Core  Patient-Reported 
Outcomes  in Cancer  
Clinical  Trials  
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DRAFT GUIDANCE 
 
 
 
 
 
  This guidance document is being distributed for comment purposes only.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publication in the  Federal Register  of the notice announcing the availability of the draft  
guidance.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  (OCE) Vishal Bhatnagar at  
vishal.bhatnagar@fda.hhs.gov,  (CDER) Janice Kim  at  301-796-9628, or (CBER)  Office of 
Communication, Outreach and Development, 800-835-4709 or 240-402-8010.  
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration  
Oncology Center of  Excellence (OCE)  
Center for Drug Evaluation and Research (CDER)  
Center  for Biologics Evaluation and Research (CBER)  
 
 
June  2021  
Clinical/Medical  
   
Core  Patient-Reported 
Outcomes  in Cancer  
Clinical  Trials  
Guidance for Industry  
 
Office of Communications,  Division of Drug Information   
Center for Drug Evaluation and Research  
Food and Drug Administration  
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs   
 
and/or  
 
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 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)  
 
 
June  2021  
Clinical/Medical  
 
 
   
 
TABLE OF CONTENTS  
 
 
 
I.   INTRODUCTION.............................................................................................................  1  
II.   BACKGROUND  ...............................................................................................................  2  
III.   CORE PATIENT-REPORTED OUTCOMES  ..............................................................  2  
IV.   CONSIDERATIONS FOR INSTRUMENT SELECTION TO MEASURE THE    
  CORE PATIENT-REPORTED OUTCOMES  ..............................................................  3  
V.    TRIAL DESIGN CONSIDERATIONS  ..........................................................................  6  
A.   Assessment Frequency ................................................................................................................... 6  
B.   Other Trial Design Considerations  .............................................................................................. 7  
VI.   LABELING CONSIDERATIONS ..................................................................................  7  
  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
1   Core Patient-Reported Outcomes in Cancer  Clinical  Trials  
2    Guidance for  Industry1  
3    
4    
5  This draft guidance, when finalized, will represent the  current thinking of  the  Food and Drug 
6   Administration (FDA or Agency) on this topic.  It does not  establish  any rights for any person and is not 
7   binding on FDA or the public.  You can use an alternative approach if  it  satisfies the requirements of the 
8   applicable statutes  and regulations.   To  discuss an alternative approach,  contact the FDA staff  responsible 
9   for this  guidance  as listed on the title page.   
10   
11    
12    
13    
14   I.   INTRODUCTION  
15   
16   This guidance provides recommendations  to sponsors  for collection of  a core set of  patient-
17   reported  clinical outcomes  (herein referred to  as core patient-reported outcomes)  in  cancer  
18   clinical trials  and related  considerations for instrument selection and trial design.  Although this  
19   guidance focuses on patient-reported outcome (PRO) measures, some of these recommendations  
20  may be relevant to other  clinical outcome assessments (i.e., clinician-reported outcome, 
21   observer-reported outcome, performance outcome)  in cancer  clinical trials.  Recommendations  
22   supplement previous guidance on use  of  PRO  measures in clinical trials  by  providing  additional  
23   considerations specific to the cancer  clinical trial setting.  Guidance specific to  PRO endpoints  
24   and  details  of  analytic methods are not comprehensively covered.  FDA does not endorse  any 
25  specific PRO measure  and examples within this document  are illustrative  and  should not be  
26   construed as endorsements.  
27    
28   This guidance is specific to  registration trials  for anti-cancer therapies  intended to demonstrate 
29   an effect on  survival,  tumor response,  or delay in the progression of  a malignancy.  
30  Demonstration of a  clinically meaningful  improvement  in  patient-reported symptoms or  
31   functional impacts  alone  (i.e.,  in the absence of  evidence of anti-tumor activity)  would be more  
32   applicable to  supportive care  drugs  and is outside  the scope of this guidance.  Refer to  the 
33   guidance for industry Patient-Reported Outcome  Measures: Use in Medical Product  
34   Development to Support Labeling Claims  (PRO guidance)  for situations where the PRO endpoint  
35  will be used as the primary evidence of effectiveness.2  PRO measurement  may not be feasible in  
36   all cancer trial populations (e.g.,  in patients with significant cognitive impairment).   
37    
38   The   contents of this document do not have the force and effect of law and are not meant to bind 
39   the public in any way, unless specifically incorporated into a contract. This document is intended 
40  only to provide clarity to the public regarding existing requirements under the law. FDA  
 
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 (CDRH)  at the FDA. 
2  December 2009. 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.  
  1  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
41   guidance documents, including this guidance, should be viewed only as recommendations, unless  
42   specific regulatory or statutory requirements  are cited.  The use of the  word should in Agency 
43   guidance means that something is suggested or recommended, but not required.  
44    
45    
46   II.   BACKGROUND  
47    
48   Assessment of a clinical  outcome can be made through report by a  clinician, a patient, a non-
49   clinician observer, a performance-based assessment,  or through other methods.  A  PRO is a  type  
50   of clinical outcome assessment  based on a report that comes directly from the patient about the  
51   status of a patient's health condition without amendment or interpretation of the patient's  
52   response by a  clinician or anyone else.3  Additional definitions of  patient-focused drug 
53   development terms  can be found in the Patient-Focused Drug Development Glossary.4   
54    
55   Cancer trials  typically  employ  standardized efficacy  assessments  using  overall survival and 
56   tumor measures,  and safety assessments  provided  by  clinician  reporting of adverse events.  FDA 
57   acknowledges  the  potential added value of  incorporating PRO measurement  of symptoms and 
58   functional impacts  into  the benefit/risk assessment in appropriately designed trials;  however,  
59   heterogeneity  in  PRO assessment  strategies  has  lessened  the regulatory utility of PRO data  from  
60   cancer trials.  Systematic  assessment  of a core set of  PROs  using fit-for-purpose5  PRO measures  
61   can  facilitate high quality  data on patient-reported  symptoms  and functional  impacts.   
62    
63   A  core set of  PROs  including disease symptoms, symptomatic adverse  events,  and physical  
64   function,  that may be  important contributors to a  patients health-related quality of life  (HRQOL)  
65   and that may be sensitive to the effect of  the disease and treatment  under study  has been  
66   described.6  This  guidance expands on this concept, acknowledging that a  core PRO  set can  
67   provide a minimum expectation for patient experience data across cancer settings,  but may not  
68   include  all important patient experience outcomes  to measure in specific disease contexts.   
69    
70    
71   III.   CORE  PATIENT-REPORTED OUTCOMES  
72    
73   To maximize the utility of submitted PRO information,  we recommend  collecting and separately  
74   analyzing the following core  PROs:  
75    
76       Disease-related  symptoms  
 
3  Throughout this guidance, FDA uses certain terms that appear in the FDA-NIH Biomarker Working Group, BEST  
(Biomarkers, EndpointS, and other Tools) Resource available at  https://www.ncbi.nlm.nih.gov/books/NBK338448/  
(accessed  June 1, 2021). 
4  Available at https://www.fda.gov/drugs/development-approval-process-drugs/patient-focused-drug-development-
glossary  (accessed  June 1, 2021).  
5  Fit-for-purpose is defined as  a conclusion that the level of validation associated with a tool is sufficient to support  
its context of use. See BEST  Resource.    
6  Kluetz  PG,  Slagle  A,  Papadopoulos  E,  et  al.,  2016,  Focusing on Core Patient-Reported Outcomes in Cancer  
Clinical Trials: Symptomatic Adverse Events, Physical Function, and Disease-Related Symptoms,  Clin  Can  Res,  
Apr 1;22(7):1553-8.  
 
  2  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
77       Symptomatic adverse events  
78       Overall side effect  impact summary measure   
79       Physical function  
80       Role function    
81    
82   Additional  PROs  that are important to patients,  outside of the core  concepts  in this section,  could 
83   be prospectively specified and collected in clinical studies  based on the context of a given 
84   clinical trial.  For instance, swallowing function and cognitive function may be outcomes of  
85   interest in addition to the core set in the  context of advanced esophageal  cancer and neuro-
86   oncology, respectively. Selection of outcomes outside of the core  PRO  set should be carefully 
87   considered  to minimize patient burden and improve the quality of data  collected  by focusing on 
88   the most meaningful  and measurable outcomes.  
89    
90    
91   IV.   CONSIDERATIONS  FOR INSTRUMENT SELECTION TO MEASURE THE 
92   CORE  PATIENT-REPORTED OUTCOMES  
93    
94   For  a PRO  result  to meaningfully contribute to a therapys benefit/risk assessment, the PRO  
95   instrument  used should be well-defined and reliable so that  the results presented are  accurate and  
96   not  misleading. Sponsors should provide support for the  selection of  PRO instrument(s) with  
97   available data  and/or published peer-reviewed literature guided by the principles laid out in the  
98   PRO guidance.7 The FDA is also developing a series of Patient Focused Drug Development  
99   guidances, and specifically Guidance 4 of the series will  address methodologies, standards, and 
100   technologies for the  collection, capture, storage, and analysis of clinical outcome assessment  
101   (COA) data.  
102    
103   Some commonly used PRO instruments  or measurement systems  may have been developed prior  
104   to  publication of  the PRO guidance  and may differ from  some of the  recommendations. In these  
105   cases,  the sponsor should provide a rationale for  why the endpoint measured by the PRO  
106   instrument is  well-defined, relevant,  and reliable.  For example, there may be evidence from  
107   previous trials that the measure is sensitive to  a disease- or treatment-related  change.  Some 
108   general principles to determine whether the PRO  instrument is fit-for-purpose include the  
109   following:   
110    
111       The PRO instrument is appropriate for its intended use (e.g., study design, patient  
112   population)   
113       The PRO instrument validly and reliably measures concepts that are clinically relevant  
114   and important to patients  
115       The PRO data can be communicated in a way that is accurate, interpretable, and not  
116   misleading  
117    
 
7  See also the FDA Patient-Focused Drug Development Guidance Series for Enhancing the  Incorporation of the  
Patients Voice in Medical Product Development and Regulatory Decision Making available at  
https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-
series-enhancing-incorporation-patients-voice-medical.  
  3  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
118   A PRO instrument  can be used to assess a range of concepts of interest  including  single item 
119   symptoms  (e.g., pain intensity), symptom scales (e.g., disease symptom scale consisting of  
120   multiple symptoms),  functional scales (e.g., physical function),  and  multi-dimensional complex 
121   concepts  (e.g.,  HRQOL).  To allow for  clear and  accurate analyses and  labeling, the  PRO 
122   measure  should be  well-defined. One  important aspect of a well-defined PRO  measure  is that the 
123   questions within the  measure  should all be related to the concept of interest.  For instance, a well-
124   defined physical function scale  should include questions on a range of  activities requiring 
125   physical effort  and should not contain specific questions  tied to or dependent on other concepts  
126   such as  side effects  or symptoms.8  
127    
128   In some  cases, subscales  or subsets of  questions  from existing PRO instruments  may be used to 
129   inform the benefit/risk assessment and support  labeling claims  if prospectively defined and their  
130   measurement properties  have been adequately  evaluated. Early consultation with FDA is  
131   recommended regarding selection of appropriate  instrument(s) for a  particular  cancer  clinical 
132   trial  context.  Ideally, interactions with the agency would include discussion of  the PRO 
133   instrument, trial design,  and labeling considerations.  
134    
135   PRO instrument  considerations  and examples  for the core PROs  are:    
136    
137       Disease-related  symptoms:  Where a group of common cardinal disease symptoms exist, 
138   disease symptom scales  should  be used. One example of a disease symptom scale is the 
139   Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ)  that 
140   has gone through the  FDA Drug Development Tool Qualification program.9  In  contexts  
141   where disease symptoms are heterogeneous in type and incidence, symptoms that patients  
142   have reported as being important across advanced cancer settings, such as pain, anorexia, 
143   and fatigue,  can  be measured either individually or within a symptom score with other  
144   important disease-related  symptoms.  Examples of patient-reported symptom severity 
145   assessments  that may be  fit-for-purpose include an 11-point (i.e., 0 to 10) numeric rating 
146   scale or verbal rating scale (e.g., none, mild, moderate, severe) that asks patients to rate  
147   their worst experience of  a specific disease symptom over a specified recall  period. 
148   Alternatively, a frequency scale for one or more of these items may also be considered  
149   (e.g., ranging from none  of the time to all of the time).  
150    
151       Symptomatic adverse events (AEs): FDA recommends  selecting  a concise set of  the 
152   most important symptomatic AEs  that are expected to occur  from an item library.  In  
153   trials with active controls,  symptomatic AEs  expected to occur from both treatment  
154   regimens should be assessed for all patients  in both arms.  For example,  if neuropathy is  
155   expected on active control only, an item assessing neuropathy should be included  in 
156   both the active and control arms.  FDA  considers the National Cancer  Institutes PRO  
157   version of the common terminology criteria for  adverse events (PRO-CTCAE) to be  an  
158   example of  one acceptable  item library  for  assessment of symptomatic adverse events.10  
159   Sponsors should provide a rationale  for the selection of symptomatic  AEs  that will be  
 
8  Ibid.  
9  See https://www.fda.gov/drugs/development-approval-process-drugs/ddt-coa-000009-non-small-cell-lung-cancer-
symptom-assessment-questionnaire-nsclc-saq  (accessed  June 1, 2021).    
10  See https://healthcaredelivery.cancer.gov/pro-ctcae/  (accessed  June  1, 2021).  
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Draft   Not for Implementation  
160   assessed, based on  mechanism of action, early clinical data,  and  input from patients and 
161   healthcare providers.  Sponsors  should select only the most important  and/or  high 
162   frequency AEs to reduce  question burden and consider a free-text question to mitigate  
163   concerns  for missing important symptom items.   
164    
165   Importantly, PRO  data describing symptomatic AEs are intended to complement, not  
166   replace, safety data.   
167    
168       Overall side effect  impact  summary  measure:  A summary measure of the overall side 
169   effect impact  can  inform  the tolerability of a treatment.  Because individual patients may 
170   weigh some side effects  as more important  than others, one  option to consider is a single  
171   global  impression of  severity  item. For example, Please choose the response below that  
172   best describes the severity of your  overall  side effects from treatment  over the past  
173   week  (where 0  represents  none  and 3  represents  severe).  Examples of  existing single  
174   item global side effect bother questions include the GP5 question from the  Functional  
175   Assessment of Chronic  Illness Therapy  (FACIT)  item library,11  and the Q168 question 
176   from the  European Organisation for Research and Treatment of Cancer  (EORTC)  item 
177   library.12  Existing symptom libraries should consider developing such a global side  
178   effect  item where one does not exist.  
179    
180       Physical function:  Sponsors should select scales that  measure defined  concepts and  
181   assess varying levels of ability to perform activities that require physical effort.  One 
182   option to consider  is the  Patient-Reported Outcomes  Measurement  Information System  
183   (PROMIS)  physical function item bank.13  Another commonly used physical function 
184   scale that can be considered is the EORTC  Quality of Life of Cancer Patients  QLQ-C30  
185   physical function scale.14  
186    
187       Role function:  The impact of  a treatment  on  the  ability to work and carry out  daily 
188   activities is important  to patients and may also provide some information on other  
189   functional abilities such as cognitive function.  One example of  an existing tool that  
190   assesses this concept  is the EORTC QLQ-C30 role function scale.15   
191    
192   Some of these instrument examples were developed prior to the  PRO guidance  and may not be  
193   suitable to address all clinical trial questions. For  instance, using PRO measures to support a  
194   claim of equivalence or non-inferiority between two arms is problematic without sufficient 
195   support that the sensitivity of the measure is adequate.    
 
11  See https://www.facit.org/  (accessed  June 1, 2021).  
12  See https://qol.eortc.org/questionnaires/   (accessed  June 1, 2021).  
13  See http://www.nihpromis.org/measures/measureshome  (accessed  June  1, 2021).  
14  See https://qol.eortc.org/questionnaires/  (accessed  June 1, 2021).  
15  Ibid.  
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196   V.   TRIAL DESIGN CONSIDERATIONS  
197    
198   A.   Assessment Frequency  
199    
200   The following should be considered when determining the frequency of PRO assessment for  core  
201   PROs:  
202    
203       A baseline assessment(s)  should be included  as a reference point for assessing change.   
204       Assessment frequency should be higher within the first few  treatment cycles and  
205   depending on the trial may  be less frequent in later cycles.   
206       Assessment frequency should take into account the administration schedule of the drug(s)  
207   under study.  
208       Different assessment frequencies can be selected for each  core concept  depending on the  
209   outcome and research objective.   
210    
211   It is acknowledged that other  PRO  concepts  outside of FDAs core  PRO  set  may be  of interest  to  
212   other  stakeholders  (e.g., international  regulators, health-technology assessment bodies, etc.) and  
213   may include other functional domains  (e.g.,  social function, emotional function)  that comprise  
214   overall  HRQOL.  When using a modular approach  where these elements are able to be assessed  
215   and analyzed separately,  different  assessment frequencies can be selected that can reduce the 
216   response burden to patients. A standard approach to assessment frequency over the first year of 
217   therapy would aid in consistency and interpretation across advanced cancer trials.  An example  of 
218   a PRO assessment  strategy that  assesses PRO more frequently in the first  8 weeks of treatment  
219   would be suitable across most drug administration schedules  and  is provided below:  
220    
221   Figure  1: Example PRO assessment frequency for first 12 months of advanced cancer trial  
   Standard 6 month treatment period   Follow-up  
  B  w  w  w  w  w  w  w  M  M  M  M  M  M12   *  
L   2   3   4   5   6   7   8   3   4   5   6   9  
Symptomatic   X   X   X   X   X   X   X   X   X   X   X   X   X   X  
AE16  
Single Item   X   X   X   X   X   X   X   X   X   X   X   X   X   X  
Side Effect  
Global  
Physical  X   X   X   X   X   X   X   X   X   X   X   X   X   X  
Function  
Role   X     X     X     X     X   X   X   X   X   X  
Function  
Disease  X         X         X       X     X  
Symptoms  
Other   X                 X       X     X  
HRQOL  
222   BL   baseline,  w - week,  M  - month, * - context dependent long-term follow-up   
223    
224   How a therapy is administered can affect the timing of assessments.  For instance, intermittently  
225   administered intravenous  (IV)  cytotoxic chemotherapy  often has  the maximum intensity of  
 
16  Symptomatic AEs assessed by PROs  are intended to complement, not  replace, standard CTCAE safety data.  
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Draft   Not for Implementation  
226   symptomatic  AEs  earlier in  each  cycle, whereas this  may  not  be the case with an oral  drug  
227   administered on a continuous daily schedule. Schedule of administration should  be taken into 
228   account,  and assessments  and their analysis  harmonized so as not to obscure the results of either  
229   arm.  In the case where both arms have orally administered treatments on a daily schedule,  
230   assessments could be less frequent given the lack of cyclic variability surrounding administration  
231   schedules seen with IV chemotherapies.  
232    
233   B.   Other Trial  Design  Considerations  
234    
235   The following should be considered to mitigate missing data and improve the interpretability of  
236   PRO results:  
237    
238       Prospectively establish  procedures for  mitigating  missing data, including  training for  
239   investigators  and patients, a completion monitoring strategy,  and obtaining PRO data  
240   from patients at time of early withdrawal. Include  these procedures in the protocol.  
241    
242       Methods to lessen patient burden should be explored,  including use of electronic PRO  
243   capture that may allow for assessments outside of the clinic. Sponsors should document  
244   how and where patients completed their PRO assessments (e.g., at home, in office, etc.).  
245    
246       Reasons for missing PRO data should be documented and included in the  analysis  
247   dataset.  
248     
249       Provide a pre-specified plan for the analysis of PRO data including the threshold for and 
250   interpretation of a meaningful change in score(s),  if relevant.  
251    
252       Any deviation from the instruments scoring manual should be noted and a rationale  
253   provided.  
254    
255       Carefully record the use  (including changes in dose)  of concomitant medications  or 
256   therapies  that may affect  the interpretation of the  concept(s) being measured (e.g., use  of 
257   concomitant pain medications when measuring pain).  
258    
259    
260   VI.   LABELING CONSIDERATIONS   
261    
262   Inclusion of PRO data in the product label will depend on the  adequacy of  the design and 
263   conduct of the trial, the strengths and limitations of the instrument within the given context of  
264   use, and the  quality  of submitted data.  
265    
266       Lack of  statistical superiority is not suitable evidence for  claims of no meaningful  
267   difference. A claim of  non-inferiority or equivalence should  be supported by evidence  
268   that the sensitivity of the measure is adequate  and  the trial should be adequately designed, 
269   including justification for the  selected  non-inferiority margin,  to make such  a claim  as  
270   documented  in the  statistical analysis plan.   
271    
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272       If a claim of superiority in a particular PRO  endpoint  is sought, pre-specify  the PRO  
273   hypothesis and test  it within the clinical trial. Control the overall type  I  error rate  if 
274   multiple hypotheses are  being tested. Prospectively define the  statistical analysis  
275   methods, especially procedures for handling missing values  and censoring rules if  
276   appropriate. Provide justification for the  endpoint definition, including what constitutes  
277   meaningful change,  for  FDA review and comment  in advance of initiating the clinical 
278   trial. This information should be included in the statistical analysis plan.  
279    
280       Exploratory PRO findings  (i.e., not included in the statistical hierarchy)  are considered  
281   descriptive. FDA will review these data and will evaluate and  consider whether inclusion 
282   of descriptive PRO data  in labeling is appropriate  on a case-by-case basis, taking into 
283   consideration any factors that may affect the interpretability and reliability of the  
284   findings.   
285    
286   For example, exploratory PRO results  further describing the timing, frequency,  and 
287   impact of visual disturbances were included in Section 6  Adverse Reactions  of the USPI  
288   for XALKORI, in order to complement the safety signal of vision disorder reported by 
289   clinicians.  
290    
291   Generally,  exploratory PRO findings of a comparative treatment benefit are unlikely to 
292   support inclusion in product labeling if not prespecified and statistically tested.  
  8