regarding 
acceptability of risks in the proposed population(s) considering the natural history and 
underlying comorbidities, as well as lack of satisfactory alternative therapy12 
 
  A statistical analysis plan for the cohort that includes justification of the maximum 
sample size and stopping rules for lack of activity, to minimize the number of subjects 
exposed to an ineffective drug (e.g., generally limited to 40 subjects with solid tumors 
based on a Simon two-stage model13 or 20 subjects with hematological malignancies 
when the rarity of the hematological malignancy may support initiation of efficacy trials 
based on smaller efficacy databases) 
 
  Updated safety experience from the dose-escalation portion and other expansion cohorts, 
as available 
 
In general, a sponsor intending to continue development of a drug for a new indication should 
submit a new IND to the appropriate review division to facilitate direct communication on the 
adequacy of the development program for that indication. If preliminary clinical evidence 
suggests a substantial improvement over available therapies on one or more clinically important 
efficacy endpoints in a patient population with an unmet medical need, the sponsor should ask to 
meet with FDA to discuss further development (see section VIII., Protocol Content). In the 
exceptional situation where data from an expansion cohort may provide primary support for a 
marketing application, the protocol should contain provisions ensuring adequate data quality, 
independent review of tumor-based endpoints, and justification of the selected dosage regimen as 
well as a prespecified statistical analysis plan.  
 
12 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics. 
 
13 Simon, R, 1989, Optimal Two-Stage Designs for Phase II Clinical Trials, Control Clin Trials, 10(1): 110. 
5  Contains Nonbinding Recommendations 
 
C.  Evaluating Specific PK and Pharmacodynamic Aspects 
 
Expansion cohorts designed to evaluate the effects of food intake, organ dysfunction, and 
concomitant medications on the exposure to the investigational drug should be designed with 
knowledge of the preliminary pharmacokinetics and safety profile observed in the safety and 
dose-finding phase of the phase 1 trial. Evaluation conducted in healthy subjects should be 
performed in separate clinical studies.  
 
  Food effects 
 
  PK trials in cancer patients should refer to the recommendations in the draft guidance 
for industry Assessing the Effects of Food on Drugs in INDs and NDAs  Clinical 
Pharmacology Considerations (February 2019)14 
 
  Organ dysfunction 
 
  Expansion cohort(s) studying the effects of organ dysfunction on drug exposure 
should refer to the recommendations in the draft guidance for industry 
Pharmacokinetics in Patients With Impaired Renal Function  Study Design, Data 
Analysis, and Impact on Dosing (September 2020)15 and the guidance for industry 
Pharmacokinetics in Patients With Impaired Hepatic Function: Study Design, Data 
Analysis, and Impact on Dosing and Labeling (May 2003) 
 
  Drug interactions 
 
  The dose and timing/sequence of all concomitant anticancer medications in the cohort 
should be well documented 
 
  Sponsors of drug interaction studies should refer to the recommendations in the 
guidance for industry Clinical Drug Interaction Studies  Cytochrome P450 Enzyme 
and Transporter-Mediated Drug Interactions (January 2020)  
 
D.  Further Dose/Schedule Exploration 
 
Sponsors of expansion cohort(s) intended to further assess the optimal dose/schedule of the 
investigational drug should consider the following: 
 
  Randomization to two or more dosage regimens to increase the confidence that any 
differences between treatment arms are not due to chance alone 
 
  Justification of sample size chosen to detect clinically important differences in safety and 
activity, if present 
 
14 When final, this guidance will represent the FDAs current thinking on this topic. 
 
15 When final, this guidance will represent the FDAs current thinking on this topic. 
6  Contains Nonbinding Recommendations 
 
  Results of available safety, activity, and PK information to support the new proposed 
dosage(s) 
 
  Results of exposure-response (safety and/or activity) modeling, if available, to justify 
new dosing regimens 
 
E.  Biomarker Development 
 
If an in vitro diagnostic (IVD) will be used for patient management (e.g., selection) in a clinical 
trial, the requirements for an investigational device exemption at 21 CFR part 812 must be 
assessed by the sponsor and IRBs. FDA recommends that sponsors contact the appropriate IVD 
review center (Center for Devices and Radiological Health or Center for Biologics Evaluation 
and Research) or include such information in the IND early in the development program to 
obtain a risk assessment of the device and further guidance.16 Additionally, sponsors should refer 
to FDA guidance regarding principles for codevelopment of an in vitro companion diagnostic 
device with a therapeutic product.17 
 
Sponsors using expansion cohorts for evaluating biomarker-defined populations should justify 
the use of the biomarker and employ IVD assays that are adequately analytically validated to 
allow interpretation of the results. Use of IVDs with inadequate performance characteristics (e.g., 
specificity, sensitivity) may produce spurious results and/or delay the development of a 
potentially effective drug. Sponsors should establish procedures for tumor sample acquisition, 
handling, and the testing and analysis plans as early as possible in the biomarker development 
program. FDA may ask for submission of the IVDs analytical validation data to determine 
whether the clinical results will be interpretable. The clinical validity of the exploratory 
biomarker assay(s) should be further evaluated in confirmatory trial(s).18 
 
F.  Evaluating Drug Product Changes 
 
The chemistry, manufacturing, and controls information submitted to support expansion cohort 
trials is expected to meet the level of detail appropriate for the stage of clinical development.19 
 
 
16 See the guidance for industry Investigational In Vitro Diagnostics in Oncology Trials: Streamlined  Submission 
Process for Study Risk Determination (October 2019). 
 
17 See the draft guidance for industry and FDA staff Principles for Codevelopment of an In Vitro Companion 
Diagnostic Device with a Therapeutic Product (July 2016). When final, this guidance will represent the FDAs 
current thinking on this topic. 
 
18 See the guidance for industry and FDA staff In Vitro Companion Diagnostic Devices (August 2014) and the draft 
guidance for industry and FDA staff Principles for Codevelopment of an In Vitro Companion Diagnostic Device 
with a Therapeutic Product. When final, this guidance will represent the FDAs current thinking on this topic. 
 
19 See the guidances for industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 
Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (November 1995) and 
INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and Controls Information (May 2003). 
7  Contains Nonbinding Recommendations 
The sponsor should prominently identify in the cover letter of a protocol amendment any change 
that introduces into an ongoing trial a new formulation or presentation of a drug product or major 
manufacturing changes.20 In such amendments, the sponsor should identify changes in drug 
product quality attributes that may require bridging to earlier clinical trial drug products that 
differ in their formulations, packaging configurations, manufacturing processes, and impurity 
profile to allow comparison of the clinical data across cohorts using different formulations. 
 
Expansion cohorts intended to bridge new and older formulations should have clear objectives 
and analysis plans for assessing differences in safety and pharmacokinetics. When changes in 
presentation result in significant modifications to dose preparation, human factors studies may be 
requested.21 Depending on the effect of the changes, FDA may recommend that studies of new 
drug product formulations be conducted under a new IND. 
 
Given the challenges in bridging formulation, presentation, or drug product manufacturing 
changes, FDA urges sponsors to meet with the review division to ensure that such expansion 
cohort(s) are adequately designed to meet the intended objective of bridging clinical data across 
cohorts. FDA may recommend additional clinical trials to bridge safety and efficacy data in 
support of a marketing application if drug product changes (such as formulation changes, 
production scale-up, manufacturing site changes, and manufacturing process changes during 
clinical development) are not adequately bridged. Pooling of clinical data across different 
formulations, presentation, or drug product manufacturing processes may not be feasible in the 
absence of such bridging information.  
 
G.  Evaluating More Than One Therapeutic Drug 
 
Expansion cohort trials evaluating an investigational drug administered with an approved drug or 
another investigational drug should be initiated only after the preliminary safety profile is 
characterized for each investigational drug as a single agent at the recommended phase 2 dose. 
The protocol for the expansion cohort trial should include the justification and scientific rationale 
for combining these drugs and a safety monitoring plan with attention to overlapping and 
potential synergistic toxicities. 
 
For information regarding codevelopment of two investigational drugs, see the guidance for 
industry Codevelopment of Two or More New Investigational Drugs for Use in Combination 
(June 2013). 
 
 
20 See the ICH guidance for industry Q5E Comparability of Biotechnological/Biological Products Subject to 
Changes in Their Manufacturing Process (June 2005). 
 
21 See the draft guidance for industry and FDA staff Human Factors Studies and Related Clinical Study 
Considerations in Combination Product Design and Development (February 2016). When final, this guidance will 
represent the FDAs current thinking on this topic. 
8  Contains Nonbinding Recommendations 
H.  Evaluating PK, Tolerability, and Initial Evidence of Activity in the Pediatric 
Population 
 
A sponsor should consider expansion cohorts for evaluating pediatric populations22 if the drug 
has potential relevance for the treatment of one or more pediatric cancers based on the drugs 
mechanism of action, there is safety and dosing information in adults, and there is a lack of 
satisfactory alternative therapies for the pediatric population. Appropriate investigational drugs 
include targeted drugs where the cell surface receptor, fusion protein, amplified or mutated gene, 
or cell signaling pathway drug effects are known to be responsible for the development or 
progression of one or more pediatric cancers. Prospective inclusion of one or more pediatric 
cohorts in a multiple expansion cohort trial, as an alternative to separate pediatric dose-finding 
and activity-estimating protocols, provides an opportunity to shorten the timeline to begin 
pediatric development. 
 
To ensure the prospect for direct clinical benefit from participation on a research study where 
there is a greater than minor increase over minimal risk, sponsors generally should enroll 
pediatric subjects in dose-finding and activity estimating cohorts only after a reasonably safe 
dose and preliminary activity have been established in adults. In exceptional circumstances, 
substantive nonclinical evidence of activity in tumor-derived cell lines or patient-derived 
xenografts alone may provide sufficient justification for enrollment of a pediatric cohort before 
the availability of full clinical data in adult subjects. In these situations, FDA recommends that 
sponsors consider staggered enrollment of older children or adolescents before younger children 
to minimize risk. 
 
Information to support expansion cohorts for pediatric subjects should include detailed toxicity 
monitoring plans, plans for PK assessment, and, when appropriate, pharmacodynamic study 
objectives to guide further pediatric development. For targeted drugs, confirmation of the 
putative targets presence should be documented, and eligibility should be limited to pediatric 
subjects with relapsed or refractory disease for whom no satisfactory alternative therapy exists. 
Consideration of an orally administered drugs formulation, especially for younger children who 
may be unable to swallow capsules or tablets, may require development of an age-appropriate 
formulation for investigational use.23 
 
In general, further development of the drug for one or more pediatric cancer-specific indications 
should be pursued as a separate protocol. Initial evaluation of a drug in the pediatric population 
as part of an expansion cohort should be included in the pediatric study plan. 
 
 
22 Section 505B(a)(1)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) requires that all original new 
drug applications (NDAs) or biologics license applications (BLAs) for a new active ingredient that are submitted on 
or after August 18, 2020, must submit with the application reports on the investigation described in paragraph (3) if 
the drug or biological product that is the subject of the application is- (i) intended for the treatment of an adult 
cancer; and (ii) directed at a molecular target that the [FDA] determines to be substantially relevant to the growth or 
progression of a pediatric cancer. Section 505B(a)(1) of the FD&C Act also requires NDAs and BLAs (or 
supplements to applications) for a new active ingredient, new indication, new dosage form, new dosing regimen, or 
new route of administration to contain a pediatric assessment unless the requirement is waived or deferred.  
 
23 See FD&C Act section 505B(a)(2).  
9  Contains Nonbinding Recommendations 
 
VI.  STATISTICAL CONSIDERATIONS 
 
The background information for each expansion cohort should contain its scientific rationale. 
Information supporting individual expansion cohorts should describe the prespecified stopping 
rules for that cohort, based on insufficient antitumor activity or unacceptable level of toxicity for 
that population. Finally, the analysis plan for each expansion cohort should contain adequate 
information justifying the planned sample size based on the cohort objectives. For those cohorts 
evaluating antitumor activity, the plans should specify the magnitude of antitumor activity that 
would warrant further evaluation of the drug, for example by specifying the precision and power 
considerations for detection of clinically meaningful antitumor activity. In general, in a 
nonrandomized cohort, assessment of antitumor activity is determined using a Simon two-stage 
design or other designs (e.g., Bayesian statistical design) to limit exposure of additional subjects 
to a potentially ineffective drug.24 
 
The trial design for an individual cohort should ensure that the cohorts trial objectives can be 
met. For example, sponsors should consider the need for randomization within a cohort for 
comparison of activity between different dosing regimens. In a cohort with a randomized design, 
the sample size and the inference that can be made will be based on the prespecified null and 
alternative hypotheses to be tested, the level of significance, and the power of the test. 
 
Sponsors should avoid comparisons between cohorts to which subjects were not randomly 
assigned. 
 
 
VII.  SAFETY CONSIDERATIONS 
 
A.  Safety Monitoring and Reporting Plans 
 
The sponsor is required to ensure proper monitoring of the investigations and to ensure that the 
investigations are conducted in accordance with the general investigational plan and protocols 
contained in the IND, among other responsibilities.25 
 
The sponsor should establish a systematic approach, including plans for activation of protocol 
amendments, to address serious safety issues and to ensure rapid communication of serious 
safety issues. This approach should be described in the protocol or its appendices.267 
 
 
24 Simon, R, 1989, Optimal Two-Stage Designs for Phase II Clinical Trials, Control Clin Trials, 10(1):110. 
 
25 21 CFR 312.50. See also the guidance for industry Oversight of Clinical Investigations  A Risk-Based Approach 
to Monitoring (August 2013). 
 
26 See 21 CFR 312.32; 21 CFR 312.23 (for information about safety reporting requirements and the information 
required in a protocol for an IND).  
10  Contains Nonbinding Recommendations 
The IND should contain a proposed plan for submission of a cumulative summary of safety data 
and information, on a periodic basis that is more frequent than annual.27 The plan should be 
discussed with the review division at the pre-IND meeting. The recommended frequency of the 
submissions will be dependent on specific program risks and the rapidity of subject accrual. New 
safety data that further identify, characterize, and provide insight on management of adverse 
reactions should be periodically assessed and submitted to the IND in support of modifications of 
one or more cohorts within the protocol. 
 
The interval for submission of cumulative safety reports should be agreed upon with FDA. The 
most recent cumulative safety report should be referenced in support of protocol amendments 
proposing modifications of existing or new expansion cohorts. Given the complexity of these 
trials and potential increased risks to subjects, sponsors should select medical monitors who have 
training and experience in cancer treatment and clinical trial conduct. 
 
B.  Independent Data Monitoring Committee 
 
An independent data monitoring committee (IDMC)28 or other appropriate independent entity 
structured to assess safety in addition to efficacy should be established for all FIH multiple 
expansion cohort protocols, given that the complexity of these trials (with regard to different 
cohort objectives, trial populations, and dosages evaluated simultaneously) can lead to potential 
increased risks to subjects. 
 
Responsibilities of the IDMC should include, but not be limited to, analysis of incoming 
expedited safety reports, review of cumulative summaries of all adverse events, and making 
recommendations to the IND sponsor regarding protocol modifications to reduce risks to subjects 
enrolled in the trial. The IDMC should be charged with the real-time review of all serious 
adverse events29 and meet periodically to assess the totality of safety information in the 
development program. The IDMC should be responsible for performing prespecified and ad hoc 
assessments of safety and futility for each cohort, to recommend protocol modifications, or other 
actions including, but not limited to, the following: 
 
  Changing the eligibility criteria if the risks of the intervention seem to be higher in a 
subgroup 
 
  Altering the drug product dosage and/or schedule if the adverse events observed appear 
likely to be reduced by such changes 
 
  Modifying monitoring plans for safety by the addition of more frequent or new types of 
assessments 
 
 
27 See also 21 CFR 312.33 (for information on requirements for submitting IND safety reports). 
 
28 See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring 
Committees (March 2006). 
 
29 21 CFR 312.32 (for information on IND safety reporting requirements related to serious adverse events). 
11  Contains Nonbinding Recommendations 
  Identifying information needed to inform current and future trial subjects of newly 
identified risks via changes in the informed consent document and, in some cases, 
obtaining reconsent of current subjects to continued trial participation 
 
In trials of limited sample size (no more than 90 subjects in the dose-finding portion and no more 
than 200 subjects across all dose-expansion cohorts), sponsors may wish to consider a safety 
assessment committee that is a group within the sponsors organization alone or with external 
representation. If a safety assessment is performed within the sponsors organization, a firewall 
should be established to ensure that the individuals performing those assessments are not 
otherwise involved in trial conduct or management to protect the integrity of the study. 
 
C.  IRB/Independent Ethics Committee 
 
Under FDAs regulations, a clinical investigation generally may not be initiated until it has been 
reviewed and approved by an IRB/independent ethics committee, and it remains subject to 
continuing review by an IRB throughout the duration of the trial.30 Consistent with the 
continuing review requirements,31 the investigator should provide cumulative safety information 
provided by the IND sponsor to the IRB. 
 
Because of the complexity of expansion cohorts as discussed in section V.A., Confirming Safety 
of Recommended Phase 2 Dose, in general, the sponsor should perform an assessment of safety 
more frequently than on an annual basis and, when such an assessment is done, must provide this 
information to the investigator (see section VII., Safety Considerations).32 Sponsors are required 
to keep each participating investigator informed of new observations discovered by or reported 
to the sponsor on the drug, particularly with respect to adverse effects and safe use.33 
 
The investigator is expected to convey new observations to the IRB at the time of continuing 
review, or sooner, if it is an unanticipated problem involving risk to human subjects or others.34 
The summary information conveyed to the IRB should include a description of the detailed plan 
for timely, periodic communication of trial progress, cumulative safety information, and other 
reports from the IDMC. This information is necessary to allow the IRB to evaluate the risks to 
subjects of the ongoing investigation, the risks to subjects of all protocol modifications (e.g., 
changes in dosing, addition of new cohorts), and the adequacy of the informed consent 
document. 
 
 
30 21 CFR 56.103(a); 21 CFR 56.109(f). 
 
31 21 CFR 56.109(f). 
 
32 21 CFR 312.55(b).  
 
33 21 CFR 312.55(b). 
 
34 See 21 CFR 312.66 and the guidance for clinical investigators, sponsors, and IRBs Adverse Event Reporting to 
IRBs  Improving Human Subject Protection (January 2009). 
12  Contains Nonbinding Recommendations 
To facilitate IRB review of multicenter, FIH multiple expansion cohort trials, FDA recommends 
the use of a central IRB as permitted.35 The central IRB should have adequate resources and 
appropriate expertise to review FIH multiple expansion cohort trials in a timely and thorough 
manner. When necessary, an IRB may invite individuals with competence in special areas (i.e., a 
consultant) to assist in the review of complex issues that require expertise beyond or in addition 
to that available on the IRB.36 
 
Given the increased risks to subjects participating in FIH multiple expansion cohort trials, IRBs 
should consider convening additional meetings (i.e., ad hoc meetings of an existing IRB) to 
review the evolving new safety information, provided regulatory requirements such as the 
presence of a quorum can be met.37 Alternatively, a separate, duly constituted specialty IRB can 
be established and specifically charged with meeting on short notice to review new information 
and/or modifications to FIH expansion cohort trials. Such an IRB would need to satisfy the same 
requirements of any IRB  (i.e., 21 CFR part 56), but it could be designed to facilitate a quorum 
by keeping membership to a minimum (i.e., 21 CFR 56.107 requires that each IRB have at least 
five members) and being composed of experienced members who are capable of meeting and 
reviewing FIH multiple expansion cohort trial-related materials on short notice. Ad hoc meetings 
of an existing IRB or the establishment of a separate specialty IRB designed to facilitate the 
review of FIH multiple expansion cohort trials are acceptable approaches that, if appropriately 
constituted and operated, can satisfy the regulatory requirement for IRB oversight. 
 
D.  Informed Consent Document 
 
Informed consent documents must be updated as new information is obtained during the trial that 
could affect a subjects decision to participate in or remain in the trial.38 In general, FDA requests 
submission of the original and updated informed consent forms to the IND to permit an 
evaluation of whether subjects have the information to make informed decisions regarding 
participation in the trial.39   
 
Updates to the informed consent document to reflect protocol modifications may be required.40 
In addition, many protocol amendments to FIH multiple expansion cohort trials are required to 
be submitted to the IND before they are implemented, unless immediate modifications are 
implemented for subjects safety (in which case, FDA must be subsequently notified).41 The 
 
35 21 CFR 56.114. See the guidance for industry Using a Centralized IRB Review Process in Multicenter Clinical 
Trials (March 2006). 
 
36 21 CFR 56.107(f). 
 
37 21 CFR 56.108(c). 
 
38 See 21 CFR 50.25(a) and 50.25(b)(5). 
 
39 See 21 CFR 312.23(a)(11). 
 
40 See 21 CFR 50.25(a). 
 
41 See 21 CFR 312.30(b).   
13  Contains Nonbinding Recommendations 
updated informed consent document should be submitted in each IND amendment containing 
clinically important protocol modifications. 
 
 
VIII.  PROTOCOL CONTENT 
 
FIH multiple expansion cohort protocols must contain all of the elements for clinical protocols;42 
however, sponsors should consider whether there is a need for a greater level of detail to allow 
FDA and others (investigators, IRBs) to ensure that the risks to subjects are not unreasonable and 
that the goals for each expansion cohort are clear and can be met. In addition, FDA requires most 
commercial INDs to be submitted in an electronic format (i.e., electronic common technical 
document) and highly encourages electronic submission for noncommercial INDs.43 
 
FIH trials with multiple expansion cohorts can in some instances present challenges in subjects 
oversight caused by rapid enrollment of a large number of subjects exposed to the investigational 
drug. In general, safety information will be limited at the time of trial initiation, which may 
expose subjects to higher potential risks and may be unethical if the trial is not carefully planned 
to address the specific scientific objectives of each expansion cohort. Therefore, failure to 
provide sufficient detail, either in the initial protocol or in protocol amendments, on the goals 
and conduct of the clinical protocol in a well-defined population where the risks are not 
unreasonable can result in the trial being placed on clinical hold.  In some cases, measures to 
stagger enrollment may be appropriate until adequate safety information is available to support 
exposure of a larger number of subjects.  
 
A.  Initial Protocol 
 
The initial IND submission containing an FIH multiple expansion cohort protocol should contain 
all of the information described in sections V., VI., and VII.44 Additionally, the protocol and 
IND should contain the following: 
 
  Detailed and clearly identified table of contents and protocol section headers indicating 
the dosage regimen and dose modifications for each discrete cohort, to avoid medication 
errors when treatment plans differ by cohort (dose-escalation versus dose-expansion and 
between individual expansion cohorts, if applicable) 
 
  A schema for the overall trial design 
 
 
42 21 CFR 312.23(a)(6)(iii). 
 
43 See the guidance for industry Providing Regulatory Submissions in Electronic Format  Certain Human 
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (February 2020). 
The guidance is not applicable to noncommercial INDs and INDs for devices that are regulated by CBER as 
biological products under section 351 of the Public Health Service Act and that also require the submission of an 
IND before the submission of a BLA.  This guidance is considered binding under section 745A(a) of the FD&C Act.  
 
44 See also 21 CFR 312.23 for IND content and format requirements. 
14  Contains Nonbinding Recommendations 
  A description of the plan for the data flow (data collection, analysis, and timing of data 
dissemination) 
 
  A description of the plan for submission of interim safety and efficacy results to FDA, 
other groups responsible for monitoring subject safety (e.g., IRB, IDMC), and 
investigators, to ensure that the risks to subjects are mitigated 
 
A cohort containing an FIH drug product or products regulated by the Center for Biologics 
Evaluation and Research (CBER) for which there is no existing IND in CBER cannot be 
conducted under a Center for Drug Evaluation and Research (CDER) IND. Similarly, a cohort 
containing an FIH drug product or products regulated by CDER for which there is no existing 
IND in CDER cannot be conducted under a CBER IND. The investigation of such drug products 
must proceed under a separate trial in an IND submitted to CBER or CDER, as appropriate.45 
 
B.  Protocol Amendments 
 
Protocol amendments that substantively affect the safety or scope of the protocol should contain 
a clean version of the amended protocol, a copy of the protocol with tracked changes, and the 
following supportive information, if available:46 
 
  A summary of the available adverse reaction profile observed by dose and schedule for 
subjects with adequate evaluation (i.e., subjects with at least one posttreatment adverse 
event or who have completed at least one treatment cycle with submission of safety 
information to the sponsor); 
 
  New nonclinical toxicology or pharmacology data and clinical data as appropriate to 
support the protocol modification; and/or 
 
  An updated informed consent document, as appropriate. 
 
C.  Communications and Interactions With FDA 
 
For all communication with FDA, sponsors and FDA should consult the guidance for industry 
and review staff Best Practices for Communication Between IND Sponsors and FDA During 
Drug Development (December 2017). 
 
  Sponsors should consider requesting a pre-IND meeting to discuss their plans to conduct 
an FIH multiple expansion cohort trial. When the original IND is submitted, the cover 
letter should prominently identify it as an FIH multiple expansion cohort trial. 
 
 
45 See 21 CFR  312.140. 
 
46 See 21 CFR 312.30(d) and 312.31(b) for content and format requirements for protocol amendments and 
information amendments. 
15  Contains Nonbinding Recommendations 
  The sponsor should also notify the regulatory project manager via secure email or 
telephone call 48 hours before submission of any protocol amendment that substantively 
affects the safety or scope of the protocol. 
 
  Though an amended protocol may proceed upon submission to the IND and IRB 
approval, FDA strongly encourages sponsors to submit amendments for reasons other 
than those that affect the safety of subjects (e.g., change to analysis plan or addition of a 
new treatment arm) at least 30 days before initiation of subject enrollment under the 
amendment to allow FDA time to conduct a safety review. Amendments containing 
changes implemented immediately to ensure subject safety (e.g., closure of a cohort for 
unacceptable toxicity, modification of eligibility, monitoring to mitigate the risks of 
adverse reactions) should be submitted to the IND as soon as possible. 
 
  Either FDA or sponsors may request a teleconference to discuss protocol amendments 
within 30 days of their submissions to the IND. If data from an expansion cohort or 
cohorts are intended to provide primary support a marketing application, the sponsor 
should request a formal meeting with FDA to obtain advice regarding the proposed 
cohort and the overall development plan.47 The content and the format of marketing 
applications, including the content of the clinical study report, should be discussed with 
FDA in a formal meeting.48 
 
47 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (December 2017). When final, this guidance will represent the FDAs current thinking on this topic 
 
48 For additional information, see 21 CFR 314.50, 21 CFR 601.2, and the ICH guidance for industry E3 Structure 
and Content of Clinical Study Reports (July 1996). 
16