Clinical Trial Endpoints 
for the Approval of 
Cancer Drugs and 
Biologics 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
December 2018 
Clinical/Medical 
   
Clinical Trial Endpoints 
for the Approval of 
Cancer Drugs and 
Biologics 
Guidance for Industry 
 
Additional copies are available from: 
 
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https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 December 2018 
Clinical/Medical 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Statutory and Regulatory Requirements for Effectiveness ........................................................ 2 
B.  Endpoints Supporting Past Approvals in Oncology ................................................................... 3 
III.  GENERAL ENDPOINT CONSIDERATIONS ............................................................. 4 
A.  Overall Survival ............................................................................................................................. 7 
B.  Endpoints Based on Tumor Assessments..................................................................................... 7 
1. Disease-Free Survival (and Event-Free Survival) ........................................................................... 8 
2. Objective Response Rate .................................................................................................................. 9 
3. Complete Response .......................................................................................................................... 9 
4. Time to Progression and Progression-Free Survival .................................................................... 10 
5. Time to Treatment Failure ............................................................................................................. 11 
C.  Endpoints Involving Symptom Assessment ............................................................................... 11 
1. Specific Symptom Endpoints .......................................................................................................... 11 
2. Problems Encountered with Symptom Data .................................................................................. 12 
D.  Blood or Body Fluid-Based Biomarkers .................................................................................... 12 
E.  Emerging Endpoints .................................................................................................................... 12 
IV.  CLINICAL TRIAL DESIGN AND ANALYSIS CONSIDERATIONS .................... 13 
A.  Single-Arm Studies ...................................................................................................................... 13 
B.  Randomized Studies Designed to Demonstrate Noninferiority ................................................ 13 
C.  Trial Designs for Radiotherapy Protectants and Chemotherapy Protectants ....................... 14 
D.  Clinical Trial Design Considerations ......................................................................................... 14 
E.  Clinical Trial Analysis Issues ...................................................................................................... 14 
V.  CONCLUSION ............................................................................................................... 15 
APPENDIX: INDEPENDENT REVIEW OF TUMOR ENDPOINTS ................................. 16 
i 
  Contains Nonbinding Recommendations 
 
Clinical Trial Endpoints for the Approval of Cancer 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  
 
This guidance provides recommendations to applicants on endpoints for cancer clinical trials 
submitted to the Food and Drug Administration (FDA) to support effectiveness claims in new 
drug applications (NDAs), biologics license applications (BLAs), or supplemental applications.2  
It also provides background information and discusses general regulatory principles.  The 
endpoints discussed in this guidance are for drugs to treat patients with an existing cancer.3  This 
guidance does not address endpoints for drugs to prevent or decrease the incidence of cancer. 
 
This guidance is a revision of the final guidance of the same title that published in May 2007.  
This guidance replaces the May 2007 guidance of the same title.    
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and 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.  
 
 
 
                                                 
1 This guidance has been prepared by the Oncology Center of Excellence, Center for Drug Evaluation and Research 
(CDER), and Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
3 See the guidance for industry Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and 
Biologics for recommendations specific to non-small cell lung cancer clinical trials.  See the guidance for industry 
Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an 
Endpoint to Support Accelerated Approval for recommendations specific to high-risk early-stage breast cancer.  We 
update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA web 
page.  The guidances mentioned in this document are available on the Biologics guidance web page at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, 
and/or the Drugs guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
Clinical trial endpoints serve different purposes. In conventional oncology drug development, 
early phase clinical trials evaluate safety and identify evidence of biological drug activity, such 
as tumor shrinkage.  Endpoints for later phase efficacy studies commonly evaluate whether a 
drug provides a clinical benefit such as prolongation of survival or an improvement in 
symptoms.  The following sections discuss the general regulatory requirements for efficacy and 
how they have influenced endpoint selection for the approval of cancer drugs.  Later sections 
describe these endpoints in more detail and discuss whether they might serve as measures of 
disease activity or clinical benefit in various clinical settings. 
 
A.  Statutory and Regulatory Requirements for Effectiveness 
 
The requirement that new drugs show effectiveness is based on a 1962 amendment to the Federal 
Food, Drug, and Cosmetic Act (FD&C Act).  This law requires substantial evidence of 
effectiveness and specifies that this evidence must be derived from adequate and well-controlled 
clinical investigations.  Similarly, the Public Health Service Act requires biological products to 
be safe, pure, and potent.4  Clinical benefits that have supported drug approval have included 
important clinical outcomes (e.g., increased survival, symptomatic improvement) but have also 
included effects on surrogate endpoints known to predict clinical benefit (e.g., blood pressure).  
 
The accelerated approval regulations (21 CFR part 314, subpart H and 21 CFR part 601, 
subpart E), promulgated in 1992, allow use of additional endpoints for approval of drugs or 
biological products that are intended to treat serious or life-threatening diseases and that 
generally demonstrate an improvement over available therapy or provide therapy where none 
exists.  In this setting, the FDA may grant approval based on an effect on a surrogate endpoint 
that is reasonably likely to predict clinical benefit.5  Such surrogate endpoints are less well-
established than those surrogate endpoints for traditional approvals, such as blood pressure for 
cardiovascular disease.  FDA may also grant accelerated approval based on an effect on a 
clinical endpoint that can be measured earlier than irreversible morbidity or mortality that is 
reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical 
benefit (i.e., an intermediate clinical endpoint).6  A drug is approved under the accelerated 
approval regulations on condition that the manufacturer conducts clinical studies to verify and 
describe the actual clinical benefit.7  If the postmarketing studies fail to demonstrate clinical 
benefit or if the applicant does not demonstrate due diligence in conducting the required 
studies, among other reasons, FDA may withdraw approval of the drug or indication.8  In the 
following discussion, the term traditional approval denotes the longstanding route of drug 
approval based on the demonstration of clinical benefit or an effect on a surrogate endpoint 
                                                 
4 Potency has long been interpreted to include effectiveness (21 CFR 600.3(s)). 
5 Section 506(c)(1)(B) of the FD&C Act.  21 CFR 314.510 and 601.41 provide that the Agency may consider . . . 
epidemiologic, therapeutic, pathophysiologic, or other evidence . . . in determining whether an endpoint is  
reasonably likely to predict clinical benefit.  The Food and Drug Administration Safety and Innovation Act of 2012 
provides that FDA may consider . . . epidemiological, pathophysiological, therapeutic, pharmacologic, or other 
evidence developed using biomarkers, for example, or other scientific methods or tools.  See guidance for industry 
Expedited Programs for Serious Conditions  Drugs and Biologics.   
6 See guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics.   
7 For a more comprehensive discussion of this condition of accelerated approval and a discussion of other conditions 
of approval, see the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics. 
8 See section 506(c)(3) of the FD&C Act and  314.530(a) and 601.43(a).   
  2  Contains Nonbinding Recommendations 
 
known to predict clinical benefit.  That term is distinguished from accelerated approval, which 
is associated with use of a surrogate endpoint or intermediate clinical endpoint that is 
reasonably likely to predict clinical benefit to support drug approval. 
 
The evidence needed to establish effectiveness is discussed in the guidance for industry 
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products and the 
guidance for industry FDA Approval of New Cancer Treatment Uses for Marketed Drug and 
  
Biological Products. In many cases, at least two adequate and well-controlled clinical 
investigations are needed.  In certain cases, evidence from a single adequate and well-controlled 
clinical investigation, with confirmatory evidence, can be sufficient (e.g., in cases in which a 
single multicenter study provides highly reliable and statistically strong evidence of an important 
clinical benefit).  FDA may consider data from one adequate and well-controlled clinical 
investigation and confirmatory evidence as substantial evidence, if FDA determines that such 
data and evidence are sufficient to establish effectiveness.9  For example, for drugs approved for 
treatment of patients with a specific stage of a particular malignancy, evidence from one 
adequate and well-controlled clinical investigation with confirmatory evidence may be sufficient 
to support an efficacy supplement for treatment of a different stage of the same cancer. 
 
B.  Endpoints Supporting Past Approvals in Oncology 
 
For traditional approval, applicants show direct evidence of clinical benefit or improvement in a 
surrogate endpoint known to predict clinical benefit.  In oncology, survival improvement is 
considered an appropriate measure of clinical benefit.  In addition, sponsors have used other 
endpoints for cancer drug approval.  In the 1970s, the FDA usually approved cancer drugs 
based on objective response rate (ORR), determined by tumor assessments from radiological 
tests or physical examinations.  In the early 1980s, after discussion with the Oncologic Drugs 
Advisory Committee (ODAC), the FDA determined that cancer drug approval should be based 
on more direct evidence of clinical benefit, such as improvement in survival, improvement in a 
patients quality of life, improved physical functioning, or improved tumor-related symptoms. 
These benefits may not always be predicted by, or correlate with, ORR. 
 
Over time, larger improvements in tumor reduction and delay in tumor growth have been seen, 
and tumor measurement endpoints have been used to support both traditional and accelerated 
approval.  Improvement in disease-free survival (DFS) has supported drug approval in selected 
adjuvant settings, in which a large proportion of patients were expected to have cancer 
symptoms at the time of recurrence.  Durable complete response has supported traditional 
approval in leukemia, where complete response (CR) is associated with less infection, bleeding, 
and blood product support.  A large improvement in progression-free survival (PFS) or high, 
substantiated durable ORR has been used to support traditional approval in select malignancies, 
but magnitude of effect, relief of tumor-related symptoms, and drug toxicity should also be 
considered when making the approval decision.10,11,12  For example, randomized trials for 
                                                 
9 See section 505(d) as amended by the Food and Drug Administration Modernization Act of 1997. 
10 Blumenthal GM, PG Kluetz, J Schneider, KB Goldberg, AE McKee, R Pazdur, 2017, Oncology Drug Approvals: 
Evaluating Endpoints and Evidence in an Era of Breakthrough Therapies, The Oncologist, 22(7): 762-767.    
11 Blumenthal GM and R Pazdur, 2016, Response Rate as an Approval Endpoint in Oncology: Back to the Future, 
JAMA Oncol, 2(6): 720-721.  
12 OShaughnessy and Wittes et al.,1991, Commentary Concerning Demonstration of Safety and Efficacy of 
Investigational Anticancer Agents in Clinical Trials, J Clin Oncol, 9:2225-2232. 
  3  Contains Nonbinding Recommendations 
 
hormonal drugs for breast cancer and a single arm trial of a drug for ROS1-positive metastatic 
non-small cell lung cancer have used ORR as an endpoint supporting traditional approval. 
Improvement in tumor-related symptoms in conjunction with an improved ORR and adequate 
response duration has supported traditional approval in several clinical settings. 
 
Surrogate endpoints for accelerated approval must be reasonably likely to predict clinical 
benefit (FD&C Act  506(c)(1)(A); 21 CFR part 314, subpart H; and 21 CFR part 601, subpart 
E).  While durable ORR has been used as a traditional approval endpoint in some 
circumstances, ORR has also been the most commonly used surrogate endpoint in support of 
accelerated approval.  Tumor response is widely accepted by oncologists in guiding cancer 
treatments.  Because ORR is directly attributable to drug effect, single-arm trials conducted in 
patients with refractory tumors where no available therapy exists provide an accurate 
assessment of ORR.  Whether tumor measures such as ORR or PFS are used as an accelerated 
approval or traditional approval endpoint will depend on the disease context and the magnitude 
of the effect, among other factors (see sections III.B.2 and 4). 
 
 
III.  GENERAL ENDPOINT CONSIDERATIONS 
 
This section provides an overview of general issues in cancer drug development.  A discussion of 
commonly used cancer endpoints is followed by a discussion of pertinent issues in cancer 
clinical trial design using these endpoints (see the guidances referenced in footnote 3 regarding 
non-small cell lung cancer and high-risk early-stage breast cancer for more detailed discussion 
for these diseases).  The endpoints that are discussed in this section include overall survival, 
endpoints based on tumor assessments (e.g., DFS, event-free survival (EFS), ORR, CR, time to 
progression (TTP), and PFS), endpoints involving symptom assessment, blood or body fluid-
based biomarkers, and emerging endpoints.  Tables 1 and 2 provide a comparison of endpoints in 
cancer drug approval.  Many issues relating to the proper analysis of efficacy endpoints are 
addressed in the ICH guidance for industry E9 Statistical Principles for Clinical Trials.  
Recommendations regarding the use of placebos and blinding in randomized controlled clinical 
trials are described in the draft guidance for industry Hematologic Malignancy and Oncologic 
Disease:  Considerations for Use of Placebos and Blinding in Randomized Clinical Trials for 
Drug Product Development.13  Cancer patient and caregiver experiences provide unique insights 
that contribute to important patient preference information for identifying relevant clinical trial 
endpoints to ultimately inform medical product development programs that best meet patient 
needs.  Recommendations on how stakeholders can collect and submit patient experience data14 
and other relevant information from patients and caregivers for medical product development 
and regulatory decision making are described in the draft guidance for industry, FDA staff, and 
other stakeholders Patient-Focused Drug Development: Collecting Comprehensive and 
Representative Input.15   
 
   
                                                 
13 When finalized this guidance will represent FDA current thinking on the topics it addresses. 
14 21st Century Cures Act: https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf. 
15 When finalized this guidance will represent FDA current thinking on the topics it addresses. 
  4  Contains Nonbinding Recommendations 
 
Table 1.  A Comparison of Important Cancer Approval Endpoints 
 
As noted in the table, several oncology endpoints can serve different purposes (i.e., clinical 
endpoint that represents clinical benefit for traditional approval, surrogate endpoint to support 
traditional approval, surrogate endpoint to support accelerated approval) based on the specific 
context of use.  The determination is based on the specific diseases and is highly dependent upon 
factors such as effect size, effect duration, depth of response (e.g., number of CRs), available 
therapy, disease setting, location of disease, the clinical consequences of delaying or preventing 
disease progression or delaying administration of more toxic therapies, and the risk-benefit 
relationship.  See text for details.  See section V regarding recommendations for obtaining FDA 
feedback on endpoints and protocol design. 
 
Endpoint  Type of Endpoint  Study Design Recommendations 
Clinical  Surrogate  Surrogate  Randomized  Single- Independent 
Endpoint  Endpoint  Endpoint  Arm  Blinded 
for TA*  for AA**  Review 
Overall  X      X     
Survival 
 
Symptom  X      X     
Endpoints 
(patient-
reported 
outcomes) 
Disease-Free  X  X  X  X    X*** 
Survival or 
Event-Free 
Survival 
Objective  X  X  X  X  X  X 
Response 
Rate 
Complete  X  X  X  X  X  X 
Response 
Progression- X  X  X  X    X*** 
Free Survival 
or Time to 
Progression  
 
 
 
* TA - Traditional approval, ** AA - Accelerated approval, *** Not always recommended 
 
   
  5  Contains Nonbinding Recommendations 
 
Table 2.  Advantages and Disadvantages of Important Cancer Approval Endpoints 
 
Endpoint  Advantages  Disadvantages 
Overall   Easily and precisely measured   May be affected by switch-over of 
Survival   Generally based on objective and  control to treatment or subsequent 
  quantitative assessment  therapies 
 Needs longer follow-up 
 Includes noncancer deaths 
Symptom   Generally assessed earlier and with   Blinding is important for assessing the 
Endpoints  smaller sample size compared with  endpoint 
(patient- survival studies   Potentially subject to assessment bias, 
reported  particularly in open-label studies 
outcomes)   Lack of validated instruments in many 
disease areas 
 Definitions vary among studies 
 Balanced timing of assessments among 
treatment arms is critical 
Disease-Free   Generally assessed earlier and with   Potentially subject to assessment bias, 
Survival or  smaller sample size compared with  particularly in open-label studies 
Event-Free  survival studies   Definitions vary among studies 
Survival   Generally based on objective and   Balanced timing of assessments among 
quantitative assessment  treatment arms is critical 
   Includes noncancer deaths 
Objective   Generally assessed earlier and with   Definitions vary among studies 
Response  smaller sample size compared with   Frequent radiological or other 
Rate  survival studies   assessments 
 Effect on tumor attributable to   May not always correlate with survival 
drug(s), not natural history   
 Generally based on objective and 
quantitative assessment 
Complete   Generally assessed earlier and with   Definitions vary among studies 
Response  smaller sample size compared with   Frequent radiological or other 
survival studies   assessments 
 Effect on tumor attributable to   May not always correlate with survival 
drug(s), not natural history   
 Generally based on objective and   
quantitative assessment 
Progression-  Generally assessed earlier and with   Potentially subject to assessment bias, 
Free Survival  smaller sample size compared with  particularly in open-label studies 
or Time to  survival studies    Definitions vary among studies 
Progression   Measurement of stable disease   Frequent radiological or other 
included  assessments 
 Generally based on objective and   Balanced timing of assessments among 
quantitative assessment  treatment arms is critical 
 May not always correlate with survival 
 
 
  6  Contains Nonbinding Recommendations 
 
A.  Overall Survival 
 
Overall survival is defined as the time from randomization until death from any cause and is 
measured in the intent-to-treat population.  Survival is considered the most reliable cancer 
endpoint, and when studies can be conducted to adequately assess survival, it is usually the 
preferred endpoint.  This endpoint is precise and easy to measure, documented by the date of    
death.  Bias is not a factor in endpoint measurement.  Survival improvement should be analyzed 
as a risk-benefit analysis to assess clinical benefit. 
 
Overall survival should be evaluated in randomized controlled studies.  Data derived from 
externally controlled trials are seldom reliable for time-to-event endpoints, including overall 
survival.  Apparent differences in outcome between external controls and current treatment 
groups can arise from differences other than drug treatment, including patient selection, 
improved imaging techniques, or improved supportive care.  Randomized studies minimize the 
effect of these known and unknown differences by providing a direct outcome comparison.  
Demonstration of a statistically significant improvement in overall survival can be considered 
to be clinically significant if the toxicity profile is acceptable and has often supported new drug 
approval. 
 
Difficulties in performing and analyzing survival studies include long follow-up periods in 
large trials and subsequent cancer therapy potentially confounding survival analysis. 
 
B.  Endpoints Based on Tumor Assessments 
 
This section discusses several endpoints that are based on tumor assessments.  In many cancer 
types, radiographic tumor assessments directly measure components of the disease, and tumor 
measures commonly trigger treatment decisions in clinical practice.  Therefore, tumor measure-
based endpoints are considered more clinically relevant than other biomarkers.  Tumor measure-
based endpoints may support either traditional (as a clinical endpoint that represents clinical 
benefit or a surrogate endpoint for traditional approval) or accelerated approval and include DFS 
(and EFS), ORR, CR, TTP, and PFS.  
 
Tumor assessment endpoint selection should include two judgments.  First, a determination of 
whether the endpoint may support either accelerated approval or traditional approval should be 
ascertained.  Second, the endpoint should be evaluated for the potential of bias or uncertainty. 
Drug applications using studies that rely on tumor assessment endpoints as sole evidence of 
efficacy may need confirmatory evidence from a second trial.  Accuracy in measuring tumors 
can differ among tumor settings.  Tumor measurements used in ORR determinations can be 
imprecise in locations where there is a lack of demarcated margins (e.g., pleural or peritoneal 
mesothelioma, pancreatic cancer, brain tumors). 
 
When the primary study endpoint is based on tumor measurements (e.g., PFS or ORR), tumor 
assessments generally should be verified by central reviewers blinded to study treatments (see 
Appendix) to ascertain lack of assessment bias.  Additional details regarding data collection are 
listed in the guidance for industry Clinical Trial Endpoints for the Approval of Non-Small Cell 
  7  Contains Nonbinding Recommendations 
 
Lung Cancer Drugs and Biologics, Appendix A.16  Alternatively, a random sample-based 
blinded central review auditing approach could be used with a detailed auditing plan prespecified 
including a strategy to detect potential assessment bias.  If bias cannot be excluded based upon 
the audit, a blinded central review of all radiographic images will be necessary.17  Sponsors 
should seek FDA input prior to conducting an audit based central review.  Centralized 
independent verification of tumor assessment endpoints (especially for PFS or DFS) may not be 
necessary when randomized trials are blinded (unless the adverse event profile would 
substantially unblind the trial in practice) or effect sizes are robust in large randomized trials 
where sensitivity analysis supports lack of investigator bias. 
 
1.  Disease-Free Survival (and Event-Free Survival) 
 
Generally, DFS is defined as the time from randomization until disease recurrence or death from 
any cause.  The most frequent use of this endpoint is in the adjuvant setting after definitive 
surgery or radiotherapy.  DFS also can be an important endpoint when a large percentage of 
patients achieve CRs with chemotherapy.  Although overall survival is a conventional endpoint 
for most adjuvant settings, DFS can be an important endpoint in situations where survival may 
be prolonged, making an overall survival endpoint impractical.  An endpoint that is similar to 
DFS but is differentiated from it in that randomization takes place before definitive surgery or 
radiotherapy in the adjuvant setting is EFS.  For the purpose of this guidance, EFS is defined as 
time from randomization to any of the following events: progression of disease that precludes 
surgery, local or distant recurrence, or death due to any cause.  DFS has been the primary basis of 
approval for adjuvant breast cancer hormonal therapy, adjuvant colon cancer, and adjuvant 
cytotoxic breast cancer therapy, whereas EFS is an appropriate endpoint for the evaluation of 
neoadjuvant breast cancer therapy given prior to definitive surgery.  Compared with standard 
cytotoxic therapies, hormonal therapies carry minimal side effects and thus a favorable risk-
benefit relationship.  Treatment effect measured by DFS or EFS can be a surrogate endpoint to 
support accelerated approval, a surrogate endpoint to support traditional approval, or it can 
represent direct clinical benefit based on the specific disease, context of use, magnitude of the 
effect, the disease setting, available therapy, and the risk-benefit relationship.  In December 
2003, the ODAC consensus was DFS prolongation represented clinical benefit if the magnitude 
of this benefit outweighed the toxicity of the adjuvant treatment.  In May 2004, the ODAC 
recommended that DFS be considered a clinical endpoint for colon cancer drugs in the surgical 
adjuvant setting.18  DFS has been used for traditional approval for diseases such as breast cancer, 
colorectal cancer, gastrointestinal stromal tumors, melanoma, and renal cell carcinoma.  
 
Important considerations in evaluating DFS or EFS as a potential endpoint include the estimated 
size of the treatment effect and proven benefits of standard therapies.  The protocol should 
                                                 
16 Appendices A-D in the guidance for industry Clinical Trial Endpoints for the Approval of Non-Small Cell Lung 
Cancer Drugs and Biologics, regarding tumor measurement data collection and PFS analysis also apply more 
broadly to oncology endpoints and should be used in conjunction with this guidance, as needed. 
17 Discussed during July 24, 2012 ODAC meeting.  Transcripts are available at https://wayback.archive-
it.org/7993/20170403224012/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Oncolo
gicDrugsAdvisoryCommittee/default.htm. 
18 Transcripts are available at https://wayback.archive-
it.org/7993/20170403224012/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Oncolo
gicDrugsAdvisoryCommittee/default.htm. 
 
  8  Contains Nonbinding Recommendations 
 
carefully delineate both the definition of DFS or EFS and the schedule for follow-up assessments 
and visits.  Unscheduled assessments can occur for many reasons and differences between study 
arms in the frequency, timing, or reason for unscheduled assessments can introduce bias.  Bias 
can be minimized by blinding patients and investigators to the treatment assignments, as 
appropriate.  
 
Application of the definition of DFS or EFS in a study can be complicated, particularly when 
deaths are noted without prior tumor progression documentation.  These events can be scored 
either as disease recurrences or as censored events.  Although all methods for statistical analysis 
of deaths have some limitations, considering deaths from all causes as recurrences can 
minimize bias.  DFS or EFS can be overestimated using this definition, especially in patients 
who die after a long period without observation.  Bias can be introduced if the frequency of 
long-term follow-up visits is dissimilar between the study arms or if dropouts are not random 
because of toxicity.  Some analyses count cancer-related deaths as DFS or EFS events and 
censor noncancer deaths.  This method can introduce bias in the attribution of the cause of 
death.  Furthermore, any method that censors observations on patients, whether at death or at 
the last visit, assumes that the patients with censored observations have the same risk of 
recurrence as patients with noncensored observations who have not yet experienced the event. 
 
2.  Objective Response Rate 
 
ORR is defined as the proportion of patients with tumor size reduction of a predefined amount 
and for a minimum time period.  Response duration usually is measured from the time of initial 
response until documented tumor progression.  Generally, the FDA has defined ORR as the 
sum of partial responses plus CRs.  When defined in this manner, ORR is a direct measure of a 
drug antitumor activity, which can be evaluated in a single-arm study.  Stable disease should 
not be a component of ORR.  Stable disease can reflect the natural history of disease, whereas 
tumor reduction is a direct therapeutic effect.  Also, stable disease can be more accurately 
assessed by TTP or PFS analysis (see section III.B.4).  If available, standardized criteria should 
be used to ascertain response.  A variety of response criteria have been considered appropriate 
(e.g., revised RECIST guideline (version 1.1))19  The response criteria should be predefined in 
the protocol before the start of the study.  The significance of ORR is assessed by its magnitude 
and duration, and the percentage of CRs.  Treatment effect measured by ORR can be a 
surrogate endpoint to support accelerated approval, a surrogate endpoint to support traditional 
approval, or it can represent direct clinical benefit based on the specific disease, context of use, 
magnitude of the effect, the number of CRs, the durability of response, the disease setting, the 
location of the tumors, available therapy, and the risk-benefit relationship.  
 
3.  Complete Response 
 
 
CR is defined as no detectable evidence of tumor.  CR is generally measured through imaging 
studies (e.g., CT scans) or through histopathologic assessment (e.g., bone marrow biopsy or breast 
cancer resection specimens).  Treatment effect measured by CR can be a surrogate endpoint to 
support accelerated approval, a surrogate endpoint to support traditional approval, or it can 
represent direct clinical benefit based on the specific disease, context of use, magnitude of the 
                                                 
19 Eisenhauer EA, P Therasse, J Bogaerts, LH Schwartz, D Sargent, R Ford, et al., 2009, New Response Evaluation 
Criteria in Solid Tumours: Revised RECIST guideline (version 1.1), Eur J Cancer, 45(2):228-247. 
  9  Contains Nonbinding Recommendations 
 
effect, effect duration, disease setting, location of disease, available therapy, and the risk-benefit 
relationship.  For hematologic malignancies such as acute leukemia, CR has been used as a clinical 
endpoint for traditional approval.  For early high-risk breast cancer, pathologic CR (pCR) has been 
used as a surrogate endpoint for accelerated approval.  
 
4.  Time to Progression and Progression-Free Survival 
 
TTP and PFS have served as primary endpoints for drug approval.  TTP is defined as the time 
from randomization until objective tumor progression; TTP does not include deaths.  PFS is 
defined as the time from randomization until objective tumor progression or death, whichever 
occurs first.  The precise definition of tumor progression is important and should be carefully 
detailed in the protocol. 
 
Compared with TTP, PFS is the preferred regulatory endpoint.  PFS includes deaths and thus can 
be a better correlate to overall survival.  In TTP analysis, death events are censored, either at the 
time of death or at an earlier visit representing informative censoring (nonrandom pattern of loss 
from the study).  PFS assumes that death events are randomly related to tumor progression. 
 
PFS can reflect tumor growth and be assessed before the determination of a survival benefit.  Its 
determination is not confounded by subsequent therapy.  For a given sample size, the magnitude 
of effect on PFS can be larger than the effect on overall survival.  Data are usually insufficient to 
allow a robust evaluation of the correlation between effects on overall survival and PFS.  Cancer 
trials are often small, and proven survival benefits of existing drugs are generally modest.  
Treatment effect measured by PFS can be a surrogate endpoint to support accelerated approval, a 
surrogate endpoint to support traditional approval, or it can represent direct clinical benefit based 
on the specific disease, context of use, magnitude of the effect, the disease setting, location of 
metastatic sites, available therapy, the risk-benefit relationship, and the clinical consequences of 
delaying or preventing progression in key disease sites (e.g., delay of new lesions in the brain or 
spine) or delaying administration of more toxic therapies. 
 
It is important to carefully define tumor progression criteria in the protocol.  There are no 
standard regulatory criteria for defining progression.  Applicants have used a variety of different 
criteria, including the RECIST criteria.  The broad outline presented in most published PFS 
criteria should be supplemented with additional details in the protocol and statistical analysis 
plan (SAP).   
 
Because progression data can be collected from multiple sources (including physical exams at 
unscheduled visits and radiological scans of various types) and at different times, data collection 
for each assessment visit should be limited to a specified short time interval around the 
scheduled visit.  Difficulties can arise in determining the event date and censoring date when 
data are collected over a prolonged time period.  We recommend assigning the progression date 
to the earliest time when any progression is observed without prior missing assessments and 
censoring at the date when the last radiological assessment determined a lack of progression. 
The guidance for industry Clinical Trial Endpoints for the Approval of Non-Small Cell Lung 
Cancer Drugs and Biologics, Appendices C and D provides a set of tables for potential analyses 
of PFS that can be used for primary or sensitivity analyses.  Plans for PFS data collection and 
analysis should be discussed with FDA at end-of-phase 2 meetings. 
 
  10  Contains Nonbinding Recommendations 
 
5.  Time to Treatment Failure 
 
Time to treatment failure (TTF) is defined as a composite endpoint measuring time from 
randomization to discontinuation of treatment for any reason, including disease progression, 
treatment toxicity, and death.  TTF is generally not recommended as a regulatory endpoint for 
new molecular entity drug approval.    
 
C.  Endpoints Involving Symptom Assessment 
 
Symptomatic improvement is considered a clinical benefit.  FDA drug approvals have used 
patient symptom assessments and/or physical signs representing symptomatic improvement (e.g., 
weight gain, decreased effusion) as an important efficacy endpoint.  For the improvement of 
signs and symptoms or other clinical outcome assessments (COA) to be used as efficacy 
endpoints to support cancer drug approval, symptoms should be assessed that are due to cancer 
rather than drug toxicity to the extent possible.   
 
1.  Specific Symptom Endpoints 
 
Symptom improvement/palliation is a direct measure of clinical benefit rather than a surrogate 
endpoint.  A decrease in the severity of cancer symptoms has been used to support traditional 
approval of anti-cancer agents where anti-tumor activity has also been demonstrated.  The use of 
a symptom palliation endpoint requires that the population be symptomatic at baseline, which 
can be problematic in many cancer trials where patients can often be asymptomatic at baseline.  
This endpoint can also be subject to open label response bias, the magnitude of which is not well 
described.   
 
Time to progression of cancer symptoms, an endpoint similar to TTP, is also a direct measure of 
clinical benefit rather than a potential surrogate endpoint.  As discussed earlier, problems in 
measuring progression (e.g., missing assessments) also exist in evaluating time to symptomatic 
progression.  Because few cancer trials are blinded, symptom assessments can also be subject to 
response bias.  A delay between tumor progression and the onset of cancer symptoms can occur.  
Often alternative treatments are initiated before achieving the symptom endpoint, confounding 
this analysis.  In addition, tumor symptoms can be difficult to differentiate from drug toxicity. 
 
A composite symptom endpoint or symptom scale should have components of similar clinical 
importance and an analysis of the contribution of the components should be submitted with the 
primary analysis of the overall composite endpoint.  An example is the composite symptom 
scale that includes several important symptoms of myelofibrosis, the myelofibrosis symptom 
assessment form.20  An example of a composite endpoint for clinical events exists for patients 
with cancer metastases to the skeleton.  Drugs have been approved based on delaying the time 
to skeletal-related events defined as pathological fractures, radiation therapy to bone, surgery to 
bone, and spinal cord compression. 
 
                                                 
20 Deisseroth A, E Kamiskas, J Grillo, W Chen, H Saber, HL Lu, et. al., 2012, U.S. Food and Drug Administration 
Approval: Ruxolitinib for the Treatment of Patients with Intermediate and High-Risk Myelofibrosis, Clin Cancer 
Res, 18(12): 3212-7. 
  11  Contains Nonbinding Recommendations 
 
Selection of the appropriate population can be critical for documenting symptom benefit. 
Patients symptomatic at study baseline can be evaluated with a categorical symptom response 
analysis.  In asymptomatic patients at baseline, a time-to-first-symptom analysis can be used, 
although this approach can be limited by intermittent missing data and discontinuation of the 
study drug prior to symptomatic progression.   
 
2.  Problems Encountered with Symptom Data 
 
Missing data and infrequent assessments can complicate the evaluation of symptom data 
particularly for time to deterioration analyses.  Procedures should be put in place to maximize 
completion rate during trial conduct and the statistical analysis plan should outline how missing 
data will be handled.  Data collection to support multiple symptom endpoints should be 
addressed prospectively regarding multiple hypotheses testing and the necessary statistical 
adjustments should be specified in the SAP.  Additional information on the use of patient-
reported outcomes can be found in the guidance for industry Patient Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims.     
 
D.  Blood or Body Fluid-Based Biomarkers 
 
Generally, biomarkers assayed from blood or body fluids have not served as primary endpoints 
for cancer drug approval, although paraprotein levels measured in blood and urine have been 
used as part of myeloma response criteria, and durable major molecular response is a surrogate 
endpoint used for traditional approval for therapies in chronic myelogenous leukemia.  
 
The FDA has accepted blood-based markers as elements of a composite endpoint.  The 
occurrence of certain clinical events (a significant decrease in performance status, or bowel 
obstruction) in conjunction with marked increases in CA-125 was considered progression in 
ovarian cancer patients.  In addition, blood-based biomarkers can be useful in identifying 
prognostic factors and in selection of patients and stratification factors to be considered in study 
designs. 
 
E.  Emerging Endpoints 
 
In addition to the endpoints discussed in this section, FDA recognizes that advances in science 
are facilitating development of oncology products, which may also result in the identification of 
additional endpoints that may be used to support approval of oncology products.  As examples, 
minimal residual disease21 has been used as a surrogate endpoint for accelerated approval for a 
therapy in acute lymphoblastic leukemia and metastasis-free survival has been used as a clinical 
endpoint for traditional approval for a therapy in non-metastatic castration-resistant prostate 
cancer.  If a sponsor is planning to use an emerging endpoint in its clinical development 
program, we recommend discussing such use with the applicable FDA Division or Office prior 
to initiating a trial (see section V). 
 
                                                 
21 See draft guidance for industry Hematologic Malignancies: Regulatory Considerations for Use in Minimal 
Residual Disease in Development of Drug and Biological Products for Treatment for information to assist sponsors 
planning to use minimal residual disease to support marketing approval of drugs and biological products for the 
treatment of specific hematologic malignancies.  When finalized this guidance will represent FDA current thinking 
on the topics it addresses.   
  12  Contains Nonbinding Recommendations 
 
 
IV.  CLINICAL TRIAL DESIGN AND ANALYSIS CONSIDERATIONS 
 
Per 21 CFR 314.126, the FDA approves drugs based on substantial evidence of efficacy from 
adequate and well-controlled investigations, as described in the regulations.  Studies must 
allow a valid comparison to a control and must provide a quantitative assessment of the drugs 
effect.22  The most reliable method for demonstrating efficacy is to show a statistically 
significant improvement in a clinically meaningful endpoint in randomized controlled trials 
(i.e., superiority).  The following sections discuss other approaches that may be indicated when 
a randomized controlled trial demonstrating superiority is not feasible or ethical.  If a sponsor 
is planning to use one of these approaches, we recommend discussing such use with the 
applicable FDA Division or Office prior to initiating a trial (see section V). 
 
A.  Single-Arm Studies 
 
In settings where there is no available therapy and where major tumor regressions can be 
presumed to be attributed to the tested drug, the FDA has sometimes accepted ORR and 
response duration observed in single-arm studies as substantial evidence supporting accelerated 
approval.  Response rates have been used in settings such as acute leukemia for traditional 
approval where CRs have been associated with decreased transfusion requirements, decrease in 
infections, and increased survival.  Single-arm trials do not adequately characterize time-to-
event endpoints such as overall survival, DFS (and EFS), TTP, or PFS.  Because of variability 
in the natural history of many forms of cancer, a randomized study is necessary to evaluate 
time-to-event endpoints. 
 
B.  Randomized Studies Designed to Demonstrate Noninferiority 
 
A noninferiority (NI) trial should demonstrate the new drugs effectiveness by showing that the 
new drug is not less effective than a standard regimen (the active control) by a prespecified 
amount (noninferiority margin).23  This noninferiority margin should be a clinically acceptable 
loss that is not larger than the effect of the active control drug.  The standard regimen should 
have a well-characterized clinical benefit (survival benefit).  If the new drug is inferior to the 
active control by more than the noninferiority margin, it will be presumed to be ineffective. 
 
NI trials rely on externally controlled (historical) data to establish the active controls treatment 
effect size.  In cancer trials, this effect frequently has not been adequately characterized.  NI 
trials also rely on constancy assumption.  This assumption includes that the active-control effect 
has remained constant between the externally controlled study and the current study.  This 
assumes constancy of patient population characteristics, supportive care measures, and 
evaluation techniques between the current trial and the externally controlled data from which the 
active-control effect was derived.  The estimated size of the active-controls treatment effect 
should be based on a comprehensive meta-analysis of externally controlled studies.  These 
studies should reliably reproduce the active-control effect compared with placebo arm. 
                                                 
22 See 21 CFR 314.126(b)(2) and (7).   
23 See guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness.  See also the ICH guidance for 
industry E10 Choice of Control Group and Related Issues. 
 
  13  Contains Nonbinding Recommendations 
 
Difficulties in conducting NI trials include the estimation of active-control effect and the 
determination of amount of effect (NI margin) to be retained.  NI trials usually involve large 
sample sizes compared with superiority trials and involve replication of clinical trial results. 
Furthermore, subsequent therapies and crossover to the active-control arm can confound any NI 
analysis.  NI trials with endpoints other than overall survival and ORR are problematic. 
 
C.  Trial Designs for Radiotherapy Protectants and Chemotherapy Protectants 
 
Radiotherapy protectants and chemotherapy protectants are drugs designed to ameliorate the 
toxicities of therapies.  These trials usually have two objectives.  The first is to assess the 
amelioration of cancer treatment toxicity.  The second objective is to determine whether 
anticancer activity is compromised by the protectant.  The second objective usually examines 
earlier endpoints; for example, ORR or PFS, rather than overall survival. 
 
D.  Clinical Trial Design Considerations 
 
The methodology for assessing, measuring, and analyzing the endpoint(s) should be detailed in 
the protocol and SAP.   
 
Visits and radiological assessments, when applicable, should be symmetric between the two 
study arms to prevent systematic bias.  The FDA and the applicant should agree prospectively on 
the following items and the applicant should finalize the items before the initiation of the study, 
to the extent possible: 
 
  The study design 
  The definition of progression 
  The SAP 
  The methodology for handling missing data and censoring methods 
  The data to be recorded on the case report form (CRF) 
  The operating procedures of an independent endpoint review committee (IRC), 
if applicable (see Appendix) 
 
E.  Clinical Trial Analysis Issues 
 
Missing data can complicate endpoint analysis.  For endpoints based on tumor assessments, the 
protocol should define an adequate assessment visit for each patient (i.e., a visit when all 
scheduled tumor assessments have been done).  The analysis plan should outline a comparison of 
the adequacy of follow-up in each treatment arm.  Methodology for analyzing incomplete and/or 
missing follow-up visits and censoring methods should be specified in the protocol.  The analysis 
plan should specify the primary analysis and one or more sensitivity analyses to evaluate the 
robustness of the results.  Although any analyses with missing data can be problematic, the 
results can be strengthened by similar results in both the primary and the sensitivity analyses.  
When applicable, the evaluation should include the number of deaths in patients who have been 
lost to follow-up for a prolonged time period.  For example, an imbalance in such deaths could 
bias a PFS measurement by overestimating PFS in the treatment arm with less follow-up. 
 
 
  14  Contains Nonbinding Recommendations 
 
V.  CONCLUSION 
 
Although the general principles outlined in this guidance should help applicants select endpoints 
for marketing applications, we recommend that applicants meet with the FDA before submitting 
protocols intended to support NDA or BLA marketing applications.  The FDA will ensure that 
these meetings include a multidisciplinary FDA team of oncologists, statisticians, clinical 
pharmacologists, and external expert consultants as needed.  Applicants can submit protocols 
after these meetings and request a special protocol assessment that provides confirmation of the 
acceptability of endpoints and protocol design to support drug marketing applications.24  
Ultimately, of course, marketing approval depends not only on the design of clinical trials, but on 
FDA review of the results and data from all studies in the drug marketing application. 
 
 
 
   
                                                 
24 See the guidance for industry Special Protocol Assessment. 
  15  Contains Nonbinding Recommendations 
 
APPENDIX: INDEPENDENT REVIEW OF TUMOR ENDPOINTS 
 
Clinical trial results that support drug approval should be verifiable by applicants and the Food 
and Drug Administration (FDA).  Objective response rate (ORR) determined in single-arm 
studies can be evaluated by reviewing a limited number of images.  When drug approval is 
based on measurement of progression-free survival (PFS), careful planning can minimize bias 
and enable the applicant and the FDA to verify results.  An independent endpoint review 
committee (IRC) can minimize bias in radiographic interpretation of the radiological findings 
and independent adjudication of assessments.  A clearly written plan of the charter outlining the 
IRC function and process (independent review charter) should be in place before initiation of 
the study.  The plan should describe the assurance of the committees independence and 
procedure for collection, storage, and transportation of the results.  The charter also should 
include the resolution of differences in interpretation and incorporation of clinical data in the 
final interpretation of data and audit procedures.  The use of an IRC is discussed further in the 
guidance for industry Developing Medical Imaging Drug and Biological Products, Part 3: 
Design, Analysis, and Interpretation of Clinical Studies. 
 
 
 
 
 
 
 
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