Guidance for Industry
Clinical Considerations for
Therapeutic Cancer Vaccines

DRAFT GUIDANCEThis guidance document is for comment purposes only.

Submit comments on this draft guidance by the date provided in the Federal Register noticeannouncing the availability of the draft guidance. Submit written comments to the Division ofDockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. You should
identify all comments with the docket number listed in the notice of availability that publishes in
the Federal Register.
Additional copies of this guidance are available from the Office of Communication, Outreachand Development (OCOD) (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 208521448, or by calling 1-800-835-4709 or 301-827-1800, or email ocod@fda.hhs.gov, or from theInternet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers listed above.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
September 2009

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Table of Contents
I.

INTRODUCTION............................................................................................................. 1II.

BACKGROUND ............................................................................................................... 2

III.

CLINICAL TRIAL DESIGN CONSIDERATIONS ..................................................... 2A.
1.

Considerations For Both Early and Late Phase Clinical Trials ....................... 2
Patient population ............................................................................................. 22.

Monitoring the immune response ..................................................................... 4

3.

Disease progression/recurrence immediately or shortly after the initialadministration of cancer vaccines..................................................................... 5

B.
1.

Considerations For Early Clinical Trials ........................................................... 6
Starting dose and dosing schedule .................................................................... 6

2.

Dose escalation ................................................................................................. 7

3.

Single-arm versus randomized phase 2 trials in early development................. 8

1.

Considerations For Late Phase Clinical Trials .................................................. 8
Safety profile from early phase clinical trials ................................................... 92.

Endpoints for licensure ..................................................................................... 9

3.

Superiority versus noninferiority design........................................................... 94.

Control issues.................................................................................................. 10

5.

Delayed vaccine effect.................................................................................... 10

6.

Autologous vaccine trials................................................................................ 11

7.

Accelerated approval regulations.................................................................... 11

C.

D.
IV.

Concomitant Therapies ...................................................................................... 12

REFERENCE.................................................................................................................. 13i

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Guidance for Industry1
Clinical Considerations for Therapeutic Cancer Vaccines
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s)
current thinking on this topic. It does not create or confer any rights for or on any person anddoes not operate to bind FDA or the public. You can use an alternative approach if theapproach satisfies the requirements of the applicable statutes and regulations. If you want todiscuss an alternative approach, contact the appropriate FDA staff. If you cannot identify theappropriate FDA staff, call the appropriate number listed on the title page of this guidance.

I.

INTRODUCTION

This guidance provides you, sponsors who wish to submit an Investigational New Drugapplication (IND) for a therapeutic cancer vaccine, recommendations on critical clinicalconsiderations for investigational studies of these products. This guidance will discussconsiderations common to phase 1 and phase 2 clinical trials (which collectively may be referred
to as “early phase clinical trials”) and phase 3 clinical trials (which may be referred to as “latephase clinical trials”) and that are unique to specific stages of clinical development of thesebiological products.
The products discussed in this guidance are for therapeutic cancer vaccines, referred to as“cancer vaccines” throughout this document, intended to be administered to patients with anexisting cancer for the purpose of treatment. This guidance does not apply to products intended
to be administered to patients to prevent or decrease the incidence of cancer. Furthermore, thisguidance does not apply to adoptive immunotherapeutic products such as T cell or NK cell
products. Although clinical trials involving these products share certain overlapping featureswith those involving cancer vaccines, adoptive immunotherapeutic products have different
mechanisms of action and unique requirements with respect to product development.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should beviewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested orrecommended, but not required.

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This guidance has been prepared by the Office of Cellular, Tissue and Gene Therapies in FDA’s Center for
Biologics Evaluation and Research (CBER).

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Draft – Not for ImplementationII.

BACKGROUND

The mechanism of action for most cancer vaccines is thought to be mediated through amplifying
a native T-cell response, especially cytotoxic T cells. Cancer vaccines, as antigens, areprocessed by the adaptive immune system through antigen-presenting cells (APCs). These APCs
then present antigenic determinants in a Human Leukocyte Antigen (HLA) - restricted fashion to
T cells and/or B cells, which in turn can attack tumor cells that express cognate antigenic
determinants or can provide help for B cell responses that produce antibodies, which in somecases 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 considerable time invivo, especially if vaccination requires several doses. Thus, development of a cancer vaccine
can present different considerations for clinical trial design than development of a traditional
cytotoxic drug or biological product for the treatment of cancer.
FDA has held or participated in several meetings to discuss development of cancer vaccines. For
example, on February 8-9, 2007, CBER co-sponsored a workshop with the National Cancer
Institute entitled “Bringing Therapeutic Cancer Vaccines and Immunotherapies throughDevelopment to Licensure.” In consideration of the input we received from stakeholders, thisguidance provides recommendations for the design of clinical trials for cancer vaccines
conducted under an IND (21 CFR Part 312) to support a subsequent license application formarketing approval, a biologics license application (BLA), submitted to CBER.

III.

CLINICAL TRIAL DESIGN CONSIDERATIONS

During the early phase clinical trials, studies for a new cancer vaccine are conducted todetermine optimal dose and dosing schedule, potential biological activities, and safety profiles.
In contrast, during late phase clinical trials, studies are conducted to demonstrate efficacy andsafety in a defined population. The results from such trials may support an application forlicensure.
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 populationa.

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 optimal dose, schedule, andmaximum tolerated dose (MTD). When initial testing is conducted in apatient population with advanced metastatic disease, patients can be2

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enrolled, dosed, and evaluated in a reasonably short time frame. Since
most patients with advanced metastatic disease would have a relatively
quick disease progression, any potential activity of the cytotoxic agents on
the disease status would be detected during relatively short trials.
Subsequent development then examines the agent in a metastatic setting ofa single tumor type for efficacy and safety generally in a large, usuallyrandomized and controlled setting. Once its efficacy and safety aredemonstrated in the setting of metastatic disease, the same agent may thenbe developed and tested in subjects who have minimal or no evidence ofresidual disease. 2
Testing cancer vaccines using the conventional model may not allow time
for development of an anti-tumor immune response needed for
activity/effectiveness because of the potentially short time interval fromadministration of study agent to subsequent disease progression in patientswith metastatic cancer. In addition, patients with metastatic diseases
usually have received multiple treatments (e.g., cytotoxic and/or
immunosuppressive chemo- and radio-therapies) for their cancer, which
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 immune response elicited by the cancer vaccines todevelop and manifest. The disadvantage is that clinical development may
take longer. Consequently, developers of cancer vaccines need to weighthe advantages and disadvantages of testing these agents in patients withmetastatic diseases versus patients with no evidence of residual disease or
minimal burden of disease.
When standard therapies are available, consideration should be given toincorporating the timing and sequencing of these therapies with cancer
vaccine administration to optimize the evaluation of the safety andpotential biologic activities of such a treatment regimen.
b.

Patient population tumor heterogeneity

Cytotoxic agents are usually tested in phase 1 studies in a population that
includes a heterogeneous mix of tumor types at various clinical stages.
The possibility that any given agent may have a different effect on
2

See FDA’s guidances entitled “Guidance for Industry: FDA Approval of New Cancer Treatment Uses forMarketed Drug and Biological Products” dated December 1998 accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071657.pdf and“Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics” dated May 2007
accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071590.pdf.

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Draft – Not for Implementationdifferent tumor types is accepted in these trials since the primary goal of
the phase 1 studies of cytotoxic agents is often to determine the MTD andthe safety profile of the tested agents. Agents that are found to have an
acceptable toxicity are then tested in phase 2 trials with a relatively
homogenous patient population and a defined tumor type.
However, there are particular challenges with the approach of enrolling
patients with heterogeneous tumor types and stages in testing cancer
vaccines in early trials. Differences in the clinical stage of the disease andprior treatments can affect the potential response to the cancer vaccine.
This is particularly problematic with vaccines that are made fromautologous patient materials as each patient and tumor histology isdifferent, resulting in different vaccine preparations. As a result,interpretation of trial results from a heterogeneous patient population canbe especially challenging, and the objectives of the trials may not be
achieved. Thus, in selecting the patient population for cancer vaccine
testing, careful considerations should be given with regard to theheterogeneity 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,consideration should be given to developing an assay or mechanism tomeasure the target antigen expression in tumor tissues of individual
patients and using that information in patient selection as well as responsemonitoring. If the development of a novel assay is involved, the sponsor
should propose a plan for co-development of the assay with the cancer
vaccine in early discussions with FDA, before the sponsor submits its
IND, so that we, FDA, can provide advice on scientific, clinical, andregulatory issues at an appropriate stage of product development. (Ref. 1)
2.

Monitoring the immune response

The proposed mechanism of action of cancer vaccines is that they mediate theiranti-tumor activities by eliciting an immune response. Among other factors,
monitoring of the immune response can be very important for the following
reasons:o In early phase clinical trials to optimize the dose and schedule,
determine whether the vaccine induces the intended immune
responses, and aid the decision-making process concerning further
product development and later clinical trial design for the cancer
vaccine.

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Draft – Not for Implementationo In later phase clinical trials to provide data for comparison of theclinical efficacy parameters with the types and magnitudes of
immune responses.
Mounting a clinically effective anti-tumor response involves a multi-component
process coordinated to mediate the effect. Therefore, multiple monitoring assays
may be needed to identify and measure the component immune responses.
Assays that measure the immune response(s) thought to be the most important andrelevant components of the anti-tumor response should be developed. We
recommend that, if possible, at least two immunological assays should be used in
an attempt to monitor the proposed immunologically-mediated anti-tumor
response. The assay parameters, such as assay conditions, positive and negative
controls, cutoff values for determining the positive and negative test results frompatients’ 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.
Developing a specific immune response assay can be challenging if the specificantigen has not been identified or appropriate reagents specific for target antigens
are not available. In situations where antigen-specific immune monitoring assays
cannot be established, it may be possible to assay T cell or antibody responses towhole tumor cells or tumor cell lysates in vitro or in vivo by delayed typehypersensitivity (DTH) testing. When even that type of antigenic material is notavailable, the possible value of global measures of T cell or antibody levels andactivity, including DTH testing to standard antigens, can be discussed with
CBER. We encourage sponsors to have these discussions with CBER as early as
possible (Ref. 1).
3.

Disease progression/recurrence immediately or shortly after the initialadministration of cancer vaccines

In oncologic practice, patients are usually taken off current treatment when they
have disease progression/recurrence. Because cancer vaccines need time to elicit
an immune response that could manifest as biological activity (i.e., a tumor
specific immune response), a delayed effect can be expected in the subjects who
have received the vaccines. Shortly after the initial cancer vaccine administration,subjects may experience disease progression prior to the onset of biologicalactivities or effects from the vaccine (delayed effects).
One potential approach to this situation would be to clearly define a description of
disease status for which continued vaccination is intended in the clinical study
protocol. The following are potential clinical situations in which you may wish toconsider providing provisions in the protocol for continued vaccination.

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Draft – Not for Implementationo 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 entry eligibility
criteria.
o Subjects may only receive the same dose and schedule that wasgiven before disease progression/recurrence occurs/reoccurs.
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). It is also important to
explain the protocol’s provisions for these situations.
B.

Considerations For Early Clinical Trials

The primary goals of the early cancer vaccine clinical trials are to: study the safety
profile of the product; study the optimal starting dose and dosing schedule for the
product; and identify and study the potential biological activities to provide scientific dataon which to base further product development.
1.

Starting dose and dosing schedule

It is important that the selection of the starting dose and the subsequent dose
escalation schedule, as well as the dosing schedule, for initial clinical trials of acancer vaccine be supported by data generated from the preclinical in vitro and invivo studies and/or prior human experience.
Preclinical in vitro and in vivo proof-of-concept studies to establish the rationale
for the starting dose and dosing scheme in conjunction with appropriately
designed preclinical toxicology studies to assess the safety of the intended clinicalproduct should guide the clinical dose levels and dosing schedule design. The
dose levels used in the toxicology studies should be based on dose levels thatshowed biological activity in proof-of-concept studies and should bracket andexceed the proposed clinical dose levels in an attempt to identify a no-observedadverse-effect-level (NOAEL). Due to the general mechanisms of action of thesevaccine products, there is no predefined conversion factor to enable extrapolationfrom a safe dose in animals to a human starting dose. It is important that thesponsor provide justification, with supporting scientific data, for the extrapolation
modality used to determine the clinical starting dose and dosing scheme in the
IND.
The preclinical studies should incorporate a dosing schedule that mimics theintended schedule for the early phase clinical trial as closely as possible. The
sponsor should provide justification for conducting a proposed clinical trial if a
proposed clinical trial will include a greater number of immunizations with the6

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cancer vaccine than preclinical studies included. We encourage sponsors to meetwith FDA as early as possible in product development to discuss the preclinicaldata needed to support a proposed clinical trial (Ref. 1).
For cancer vaccines that have been previously administered to humans, it may bepossible to derive the starting dose and the dose escalation scheme from this priorhuman experience. We recommend that the sponsor provide comprehensive
information in the IND, including the activity and safety profile, from the existing
clinical data to support the safety of the cancer vaccine in the proposed trial.
When a particular cancer vaccine belongs to a class of agents that has been tested
extensively in clinical trials, a considerable body of safety and activity data may
already be established for this product class. In such situations, depending on therelevance of the existing clinical data that is submitted by the sponsor, the conductof additional preclinical studies may not be needed to support the starting dose.
We recommend that the sponsor contact CBER to discuss this issue prior to
conducting the additional preclinical studies.
2.

Dose escalation

The traditional standard dose escalation schedule in the development of cancer
therapeutics uses the so-called “3 + 3 design” established to avoid doses thatinvoke a treatment limiting toxicity to <20% of patients, a standard considered
acceptable as an outpatient therapeutic for patients with limited options and lifethreatening diseases. In this situation, three patients are initially enrolled at agiven dose cohort. If there is no dose limiting toxicity (DLT) observed in any ofthese subjects, the trial proceeds to enroll additional subjects to the next higher
dose cohort. If there is one subject who develops a DLT, an additional threesubjects are enrolled at that dose. Further development of DLTs in the expanded
dose cohort (>1 of 6) 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 is not identified. This
may suggest that this design may not be the most suitable approach to gathering
information from early phase cancer vaccine trials and that the dose-toxicity curve
may be so flat that the highest dose that can be administered is limited bymanufacturing or anatomic issues rather than toxicity.
Therefore, we recommend that you consider alternative clinical trial design
approaches to gather data that are informative regarding dose escalation forcancer vaccine trials. Given the relatively tolerable safety profile of some classesof cancer vaccines, alternative dose escalation approaches, such as accelerated
titration, may be considered instead of the standard 3 + 3 design. When using
such designs, acceptable parameters for the dosing endpoint (supported by data)

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should be described in the protocol. Irrespective of which dose escalation
approach is chosen, the study protocol should clearly describe the definition(s) of
DLTs, the subject “off-treatment” criteria and the study stopping rules that will
ensure patient safety.
When cancer vaccines are tested in combination with other components oradministered through invasive procedures or to anatomic sites that carry asignificant safety concern, a traditional standard dose escalation approach may be
indicated in order to determine the safety profile of the treatment without undue
risk.
3.

Single-arm versus randomized phase 2 trials in early development

We recommend that the sponsor take care to design early phase clinical trials thatprovide data to support a solid proof-of-concept, optimization of the dose andschedule, and a detailed understanding of the activity of the new agent relative towhat is currently available for the purported indication prior to the transition to
randomized late phase clinical trials that are designed to establish efficacy andconfirm safety.
When designing a phase 2 clinical trial, you should consider the advantages anddisadvantages of single-arm versus randomized phase 2 trials. Results fromsingle-arm studies usually overestimate the treatment effect of the investigational
agent, and when performed in single study centers, the subjects enrolled may not
be completely representative of the true patient population. Single-arm studies
can be, and often are, used to demonstrate tumor shrinkage by cytotoxic agents;
however, 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. Time-to-event endpoints in the single-arm setting must rely on
historical controls and are therefore subject to bias and confounding. Randomized
phase 2 trials, although typically lacking the statistical power for conclusive
demonstration of the treatment effect of the investigational agent, can provide
value in the design of the later phase confirmatory trials (e.g., helping todetermine the appropriate sample size and estimating treatment effect).
C.

Considerations For Late Phase Clinical Trials

Early phase clinical trials evaluate safety, optimize the dose and schedule, and identify
evidence of biological drug activity. Later phase efficacy studies evaluate clinicalbenefit. The following sections discuss endpoint selection for clinical trials to evaluate
cancer vaccines. Sponsors are encouraged to meet with FDA to discuss a late phaseclinical trial design, including endpoint selection. 3
3

See FDA’s “Guidance for Industry: Special Protocol Assessment” dated May 2002 (May 17, 2002), accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm080571.pdf.

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1.

Safety profile from early phase clinical trials

Late phase clinical trial design should be based on the safety data from earlyphase clinical trials to define eligible patient populations, primary and secondary
trial endpoints, assumptions of treatment effect and sample size as well as other
trial parameters.
It is important that a product have an adequate safety profile before moving
forward to phase 3 clinical trials. Sponsors are encouraged to discuss safetyissues with CBER at meetings such as end-of-phase 2 meetings (Ref. 1). If safetyissues are identified in the early phase clinical trials, these issues need to beevaluated carefully during phase 3 clinical trials with appropriate patientmonitoring. For cancer vaccines, autoimmune phenomena, for example, represent
a potentially devastating side effect that will need monitoring during the progressof the trial and in long-term follow-up.
2.

Endpoints for licensure

One of the most important aspects in designing a late phase trial is to choose aclinically 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.
We recommend consideration of the recommendations in FDA’s “Guidance forIndustry: Clinical Trial Endpoints for the Approval of Cancer Drugs andBiologics” dated May 2007, accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM071590.pdf, and FDA’s “Guidance for Industry:
Cancer Drug and Biological Products – Clinical Data in Marketing Applications”
dated October 2001, accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM71323.pdf, prior to discussions with us regarding
your choice of endpoints for your late phase clinical cancer vaccine trial. Whilethese guidances may be helpful to you, it is important to keep in mind that
endpoints based on tumor assessments, which are discussed in the guidances in
sections III.B and III.D, respectively, may not necessarily be appropriate
endpoints in a late phase clinical trial for a cancer vaccine.
3.

Superiority versus noninferiority design

Although cancer vaccines may have mechanisms of actions that differ markedly
from those of current, conventional chemotherapeutic agents, their overall clinicaleffect should be evaluated in the context of the currently available therapeutic
options. Because these differences in mechanism of action may contribute to9

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Draft – Not for Implementationdifficulty in determining a noninferiority margin relative to an establishedtherapeutic agent, we recommend use of a superiority trial design to demonstrate
a cancer vaccine’s treatment effect on a chosen endpoint over the control.
However, in certain clinical settings in which an FDA-approved treatment isavailable, the effect size of the available therapy may be well established. In
these limited cases, a noninferiority (NI) trial design and analysis may beconsidered. When an equivalence/NI trial is designed, the statistical analysis planof the clinical protocol should specify a priori the NI margin chosen and thejustifications for the chosen margin. We recommend early consultation with the
FDA if an equivalence/NI trial design is being considered.
4.

Control issues

To avoid the biases that can be introduced in the conduct of the trial and in theanalyses of the trial results, cancer vaccine trials should have appropriate controls,
either using an active comparator or placebo control. If using a placebo, thewithholding of treatment should not lead to serious harm, such as death orirreversible morbidity. Studies involving a placebo should be carefully
considered and planned. Either cancer vaccines or co-administered immune
stimulatory agents can cause reactions that make the patients treated with cancer
vaccines easily identifiable in these trials. To maintain this blind, the teamadministering the product may need to separate from the teams performing postprocedure subject care and endpoint assessment. We recommend consulting with
FDA on selection of a control.
5.

Delayed vaccine effect

As a consequence of their immunological mechanisms of action, considerable
time might be needed for cancer vaccines to induce immunity afteradministration, and it frequently has been proposed that tumors in some subjects
treated with cancer vaccines may show early progression followed by subsequent
response.
To take the potential of this phenomenon into consideration in the later phaseclinical trials of products for which nonclinical data or early phase clinical trials
suggest that it may exist, we recommend that the statistical analysis plan containspecific definitions of outcome events (e.g., protocol specific criteria for
responder and non-responder subjects) for the following scenarios:ooInitial tumor progression followed by subsequent regression with
continued administration of cancer vaccine.
Initial tumor progression followed by subsequent regression with
continued administration of cancer vaccine and then followed byadditional progression.

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In general, time-to-event endpoints are measured from the time of randomization.
Due to delayed effect of the vaccine, the endpoint curves of the trial results may
show no effect for the initial portion of the study. If the treatment is effective,
separation of the curves may occur later in the study after the vaccine effect has
become established. This may violate the proportional hazard assumptions
necessary when applying Cox modeling and may necessitate an increase insample size to provide sufficient power to test a statistical hypothesis. 4
6.

Autologous vaccine trials

Design of studies using autologous vaccine products that are derived from thepatients’ own tumors poses unique challenges and deserves some special
considerations. Manufacturing such vaccines can take a considerable period oftime and in some instances, may take up to several months. If complete remission
or stable disease are eligibility criteria, the time required for manufacture may
mean that, some trial subjects may not remain eligible 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, asponsor’s inability to treat enrolled subjects with active product will adversely
affect the statistical power of the clinical study. Therefore, consideration should
be given to optimization of the vaccine manufacturing process prior to late phaseclinical trials in an effort to increase the proportion of the patients who are
randomized to the treatment arm and receive the active product.
7.

Accelerated approval regulations

FDA’s accelerated approval regulations in 21 CFR Part 314, Subpart H (fordrugs) and 21 CFR Part 601, Subpart E (for biologics) apply to new drug andbiological products that (1) have been studied for their safety and effectiveness intreating 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 clinical4

In brief, a Cox model is a statistical technique for exploring the relationship between the survival of a patient andseveral explanatory variables.

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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). 5
FDA has accepted tumor shrinkage as an appropriate surrogate endpoint in thesetting of a population of cancer patients with advanced disease and tumors thatare refractory to existing therapies. However, as previously discussed, cancer
vaccines may not be expected to induce tumor shrinkage.
Time-to-event endpoints other than survival have in some situations also been
considered to be appropriate surrogate endpoints for clinical benefit in thelicensure of cancer therapeutics.
Approval under the accelerated approval regulations will be subject to therequirement that the applicant study the biological product further, to verify anddescribe its clinical benefit, where there is uncertainty as to the relation of thesurrogate endpoint to clinical benefit, or of the observed outcome. Postmarketingstudies would usually be studies already underway. If a sponsor is contemplating
licensure by the accelerated approval pathway, the sponsor should consider theneed to develop a plan to confirm clinical benefit following licensure. If thepostmarketing studies fail to demonstrate clinical benefit or the applicant fails toperform the required post-marketing study with due diligence, FDA may
withdraw approval, following a Part 15 hearing.
D.

Concomitant Therapies

One of the recent advances in the immunotherapy field is the realization that effective
destruction of a tumor involves multiple coordinated immune mechanisms. Thesemechanisms 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 othercytotoxic or immunomodulatory treatments. Effects of this nature should be consideredin the overall product development plan and specifically in the clinical trial design. You
should provide justification for any concomitant therapy, including the mode action, dose
5

These regulations do not explicitly define the term available therapy. The Center for Drug Evaluation andResearch 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 labelingof 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 purposesof 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 establishedoncologic treatments) be considered available therapy.. See FDA’s “Guidance for Industry: Available Therapy”(July 2004) (July 23, 2004, 69 FR 44039) accessible at
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126637.pdf. The guidance also discusses thephrase “meaningful therapeutic benefit to patients over existing treatments”.

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Draft – Not for Implementationand schedule of the concomitant therapy (e.g., chemotherapy, biotherapy, radiotherapy),
and interactions of the concomitant therapy with the vaccine. In addition, paralleldevelopment of diagnostic tests to be used to determine patient eligibility or staging may
raise similar considerations.
In certain instances, the use of other therapies may constitute a combination product(21 CFR 3.2(e)). You should discuss these issues with FDA during the early stages of
product development so that we can provide you guidance that is tailored to your product.

IV.
1.

REFERENCE
Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA
Products (February 2000) accessible at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM079744.pdf

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