Guidance for Industry
 
 
Clinical Considerations for 
Therapeutic Cancer Vaccines 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Outreach 
and Development (OCOD), (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-
1448, or by calling 1-800-835-4709 or 301-827-1800, or email ocod@fda.hhs.gov, or from the 
Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm. 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
October 2011  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  CLINICAL TRIAL DESIGN CONSIDERATIONS.....................................................2 
A.  Considerations for Both Early and Late Phase Clinical Trials........................3 
1.  Patient population.............................................................................................3 
2.  Monitoring the immune response.....................................................................5 
3.  Biomarkers as evidence of efficacy..................................................................6 
4.  Adjuvants used to stimulate immune response.................................................6 
5.  Multi-antigen vaccines......................................................................................7 
6.  Disease progression/recurrence immediately or shortly after the initial 
administration of cancer vaccines.....................................................................7 
7.  Concomitant and subsequent therapies.............................................................8 
B.  Considerations for Early Phase Clinical Trials..................................................8 
1.  Starting dose and dosing schedule....................................................................9 
2.  Booster and maintenance therapy...................................................................10 
3.  Dose escalation...............................................................................................10 
4.  Single-arm versus randomized phase 2 trials in early development...............11 
C.  Considerations for Late Phase Clinical Trials.................................................11 
1.  Safety profile from early phase clinical trials.................................................12 
2.  Endpoints........................................................................................................12 
3.  Statistical issues..............................................................................................12 
4.  Control issues..................................................................................................13 
5.  Delayed vaccine effect....................................................................................13 
6.  Autologous vaccine trials................................................................................14 
7.  Accelerated approval regulations....................................................................14 
IV.  REFERENCES................................................................................................................16 
i  Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
 
Clinical Considerations for Therapeutic Cancer Vaccines 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 
 
 
I.  INTRODUCTION 
 
This guidance provides sponsors who wish to submit an Investigational New Drug application 
(IND) for a therapeutic cancer vaccine with recommendations on critical clinical considerations 
for investigational studies of these products.  This guidance will discuss considerations common 
to phase 1 and phase 2 clinical trials (collectively referred to as early phase clinical trials) and 
phase 3 clinical trials (referred to as late phase clinical trials), as well as considerations that are 
unique to specific stages of clinical development of therapeutic cancer vaccines.  This guidance 
provides recommendations for the design of clinical trials for cancer vaccines conducted under 
an IND (Title 21 Code of Federal Regulations (21 CFR) Part 312) to support a subsequent 
biologics license application (BLA) for marketing approval.  This guidance finalizes the draft 
guidance of the same title dated September 2009. 
 
The products discussed in this guidance are therapeutic cancer vaccines intended to result in 
specific responses to a tumor antigen, and are intended for the treatment of patients with an 
existing diagnosis of cancer.  These products are regulated by the Center for Biologics 
Evaluation and Research (CBER) and are referred to as cancer vaccines throughout this 
document.  These cancer vaccines mediate their therapeutic effect through in vivo induction or 
amplification of the antigen-specific host immune response.  This guidance does not apply to 
vaccines for preventative and therapeutic infectious disease indications, to products intended to 
induce or augment a non-specific immune response, or to products intended to prevent, or 
decrease the incidence of cancer in individuals without a prior history of that cancer.  
Furthermore, this guidance does not apply to adoptive immunotherapeutic products which may 
mediate their therapeutic effect by targeting the tumor directly, such as T cell or NK cell 
products.  Adoptive immunotherapeutic products and cancer vaccines have different mechanisms 
of action and therefore this guidance is not applicable to development of those products.  
 
                                                 
1 This guidance has been prepared by the Office of Cellular, Tissue and Gene Therapies in FDAs Center for 
Biologics Evaluation and Research. 
1  Contains Nonbinding Recommendations 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe FDAs 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 FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
The mechanism of action for most cancer vaccines is thought to be mediated through induction 
of an antigen-specific T cell response or amplifying a pre-existing antigen-specific T cell 
response, especially cytotoxic T cell responses.  Cancer vaccines induce responses to tumor-
specific antigens that are processed by the immune system through antigen-presenting cells 
(APCs).  These APCs then present antigenic determinants in a Human Leukocyte Antigen 
(HLA)-restricted fashion to T cells which in turn can attack tumor cells that express cognate 
antigenic determinants.  T cells can also provide help for B cell responses that produce 
antibodies, which in some cases could lead to tumor cell death.  The course of antigen 
presentation and processing, activation of lymphocytes, and tumor cell killing, is expected to 
require a substantial time in vivo.  Thus, development of a cancer vaccine can present different 
considerations for clinical trial design than development of a more traditional biological product 
or cytotoxic drug for the treatment of cancer. 
 
FDA has held or participated in several meetings to discuss development of cancer vaccine 
products.  For example, on February 8-9, 2007, CBER co-sponsored a workshop with the 
National Cancer Institute entitled, Bringing Therapeutic Cancer Vaccines and Immunotherapies 
through Development to Licensure.  In consideration of the input FDA received from 
stakeholders, this guidance provides recommendations for the design of clinical trials for cancer 
vaccines conducted under an IND to support a subsequent BLA for marketing approval. 
 
 
III.  CLINICAL TRIAL DESIGN CONSIDERATIONS 
 
During the early phase clinical trials, studies for a new cancer vaccine are normally conducted to 
determine optimal dose and dosing schedule, potential biological and clinical activity, and safety 
profile.  In contrast, during late phase clinical trials, studies are conducted to demonstrate 
efficacy and safety in a defined population.  The results from late phase trials may potentially 
support a BLA submission. 
2  Contains Nonbinding Recommendations 
 
 
A.  Considerations for Both Early and Late Phase Clinical Trials 
 
Clinical considerations that are relevant to both early and late phase clinical trials include 
the following: 
 
1.  Patient population 
 
a.  Disease setting  
 
The conventional model for clinical development of a chemotherapeutic 
agent involves initial testing in patients with advanced metastatic diseases 
and different tumor types to determine the maximum tolerated dose 
(MTD) and optimal schedule as well as assessment of clinical activity 
through tumor shrinkage (objective tumor responses).  Therefore, 
assessment of the MTD and clinical activity, through tumor shrinkage that 
is apparent within the first 8 weeks on investigational therapy, can be 
assessed with short observation periods in clinical trials of traditional 
cytotoxic therapy.  Subsequent development then examines the agent in a 
metastatic setting of a single tumor type for efficacy and safety generally 
in a large, usually randomized and controlled setting.  Once its efficacy 
and safety are demonstrated in the setting of metastatic disease, the same 
agent may then be developed and tested in subjects who have minimal 
burden of disease or no evidence of residual disease (Refs. 1 and 2). 
 
In contrast, the time to development of an anti-tumor immune response 
needed for activity/effectiveness of a cancer vaccine generally requires 2-3 
months. 
 
In addition, patients with relapsed or recurrent metastatic disease usually 
have received multiple treatments (e.g., cytotoxic and/or 
immunosuppressive chemo- and radio-therapies) for their cancer.  These 
therapies may be detrimental to the immune system, minimizing the 
potential responsiveness to the cancer vaccine being tested.  In contrast, 
testing cancer vaccines in patients with no evidence of residual disease or 
minimal burden of disease, as discussed in this guidance, may provide 
adequate time for the cancer vaccine to elicit a detectable immune 
response.  However, demonstration of efficacy would require following 
the subjects for evidence of disease recurrence.  Therefore, the 
disadvantage of this approach is that clinical development may require 
more patients and time.  Consequently, developers of cancer vaccines need 
to weigh the advantages and disadvantages of testing these agents in 
patients with metastatic diseases versus patients with no evidence of 
residual disease or minimal burden of disease. 
 
3  Contains Nonbinding Recommendations 
 
b.  Patient population tumor heterogeneity 
 
Cytotoxic agents are usually tested in phase 1 clinical trials in a population 
that includes a heterogeneous mix of tumor types at various clinical stages.  
The primary goal of these phase 1 studies is often to determine the MTD 
and the safety profile of the tested agents; therefore, the possibility that 
any given agent may have a different effect on different tumor types is 
accepted in these trials.  Agents that are found to have an acceptable 
toxicity are then tested in phase 2 clinical trials with a relatively 
homogenous patient population and a defined tumor type. 
 
Although it may be acceptable to test heterogeneous patient populations 
with a common antigen in early phase trials, this approach is unlikely to 
provide interpretable evidence of efficacy for the purposes of licensure.  In 
addition, there are particular challenges with the approach of enrolling 
patients with heterogeneous tumor types and stages into early phase trials 
of cancer vaccines.  Differences in the clinical stage of the disease and 
prior treatments can affect the potential response to the cancer vaccine.  
This is especially problematic with vaccines that are made from 
autologous patient materials, as each patient and tumor histology is 
different, resulting in different vaccine preparations.  As a result, 
interpretation of trial results from a heterogeneous patient population can 
be especially challenging, and the objectives of the trials may not be 
achieved.  Thus, in selecting the patient population for cancer vaccine 
testing in early phase trials, careful consideration should be given to the 
heterogeneity of the patient population. 
 
c.  Co-development of cancer vaccines and tests for targeted antigen 
 
When the proposed mechanism of action involves a specific antigen or 
other therapeutic target, consideration also should be given to developing 
an assay or mechanism to measure the target antigen expression in tumor 
tissues of individual patients and using that information in subject 
selection or response monitoring.  These assays are generally regulated by 
the Center for Devices and Radiological Health (CDRH).  Therefore, 
sponsors developing cancer vaccines who are considering including the 
use of an assay in the labeling of the cancer vaccine, or sponsors of such 
assays who are planning to develop the assay for use with a specific 
cancer vaccine should request a meeting with both the relevant product 
review office (CBER) and the relevant device review division (CDRH).  
Discussions begun early in the development process, ideally before 
submission of an IND and/or Investigational Device Exemption (IDE), 
may help ensure that product development provides data that establish the 
safety and effectiveness of the therapeutic product and assay pair.  This is  
4  Contains Nonbinding Recommendations 
 
particularly important where use of the assay turns out to be necessary to 
the safe and effective use of the therapeutic product (referred to as 
companion diagnostics) (Refs. 3-5). 
 
2.  Monitoring the immune response  
 
The proposed mechanism of action of cancer vaccines is that they mediate their 
anti-tumor activities by eliciting or amplifying an immune response.  We consider 
immune monitoring as mainly exploratory, especially in early phase clinical trials, 
with the major goals of establishing proof-of-principle for the proposed 
pharmacological effect and showing immunogenicity of the administered 
antigens.  To this end, monitoring of the immune response can be useful as 
follows: 
 
o  To assess variations in immunocompetency that may affect the study 
results.  Responses against known immunogens (e.g., keyhole limpet 
hemocyanin or tetanus for humoral immunity; phytohemagglutinin for 
cellular responses) and HLA typing could assess patient population 
heterogeneity and assess any HLA link/bias to product activity. 
 
o  In early phase clinical trials, to optimize the dose and schedule, determine 
whether the vaccine induces the intended immune responses, assess 
immune tolerance, provide proof-of-concept, and aid the decision-making 
process concerning further product development and later clinical trial 
design. 
 
o  In later phase clinical trials, to provide data regarding the types, 
magnitudes and duration of response and the possible correlation with 
clinical efficacy parameters. 
 
A clinically effective anti-tumor response involves a multi-component process; 
therefore, multiple monitoring assays may be needed to identify and measure the 
components of the immune responses.  Assays that measure the immune 
response(s) thought to be the most important and relevant components of the anti-
tumor response should be developed.  If possible, at least two immunological 
assays should be used in an attempt to monitor the proposed immunologically-
mediated anti-tumor response.  Assay standardization should include specific 
parameters to control for general variability in an immune response across study 
sites.  The assay parameters, such as assay conditions, sensitivity and specificity 
of the assay, any in vitro amplification step involved, positive and negative 
controls, cutoff values for determining the positive and negative test results from 
patients specimens, and the statistical analytical methods to be used for the test 
results, should be clearly described in the clinical protocol prior to the initiation of 
the clinical trials. 
 
5  Contains Nonbinding Recommendations 
 
If the specific antigen has not been identified or appropriate reagents specific for 
target antigens are not available, then developing a specific immune response 
assay can be challenging.  In situations where antigen-specific immune 
monitoring assays cannot be established, it may be possible to assay T cell or 
antibody responses to whole tumor cells or tumor cell lysates in vitro or in vivo 
by delayed type hypersensitivity (DTH) testing to standard antigens.  To 
determine the specificity of host immune response, appropriate controls 
(including common antigens (e.g., influenza, Candida, tetanus toxoid)) should be 
included in the DTH assay.  Even when common antigens are not available, the 
possible value of global measures of T cell or antibody levels and activity can be 
discussed with CBER.  We encourage sponsors to have these discussions with 
CBER as early as possible (Ref. 3). 
 
Exploratory studies that evaluate the elimination of antigens on tumors may be 
helpful in monitoring immune response or evaluating mechanisms of resistance to 
immunotherapies.  However, elimination of antigens may not be indicative of 
efficacy and therefore cannot be the primary evidence of efficacy in a BLA. 
 
3.  Biomarkers as evidence of efficacy 
 
FDA supports development of exploratory biomarkers for proof-of-concept and 
scientific understanding of mechanism of action.  However, the development of 
biomarkers as surrogates for efficacy is beyond the scope of this guidance. 
 
4.  Adjuvants used to stimulate immune response 
 
Cancer vaccine formulations may contain adjuvants used in conjunction with 
vaccine antigens to augment or direct the specific immune response to an antigen.  
Prior to clinical administration of the vaccine-adjuvant combination, the potential 
toxicity of the adjuvant alone, and of the investigational clinical vaccine-adjuvant 
combination, should be assessed in preclinical studies as appropriate.  The design 
of these preclinical studies should mimic the planned clinical immunization 
regimen and route of administration.  General requirements for inclusion of such 
adjuvants in licensed biological products are described in 21 CFR 610.15.  These 
requirements include submission of evidence that adding the proposed adjuvant to 
a product does not adversely affect the safety or potency of the product  
(21 CFR 610.15(a)).  Information supporting the value of adding the adjuvant 
should be provided, preferably at an early stage of vaccine development, and may 
include evidence of enhanced immune response or antigen-sparing effects, and 
data supporting selection of the dose of the adjuvant. 
 
When products which may have independent clinical activity (e.g., cytokines) are 
used as adjuvants to enhance the effects of vaccine antigens, the study design and 
control group(s) should be discussed with FDA.  Study design requirements will 
be considered on a case-by-case basis. 
6  Contains Nonbinding Recommendations 
 
 
5.  Multi-antigen vaccines 
 
Cancer vaccine formulations may contain multiple tumor-associated antigens in 
order to generate multiple tumor-specific immunologic responses and potentially 
hinder potential tumor escape mechanisms.  In general, each component of a 
multi-antigen vaccine may not need to be individually evaluated for safety and 
activity, this will be considered on a case-by-case basis. 
 
6.  Disease progression/recurrence immediately or shortly after the initial 
administration of cancer vaccines 
 
In oncologic practice, investigational and approved treatments are generally 
discontinued when patients experience disease progression.  Because of the time 
required for the host (patient) to elicit or amplify an immune response to a cancer 
vaccine (i.e., tumor-specific immune response), the vaccine may have a delayed 
effect in the study subjects.  In this situation, clinical progression may occur 
before the vaccine has had sufficient time to be effective.  Therefore, clinical 
progression that is asymptomatic and/or is not likely to result in life-threatening 
complications with further progression (e.g., Central Nervous System (CNS) 
metastases or impending fractures from bony metastases) may not be sufficient 
reason for discontinuation of administration of a cancer vaccine. 
 
One potential approach to this situation would be for the study protocol to clearly 
define the extent and location of clinical disease progression for which continued 
vaccination will be continued.  The following are potential clinical situations in 
which sponsors may wish to consider providing provisions in the protocol for 
continued vaccination despite evidence of disease progression: 
 
o  Subjects continue to meet all other study protocol eligibility criteria. 
o  No dose limiting toxicity (DLT) has been observed, and all toxicities 
resolved to the baseline level, consistent with the study eligibility criteria. 
o  No deterioration of subject performance status. 
o  No curative salvage therapy exists for the indication (e.g. resection of 
pulmonary metastases in osteosarcoma patients).  
o  Does not delay imminent intervention to prevent serious complications of 
disease progression (e.g., CNS metastases).  
o  Clinical evidence from early phase clinical trials suggests delayed effects.  
 
 
The informed consent document provided to subjects must describe any 
reasonably foreseeable risks or discomforts to the subject (21 CFR 50.25(a)(2)) 
(e.g., the possibility of disease progression or recurrence) and other alternative 
treatment options.  
 
7  Contains Nonbinding Recommendations 
 
7.  Concomitant and subsequent therapies 
 
One of the recent advances in the immunotherapy field is the realization that 
effective destruction of a tumor involves multiple coordinated immune 
mechanisms.  These mechanisms include, but are not limited to, enhancement of 
the activities of antigen presenting cells, activation of effector T cells, and 
removal of suppressor T cells.  The ultimate therapeutic effect of cancer vaccines 
may be diminished or enhanced by other cytotoxic or immunomodulatory 
treatments.  Therefore, such cytotoxic or immunomodulatory effects of other 
treatments should be considered in the overall product development plan and 
specifically in the clinical trial design.  Justification should be provided for the 
use of concomitant therapy (e.g., chemotherapy, biotherapy, radiotherapy, laser 
therapy), including the mode of action, dose and schedule of the concomitant 
therapy, and potential for negative or positive interactions of the concomitant 
therapy with the vaccine. 
 
When standard therapies are available, consideration should be given to the 
timing and sequencing of these therapies, relative to the schedule of cancer 
vaccine administration, to optimize the evaluation of the safety and potential 
biological activities of the cancer vaccine.  Preclinical exploration of the different 
options of timing and sequencing of cancer vaccine and standard therapy (such as 
cytotoxic chemotherapy) can help guide clinical development.  Trial design 
details, including eligibility criteria and stratification factors, should be carefully 
considered in order to minimize the impact of standard therapies on the studys 
ability to detect the cancer vaccines biological activity. 
 
In certain instances, the use of other therapies may constitute a combination 
product (21 CFR 3.2(e)).  The implications of development of a potential 
combination product should be discussed with FDA during the early stages of 
product development to obtain recommendations that are tailored to a specific 
product/combination product. 
 
Induction of an effective response to a cancer vaccine may affect the efficacy of 
subsequent cytotoxic, targeted or other cancer therapy.  Therefore, the nature and 
duration of subsequent therapies should be documented. 
 
B.  Considerations for Early Phase Clinical Trials 
 
The primary goals of the early phase clinical trials of a cancer vaccine are to:  assess the 
safety of the product; determine the optimal dose and dosing schedule for the product; 
and identify and study the potential biological activities to provide scientific data to guide 
further product development.   
8  Contains Nonbinding Recommendations 
 
 
1.  Starting dose and dosing schedule 
 
The selection of the starting dose and the subsequent dose escalation scheme, as 
well as the dosing schedule, for initial clinical trials of a cancer vaccine should be 
supported by data generated from the preclinical studies and/or prior human 
experience. 
 
When feasible, preclinical in vitro and in vivo proof-of-concept (POC) studies are 
recommended to provide the rationale for the proposed clinical trial.  These 
studies, in conjunction with appropriately designed preclinical studies 
characterizing the toxicology of the cancer vaccine, should guide the clinical 
doses and initial clinical dosing schedule.  The dose levels used in the preclinical 
toxicology studies should be based on dose levels that showed biological activity 
in preclinical POC studies.  The objective of these preclinical studies is to identify 
a dose level, such as a no-observed-adverse-effect-level, if applicable, that can 
guide initiation of clinical dosing, after consideration of relevant biological or 
physiological parameters (e.g., body weights, antigen expression, clinical 
pathology, pathology). 
 
Since potential vaccine-related toxicities may be related to the presence of the 
target antigen in normal tissues, or to the presence of an unrelated protein in 
normal tissues that may contain a peptide sequence similar to a peptide in the 
vaccine, the presence of target antigen in normal human tissues should be 
determined.  For peptide vaccines, sequence homology searches should be 
conducted to assist in prediction of potential vaccine-related toxicities. 
 
Assessment of the kinetics of the immune response of the cancer vaccine product 
in preclinical studies may also provide insight into the potential in vivo activity 
and safety profile of the vaccine, and help guide dose selection and the timing of 
subsequent vaccinations in humans. 
 
In general, due to the predicted mechanism(s) of action of these vaccine products, 
as well as species-specific variation in immune response activity, there is no 
predefined conversion factor to enable extrapolation from a safe dose in animals 
to a potentially safe starting dose in humans.  The sponsor should submit 
justification, with supporting scientific data, for the extrapolation modality used to 
determine the proposed clinical starting dose, dose escalation scheme, and dosing 
schedule. 
  
When a particular cancer vaccine belongs to a class of agents that has been 
previously administered to humans, a body of safety and activity data may already 
exist.  In such situations, depending on the relevance of the available clinical data, 
additional preclinical studies may not be needed to support the starting dose and  
9  Contains Nonbinding Recommendations 
 
dosing schedule.  The sponsor should provide comprehensive information in the 
IND, including existing clinical data regarding the activity and safety profile, to 
support the safety of the cancer vaccine in the proposed trial. 
 
2.  Booster and maintenance therapy 
 
Sponsors may wish to explore vaccination boosters and maintenance therapy to 
evaluate long-term immunogenicity and its correlation with clinical outcomes.  
The conduct of preclinical studies to evaluate such regimens is recommended, and 
subsequent clinical studies should be designed to support the safety and 
effectiveness of such regimens. 
 
3.  Dose escalation 
 
The traditional standard dose escalation schedule in the development of cancer 
therapeutics uses the so-called 3 + 3 design to avoid selection of a phase 2 
clinical trial dose that causes a treatment-limiting toxicity in more than 17% of 
subjects, a standard considered acceptable as an outpatient therapeutic for patients 
with limited options and life-threatening diseases.  In a 3 + 3 design, three 
patients are initially enrolled into a given dose cohort.  If there is no DLT 
observed in any of these subjects, the trial proceeds to enroll additional subjects 
into the next higher dose cohort.  If one subject develops a DLT at a specific dose, 
an additional three subjects are enrolled into that same dose cohort.  Development 
of DLTs in more than 1 of 6 subjects in a specific dose cohort suggests that the 
MTD has been exceeded, and further dose escalation is not pursued. 
 
Many cancer vaccine trials have used the 3 + 3 design, and the results show 
that, except in very rare situations, an MTD for a cancer vaccine may not be 
identified.  In these trials, the dose-toxicity curve may be so flat that the highest 
dose that can be administered is limited by manufacturing or anatomic issues 
rather than toxicity.  Therefore, this 3 + 3 design may not be the most suitable 
approach to gathering information from early phase trials of cancer vaccines, and 
alternative trial designs should be considered. 
 
Given the relatively acceptable safety profile of some classes of cancer vaccines, 
alternative dose-escalation approaches, such as accelerated titration or continuous 
reassessment, may be considered instead of the standard 3 + 3 design.  When 
using such designs, the protocol should describe acceptable parameters for the 
dosing endpoint (supported by data).  Irrespective of which dose-escalation 
approach is chosen, the study protocol should clearly define DLTs, the subject 
off-treatment criteria, and the study stopping rules that will ensure subject 
safety.  When no DLT is expected or achieved, optimization of other outcomes, 
such as the immune response, can be useful to identify doses for subsequent 
studies. 
 
10  Contains Nonbinding Recommendations 
 
When cancer vaccines are tested in combination with other therapeutic agents or 
devices, or administered through invasive procedures, or to anatomic sites that 
carry a significant safety concern, a standard dose-escalation approach may be 
indicated to determine the safety profile of the vaccine or combination. 
 
4.  Single-arm versus randomized phase 2 trials in early development 
 
FDA recommends that IND sponsors take care to design early phase clinical trials 
that provide POC data, optimize the dose and dosing schedule, and provide a 
detailed understanding of the activity of the new agent relative to therapies 
currently available for the purported indication.  This early phase data should be 
available prior to the transition to randomized late phase clinical trials that are 
designed to establish efficacy and confirm safety. 
 
When designing a phase 2 clinical trial, the advantages and disadvantages of 
single-arm versus randomized phase 2 trials should be considered.  Results from 
single-arm studies may overestimate the time-to-event treatment effects of the 
investigational agent for various reasons.  In addition, time-to-event endpoints in 
the single-arm setting must rely on historical controls and are therefore subject to 
selection bias in identification of that historical population, and confounding by 
the change in the standard of care over time. 
 
Single-arm studies can be, and often are, used to demonstrate tumor shrinkage by 
cytotoxic agents; however, such evidence of therapeutic activity is more difficult 
to obtain in situations where the product is a cancer vaccine that may not be 
expected to cause tumor shrinkage.  Therefore, due to their mechanism of action, 
single-arm studies of cancer vaccines may not provide reliable anti-tumor activity 
data to guide subsequent product development, although such studies may better 
characterize and estimate immunologic effects.   
 
Randomized phase 2 trials, due to their limited sample sizes, typically lack the 
statistical power for conclusive demonstration of the treatment effect of the 
investigational agent and provide a more limited patient experience for 
generalization of treatment effects to the general patient population.  However, 
such randomized phase 2 trials can provide more reliable data to guide the design 
of the later phase confirmatory trials (e.g., help to determine the appropriate 
sample size and estimate treatment effect) and take into account potential negative 
effects, including tolerance induction. 
 
C.  Considerations for Late Phase Clinical Trials 
 
Early phase clinical trials evaluate safety, optimize the dose and dosing schedule, and 
provide evidence of biological drug activity.  Later phase studies are intended to gather 
additional information about effectiveness and safety.  FDA encourages sponsors to 
initiate late phase trials using the most biologically effective dose and schedule based on  
11  Contains Nonbinding Recommendations 
 
early phase clinical studies.  The following sections discuss endpoint selection for clinical 
trials to evaluate cancer vaccines.  Sponsors are encouraged to meet with FDA to discuss 
a late phase clinical trial design, including endpoint selection (Ref. 6). 
 
1.  Safety profile from early phase clinical trials 
 
Late phase clinical trial design should consider the safety data from early phase 
clinical trials.  It is important that a product have an adequate safety profile before 
moving forward to phase 3 clinical trials.  Sponsors are encouraged to discuss 
safety issues with CBER at meetings such as end-of-phase 2 meetings (Ref. 3).  If 
safety issues are identified in the early phase clinical trials, these issues need to be 
evaluated carefully during phase 3 clinical trials, including appropriate subject 
monitoring.  For example, for cancer vaccines, autoimmune phenomena may 
represent a potentially debilitating side effect that will need monitoring during the 
progress of the trial and in long-term follow-up.  The length of follow-up will 
depend on a number of factors, including natural history of the disease and 
product characteristics.  For gene therapy studies, please see the FDA guidance 
entitled Guidance for Industry:  Gene Therapy Clinical Trials  Observing 
Subjects for Delayed Adverse Events, dated November 2006 (Ref. 7). 
 
2.  Endpoints 
 
One of the most important aspects of designing a late phase trial is to choose a 
clinically meaningful endpoint.  Demonstrable clinical benefits vary with cancer 
type and status of disease.  Clinical benefits that have supported drug approval 
have included important clinical outcomes (e.g., increased survival, symptomatic 
improvement) but also have included effects on established surrogate endpoints.  
Consideration of the recommendations in the FDA guidances entitled Guidance 
for Industry:  Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, dated May 2007 (Ref. 2), Guidance for Industry: Providing Clinical 
Evidence of Effectiveness for Human Drug and Biological Products, dated May 
1998 (Ref. 8), and Guidance for Industry: Patient-Reported Outcome Measures: 
Use in Medical Product Development to Support Labeling Claims, dated 
December 2009 (Ref. 9), may be particularly useful for both design and endpoint 
selection.  Endpoints based on tumor assessments, as discussed in section III.B of 
the May 2007 guidance, may not be appropriate endpoints for a late phase clinical 
trial for a cancer vaccine. 
 
3.  Statistical issues 
 
The overall clinical effect of a cancer vaccine should be evaluated in the context 
of the currently available therapeutic options.  FDA recommends use of a 
superiority trial design to demonstrate a cancer vaccines treatment effect on a 
chosen endpoint. 
 
12  Contains Nonbinding Recommendations 
 
In certain clinical settings, the effect size of the available therapy(ies) may be well 
established.  In these limited situations, a noninferiority (NI) trial design and 
analysis may be considered.  However, the design of a NI trial is complex; 
therefore, sponsors should include early consultation with the FDA and careful 
consideration of the recommendations in the FDA draft guidance entitled 
Guidance for Industry: Non-Inferiority Clinical Trials,2 dated March 2010  
(Ref. 10). 
 
Adaptive trial designs will be considered on a case-by-case basis.  Sponsors 
should consider the recommendations in the FDA draft guidance entitled 
Guidance for Industry: Adaptive Design Clinical Trials for Drugs and 
Biologics3, dated February 2010 (Ref. 11). 
 
Imbalances in subsequent therapies may confound the interpretation of study 
results, particularly when the primary endpoint is overall survival. Therefore, the 
study should document the nature and duration of subsequent therapies, and 
appropriate sensitivity analyses should be pre-specified. 
 
4.  Control issues 
 
To avoid the biases that can be introduced in the conduct of the trial and which 
confound the analyses of the trial results, cancer vaccine trials should have 
appropriate controls, either an active comparator or placebo.  Studies involving a 
placebo should be carefully considered and planned.  Withholding an available 
therapy with proven safety and efficacy may be unethical. 
 
Blinding of subjects, investigators, and evaluators may be helpful to decrease the 
risk of bias in the study results.  However, either cancer vaccines or co-
administered immune stimulatory agents can cause reactions that make the 
subjects treated with the vaccine easily identifiable.  To maintain blinding of 
treatment assignment, the study may need to provide separate personnel for each 
of the following: study agent administration; post-administration subject care; and 
endpoint assessment. 
 
5.  Delayed vaccine effect 
 
As a consequence of their immunological mechanisms of action, cancer vaccines 
may require considerable time after administration to induce immunity.  
Therefore, tumors in subjects treated with cancer vaccines may show early 
progression followed by subsequent response.  This potential phenomenon should 
be considered in the design of later phase clinical trials, particularly if nonclinical 
data or early phase clinical trials suggest that the phenomenon exists and time-to-
event endpoints are used.  Due to delayed effect of the vaccine, the endpoint 
curves may show no effect for the initial portion of the study.  If the vaccine is 
                                                 
2  This draft guidance, when finalized, will represent FDAs current thinking on this topic. 
3  This draft guidance, when finalized, will represent FDAs current thinking on this topic. 
13  Contains Nonbinding Recommendations 
 
effective, evidence of the effect may occur later in the study.  This delay in the 
effect may lead to an average effect that is smaller than expected and thus may 
require both an increase in sample size to compensate for the delay and a careful 
assessment of trial maturity for the primary analysis.  In addition, possible 
violation of the proportional hazards assumption should be considered when 
selecting a statistical method for the primary analysis. 
 
6.  Autologous vaccine trials 
 
Design of studies using autologous vaccine products that are derived from the 
subjects own tumors poses unique challenges and deserves special consideration.  
Manufacturing such vaccines may take up to several months.  If complete 
remission or stable disease is an eligibility criterion, the time required for 
manufacture may mean that some trial subjects may become ineligible for vaccine 
administration because of disease recurrence or progression. 
 
Additionally, manufacture of autologous vaccine product may not be possible for 
every subject for a wide variety of source material and/or manufacturing process 
reasons.  Regardless of the cause, a sponsors inability to treat randomized 
subjects with the vaccine may adversely affect the statistical power of the clinical 
study.  Therefore, consideration should be given to optimization of the vaccine 
manufacturing process before the late phase clinical trials are initiated, to increase 
the proportion of the randomized subjects who receive the vaccine. 
 
7.  Accelerated approval regulations 
 
FDAs accelerated approval regulations in 21 CFR Part 314, Subpart H (for 
drugs) and 21 CFR Part 601, Subpart E (for biologics) apply to new drug and 
biological products that (1) have been studied for their safety and effectiveness in 
treating serious or life-threatening illnesses, and (2) provide meaningful 
therapeutic benefit to patients over existing treatments (e.g., ability to treat 
patients unresponsive to, or intolerant of, available therapy, or improved patient 
response over available therapy) (21 CFR 314.500 and 601.40).  In this setting, 
FDA may grant approval on the basis of adequate and well controlled clinical 
trials establishing that the drug or biological product has an effect on a surrogate 
endpoint that is reasonably likely, based on epidemiologic, therapeutic, 
pathophysiologic, or other evidence, to predict clinical benefit  
(21 CFR 314.510 and 601.41).4 
                                                 
4 These regulations do not explicitly define the term available therapy.  The Center for Drug Evaluation and 
Research (CDER) and CBER have determined that in regulations where the terms are not otherwise defined, the 
terms available therapy and existing treatments should be interpreted as therapy that is specified in the approved 
labeling of regulated products, with only rare exceptions.  FDA recognizes that there are cases where a safe and 
effective therapy for a disease or condition exists but is not approved for that particular use by FDA.  However, for 
purposes of the accelerated approval regulations, only in exceptional cases will a treatment that is not FDA-
regulated (e.g., surgery) or that is not labeled for use but is supported by compelling literature evidence (e.g., certain 
established oncologic treatments) be considered available therapy.  See the FDA guidance entitled Guidance for 
14  Contains Nonbinding Recommendations 
 
 
FDA has accepted tumor shrinkage as an appropriate surrogate endpoint in the 
setting of a population of cancer patients with advanced disease and tumors that 
are refractory to existing therapies.  However, as previously discussed, cancer 
vaccines may not induce tumor shrinkage; therefore, accelerated approval based 
on tumor responses may not represent a feasible path to licensure for cancer 
vaccines.   
 
Approval under the accelerated approval regulations is subject to the requirement 
that the applicant study the biological product further, to verify and describe its 
clinical benefit, where there is uncertainty as to the relation of the surrogate 
endpoint to clinical benefit, or of the observed clinical benefit to ultimate 
outcome.  A single late phase trial may support both accelerated approval, based 
on an intermediate endpoint, and confirmation of effectiveness, based on further 
follow-up of survival in the same trial.  Thus, confirmatory postmarketing studies 
could be underway at the time of accelerated approval.  If a sponsor is 
contemplating licensure by the accelerated approval pathway, the sponsor should 
consider the need to develop a plan to confirm clinical benefit following 
licensure.  If the postmarketing studies fail to demonstrate clinical benefit or the 
applicant fails to perform the required postmarketing study with due diligence, 
FDA may withdraw approval, following the withdrawal procedures set forth in 
the regulations at 21 CFR 601.43. 
 
                                                                                                                                                             
Industry: Available Therapy, dated July 2004 (Ref. 12).  The guidance also discusses the phrase meaningful 
therapeutic benefit to patients over existing treatments.   
15  Contains Nonbinding Recommendations 
 
IV.  REFERENCES 
 
1.  Guidance for Industry:  FDA Approval of New Cancer Treatment Uses for Marketed Drug 
and Biological Products (December 1998) accessible at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/ucm071657.pdf. 
2.  Guidance for Industry:  Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (May 2007) accessible at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM071590.pdf. 
3.  Guidance for Industry:  Formal Meetings With Sponsors and Applicants for PDUFA 
Products (February 2000) accessible at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM079744.pdf. 
4.  Guidance on IDE Policies and Procedures (January 1998) accessible at: 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc
m080202.htm. 
5.  Draft Guidance for Industry and Food and Drug Administration Staff:  In Vitro Companion 
Diagnostic Devices (July 2011) accessible at: 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo
cuments/UCM262327.pdf. 
6.  Guidance for Industry:  Special Protocol Assessment (May 2002) accessible at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/ucm080571.pdf.  
7.  Guidance for Industry:  Gene Therapy Clinical Trials  Observing Subjects for Delayed 
Adverse Events (November 2006) accessible at 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
ormation/Guidances/CellularandGeneTherapy/ucm078719.pdf.  
8.  Guidance for Industry:  Providing Clinical Evidence of Effectiveness for Human Drug and 
Biological Products (May 1998) accessible at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM078749.pdf. 
9.  Guidance for Industry:  Patient-Reported Outcome Measures:  Use in Medical Product 
Development to Support Labeling Claims (December 2009) accessible at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM193282.pdf. 
10. Draft Guidance for Industry:  Non-Inferiority Clinical Trials (March 2010) accessible at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM202140.pdf. 
11. Draft Guidance for Industry:  Adaptive Design Clinical Trials for Drugs and Biologics 
(February 2010) accessible at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM201790.pdf. 
12.Guidance for Industry:  Available Therapy (July 2004) accessible at 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126637.pdf.  
16