Optimizing the Dosage 
of Human Prescription 
Drugs and Biological 
Products for the 
Treatment of Oncologic 
Diseases 
Guidance for Industry 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit electronic comments to https://www.regulations.gov. Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Mirat Shah at 301-796-8547 or Stacy Shord 
at 301-796-6261.  
 
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) 
January 2023 
Clinical/Medical   
Optimizing the Dosage 
of Human Prescription 
Drugs and Biological 
Products for the 
Treatment of Oncologic 
Diseases 
Guidance for Industry 
Additional copies are available from: 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD 20993-0002  
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https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
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Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
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) 
January 2023 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  DOSE OPTIMIZATION RECOMMENDATIONS ...........................................3 
A.  Collection and Interpretation of Clinical Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Data ............................................................................................................. 3 
B.  Trial Designs to Compare Multiple Dosages ................................................................... 5 
C.  Safety and Tolerability ...................................................................................................... 5 
D.  Drug Formulation.............................................................................................................. 6 
E.   Subsequent Indications and Usages ................................................................................. 6 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Optimizing the Dosage of Human Prescription Drugs and Biological 
2  Products for the Treatment of Oncologic Diseases 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
9  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14                                                                       
15  I.  INTRODUCTION  
16  This guidance is intended to assist sponsors in identifying the optimal dosage(s)2 for human 
17  prescription drugs3 or biological products for the treatment of oncologic diseases during clinical 
18  development and prior to submitting an application for approval for a new indication and usage. 
19  This guidance should be considered along with the International Conference on Harmonisation 
20  (ICH) E4 guidance on Dose-Response Information to Support Drug Registration when 
21  identifying the optimal dosage(s).4 
22  Additional information on related topics can be found in:  
23    Draft guidance for industry Population Pharmacokinetics (July 2019).5  
24    Guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, 
25  and Regulatory Applications (April 2003).  
26  This guidance does not address selection of the starting dosage for first-in-human trials nor does 
27  it address dosage optimization for radiopharmaceuticals, cellular and gene therapy products, 
28  microbiota, or cancer vaccines. 
29  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
30  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
 
1 This guidance has been prepared by the Oncology Center of Excellence (OCE), the Center for Drug Evaluation and 
Research (CDER), and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug 
Administration.  
2 For the purpose of this guidance, dosage refers to the dose and schedule (i.e., the recommended interval between 
doses and duration of treatment) and dose refers to the quantity of the drug. Optimal dosage is the dosage that can 
maximize the benefit/risk profile or provide the desired therapeutic effect while minimizing toxicity. 
3 For the purposes of this guidance, references to drugs include drugs approved under section 505 of 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). 
4 See guideline for industry ICH Topic E4 Dose Response Information to Support Drug Registration (November 
1994). We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web 
page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
5 When final, this guidance will represent the FDAs current thinking on this topic.  
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
31  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
32  the word should in FDA guidance means that something is suggested or recommended, but not 
33  required.  
34   
35  II.  BACKGROUND 
36  Dose-finding trials (e.g., trials that include dose-escalation and dose-expansion portions with the 
37  primary objective of selecting the recommended phase II dose) for oncology drugs have 
38  historically been designed to determine the maximum tolerated dose (MTD).  This paradigm was 
39  developed for cytotoxic chemotherapy drugs based on their observed steep dose-response, their 
40  limited drug target specificity, and the willingness of patients and providers to accept substantial 
41  toxicity to treat a serious, life-threatening disease. The MTD was identified by evaluating 
42  stepwise, increasing doses in a small number of patients at each dose for short periods of time 
43  until a prespecified rate of severe or life-threatening dose-limiting toxicities (DLTs) was 
44  observed. Sponsors typically administered the MTD, or a dosage close to the MTD, in 
45  subsequent clinical trials without further efforts to optimize the dosage.  
46  Most modern oncology drugs, such as kinase inhibitors and monoclonal antibodies, are designed 
47  to interact with a molecular pathway unique to an oncologic disease(s) (i.e., targeted therapies). 
48  These targeted therapies demonstrate different dose-response relationships compared to 
49  cytotoxic chemotherapy, such that doses below the MTD may have similar efficacy to the MTD 
50  but with fewer toxicities. Additionally, the MTD may never be reached in certain situations. 
51  Compared to, for example, cytotoxic chemotherapies, patients may receive targeted therapies for 
52  much longer periods, potentially leading to lower grade but persistent symptomatic toxicities, 
53  which can be more challenging to tolerate over time. Nevertheless, the dosage administered in a 
54  registration trial(s) (i.e., the trial or substudy designed to evaluate safety and effectiveness and 
55  support a marketing application) for these targeted therapies is often the MTD or the highest 
56  dosage administered in the dose-escalating trial if the MTD is not defined. This paradigm can 
57  result in a recommended dosage that is poorly tolerated, adversely impacts functioning and 
58  quality-of-life, and moreover, affects a patients ability to remain on a drug and thereby derive 
59  maximal clinical benefit. Additionally, patients who experience adverse reactions from one 
60  treatment may have difficulty tolerating future treatments, especially if there are overlapping 
61  toxicities.  
62  The traditional MTD paradigm often does not adequately evaluate other data, such as low-grade 
63  symptomatic toxicities (i.e., grade 1-2), dosage modifications, drug activity, dose- and exposure-
64  response relationships, and relevant specific populations (defined by age, organ impairment, 
65  concomitant medications or concurrent illnesses). Dose-finding trials that investigate a range of 
66  dosage(s) and select the dosages to be further investigated based on clinical data and an 
67  understanding of dose- and exposure-response, represent a more informed approach to identify 
68  the optimal dosage(s).  
69  Despite therapeutic progress, most advanced cancers remain incurable, and patients continue to 
70  have high unmet medical need for effective and tolerable therapies. Rapid access to safe and 
71  efficacious therapies remains critical. Some oncology development programs follow a seamless 
72  approach, characterized by rapid transitions between initial dose-finding trials and registration 
73  trial(s) to expedite development. With sufficient planning, identifying an optimal dosage(s) can 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
74  be aligned with the goal of expediting clinical development, and strategies to optimize the 
75  dosage can be merged into a seamless development program.6  
76  Dosage optimization prior to approval is recommended because delaying until after approval 
77  may result in large numbers of patients being exposed to a poorly tolerated dosage or one 
78  without maximal clinical benefit. Furthermore, conducting clinical trials to compare multiple 
79  dosages may be challenging to complete once a drug is approved for a given indication.  
80   
81  III.  DOSE OPTIMIZATION RECOMMENDATIONS 
82  Dosages selected for administration in a clinical trial(s) should be adequately supported by data 
83  appropriate to the stage of development for each indication and usage. Relevant nonclinical7 and 
84  clinical data, as well as the dose- and exposure-response relationships for safety and efficacy 
85  should be evaluated to select a dosage(s) for clinical trial(s). An approach where a dosage is 
86  chosen for a trial without adequate justification or consideration of relevant data may not be 
87  acceptable because FDA may determine that patients are exposed to unreasonable and significant 
88  risk, or there is insufficient information to determine risk, or the design of the trial is deficient to 
89  meet its stated objectives.8  
90  Sponsors, including sponsors pursuing development of a drug under an FDA expedited program 
91  (e.g., breakthrough therapy designation), should plan their development programs such that 
92  identification of the optimal dosage(s) can occur prior to or concurrently with the establishment 
93  of the drugs safety and effectiveness. Sponsors should note that development of a drug under an 
94  FDA expedited program (e.g., breakthrough therapy designation) is not a sufficient justification 
95  to avoid identifying an optimal dosage(s) prior to submitting a marketing application. FDA is 
96  available to discuss strategies to determine the optimal dosage(s), and sponsors are strongly 
97  encouraged to discuss their plans for dosage optimization with FDA at relevant milestone 
98  meetings. 
99  FDA recommends the following to identify the optimal dosage(s): 
100  A.  Collection and Interpretation of Clinical Pharmacokinetic, Pharmacodynamic, and 
101  Pharmacogenomic Data 
102    Dose-finding trials should include PK sampling and an analysis plan such that PK 
103  data are of sufficient quality and quantity to allow an adequate characterization of the 
104  PK (e.g., linearity, absorption, elimination) of an oncology drug following the 
105  administration of multiple dosages.9  
 
7 See guidance for industry Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of 
Oncology Drugs and Biologics (March 2022). 
7 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.   
8 See 312.42(b). 
9 See draft guidance for industry Population Pharmacokinetics (July 2019). When final, this guidance will represent 
the FDAs current thinking on this topic.   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
106    The PK sampling and analysis plan should also be sufficient to support population PK 
107  and dose- and exposure-response analyses for safety and efficacy.10  
108    Following the completion of the dose-finding trial(s), population PK9 and exposure-
109  response10 analyses, data should be evaluated along with the anti-tumor activity, 
110  safety, and tolerability data to select dosage(s) for further evaluation. 
111    For oral drugs, the effect of food on PK and safety should be evaluated early in drug 
112  development to support the relative administration of the dosage(s) selected for 
113  evaluation in a registration trial(s) with food.11 
114    Clinical trials should enroll an appropriately broad population12,13,14,15,16 to allow 
115  assessment of the dosage(s) across relevant subpopulations. 
116    Population PK data should be evaluated to identify specific populations (e.g., defined 
117  based on weight, age, sex, race and ethnicity, or organ impairment) in which the PK 
118  demonstrate clinically meaningful differences in exposure.  
119    Relevant covariates should be incorporated into the exposure-response analyses to 
120  identify potential differences in safety or effectiveness for relevant subpopulations.10   
121    When appropriately justified, simulated exposure metrics may be used to conduct 
122  exposure-response analyses to evaluate alternative dosages, if applicable, in the 
123  relevant subpopulations. Alternative dosages for relevant subpopulations should be 
124  incorporated into a registration trial(s) when feasible and appropriate.  
125    A sampling and analysis plan for PD and pharmacogenetic data17,18 should be 
126  considered if appropriate.  
127    The proposed sampling and analysis plan(s) should be submitted to FDA for review. 
 
10 See guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and Regulatory 
Applications (April 2003). 
11 See draft guidance for industry Assessing the Effects of Food on Drugs in INDs and NDAs  Clinical 
Pharmacology Considerations (February 2019). When final, this guidance will represent the FDAs current thinking 
on this topic. 
12 See guidance for industry and FDA staff Collection of Race and Ethnicity Data in Clinical Trial (October 2016). 
13 See guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, 
Enrollment Practices, and Trial Designs (November 2020). 
14 See draft guidance for industry Cancer Clinical Trial Eligibility Criteria: Available Therapy in Non-Curative 
Settings (June 2021). When final, this guidance will represent the FDAs current thinking on this topic. 
15 See guidance for industry Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or 
Concurrent Malignancies (July 2020). 
16 See draft guidance for industry Diversity Plans to Improve Enrollment of Participants From Underrepresented 
Racial and Ethnic Populations in Clinical Trials (April 2022).  When final, this guidance will represent the FDAs 
current thinking on this topic. 
17 See guidance for industry Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies 
and Recommendations for Labeling (January 2013). 
18 See guidance for industry E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, 
Genomic Data and Sample Coding Categories (April 2008). 
 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
128  B.  Trial Designs to Compare Multiple Dosages 
129    Multiple dosages should be compared in a clinical trial(s) designed to assess activity, 
130  safety, and tolerability to decrease uncertainty with identifying an optimal dosage(s) 
131  in a marketing application.  
132    These dosages should be selected based on the relevant nonclinical and 
o
133  clinical data that provide a preliminary understanding of dose- and exposure-
134  response relationships for activity, safety, and tolerability. 
135    Prior to initiating a trial directly comparing multiple dosages, it may be 
o
136  reasonable to add more patients to dose-level cohorts in a dose-finding trial 
137  which are being considered for further development. This would allow for 
138  further assessment of activity and safety. 
139    A recommended trial design to compare these dosages is a randomized, parallel dose-
140  response trial.  
141    Randomization when feasible (rather than enrolling patients to non-
o
142  randomized dosage cohorts) ensures similarity of patients receiving each 
143  dosage and interpretability of dose- and exposure-response relationships. 
144    The trial should be sized to allow for sufficient assessment of activity, safety, 
o
145  and tolerability for each dosage. The trial does not need to be powered to 
146  demonstrate statistical superiority of a dosage or statistical non-inferiority 
147  among the dosages. 
148    An adaptive design to stop enrollment of patients to one or more dosage arms 
o
149  of a clinical trial following an interim assessment of efficacy and/or safety 
150  could be considered. 
151    Multiple dosages may be compared prior to a registration trial(s) or as part of a 
152  registration trial(s) by adding an additional dosage arm(s).  
153    When a registration trial contains multiple dosages and a control arm and is 
o
154  designed to establish superior efficacy of one of the dosages compared to the 
155  control arm, the trial design should provide strong control of Type I error. 
156  The analysis plan should specify a multiple-testing procedure which accounts 
157  for testing multiple treatments versus a control as well as any interim 
158  assessments after which an inferior arm is dropped. 
159    If safety and efficacy data from multiple dosages will be used to support a marketing 
160  application, this approach should be discussed with FDA early in clinical 
161  development. 
162  C.  Safety and Tolerability 
163    The duration of exposure; the proportion of patients who are able to receive all 
164  planned doses; the percentage of patients that require dosage interruptions, dose 
165  reductions, and drug discontinuations for adverse reactions; and the percentage of 
166  patients with serious adverse reactions (including fatal adverse reactions), should be 
167  compared across the multiple dosages.  
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
168    Safety monitoring rules should be pre-specified for trial designs that include dosages 
169  associated with a high percentage of dosage modifications or serious adverse 
170  reactions. The protocol should clearly state what action will be taken if the percentage 
171  of dosage modifications or serious adverse reactions is too high. Such actions may 
172  include pausing the trial so the safety monitoring committee can review these events, 
173  changing the starting dosage for future patients, and/or discontinuing the trial. 
174    Specific adverse reactions, including those that are symptomatic and may be reported 
175  as less severe (e.g., Grade 1-2 diarrhea), may still significantly affect a patients 
176  ability to remain on the drug for extended periods. The frequency and impact (i.e., the 
177  frequency of drug discontinuation, or paused/reduced dose) of such reactions should 
178  be carefully assessed and considered in selecting the dosage(s) for subsequent clinical 
179  trials. 
180    Some oncology drugs may be associated with early-onset, serious, or life-threatening 
181  toxicities which may lessen in severity or not occur with subsequent administration. 
182  Evaluation of an alternative dosing strategy, such as stepwise dosing (i.e., titration), 
183  to improve tolerability could be considered.  
184    Patient-reported outcomes (PRO) can provide a systematic and quantitative 
185  assessment of expected symptomatic adverse events and their impact on function. 
186  Inclusion of PROs should be considered to enhance the assessment of tolerability in 
187  early phase dosage finding trials. Recommendations for PRO instrument selection 
188  and assessment frequency can be found in the draft Guidance for Industry, Core 
189  Patient-Reported Outcomes in Cancer Clinical Trials (June 2021).19 
190    Engaging with patients and other key stakeholders, such as advocacy groups in a 
191  given disease area, will provide valuable input on important safety and tolerability 
192  considerations when selecting the optimal dosage(s).  
193  D.  Drug Formulation 
194    Various dose strengths should be available to allow multiple dosages to be evaluated 
195  in clinical trials. Perceived difficulty in manufacturing multiple dose strengths is an 
196  insufficient rationale for not comparing multiple dosages in clinical trials.  
197    For oral use, the appropriateness of the size and number of tablets or capsules 
198  required for an individual dose should be considered when selecting the final dosage 
199  form and strength(s).  
200    For parenteral use, the appropriateness of the final concentration and volume to be 
201  administered should be considered when selecting the final dosage form and 
202  strength(s). 
203  E.   Subsequent Indications and Usages 
204    Different dosages may be needed in different disease settings or oncologic diseases 
205  based on potential differences in tumor biology, patient population, treatment setting, 
206  and concurrent therapies (for combination regimens), among other factors.  
207  Applicable nonclinical and clinical data should be considered to support the proposed 
 
19 When final, this guidance will represent the FDAs current thinking on this topic. 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
208  dosage to be evaluated in a registration trial(s) to support a subsequent indication and 
209  usage. 
210   
211    Strong rationale for choice of dosage should be provided before initiating a 
212  registration trial(s) to support a subsequent indication and usage, especially for 
213  oncologic diseases not adequately represented in completed dose-finding trials or for 
214  new combination regimens. If sufficient rationale for choice of dosage cannot be 
215  provided, additional dose-finding should be conducted. 
7