Clinical Trial Endpoints 

for the Approval of Non-

Small Cell Lung Cancer 

Drugs and Biologics 

Guidance for Industry 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
Center for Biologics Evaluation and Research (CBER) 
 
 
April 2015 

Clinical/Medical 

   
Clinical Trial Endpoints 

for the Approval of Non-

Small Cell Lung Cancer 

Drugs and Biologics 

Guidance for Industry 

 
 
 
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U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
Center for Biologics Evaluation and Research (CBER) 
 
 
April 2015 

Clinical/Medical 

 
   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
A.   Endpoints Supporting Past Approvals .........................................................................................2
  
B.   Summary of Workshop and Advisory Committee Discussions ..................................................7
  
III.   RECOMMENDATIONS.................................................................................................. 8 
 
APPENDIX A: TUMOR MEASUREMENT DATA COLLECTION .................................. 11 
 
APPENDIX B: ISSUES TO CONSIDER IN PFS ANALYSIS ............................................. 12 
 
APPENDIX C:  EXAMPLE TABLES FOR PRIMARY PFS ANALYSIS ........................... 14 
 
APPENDIX D:  EXAMPLE TABLES FOR PFS SUPPORTIVE ANALYSIS .................... 15 
 
 
  Contains Nonbinding Recommendations 
Clinical Trial Endpoints for the Approval of  

Non-Small Cell Lung Cancer Drugs and Biologics 

1
 
Guidance for Industry  
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not create 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 staff responsible for this guidance as listed on the title 
page. 
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to provide recommendations to applicants on endpoints for non-
small cell lung cancer (NSCLC) clinical trials of drugs that are 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  This guidance is a 
companion to the guidance for industry Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics.3   
 
This guidance addresses the FDAs current thinking regarding efficacy endpoints in trials to 
evaluate drugs to treat lung cancer and takes into account discussions held at a public workshop 
(April 15, 2003) and at a meeting of the FDAs Oncologic Drugs Advisory Committee (ODAC) 
(December 16, 2003).4  This guidance does not address efficacy endpoints for drugs intended to 
prevent or decrease the incidence of lung cancer.   
 
                                                 
1 This  guidance has been  prepared by the Division of  Oncology Products 2 in the Center for Drug Evaluation and 
Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and 
Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  unless otherwise specified.  
 
3  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
4 Transcripts are available at 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm117709.htm#lung  
and http://www.fda.gov/ohrms/dockets/ac/03/transcripts/4009T1.pdf. 
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 Contains Nonbinding Recommendations 
This guidance also does not contain discussion of the general issues of clinical trial design or 
statistical analysis. Those topics are addressed in the ICH guidances for industry E9  Statistical 
Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
Trials. This guidance focuses on specific drug development and trial design issues that are 
unique to the study of lung cancer drugs. 
 
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. 
 
 
II.  BACKGROUND 
 
According to American Cancer Society estimates, during 2013 there would be nearly 228,190 
new cases of lung cancer. Lung cancer accounts for approximately 14 percent of all new cancers 
and it is the leading cause of cancer deaths, accounting for about 27 percent of all cancer deaths.  
Evaluation of new drugs for the treatment of lung cancer is based on well-conducted and 
controlled trials assessing appropriate endpoints to establish clinical benefit and support 
approval.5  
 
A.  Endpoints Supporting Past Approvals 
 
For regular approval of an NDA or BLA, the applicant must show direct evidence of clinical 
benefit or improvement in an established, validated surrogate for clinical benefit.  FDAs 
accelerated approval pathway,6 allows for the use of two additional types of endpoints to support 
approval of drugs or biological products that are intended to treat serious or life-threatening 
diseases and that provide a meaningful therapeutic benefit over existing treatments (e.g., 
demonstrate an improvement over available therapy or provide therapy where none exists).7   
Specifically, accelerated approval may be based on:  (1) an effect on a surrogate endpoint that is 
reasonably likely to predict clinical benefit; or (2) an effect on a clinical endpoint that can be 
measured earlier than irreversible morbidity or mortality and that is reasonably likely to predict an 
effect on irreversible morbidity or mortality or other clinical benefit.8,9    
                                                 
5 See the guidance for industry Clinical Trial  Endpoints for the Approval  of Cancer Drugs and Biologics for 
information regarding regulatory  requirements for effectiveness.  
 
6 See section  506(c)  of the Federal Food, Drug, and Cosmetic Act and 21 CFR part 314, subpart H, and part  601, 
subpart E. 
 
7 See Johnson, JR, G Williams, R Pazdur, 2003, Endpoints and United  States Food and  Drug Administration  
Approval of Oncology Drugs, J Clin Oncol, 21:1404-1411;  and Dagher, R, J Johnson, G Williams, P Keegan, R 
Pazdur, 2004, Accelerated Approval of Oncology Products:  A Decade of Experience, JNCI, 96:1500-1509.  
 
8 See the guidance for industry Clinical Trial  Endpoints for the Approval  of Cancer Drugs and Biologics for a 
detailed discussion on  general endpoint and respective trial design considerations.  
 
9 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics.    
2 
 Contains Nonbinding Recommendations 
 
In the past, three commonly used efficacy endpoints in trials assessing treatments of lung cancer 
were overall survival (OS), time to progression (TTP) or progression-free survival (PFS), and 
objective tumor response rates (ORR) (see Table 1).  Reduction in patients tumor-related 
symptoms has also been used as an efficacy endpoint (see Table 1).  The majority of drug 
approvals for NSCLC have been based on a significant improvement in OS, as the median 
survival was relatively short (less than a year) and thus rarely increased the duration of the trial 
over use of PFS or ORR as a primary outcome measure.  Additionally, OS is an optimal endpoint 
because the measurement is accurate, is observed on a daily basis, and provides direct evidence 
of clinical benefit to the patient.  Regular approval was granted on the basis of a significant 
improvement in OS.  Similarly, reduction in patients tumor-related symptoms can also provide 
direct evidence of clinical benefit and can support regular approval. 
 
When the observed differences in TTP or PFS are of a substantial magnitude, then TTP or PFS 
may provide evidence of clinical benefit sufficient to support approval.  The magnitude of the 
treatment effect is viewed in the context of the toxicity of the drug, the relatively short survival 
for NSCLC, especially in those with recurrent or treatment-refractory disease, available therapy 
for the stage, histologic or genetic subtype of NSCLC, and extent of prior treatment.  Because of 
the significance of these individual factors, a fixed magnitude of effect that generally will 
support approval cannot be specified. 
 
Treatment effects on ORR have not been demonstrated to reliably predict corresponding effects 
on survival in NSCLC.  We consider demonstration of ORR alone to be a surrogate endpoint 
reasonably likely to predict clinical benefit only when the treatment effect size is large and the 
responses are durable. In these circumstances, ORR has been used as the basis only for 
accelerated approval for NSCLC. In other circumstances, such as when clinical trials have 
shown that ORR correlated with well-documented improvements in patient tumor-related 
symptoms (e.g., photodynamic therapy for treatment of obstructing endobronchial therapy), ORR 
has supported regular approval. 
  
The criteria for disease progression and tumor response are based on subjective interpretation of 
radiographic images and clinical evaluation.  These subjective interpretations have potential to 
introduce bias, particularly when evaluated in open-label trials.  Specifically, primary lung 
tumors and regional nodal disease frequently have ill-defined borders that can be difficult to 
accurately and reproducibly measure radiographically.  Therefore, confidence in tumor 
measurement-based outcomes depends on the frequency of assessments as well as clear, 
objective criteria for defining disease progression and tumor response.  Substantial numbers of 
missing tumor assessments can potentially overestimate or underestimate treatment differences. 
 
Patient-reported outcome (PRO) measures of tumor-related symptoms and functioning can 
provide direct evidence of treatment benefit if demonstrated to be well-defined and reliable 
assessments of a clinically meaningful concept or set of concepts, and if evaluated in well-
conducted, placebo-controlled or double-blinded, randomized trials.10  Well-defined and reliable 
                                                 
10 See the transcripts of the Oncologic Drugs  Advisory Committee Endpoints in Clinical Cancer Trials and  
Endpoints in Lung Cancer Clinical Trials, December 16, 2003, pp 188-368  
(http://www.fda.gov/ohrms/dockets/ac/03/transcripts/4009T1.pdf). 
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 Contains Nonbinding Recommendations 
assessments include those that have documented evidence of content validity, construct validity, 
reliability, and ability to detect change, in addition to established methods for interpreting trial 
results.11   Well-conducted clinical trials include protocols with defined schedules for PRO 
assessment at frequencies that correspond to the intended claims, plans to minimize unintentional 
unblinding, and prespecified statistical strategies for handling missing data, particularly at or 
near the time of disease progression. 
 
                                                 
11 See the guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
Support Labeling Claims. 
4 
 Contains Nonbinding Recommendations 
Table 1. Regulatory Experience With New Drug Approvals for the Treatment of NSCLC  
Drug  Trial Design   Approval Endpoints/Year Approved  
First-Line Inoperable/Metastatic NSCLC 
Vinorelbine monotherapy  Open-label, randomized, active-controlled trial vs. 5-FU/leucovorin  OS, ORR/1994 
Vinorelbine in combination with  cisplatin  Open-label, randomized, active-controlled trial vs. cisplatin  OS, ORR/1994  
Docetaxel in combination  with cisplatin   Open-label, randomized, active-controlled trial, docetaxel/cisplatin vs.  OS,  TTP, ORR/1999   
vinorelbine/cisplatin    
Gemcitabine in combination with cisplatin   (1) Open-label, randomized, active-controlled trial vs. cisplatin   OS/1998 
(2) Open-label, randomized, active-controlled trial, gemcitabine + cisplatin    
vs. etoposide + cisplatin  TTP, ORR  
Bevacizumab in combination  with   Open-label, randomized, active-controlled trial vs. paclitaxel/carboplatin    OS/2006 
paclitaxel/carboplatin1  
Paclitaxel in combination  with cisplatin   Open-label, active-controlled, dose-ranging,  randomized, three-arm trial,  TTP, ORR, OS/1998 
paclitaxel (135 mg/m2)/cisplatin vs. paclitaxel (250 mg/m2)/cisplatin vs.   
etoposide/cisplatin   
Pemetrexed in combination with  cisplatin1,2,3   Open-label, active-controlled, randomized trial; pemetrexed/cisplatin vs.  OS measured in a subset  of patients/2008  
gemcitabine/cisplatin 
Anaplastic Lymphoma Kinase Positive Locally Advanced or Metastatic NSCLC 
Crizotinib monotherapy2   Single-arm trial  Durable ORR/2011 
First-Line Metastatic NSCLC Whose Tumors Have Epidermal Growth Factor Receptor Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations  
Erlotinib monotherapy  Open-label, randomized, active-controlled trial vs. platinum-based doublet  PFS/2013 
chemotherapy  
Maintenance Therapy   
Pemetrexed  in patients whose  disease has   Randomized, double-blind, placebo-controlled trial   OS/2009 
not progressed after four  cycles of platinum-
based first-line chemotherapy1  
Erlotinib in patients whose disease has not  Randomized, double-blind, placebo-controlled trial   OS/2010 
progressed after four cycles of platinum-
based first-line chemotherapy  
Second-Line NSCLC  
Docetaxel  Randomized, placebo-controlled trial, docetaxel vs. best supportive care   OS, TTP, ORR/1999 
continued  
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 Contains Nonbinding Recommendations 
Table 1, continued  
Drug  Trial Design   Approval Endpoints/Year Approved  
Erlotinib  Randomized, placebo-controlled trial, erlotinib vs. best supportive care   OS, TTP, ORR/2004 
Pemetrexed1,2   Randomized, open-label trial vs. docetaxel   Durable ORR,  Toxicity/2004 
Third-Line NSCLC  
Erlotinib  Randomized, placebo-controlled trial erlotinib  vs. best supportive care  OS, TTP, ORR/2004 
Gefitinib2,4   Single-arm trial  Durable ORR/2003 
Partially or Completely Obstructing Endobronchial  Tumor NSCLC  and Microinvasive Endobronchial  NSCLC in Nonsurgical Candidates  
Porfimer sodium and photodynamic therapy   Randomized, open-label, active-controlled trial vs. YAG laser   Improvement in  disease-related 
  symptoms/1998  
1 Limited to non-squamous, non-small cell lung cancer. 

2 Accelerated approval. 

3 Because the approval was based on a subgroup of patients, confirmatory evidence in the subgroup came from  an on-going study as required under the accelerated approval. 

4 Subsequent studies did not confirm  clinical benefit; indication withdrawn in September 2011. 
 
 
6 
 Contains Nonbinding Recommendations 
B.  Summary of Workshop and Advisory Committee Discussions 
 
The American Society of Clinical Oncology (ASCO) and the FDA held a public workshop on 
lung cancer endpoints on April 15, 2003, with participants that included representatives from the 
FDA, ASCO, the National Cancer Institute, academia, advocacy groups, and industry.12  The 
workshop primarily addressed advanced and metastatic NSCLC, and participants discussed the 
pros and cons of using OS, tumor assessment-based endpoints, and PRO measures in evaluating 
drugs for marketing approval.  These discussions recognized that although ORR is a commonly 
used endpoint, it does not predict effects on OS.  The clinical significance of small differences in 
TTP may be unclear, especially when evaluating toxic therapy.  TTP is subject to ascertainment 
bias in open-label trials, and bias can occur if follow-up schedules are asymmetric among trial 
arms. 
 
Speakers at the workshop noted that assessment of disease progression at frequent intervals is 
labor intensive and can be expensive.  PRO measures can constitute important clinical benefit 
endpoints, particularly in a predominantly symptomatic disease such as NSCLC.  However, 
adequate evaluation of treatment effect based on PRO measures involves blinded, randomized 
trials using instruments that reliably and validly measure concepts that define treatment benefit 
in the targeted clinical trial population, with response options and a recall period that have been 
demonstrated to be appropriate and interpretable in the subset of patients studied.  Analytical 
challenges, including sensitive but uninterpretable instruments or large amounts of missing data, 
pose additional difficulties in evaluating an experimental therapy based on PRO data.  OS is 
considered the most appropriate endpoint that is definitive and easy to determine.  An observed 
OS benefit in a well-conducted, randomized trial can be directly attributed to the experimental 
therapy. 
 
Subsequent to the above-mentioned public workshop, an ODAC meeting was held on December 
16, 2003, in which the workshop discussions regarding lung cancer endpoints were presented to 
the committee. 
 
(1)  The committee voted 17 to 2 that since no drug was approved for the adjuvant treatment 
of NSCLC, hypothetically disease-free survival can be a reasonable endpoint to evaluate 
new therapy in an adjuvant setting. 
 
(2)  As of the date of the meeting, approval for the treatment of metastatic NSCLC generally 
had been based on demonstration of improvement in OS.  The committee considered 
whether studies incorporating a tumor-based time-to-event endpoint such as PFS or TTP 
as a primary endpoint could support regular approval, or only accelerated approval.  The 
committee recommended that the tumor-based endpoint of PFS be considered to be 
preferable to TTP, since PFS includes deaths particularly when there are missing 
assessments.  The uncertainties in measuring PFS were recognized (e.g., measure 
provides indirect evidence of clinical benefit, unclear clinical meaning of small 
differences in PFS, the noise and variability in the assessments caused by imaging or 
                                                 
12 See the workshop summary:  American Society of Clinical Oncology/FDA Lung Cancer Endpoints  Workshop,  
April 15, 2003 at 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm117709.htm#lung. 
7 
 Contains Nonbinding Recommendations 
timing of assessments, missing and unevaluable data).  The committee voted 11 to 8 that 
PFS may be used as an endpoint to evaluate drug effect in metastatic disease for 
consideration of regular approval. 
 
(3)  Regarding the evaluation of drug effect in inoperable or locally advanced disease, the 
committee voted 15 to 3 that an effect on PFS should not be considered sufficient to 
support regular approval and that new drugs should be evaluated based on OS.  To 
consider differences in PFS as the basis for accelerated approval, the committee was of 
the opinion that the treatment differences based on PFS had to be substantial (e.g., 3 
months or more). It was also recognized that PRO endpoints, such as delay in symptom 
progression, are important and that better tools are needed to minimize bias and to define 
what constitutes a benefit. 
 
(4)  The committee also discussed the challenges in using noninferiority trial designs with OS 
and PFS endpoints. A trial with a noninferiority hypothesis should be considered only if 
the active control has established efficacy, the active control effect size can be estimated 
for patients with the indication under consideration, and the percent of active control 
effect size to be retained can be prespecified.13  The effect size of the active control on 
the primary endpoint of interest should be established based on meta-analysis of 
historical, randomized trials.  It is not possible to prespecify the percent of active control 
effect size to be retained when the active control effect size is not well established.  When 
considering trials with a noninferiority hypothesis, an assumption that should be assessed 
is the constancy of the treatment effect over time attributed to the active comparator.  
Because medical practice, clinical trial conduct, the timing of tumor progression 
assessments, the radiological modalities used, and the criteria and definition for assessing 
progression that have evolved over time vary between trials, especially when trials are 
conducted in different geographic regions, it is difficult to verify the constancy 
assumption with PFS as primary endpoint. 
 
Based on these recommendations from the 2003 advisory committee meeting, we have continued 
to recommend OS as the primary endpoint for NSCLC clinical trials.  However, a clinical trial 
demonstrating a large improvement in PFS, with acceptable toxicity, could potentially lead to 
regular approval, particularly in an unmet medical need population. 
 
 
III.  RECOMMENDATIONS 
 
We consider OS to be the standard clinical benefit endpoint that should be used to establish 
efficacy of a treatment in patients with locally advanced or metastatic NSCLC.  However, other 
endpoints can be considered for regulatory decision-making based on the population and risk-
benefit profile of a drug. We also recognize that it may not always be feasible to conduct 
separate trials in patients with locally advanced and metastatic NSCLC. 
 
                                                 
13 See the draft guidance for industry Non-Inferiority Clinical Trials. When  final, this guidance will represent the 
FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA Drugs guidance  
Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
8 
 Contains Nonbinding Recommendations 
PFS may be appropriate as the primary endpoint to establish efficacy for drug approval if the 
trial is designed to demonstrate a large magnitude for the treatment effect as measured by both 
the hazard ratio and absolute difference in median PFS and an acceptable risk-benefit profile of 
the drug is demonstrated.  Sponsors should justify use of PFS as the primary efficacy endpoint 
and the magnitude of PFS effect considered likely to predict OS or to represent clinical benefit 
versus the risk of the drug in the context of the lung cancer stage and results of treatment with 
alternative therapy. Because of the subjectivity in the measurement of PFS assessments and the 
fact that the assessments depend on frequency, accuracy, reproducibility, and completeness, the 
observed magnitude of effect should be substantial and statistically robust.  If investigator-
assessed PFS is considered the primary endpoint for establishing efficacy, then evidence of lack 
of bias should be provided, for example, by verification of investigator assessment in a random  
sample audit conducted by an independent review committee.  
 
Planned interim efficacy analyses based on OS may be appropriate.  However, interim efficacy 
analyses of PFS before completion of patient accrual are discouraged.  Early interim efficacy 
analyses of PFS that cross a stopping boundary often overstate the magnitude of the effect.  An 
interim PFS efficacy analysis is unlikely to provide an accurate or reproducible estimate of the 
treatment effect size because of inadequate follow-up, missing assessments, inconsistent readings 
between radiological reviewers, and/or lack of concordance between investigators and 
independent assessors.  Stopping a trial based on  interim PFS efficacy results that may not be 
verifiable after adjudication can render the trial results uninterpretable.  In addition, a statistically 
significant difference in PFS that is small in magnitude may not be deemed clinically 
meaningful.  Interim analyses to detect harmful effects or futility for PFS or OS endpoints may 
be appropriate. 
 
We encourage the development of well-defined and reliable PRO instruments that capture the 
essential treatment benefit concepts in the targeted population.  To interpret PRO data, it is 
generally useful to gather a complete record of all doses of the concomitant medications, such as 
analgesics, antidepressants, antiemetics, and antidiarrheals, that may confound interpretation of 
the PRO of interest and limit the ability to differentiate anticancer treatment effects from the 
effects of concomitant medication.  Recording of concomitant medications can be accomplished 
using PRO instruments (i.e., event logs) or other assessment tools.  We will review the adequacy 
of all PRO measures based on the principles outlined in the guidance for industry Patient-
Reported Outcome Measures: Use in Medical Product Development to Support Labeling 
Claims. 
 
Regardless of which efficacy endpoints are chosen, NSCLC is a heterogeneous disease with 
varying response to treatment across different molecular and histopathologic subgroups (e.g., 
pemetrexed, erlotinib).  We recommend that clinical trials be prospectively designed to evaluate 
such differences in treatment effect.14  
 
Although 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.  These meetings will include 
                                                 
14 See the draft guidance for industry Non-Inferiority Clinical Trials. When  final, this guidance will represent the 
FDAs current  thinking on this topic.  
9 
 Contains Nonbinding Recommendations 
a multidisciplinary FDA team of oncologists, statisticians, clinical pharmacologists, 
measurement experts, and often external expert consultants.  Applicants can also submit a 
request for special protocol assessment to obtain confirmation of the appropriateness of endpoint 
measures and protocol design for individual trials, considered within the context of the overall 
development program, intended to support drug marketing applications.15  Marketing approval 
depends not only on the design of clinical trials, but on FDA review of the results and data from  
all trials in the marketing application.  Applicants who plan to prospectively evaluate treatment 
effects in a defined subgroup of NSCLC (e.g., a molecularly defined subgroup) should identify 
such a development program early and refer to guidance on co-development of drugs and devices 
in the guidance for industry and Food and Drug Administration staff In Vitro Companion 
Diagnostic Devices. 
 
                                                 
15 See the guidance for industry Special Protocol Assessment. 
10 
  Contains Nonbinding Recommendations 
APPENDIX A:  TUMOR MEASUREMENT DATA COLLECTION16  
 
The following are important considerations for tumor measurement data.  We recommend that: 
 
 	  The case report form (CRF) and electronic data document the target lesions identified during 
the baseline visit before treatment.  The possibility of bias cannot be eliminated when 
retrospective identification of  lesions is made for local site evaluations of tumor-based 
endpoints. 
 
 	  Tumor lesions be assigned a unique identifying letter or number.  This assignment 
differentiates among multiple tumors occurring at one anatomic site and matches tumors 
measured at baseline with tumors measured during follow-up. 
 
 	  A mechanism be in place that ensures complete data collection at critical times during 
follow-up. The CRF should ensure that all target lesions are assessed at baseline and that the 
same imaging or measuring method is used for all tests required at baseline and follow-up. 
 
 	  The CRF contains data fields that indicate whether scans were performed at each visit.  
 
 	  A zero be recorded when a lesion has completely resolved.  Otherwise, disappearance of a 
lesion cannot be differentiated from a missing value. 
 
 	  Follow-up tests provide for timely detection of new lesions both at initial and at new sites of  
disease. The occurrence and location of new lesions should be recorded in the CRF and in 
the submitted electronic data for both protocol-specified evaluations and those identified on 
unscheduled visits. 
 
                                                 
16 For the purposes of this appendix, tumor data refers to  data in SAS transport files, not images.  Generally, images 
are not submitted to the NDA  or BLA but can be audited  by the FDA during the review process.  
11 
  Contains Nonbinding Recommendations 
APPENDIX B:  ISSUES TO CONSIDER IN PFS ANALYSIS 
 
 
The protocol and statistical analysis plan (SAP) should detail the primary analysis of PFS.  This 
analysis should include a detailed description of the endpoint, appropriate modalities for 
evaluating tumors, and procedures for minimizing bias.  One or two secondary analyses should 
be specified to evaluate anticipated problems in trial conduct and to assess whether results are 
robust. The following important factors should be considered. 
 
	   Definition of progression date.  In survival analyses, the exact death date is known. In PFS 
analyses, the exact progression date is unknown.  The following two methods can be used for 
defining the recorded progression date (PDate) used for PFS analysis. 
 
1.	   PDate assigned to the first time at which progression can be declared.  
 
	   For progression based on a new lesion, the PDate is the date of the first observation 
that the new lesion was detected.  
 
	   If multiple assessments based on the sum of target lesion measurements are done at 
different times, the PDate is the date of the first observation or radiological 
assessment of target lesions that shows a predefined increase in the sum of the target 
lesion measurements. 
 
2.	   PDate as the date of the protocol-scheduled clinic visit immediately after all radiological 
assessments (which collectively document progression) have been done.  Generally, this 
is recommended for sensitivity analysis.  
 
	   Definition of censoring date.  Censoring dates are defined in patients with no documented 
progression before data cutoff or dropout.  In these patients, the censoring date is often 
defined as the last date on which progression status was adequately assessed.  One acceptable 
approach uses the date of the last assessment performed.  However, multiple radiological 
tests can be evaluated in the determination of progression.  A second acceptable approach 
uses the date of the clinic visit corresponding to these radiological assessments.  
 
	   Definition of an adequate PFS evaluation. In patients with no evidence of progression, 
censoring for PFS often relies on the date of the last adequate tumor assessment. A careful 
definition of what constitutes an adequate tumor assessment includes adequacy of target 
lesion assessments and adequacy of radiological tests both to evaluate nontarget lesions and 
to search for new lesions.  
 
	   Analysis of partially missing tumor data.  Analysis plans should describe the method for 
calculating progression status when data are partially missing from  adequate tumor 
assessment visits. 
 
	   Completely missing tumor data.  Assessment visits where no data are collected are 
sometimes followed by death or by assessment visits showing progression.  In other cases, 
the subsequent assessment shows no progression.  In the latter case, it may seem appropriate 
12 
  Contains Nonbinding Recommendations 
to continue the treatment and continue monitoring for progression.  However, this approach 
treats missing data differently depending upon subsequent events and can represent 
informative censoring when progression or death is recorded subsequently.  Another possible 
approach is to include data from subsequent PFS assessments.  This can be appropriate when 
evaluations are frequent and when only a single follow-up visit is missed.  Censoring at the 
last adequate tumor assessment can be more appropriate when there are two or more missed 
visits. 
 
The SAP should detail primary and secondary PFS analyses to evaluate the potential effect of 
missing data.  Reasons for dropouts should be incorporated into procedures for determining 
censoring and progression status. For instance, for the primary analysis, patients going off-
study for undocumented clinical progression, change of cancer treatment, or decreasing 
performance status can be censored at the last adequate tumor assessment.  The secondary 
sensitivity analysis would include these dropouts as progression events.  Although missed 
visits for progression can be problematic, all efforts should be made to keep following 
patients for disease progression irrespective of the number of visits missed.  Another analysis 
could ignore these missing assessments and consider the date that progression or death is 
recorded in a subsequent assessment as the time to event.  
 
 	  Progression of nonmeasurable disease.  When appropriate, progression criteria should be 
described for each assessment modality (e.g., CT scan, bone scan).  
 
 	  Suspicious lesions.  An algorithm should be provided for evaluating and following 
indeterminate lesions for assignment of progression status at the time of analysis. 
 
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  Contains Nonbinding Recommendations 
APPENDIX C:  EXAMPLE TABLES FOR PRIMARY PFS ANALYSIS  
 
Examples of prespecified censoring scheme that can be used are provided in the following tables. 
 
Table C1. Example 1 for censoring scheme for PFS  
Situation   Date of  Progression or Censoring   Outcome  
Incomplete or  no baseline tumor  Randomization  Censored   
assessments 
Progression  documented between scheduled   Earliest of:   Progressed 
visits     Date of progression assessment showing new 
lesion (if progression  is based  on new  lesion);  
or   
   Date of last progression assessment  
No progression   Date of last progression assessment with no   Censored 
documented progression   
Treatment discontinuation for   Date of last progression assessment with no  Censored 
undocumented progression   documented progression  
Treatment discontinuation for toxicity or   Date of last  progression with  no documented  Censored  
other reason   progression  
New anticancer treatment started   Date of last progression assessment with   Censored  
documented nonprogression before start of new 
treatment 
Death  before  first PD assessment  Date of  death  Progressed 
Death between adequate  assessment visits    Date of  death   Progressed  
Death or  progression after more than  one  Date of last progression assessment with  Censored  
missed visit   documented nonprogression  
 
 
 
Table C2. Example 2 for censoring scheme for PFS  
Situation   Date of  Progression or Censoring   Outcome  
Incomplete or  no baseline tumor  Randomization  Censored   
assessments 
Progression  documented between scheduled   Earliest of:   Progressed 
visits     Date of progression assessment showing new 
lesion (if progression  is based  on new  lesion);  
or   
   Date of last progression assessment  
No progression   Date of last progression assessment with no   Censored 
documented progression   
Treatment discontinuation for   Date of last progression assessment with no  Censored 
undocumented progression   documented progression  
Treatment discontinuation for toxicity or   Date of  documented  progression with protocol   Progressed 
other reason   specified continued follow-up in all treatment arms  
New anticancer treatment started  Date of documented progression with protocol   Progressed 
specified continued follow-up in all treatment arms  
Death  before  first PD assessment  Date of  death  Progressed 
Death between adequate  assessment visits    Date of  death   Progressed  
Death or  progression after more than  one  Date of documented progression   Progressed 
missed visit  
 
14 
  Contains Nonbinding Recommendations 
APPENDIX D:  EXAMPLE TABLES FOR PFS SUPPORTIVE ANALYSIS  
 
Sensitivity analyses can be helpful in determining whether the PFS analysis is robust.  However, 
these sensitivity analyses are exploratory and supportive of the results of the primary analysis, 
and efficacy may not be claimed based on sensitivity analysis alone.  Different sensitivity 
analyses can be described in tables that specify how dates of progression events and dates for 
censoring of progression data can be assigned.  The following three tables describe examples of 
three different sensitivity analyses. 
 
The sensitivity analysis in Table D1 corrects for potential bias in follow-up schedules for tumor 
assessment by assigning the dates for censoring and events only at scheduled visit dates.  
However, this approach can introduce bias if the progression occurred closer to the last visit. 
 
Table D1. PFS 1 (uniform progression and assessment dates)  
Situation   Date of  Progression or Censoring   Outcome  
No baseline tumor assessments  Randomization  Censored 
Progression documented  between   Date of  next scheduled visit   Progressed 
scheduled visits  
No progression   Date of last visit with adequate assessment  Censored  
Treatment discontinuation for   Date of last visit with adequate assessment  Censored 
undocumented progression  
Treatment discontinuation for toxicity   Date of last visit with adequate assessment  Censored 
or other reason  
New anticancer treatment started  Date of last  visit with adequate assessment  Censored 
Death  before  first PD assessment   Date of  death  Progressed 
Death between  adequate assessment   Date of  death  Progressed 
visits  
Death or  progression after more than   Date of last visit with adequate assessment  Censored 
one missed visit 
 
 
The sensitivity analysis in Table D2 uses a conservative approach by assigning the dates of 
discontinuation, change of treatment, or missed visit as an event date. 
 
Table D2. PFS 2 (any change considered as progression event)  
Situation   Date of  Progression or Censoring   Outcome  
No baseline tumor assessments  Randomization  Censored   
Progression  documented between scheduled   Earliest of:   Progressed 
visits     Date of  radiological assessment showing new 
lesion (if progression  is based  on new  lesion);  
or   
   Date of last  radiological assessment of 
measured lesions (if progression is based on  
increase in sum of measured lesions)  
No progression   Date of last radiological assessment of measured   Censored 
lesions  
Treatment discontinuation for   Date of  discontinuation  Progressed 
undocumented progression  
continued  
15   Contains Nonbinding Recommendations 
Table D2, continued  
Situation   Date of  Progression or Censoring   Outcome  
Treatment discontinuation for toxicity or   Date of  discontinuation  Progressed 
other reason  
New anticancer treatment started  Date of start of new anticancer treatment  Progressed 
Death  before  first PD assessment   Date of  death  Progressed 
Death between adequate  assessment visits    Date of  death   Progressed  
Death or  progression after more than  one  Date of first missed  visit  Progressed 
missed visit  
 
 
The sensitivity analysis in Table D3 evaluates PFS according to the investigators assessment.  

However, this approach can introduce bias if the progression occurred closer to the last visit. 

 
Table D3. PFS 3 (includes clinical progression) 
Situation   Date of  Progression or Censoring   Outcome  
No baseline assessment  Randomization  Censored  
Progression documented  between   Next scheduled visit   Progressed  
scheduled visits  
No progression   Date of last visit with adequate disease progression   Censored 
assessment 
Investigator claim of clinical  progression   Scheduled  visit (or next scheduled visit if  between   Progressed 
visits) 
Treatment discontinuation for toxicity or   Date of last visit with adequate disease progression   Censored 
other reason   assessment 
New anticancer treatment started with no  Date of last visit with adequate disease progression   Censored 
claim of progression   assessment 
Death  before  first PD assessment   Date of  death  Progressed 
Death between  adequate assessment   Date of  death  Progressed 
visits or after patient misses one 
assessment visit 
Death after an extended lost-to-follow- Date of last visit with adequate disease progression   Censored 
up time (two or more missed   assessment 
assessments) 
 
16