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
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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
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.
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 cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
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.
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.
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:
- The study is not intended to support FDA
approval of a new indication or a significant change in the
product labeling.
- The study is not intended to support a
significant change in the advertising for the product.
- 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.
- 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).
- 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 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.”
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.
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).
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 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)).
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 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
Agency’s 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.
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.
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.
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 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 investigator’s 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.
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 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:
·
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)).