Guidance for Industry
IND Exemptions for Studies of Lawfully
Marketed Drug or Biological Products
for the Treatment of Cancer
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)
January 2004
Clinical Medical
Revision 1 Guidance for Industry
IND Exemptions for Studies of Lawfully
Marketed Drug or Biological Products
for the Treatment of Cancer
Additional copies are available from:
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Food and Drug Administration
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or
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 Food and Drug Administration
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(Internet)   http://www.fda.gov/cber/guidelines.htm.  
Mail: the Voice Information System at 800-835-4709 or 301-827-1800
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)
January 2004
Clinical Medical
Revision 1 TABLE OF CONTENTS
I. INTRODUCTION.................................................................................................................1
II. BACKGROUND...................................................................................................................2
A. Regulations.....................................................................................................................................2
B. 1996 Agency Cancer Initiative......................................................................................................3
III. RISK/BENEFIT ANALYSIS IN THE PRACTICE OF ONCOLOGY...........................3
IV. DETERMINING APPLICATION STATUS......................................................................4
A. Agency Determination...................................................................................................................4
B. Investigator Determination...........................................................................................................5
V. EXAMPLES OF STUDIES..................................................................................................5
A. Studies That Generally Are Exempt............................................................................................5
B. Studies That Generally Are Not Exempt.....................................................................................7 Contains Nonbinding Recommendations
1
Guidance for Industry
IND Exemptions for Studies of Lawfully Marketed
Drug or Biological Products for the 
Treatment of Cancer
This guidance represents 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 and does not operate to bind FDA or the public.
You can use an alternative approach if that approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
I.  INTRODUCTION  
This guidance is intended to assist sponsors in deciding whether a study of marketed drugs or
biological products for treating cancer falls within the exemption under  312.2(b)(1) (21 CFR
312.2(b)(1)) from the general requirement to submit an investigational new drug application
(IND).  The guidance discusses the Agency's current thinking on when studies of marketed
cancer products are exempt from IND regulation based on a risk assessment.  The Agency hopes
that clarifying its policy will help sponsors identify which studies are exempt, thus saving them
from submitting unnecessary IND applications. 
This guidance revises the guidance of the same title published in September 2003.  In the
September 2003 version, the Agency's final statement was that it believed that most randomized
studies of a size that could support a labeling supplement would likely not be exempt from IND
regulation under  312.2(b)(1)(i), (ii).  This is because they would be intended to support
approval of a new indication, a significant change in the product labeling, or a significant change
in advertising.  Experience has shown that this interpretation was formulated too broadly and
inappropriately referred to size alone.  The Agency has decided to revise this guidance by
removing that statement (the last sentence in section V.B).  Whether a study could support a
change in labeling is a complex determination, based on study design, size, and other factors.
 
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
                                                
1 This guidance has been prepared by the Division of Oncology Drug Products in the Center for Drug Evaluation
and Research (CDER) and by the Center for Biologics Evaluation and Research (CBER) at the Food and Drug
Administration.
 
1 Contains Nonbinding Recommendations
cited.  The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
II.  BACKGROUND
Generally, regulations in part 312 (21 CFR part 312) require sponsors who wish to study a drug
or biological product in humans to submit an IND to the Agency.2   However, these regulations
also provide for the exemption of some studies from the requirement to submit an IND if they
meet certain criteria.   Each year, many INDs for cancer drugs are submitted that contain studies
that the Agency determines are exempt.  This guidance is intended to help applicants identify
which studies may be exempt.
A.  Regulations 
Regulations in  312.2(b)(1) provide for the exemption of some studies for some drugs from IND
regulations if the studies meet the following five criteria:
 
1.  The study is not intended to support FDA approval of a new indication or a significant
change in the product labeling. 
2.  The study is not intended to support a significant change in the advertising for the
product.
3.  The investigation does not involve a route of administration or dosage level or use in a
patient population or other factor that significantly increases the risks (or decreases the
acceptability of the risks) associated with the use of the drug product.
4.  The study is conducted in compliance with institutional review board (IRB) and informed
consent regulations set forth in parts 56 and 50 (21 CFR parts 56 and 50).
5.  The study is conducted in compliance with  312.7 (promotion and charging for
investigational drugs).
 
Requirements 1, 2, 4, and 5 are not directly related to the specific protocol submitted, and their
interpretation is similar for oncologic and nononcologic therapies.  Requirement 3 is protocol
related and has special meaning in the oncology therapy setting, particularly with respect to
doses above the labeled dose, use with other treatments, and use in different populations. 
 
In the preamble to the IND regulations, which published in the Federal Register on March 19,
1987, the Agency explained that the exemption was not necessarily intended to tie the
investigator to the doses and routes of administration and patient population described in the
                                                
2 Part 312 applies to all clinical investigations of products that are subject to section 505 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 355) or to the licensing provisions of the Public Health Service Act (58 Stat. 632, as
amended (42 U.S.C. 201 et seq.)).
2 Contains Nonbinding Recommendations
approved labeling, but to permit deviations from the approved labeling to the extent that such
changes are supported by the scientific literature and generally known clinical experience.  The
Agency recognizes that a considerable amount of professional judgment is exercised in
determining whether the planned investigation significantly increases the risk associated with the
use of the drug.  FDA maintains that because the assessment of risks involved in a therapeutic
procedure is an everyday part of the practice of medicine, the individual investigator should
usually be able to determine the applicability of the exemption.3
B.  1996 Agency Cancer Initiative
In 1996, as part of the President's National Performance Review, the Agency launched its
Reinventing the Regulation of Cancer Drugs initiative with the goal of accelerating the approval
of and expanding patient access to cancer drugs.4  As part of this initiative, the Agency explained
that many sponsor-investigators were submitting INDs for exploratory studies for so-called off-
label indications for two reasons:  (1) IRBs incorrectly believe an IND is required, or (2) the
pharmaceutical manufacturer agrees to provide a drug free of charge, but mistakenly concludes
that the FDA will view this as promotional activity.  With the intent of clarifying the Agency's
policy and decreasing the number of unnecessary submissions, the Agency emphasized that it
would no longer accept INDs considered exempt under  312.2(b)(1).  (See  312.2(b)(4).)
Furthermore, FDA stated that providing a drug for study would not, in and of itself, be viewed as
a promotional activity if the manufacturer or distributor provides the product for a physician-
initiated, bona fide clinical investigation.  The Agency explained that it is the responsibility of
the investigator to determine whether an IND is necessary.
Despite the Agency's attempts to clarify its policy on IND exemptions, many cancer drug IND
applications that the Agency determines are exempt from IND regulation are still being
submitted unnecessarily.  From 1997 to 1999, a majority of investigator IND submissions for
marketed cancer drugs were considered exempt (204, 205, and 140 applications in 1997, 1998,
and 1999, respectively). 
III. RISK/BENEFIT ANALYSIS IN THE PRACTICE OF ONCOLOGY
As noted above, a critical question in determining whether a study is exempt involves criterion 3
in the exemption regulations ( 312.2(b)(1)(iii)):  The investigation may not significantly
increase the risk associated with use of a drug product.  The question of increased risk is
determined by assessing the deviation in the planned investigation from the use described in the
approved label.  In oncology, modifications of labeled dosing recommendations are common and
                                                
3 New Drug, Antibiotic, and Biologic Drug Product Regulations, Federal Register, March 19, 1987, Vol. 52, Nr. 53,
p. 8802.
4 Reinventing the Regulation of Cancer Drugs  Accelerating Approval and Expanding Access (March 1996),
CBER, Office of Communication, Training, and Manufacturer Assistance, Voice Information System at 1-800-835-
4709 or 301-827-1800, document ID number 0281.  Available on the Internet at
http://www.fda.gov/cber/genadmin/reincanc.htm
3 Contains Nonbinding Recommendations
occur as part of oncologists' clinical practice.  As outlined below, oncologists are familiar with
evaluating the risk of  off-label dosing regimens for cancer drug and biological products. 
  Treatment with cancer drugs may be associated with significant risk from known toxicity.
Because effectiveness is often related to dose, a dose close to the maximal tolerated dose
is often selected for studies of cancer drugs.  This same dose usually becomes the
recommended dose in labeling when the new cancer drug is approved with the
knowledge that the dose may be altered if it is not tolerated by a patient.   Because it is
not generally possible to have maximal efficacy in a population without inducing toxicity
in some patients, it is not uncommon to observe severe or even lethal side effects from
cancer drugs in some patients.  In general, these circumstances mean that the toxicity,
even potentially lethal toxicity, of cancer drugs is described in approved labeling. 
  Off-label therapy with cancer drugs is common in practice.  When there is no established
therapy for a cancer, or stage of cancer, it is common for oncologists to try different
regimens or combinations of established drugs.  A 1996 GAO report (Prescription
Drugs, Implications of Drug Labeling and Off-Label Use) showed that there was
substantial off-label use in situations where satisfactory treatment was not available, and
lower rates of off-label use when there was an effective therapy.  In their daily practice,
many oncologists treat cancer patients with regimens that include off-label use of drugs.
They evaluate the published data and past clinical experience to assess the risk of such
treatments.  Such treatment of individual patients with approved drugs within their
clinical practice does not require an IND ( 312.2(d)).  
  In many cases, as discussed in the examples in section V below, drug administration to
patients with similar off-label regimens in the context of an investigation seems to
involve no increased risk to patients, and an investigator could conclude that such a study
would not significantly increase the risk associated with the labeled use of a drug product
and the study could be conducted without an IND.  Oversight by an IRB and informed
consent in compliance with parts 56 and 50, respectively, would be required as usual 
( 312.2(b)(1)(iv)).  On request, FDA will advise on the applicability of the IND
exemption to a planned clinical investigation ( 312.2(e)).
 
IV. DETERMINING APPLICATION STATUS 
A. Agency Determination
As explained in FDA's 1996 cancer initiative and the IND exemption regulation, FDA will not
accept applications for clinical studies that it determines to be exempt from the requirement for
an IND ( 312.2(b)(4)).  Although  312.2(b)(1) does not require a submission for a
determination of exempt status, whenever an IND application is submitted, FDA staff perform an
initial limited review of the application to determine whether the study is exempt.  The protocol-
related criterion FDA considers in assessing exemption is:  The investigation may not involve a
route of administration or dosage level or use in a patient population or other factor that
significantly increases the risks (or decreases the acceptability of the risks) associated with the
4 Contains Nonbinding Recommendations
use of the drug product ( 312.2(b)(1)(iii)).  Thus, when determining if the risk is significantly
increased, FDA staff examine the parts of the protocol that concern dose, schedule, route of
administration, and patient population.  If the Agencys initial limited review determines that a
study protocol is exempt from the requirement for an IND, the Agency performs no further
review of the application.  A letter is sent to the sponsor giving notice of the exemption.
B. Investigator Determination
When determining if an IND needs to be submitted to study marketed drugs for treating cancer,
investigators must apply the exemption criteria listed in  312.2(b)(1)(i-v) in light of the
discussion in this guidance.  Planned studies may be considered exempt from the requirements of
an IND if the studies involve a new use, dosage, schedule, route of administration, or new
combination of marketed cancer products in a patient population with cancer and the following
conditions apply:
  The studies are not intended to support FDA approval of a new indication or a significant
change in the product labeling.
  The studies are not intended to support a significant change in the advertising for the
product.
  Investigators and their IRBs determine that based on the scientific literature and
generally known clinical experience, there is no significant increase in the risk
associated with the use of the drug product.
  The studies are to be conducted in compliance with IRB and informed consent
regulations, pursuant to parts 50 and 56.
  The studies will not be used to promote unapproved indications, in compliance with 
312.7.
V. EXAMPLES OF STUDIES 
The following examples of studies are being provided to illustrate the Agency's current thinking
on the types of studies that the Agency considers to be exempt from IND regulation based on a
risk assessment.
A. Studies That Generally Are Exempt
As noted above, of the five criteria in  312.2(b)(1), four are not protocol related and one is
protocol related.  The following are examples of general categories of studies of marketed cancer
drugs that would likely be exempt from IND regulation based on protocol-related issues.
1.  Single-arm, phase 2 trials using marketed drugs to treat a cancer different from that
indicated in the approved labeling and using doses and schedules similar to those in
5 Contains Nonbinding Recommendations
the marketed drug labeling are usually exempt.  An exception may exist when
standard therapy in the population to be studied is very effective (e.g., is associated
with a survival benefit); in that case, use of another regimen may expose patients to
the risk of receiving an ineffective therapy and an IND would be necessary. 
2.  Phase 1 oncology trials of marketed drugs may be considered exempt if such therapy
is appropriate for the patient population (i.e., if patients have residual cancer) and if
there is no effective therapy (i.e., therapy producing cure or a documented increase in
survival) that the patients have not yet received.  It remains the investigators
responsibility to use starting doses that appear safe based on approved labeling or
detailed literature reports, use incremental changes in dose or schedule, and carefully
evaluate toxicity prior to dose escalation.
  
3.  The study of new combinations of drugs would not ordinarily constitute a significant
risk if these combinations have been described in the professional medical literature.
Even when the regimen described in the literature does not use exactly the doses
planned for study, incremental differences in doses from those described in the
literature would not normally pose a significant risk and would not require an IND.  
Because of the danger of synergistic toxicity (i.e., enhanced effects from the
combination) occurring with a new drug combination, if there are no data from the
literature on its safety, the initial study of a new drug combination should ordinarily
be performed under an IND.  Synergistic toxicity may be anticipated when one agent
interferes with the metabolism or elimination of the other agent; when both agents
target the same metabolic pathway or cellular function; or when one agent targets
signaling pathways that are reasonably expected to modulate sensitivity to the other
agent.  If it is determined that synergistic toxicity is likely, animal studies should be
considered for determining a safe starting dose for the drug combination in humans.
 
4.  Studies of new routes or schedules of administration not described in the approved
labeling are generally exempt if there is sufficient clinical experience described in the
literature documenting safety to determine that treatment is safe.   On the other hand,
initial experience with a new route of administration should be based on studies in
animals, and an IND should be submitted.
 
5.  Studies of  high-dose therapy in cancer patients are likely to be considered exempt if
the studies use adequately evaluated regimens that appear to have an acceptable
therapeutic ratio for the population being studied. Similarly, phase 1 studies involving
incremental changes from such well-described regimens are generally exempt.
6 Contains Nonbinding Recommendations
 
B. Studies That Generally Are Not Exempt
 
A  s noted above, of the five criteria in  312.2(b)(1), four are not protocol related and one
is protocol related.  The following are examples of general categories of studies of
marketed cancer drugs that would likely not be exempt from IND regulation because of
protocol-related issues.
 
1.  Studies of cytotoxic drugs are normally not exempt in patients for whom cytotoxic
therapy would not be considered standard therapy and would require special
justification.  Any use of cytotoxic agents in nonmalignant disease (e.g., rheumatoid
arthritis, multiple sclerosis) would, most likely, be considered to alter the
acceptability of the risk of the agent. 
2. Studies of adjuvant chemotherapy (chemotherapy given after surgery to remove
cancer) are likely not exempt for the following reasons:  
  If the population studied has a low risk of cancer recurring after surgery,
treatment with any toxic therapy may indicate a significantly increased risk.
  If standard adjuvant therapy is available and produces a survival benefit,
substitution of new therapy for standard therapy poses a significant risk that the
new therapy will not produce the same survival benefit.
  If adjuvant trials are properly designed, they usually will be able to demonstrate
whether the new therapy is safe and effective, and such results may lead to a
marketing application.  As discussed earlier, under regulations at  312.2(b)(1),
all investigations intended to support marketing of a new product indication,
significant change in product labeling, or a significant change in the advertising
for a product require an IND.  During FDA review of INDs intended to support
marketing applications, the Agency will provide feedback about the acceptability
of trial design for this purpose. 
 
3.  Studies involving substitution of a new agent of unproven activity are generally not
exempt in settings where standard therapy provides a cure or increase in survival.
For instance, in the first-line treatment of testicular cancer, ovarian cancer, breast
cancer, leukemia, and lymphoma, studies of new agents without proven efficacy
would likely not be exempt.  In this case, the critical judgment is whether it is ethical
to withhold standard therapy while testing a new agent.
4.  Studies are generally not exempt in settings where animal studies should be
conducted to determine a safe starting dose or schedule.
For example:
 
7 Contains Nonbinding Recommendations
  Initial studies of a marketed drug given by a new route of administration are
likely not exempt.
 
  Unless adequately described in the literature, initial studies of new drug
combinations should usually be performed under an IND because of the possible
occurrence of synergistic toxicity.  As noted earlier, synergistic toxicity may be
anticipated when one agent interferes with the metabolism or elimination of the
other agent; when both agents target the same metabolic pathway or cellular
function; or when one agent targets signaling pathways that are reasonably
expected to modulate sensitivity to the other agent.
  Initial studies in humans of changes in the schedule of drug administration should
generally be submitted in an IND.  Some drugs have demonstrated significantly
greater toxicity when given by an alternative schedule (e.g., methotrexate
demonstrates much more hematologic toxicity when given by prolonged
administration compared to intermittent administration). 
  Initial studies of drugs intended to be chemosensitizers, radiosensitizers, or
resistance modulators should generally be submitted in an IND.  Animal studies
should be used to estimate the effect of the modulator on toxicity and to allow
estimation of a safe starting dose in humans.
5. Studies intended to support approval of a new indication, a significant change in the
product labeling, or a significant change in advertising are not exempt 
( 312.2(b)(1)(i), (ii)). 
8