of generally available treatment options and an explanation as to why
they are not preferable, criteria for patient selection, a description
of the patient's disease or condition (including recent medical
history), and previous treatment use (for an individual patient
submission).
    (Response) The submission requirements are sponsor requirements and
thus are intended to apply to both sponsors and sponsor-investigators.
The listing of general submission requirements in Sec.  312.305 is not
intended to convey the impression that each element of the submission
be contained in a separate document. As the comment points out, certain
required submission elements are topics that are appropriate for
inclusion in a single protocol. Other elements, such as pharmacology/
toxicology and chemistry, manufacturing, and controls (CMC), may more
typically be found in separate documentation. FDA's primary concern is
not with the number of individual documents submitted, but that the
required elements be submitted in a form that makes the information
readily accessible and leaves no question that the submission contains
the necessary information.
    a. Submissions for individual patient expanded access.
    (Comment 42) Several comments expressed concern that individual
physicians would not be able to comply with the submission requirements
for expanded access for an individual patient. The comments stated that
most individual physicians will not have access to the drug's CMC or
pharmacology and toxicology information. One comment stated that FDA
sometimes raises difficult manufacturing, pharmacology, toxicology,
pharmacokinetic, clinical, and statistical issues, and these issues
sometimes result in physicians withdrawing expanded access requests.
One comment opined that the submission requirements for individual
patient expanded access may have the unintended effect of rendering the
proposed rule relatively meaningless for the vast majority of the
patient population if there is no existing IND or if the sponsor of the
IND will not provide the information needed to support the expanded
access request. The comment added that physicians may not know whether
an IND exists or how to find that out.
    (Response) In FDA's experience, the vast majority of expanded
access INDs for individual patients are for investigational drugs in
development, and submissions are made on behalf of patients unable to
participate in clinical trials. In these situations, the submission
requirements are not onerous. The commercial sponsor that is developing
the drug may make a submission for individual patient access as a
protocol amendment to its existing IND, in which case the licensed
physician must only provide the sponsor with the required information
about the individual patient. Alternatively, the commercial sponsor may
elect only to provide the drug and require the physician to submit his
or her own IND. In this situation, the commercial sponsor routinely
permits the licensed physician to refer to any needed information in
its existing IND, so, again, the licensed physician usually only has to
provide the relevant information about the physician's patient. In each
of these scenarios, the information the licensed physician must provide
is ordinarily readily available in patient medical records.
    In rare circumstances, a licensed physician may seek to obtain
access for an individual patient to an investigational drug not being
developed. If a drug is not being developed and has never been the
subject of an IND, the submission requirements become more complex.
There may be other sources that could provide some of the necessary
information (e.g., materials data sheets) to minimize the burden on the
physician to an extent. However, FDA must have reasonable assurances
about the integrity and safety of the product, so the IND submission
will require a significant amount of information concerning the
manufacturing of the product and its pharmacology/toxicology profile
for FDA to permit use of the drug for the expanded access use. FDA's
guidance for industry entitled ``Content and Format of Investigational
New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including
Well-Characterized, Therapeutic, Biotechnology-derived Products,''
provides some insight into the amount and nature of the information
that would be required in these situations. However, because these
situations are rare, FDA does not believe that the submission
requirements present an obstacle to the vast majority of patients who
seek to obtain investigational drugs for treatment use under the
expanded access regulations, and the agency is convinced that the
requirements are an essential component of human subject protection.
    (Comment 43) Two comments expressed the view that many parts of
Form FDA 1571 may not be appropriate for use by an individual doctor
for expanded access purposes. The comments asked that FDA provide a
streamlined version of Form FDA 1571 that is specific to individual
patient expanded access. One comment recommended that FDA encourage or
require standard nomenclature on expanded access submissions so such
submissions could be readily distinguished from non-expanded access
submissions. The comment stated that for a treatment IND, the sponsor
should make two entries to Item 11 of the 1571: Check the box for
INITIAL INVESTIGATIONAL NEW DRUG APPLICATION, and enter ``OTHER:
Treatment IND'' on the blank line. For an expanded access protocol
under an existing IND, the comment suggested that the sponsor also make
two entries to Item 11 of the 1571: Check the box for PROTOCOL
AMENDMENT: NEW PROTOCOL, and enter ``OTHER: New Protocol for Expanded
Access'' on the blank line.
    (Response) FDA agrees that it is desirable to be able to readily
distinguish expanded access submissions from non-expanded access
submissions. FDA does not believe, however, that a new form specific to
expanded access is necessary to accomplish this task. FDA believes that
instructions for filling out Form FDA 1571 for expanded access purposes
and standardized nomenclature will suffice, helping sponsors to
complete the form appropriately and helping FDA to readily identify
expanded access submissions. FDA may develop guidance to provide
instructions for completing Form FDA 1571 and sample completed forms
for each type of expanded access.
    b. Intermediate-size population IND submission requirements.
    In addition to the general submission requirements, proposed Sec.
312.315(c) describes requirements specifically applicable to
submissions for intermediate-size population expanded access INDs.
Proposed Sec.  312.315(c)(1) requires that the submission state whether
the drug is being developed or not being developed. For a drug not
being developed, proposed Sec.  312.315(c)(2) requires that the sponsor

explain why the drug cannot currently be developed and under what
circumstances the drug could be developed.
    (Comment 44) One comment requested that the requirements in
proposed Sec.  312.315(c)(2) and (c)(3) be removed because they do not
seem relevant to the determination of whether access is appropriate for
the intermediate-size group.
    (Response) FDA disagrees. One of FDA's primary concerns with making
investigational drugs available for treatment use is the potential for
treatment use to prevent the development of information necessary to
demonstrate safety and effectiveness by usurping a population that
could have been enrolled in a clinical trial. FDA believes that section
561 of the act contemplates that expanded access to investigational
drugs is not appropriate when that access prevents the development of
important safety and effectiveness information that could have been
developed if there were no expanded access. Requiring a sponsor to
explain why no development is possible when a drug is not being
developed at all, or why a clinical trial cannot be conducted to study
the treatment use when a drug is being developed for a use other than
the treatment use, squarely addresses FDA's concerns.
    (Comment 45) One comment recommended that before concluding that a
patient or patient population is ineligible to enroll in a clinical
trial for purposes of this requirement, the investigator, sponsor, and
FDA should carefully consider whether the clinical study protocol could
be amended to include the patient population contemplated for treatment
use without affecting the safety of the subjects or the integrity of
the study.
    (Response) FDA agrees that the optimal solution would be to somehow
incorporate the potential intermediate-size treatment use population in
an ongoing clinical trial by modifying the inclusion/exclusion criteria
while not compromising safety or study integrity, or to enroll that
population in a new study. FDA expects that sponsors would have
explored all reasonably possible avenues for studying the patient
population before seeking an expanded access IND for treatment use in
that population and that the submission would explain why those avenues
were foreclosed. By requiring the sponsor to explain why the population
for which an intermediate-size expanded access IND is sought is not
eligible to be enrolled in a clinical trial, FDA is encouraging, at
least implicitly, this thought process.
    (Comment 46) One comment asked where in the electronic common
technical document (eCTD) to include the submission information that is
specific to intermediate-size patient population INDs.
    (Response) The eCTD does not distinguish INDs of different-size
patient populations. The information specific to an intermediate-size
patient population IND would go in the same location as one for a
treatment IND or a single patient treatment IND.
5. Safeguards for Expanded Access
    Proposed Sec.  312.305(c) explains how the responsibilities of
sponsors and investigators set forth in subpart D (Responsibilities of
Sponsors and Investigators) of part 312 apply to expanded access INDs.
Proposed Sec.  312.305(c)(1) states that a licensed physician under
whose immediate direction an investigational drug is administered or
dispensed for expanded access use is considered an investigator for
purposes of part 312 and, therefore, must comply with the
responsibilities for investigators set forth in subpart D to the extent
they are applicable to the expanded access use. Proposed Sec.
312.305(c)(2) states that an individual or entity that submits an
expanded access IND or protocol under subpart I is considered a sponsor
for purposes of part 312 and must comply with the responsibilities for
sponsors set forth in subpart D to the extent they are applicable to
the expanded access use. Proposed Sec.  312.305(c)(3) states that a
licensed physician under whose direction an investigational drug is
administered or dispensed, and who submits an expanded access IND, is
considered a sponsor-investigator and must comply with the
responsibilities of sponsors and investigators in subpart D to the
extent applicable to the expanded access use.
    Proposed Sec.  312.305(c)(4) provides that for all expanded access
INDs, investigators are responsible for reporting adverse events to the
sponsor, ensuring that the informed consent requirements in part 50 (21
CFR part 50) are met, ensuring that an IRB review of the expanded
access use is obtained in a manner consistent with the requirements of
part 56 (21 CFR part 56), and maintaining accurate case histories and
drug disposition records and retaining records in a manner consistent
with the requirements of Sec.  312.62.
    a. ``Person'' v. ``individual or entity.''
    (Comment 47) One comment recommended that proposed Sec.
312.305(c)(2) (which states that an individual or entity that submits
an expanded access IND or protocol under subpart I is considered a
sponsor for purposes of part 312) use the term ``person'' rather than
``individual or entity.'' The comment pointed out that ``person'' is
defined in the act and includes ``individual, partnership, corporation,
and association.''
    (Response) The term ``individual or entity'' is based on, and
intended to be shorthand for, language in the definition of a
``sponsor'' in Sec.  312.3(b) that states that a sponsor may be an
``individual or pharmaceutical company, governmental agency, academic
institution, private organization, or other organization.'' Because the
term relates to an existing definition of sponsor in the IND
regulations, and because in FDA's experience that definition has been
clear and effective in describing who or what may be considered a
sponsor for purposes of part 312, FDA prefers to retain the language in
the proposed rule.
    b. Sponsor and investigator responsibilities.
    Proposed Sec.  312.305(c)(5) provides that for all expanded access
INDs, sponsors are responsible for submitting IND safety reports and
annual reports (when the IND or protocol continues for 1 year or
longer) to FDA as required by Sec. Sec.  312.32 and 312.33, ensuring
that licensed physicians are qualified to administer the
investigational drug for expanded access use, providing licensed
physicians with the information needed to minimize the risk and
maximize the potential benefits of the investigational drug (e.g.,
providing the investigator's brochure if there is one), maintaining an
effective IND for the expanded access use, and maintaining adequate
drug disposition records and retaining records in a manner consistent
with the requirements of Sec.  312.57.
    Proposed Sec.  312.310(c)(3) further provides that FDA may also
require sponsors to monitor an individual patient expanded access use
if the use is for an extended duration. Proposed Sec.  312.315(d)(2)
states that the sponsor is responsible for monitoring the intermediate-
size population expanded access protocol to ensure that licensed
physicians comply with the protocol and the regulations applicable to
investigators. Proposed Sec.  312.320(c) states that the sponsor is
responsible for monitoring the treatment protocol to ensure that
licensed physicians comply with the protocol and the regulations
applicable to investigators.
    (Comment 48) One comment stated that making physicians
investigators for purposes of part 312 will be daunting and extremely
time-consuming and that the typical gastroenterologist not affiliated
with a large teaching or

research hospital will not be able to satisfy these requirements.
    (Response) FDA disagrees. For a licensed physician providing access
under an individual patient IND, the responsibilities of an
investigator closely parallel those necessary for providing routine
patient care. For example, the information about a patient that a
physician is required to submit to obtain an IND would usually be
derived from the patient history and progress notes. In most cases, the
remaining IND submission requirements would be largely satisfied by
obtaining a right of reference to an IND maintained by a commercial
sponsor, which is usually easily obtained. Any required monitoring of
the course of treatment with the investigational drug would be similar
to the type of monitoring provided as part of routine patient care. The
patient outcomes information required to be submitted after treatment
with the investigational drug would closely parallel the content of a
typical discharge summary. Therefore, FDA believes that, in most cases,
the IND obligations imposed on licensed physicians by this final rule
would not be significantly more burdensome than the recordkeeping and
patient evaluation required in the course of routine clinical care of a
patient.
    c. Adverse event reporting.
    (Comment 49) One comment from a pharmaceutical company asked
whether licensed physicians who obtain an investigational drug for
expanded access use under their own INDs are required to report adverse
events to both the pharmaceutical company supplying the drug and FDA.
The comment maintained that it is important for the pharmaceutical
company developing the drug to be informed of any adverse events
observed in expanded access use.
    (Response) Because the physician IND holder is both investigator
and sponsor in this scenario, the physician is not required by the IND
regulations to report adverse events to the drug manufacturer who
provided the drug to the physician. The regulations require only that
adverse events observed by the investigator (the physician) be reported
to the sponsor, who is also the physician in this scenario. The
physician, in his or her capacity as a sponsor, is required to report
adverse events to FDA and other investigators (not relevant for
individual patient access), including reporting of serious and
unexpected adverse events in an expedited manner. However, although
there is no regulatory provision that would require physicians to
report adverse events to the drug manufacturer/supplier, FDA sees no
obstacle to the drug manufacturer/supplier requiring, as a condition of
making the drug available to the physician, that the physician agree to
provide the drug manufacturer/supplier with copies of all adverse event
reports provided to FDA.
    In addition, in the preamble to the proposed rule (71 FR 75147 at
75153), FDA expressed a strong preference for having commercial
sponsors make investigational drugs available for treatment use under
amendments to their INDs rather than requiring physicians to obtain
their own INDs. In that scenario, the physician is required to report
adverse events to the commercial sponsor under Sec.  312.64.
    (Comment 50) One comment suggested that adverse events for
individual patient INDs should be addressed in a separate section of
the NDA or biologics license application (BLA) instead of being
included in the integrated summary of safety. The comment stated that
this approach would help alleviate manufacturers' concerns that
allowing individual patient INDs (typically involving especially sick
patients) would exaggerate adverse events for the broader population.
    (Response) FDA does not believe it is necessary or helpful to
exclude adverse events information from individual patient INDs from
the integrated summary of safety (ISS) in an NDA. The ISS is intended
to evaluate adverse events information from the total population
exposed to a drug. The analysis takes into account the relative
strength of the data and the characteristics of subjects who
experienced adverse events that may bear on causality. For example,
data indicating that an adverse event occurred in multiple subjects in
the drug treatment arm of a controlled trial is much more reliable than
adverse events information from uncontrolled, individual patient
expanded access exposures in patients who are very ill. The implication
that inclusion of adverse events information from individual patient
expanded access exposures over-emphasizes negative safety information
is unfounded and plainly inconsistent with the methodology FDA uses to
analyze drug safety.
    (Comment 51) Two comments stated that, for investigational new
molecular entities, adverse event reporting for expanded access use
should be limited to serious adverse events and deaths unless there are
specific adverse events that are identified a priori because they are
related to an identified safety concern that may affect the risk-
benefit assessment.
    (Response) FDA strongly disagrees. FDA believes that all adverse
events identified in expanded access uses should be reported to FDA in
the manner described in Sec. Sec.  312.32 and 312.33. FDA's primary
interest is the expedited reporting of serious and unexpected events as
required by Sec.  312.32(c). Data collected on nonserious or expected
events from expanded access use, in particular from exposure of an
individual patient or small number of patients to a drug, is not as
useful as data collected from controlled trials that may identity
differences in event rates across treatment groups (e.g., control
group, across different doses). Nonetheless, information from expanded
access exposures on these types of adverse events can still contribute
to the safety assessment of a new molecular entity (e.g., corroborate
observations in other settings). In general, FDA believes it is
important that a drug's safety assessment consider adverse events
observed in the entire population exposed to a drug.
    (Comment 52) One comment inquired about how to report adverse
events for approved drugs made available under an expanded access IND.
    (Response) For an approved drug made available under an expanded
access IND (e.g., in a circumstance in which an approved drug is
subject to a restricted distribution agreement that limits prescribing
to a certain disease or condition, and a patient is seeking access to
the drug for another use), adverse events must be reported to FDA under
the IND in accordance with Sec.  312.305(c)(5).
    d. Obtaining Informed Consent for Expanded Access Use.
    (Comment 53) Many comments from individual consumers stated that it
is particularly important for patients receiving investigational drugs
in expanded access programs to receive full disclosure of the risks,
and to fully understand the risks, associated with the investigational
therapy. Two comments were very concerned that patients receiving
investigational drugs for treatment use not be misled about the
likelihood that the treatment will be beneficial. One comment stated
that many patients are led to believe that access to an investigational
intervention is their best hope, but often it is a false hope. Another
comment stated that patients with immediately life-threatening
conditions are extremely vulnerable and may not fully comprehend the
information they are provided about a drug by health care

practitioners. Another comment recommended that FDA provide guidance on
how to obtain informed consent from patients who are candidates to
receive an investigational drug for treatment use.
    (Response) FDA agrees that patients who are candidates to receive
investigational drugs under expanded access programs, because they have
serious or immediately life-threatening diseases or conditions and have
exhausted other treatment options, are a particularly vulnerable
population. Therefore, they should be afforded a rigorous informed
consent process that effectively communicates the risks and potential
benefits of any investigational therapy to be used for treatment use in
a way that does not raise false expectations about a positive outcome
from treatment and makes clear what is unknown about the drug. Because
of the vulnerable nature of expanded access patients, FDA encourages
submission of informed consent documents intended to be used for
expanded access programs to FDA for review. FDA will also consider
whether guidance on how to obtain informed consent from such patients
is needed.
    (Comment 54) One comment stated that because expanded access does
not technically involve ``research'' or a ``clinical investigation,''
the requirements and principles for obtaining the informed consent of
subjects participating in clinical investigations in part 50 may not
adequately address the range of issues that would arise in obtaining
the informed consent of patients receiving investigational drugs under
expanded access programs. The comment recommended that the expanded
access regulations include requirements concerning the specific
information that must be included in informed consent documents for
expanded access programs.
    (Response) Again, because of the vulnerable nature of the typical
patient or population to receive an investigational drug under an
expanded access program, FDA agrees that patients in expanded access
programs should be afforded a rigorous informed consent process
tailored to the unique issues that arise in the expanded access
context. FDA does not believe, however, that it is necessary to add
specific informed consent requirements to the expanded access
regulations or to amend the informed consent regulations to incorporate
specific requirements for expanded access. FDA believes that existing
informed consent regulations adequately address the range of issues
relevant to informed consent for expanded access problems, in
particular issues concerning informed consent in vulnerable populations
(see, e.g., parts 50 and 56).
    (Comment 55) One comment stated that informed consent documents
must reflect that patients cannot expect to personally benefit from the
drug, but that the knowledge gained from the experiment will help other
patients in the future.
    (Response) FDA disagrees. The comment seems to misunderstand the
overarching purpose of expanded access--to make investigational drugs
available for treatment purposes to patients with serious or
immediately life-threatening diseases or conditions and with no other
treatment options because the investigational drugs could conceivably
benefit these patients--not to systematically investigate the use of
the drug for the disease or condition. Treatment use under an expanded
access mechanism, in contrast to evaluation of an investigational drug
in a clinical trial, is not intended primarily to develop data that
could be used to benefit future patients. However, as FDA made clear in
response to comment 54, patients receiving investigational drugs for
treatment use should be afforded a rigorous informed consent process
that is careful not to overstate the expected benefits of the
investigational drug and is otherwise cognizant of the inherent
vulnerabilities and information needs of patients seeking access to
investigational drugs for treatment use.
    (Comment 56) One comment recommended that before an IRB can be
allowed to review expanded access programs, FDA should require the IRB
to establish special criteria to ensure that physicians have discussed
all treatment options with patients as part of the informed consent
process and that patients and their families fully understand the
experimental and investigational nature of a drug or other therapy, the
types and degrees of unknown risks, and the potential positive and
negative health outcomes.
    (Response) Because patients seeking access to investigational drugs
for treatment use are a particularly vulnerable group and the intent is
treatment of a disease or condition, as opposed to a clinical
investigation of the use, FDA believes it is important for IRB review
to be particularly sensitive to the unique issues raised by use of
investigational drugs in expanded access programs. FDA agrees that it
would be useful for an IRB that is likely to review expanded access use
to be familiar with the nature of expanded access protocols, the rules
and processes related to obtaining access, and the particular concerns
related to obtaining informed consent from patients receiving
investigational drugs for treatment use. FDA does not believe, however,
that it is necessary to require in regulation that IRBs have special
processes and procedures for reviewing expanded access protocols.
Existing regulations already require IRBs to consider the vulnerable
nature of the population that will receive an investigational drug and
to ensure that risks are minimized (which would necessarily involve
some consideration of whether there are any lower-risk treatment
options), and Sec.  50.25(a)(4) requires that an informed consent
disclose appropriate alternative procedures or courses of treatment, if
any, that might be advantageous to the subject.
    (Comment 57) One comment stated that a patient receiving expanded
access should be competent to give informed consent.
    (Response) While FDA agrees that valid informed consent is a
necessary prerequisite to receiving an investigational product in an
expanded access setting, FDA does not agree that access to
investigational drugs under expanded access programs should be limited
to only those who are competent to give their own informed consent, if
that is the intended implication of the comment. FDA's regulations
concerning protection of human subjects informed consent (part 50)
recognize that a subject may not be competent to give informed consent
and that valid informed consent may be given by the subject's legally
authorized representative. Section 50.20 defines ``legally authorized
representative'' as an individual or judicial or other body authorized
under applicable law to consent on behalf of a prospective subject to
the subject's participation in the procedure(s) involved in the
research. The same definition should apply to treatment with an
investigational product under an expanded access program.
    (Comment 58) One comment recommended requiring that IRBs establish
criteria for the length and readability of informed consent documents.
    (Response) This comment is beyond the scope of this rule. The rule
does not address the requirements on IRBs and the comment raises a
concern broader than expanded access.
    e. IRB review of expanded access use.
    (Comment 59) Some comments were concerned that the requirement for
IRB review was a potential obstacle to making investigational drugs
available

for treatment use under expanded access INDs, particularly for
individual patient INDs. One comment maintained that the IRB review
process is slow, tedious, cumbersome, and requires too much
documentation, and that physicians are not familiar with the IRB
process. The comment suggested that some type of centralized IRB may be
needed for small- to medium-sized access programs. Another comment
noted that in academic research settings, there is intensive IRB
approval and oversight, and recommended that FDA explore standardizing
expanded access program protocols so that some of the administrative
work, in particular IRB submissions, can be lessened. One comment
recommended that, for individual patient expanded access INDs, FDA
reduce or limit the scope of the requirement for IRB review because of
the time, difficulty, and, in some cases, the expense (e.g., when a
commercial IRB must be used) of obtaining IRB review. The comment
recommended that FDA permit review by a subset of the full IRB or waive
IRB review if a drug has completed phase 1 safety testing (see response
to comment 60 for discussion of why waiver of IRB review is not a
viable option).
    (Response) FDA recognizes that there are circumstances in which IRB
review for an expanded access use, particularly an individual patient
use, may be difficult to obtain because an institution's IRB cannot or
will not provide a timely review or because the hospital or other
clinical setting does not have an affiliated IRB. FDA recommends that
IRBs affiliated with institutions that are likely to have patients
seeking access to investigational drugs for treatment use under
individual patient access INDs consider establishing processes or
procedures to facilitate timely IRB review of these INDs. In addition,
use of centralized IRB review and other cooperative arrangements could
facilitate IRB review at these institutions as well as in settings that
are not affiliated with IRBs. FDA fully supports centralized IRB review
under appropriate circumstances and encourages sponsors to help make
this option available where possible. FDA believes these mechanisms
could ease the burdens associated with obtaining IRB review of
individual patient INDs and limit the need to rely on commercial INDs.
Therefore, FDA is not persuaded that obtaining IRB review is an
excessive burden and potential obstacle to obtaining access to
investigational therapies under expanded access INDs.
    FDA does not believe that current regulations provide authority for
IRB review of individual patient expanded access INDs by less than the
full IRB. The IRB regulations provide for expedited review--under which
an IRB review may be done by only one or a small number of IRB
members--of new INDs or protocols only under minimal risk situations
(Sec.  56.110(b)). Use of an investigational drug for treatment
purposes would not be considered minimal risk and, therefore, does not
meet the criteria for expedited review. Revising the IRB regulations to
provide for a more limited IRB review of individual patient expanded
access INDs involves significant human subject protections issues that
were not considered in this rulemaking and, therefore, such revision is
beyond the scope of this rulemaking.
    (Comment 60) One comment stated that FDA should eliminate the
proposed requirements for IRB review and obtaining informed consent for
individual patient treatment use INDs. The comment maintained that the
use of an investigational drug for treatment use is not part of a
clinical investigation and therefore beyond the intended scope of parts
56 and 50. The comment further argued that these safeguards are
unnecessary for individual patient treatment use because there is an
established physician-patient relationship and, therefore, individual
patient treatment use is analogous to the physician-patient
relationship in a typical clinical setting in which such safeguards are
unnecessary.
    (Response) FDA does not agree that it lacks legal authority to
require IRB review and informed consent for individual patient expanded
access use or any other expanded access use. Expanded access use
involves administration of unapproved products that have not yet been
shown to be safe and effective, and raises sufficiently similar
concerns to clinical research that informed consent and IRB review are
warranted. Moreover, section 561 of the act contains numerous
references to ``conditions determined by the Secretary'' and to
protocol compliance with ``regulations promulgated under section
505(i)'' (which include informed consent and IRB regulations),
indicating that Congress intended FDA to require conditions such as
informed consent and IRB review, consistent with FDA's long-standing
practice regarding treatment use with investigational products. In
addition, FDA strongly believes that recipients of investigational
products under any type of expanded access IND should be afforded the
same human subject protections provided clinical trial participants by
the IRB review process. FDA equally strongly believes that all patients
considering treatment with an investigational therapy under an expanded
access IND should be fully informed about the risks and potential
benefits of the experimental therapy, including disclosure that safety
and effectiveness have not been established, and give their informed
consent prior to being treated with an investigational therapy.
Patients seeking access to investigational therapies under expanded
access programs often are in somewhat dire clinical circumstances and
thus are a particularly vulnerable population. Therefore, such patients
are, arguably, even more in need of the human subjects protections
provided by IRB review and informed consent than many clinical trial
participants.
    (Comment 61) One comment recommended the elimination of the
requirements for prior IRB review and approval in accordance with part
56 and the requirement for written informed consent in accordance with
part 50 for individual patient expanded access use (but recommended the
retention of these requirements for intermediate-size population and
treatment INDs). The comment argued that use of an investigational drug
for the emergency treatment of individual patients is not part of a
clinical investigation and thus is not consistent with the scope of
parts 50 and 56. The comment stated that eliminating the requirement
would solve problems and avoid confusion related to differences between
FDA's IRB regulations and IRB regulations applicable to Federal
agencies and grantees under 45 CFR part 46 (the so-called ``Common
Rule''). Current FDA regulations (Sec. Sec.  56.104(c) and 50.23) allow
for the emergency use of an investigational drug without prospective
IRB review and approval and a waiver of the requirement for prospective
informed consent of the involved patient-subject, but the Common Rule
specifies that all research involving human subjects must be
prospectively reviewed and approved by a convened IRB committee (with
the exception of certain minimal risk categories of research, which do
not include expanded access use). The comment maintained that the
Common Rule applies unless the requested emergency use is considered
``treatment'' rather than ``research'' and thus is not subject to prior
IRB review and approval under the Common Rule. The comment maintained
that prior FDA review of individual patient expanded access would
suffice to ensure patient safety

and compliance with the protocol and applicable regulations.
    (Response) Although FDA agrees that it is accurate to characterize
the use as ``expanded access'' or ``treatment use'' rather than a
``clinical investigation'' of the drug, which places individual patient
INDs outside the scope of the Common Rule, FDA disagrees that prior FDA
review, without additional review by a qualified third party, provides
adequate safeguards. The types of patients that would typically be
eligible to obtain investigational drugs under expanded access programs
are vulnerable and have somewhat desperate clinical circumstances and,
therefore, are in particular need of the protections afforded by IRB
review and the informed consent process. FDA acknowledges that in
emergency situations involving individual patient access, there is not
always prospective IRB review. However, FDA believes that some type of
retrospective IRB review is still important in most cases, especially
if treatment with the investigational drug is ongoing. FDA also
believes that informed consent is an important element of any treatment
use, even in emergency situations. From a medical ethics perspective,
the need for informed consent increases with the seriousness of the
disease or condition and the exigency of the clinical situation, so it
would be all the more important in emergency situations with individual
patients. The purported advantages of eliminating any prospective
third-party IRB review and informed consent are not enough to offset
the potential harm.
    f. Investigator reporting responsibilities for individual patient
INDs.
    Proposed Sec.  312.310(c)(2) states that ``at the conclusion of
treatment, the licensed physician or sponsor must provide a summary of
the results of the expanded access use, including unexpected adverse
effects.''
    (Comment 62) One comment recommended that the licensed physician be
required to provide a summary of ``all adverse effects possibly related
to the investigational drug'' rather than only ``unexpected adverse
effects.'' The comment stated that it is likely that many private
practice physicians requesting expanded access for the emergency
treatment of their individual patients will not be familiar with all of
the current information related to the adverse event profile of the
investigational drug and/or FDA's regulatory definition of ``unexpected
adverse effects.'' The comment added that requiring physicians to
report all adverse effects possibly related to the investigational drug
would be consistent with the investigator reporting requirements in
Sec.  312.64(b).
    (Response) FDA agrees that the licensed physician may be unaware of
what events are expected or unexpected and, therefore, should be
required to include information on all observed adverse events.
Therefore, section 312.310(c)(2) has been revised to state that at the
conclusion of treatment, the licensed physician or sponsor must provide
FDA with a written summary of the results of the expanded access use,
including adverse effects.
    (Comment 63) One comment stated that adverse event reporting for
expanded access use should take advantage of technological
modernization in adverse event reporting, such as by using a
centralized electronic database. The comment stated that such a
database could provide access to basic tabulation and analysis of the
voluminous serious adverse event reports that, in their present form,
are virtually useless to individual site investigators and site IRBs.
    (Response) FDA has no plans to implement an electronic data capture
and analysis system for adverse events that is devoted exclusively to
adverse events observed during expanded access use. FDA is actively
involved in efforts to develop and implement electronic data systems
for adverse event reporting generally, for both pre- and postmarketing
adverse event reporting. FDA believes these systems will also
contribute to improved data collection and analysis of adverse events
information obtained from exposure to investigational drugs in expanded
access programs.
    g. Qualifications of licensed physicians to participate in expanded
access.
    Proposed Sec.  312.305(c)(5) requires, among other things, that
sponsors ensure that licensed physicians participating in expanded
access programs are qualified to administer the investigational drug
for the expanded access use.
    (Comment 64) One comment recommended that FDA revise Sec.
312.305(c)(5) to state: ``In general any licensed physician may
participate in an expanded access protocol. Additional specific
qualifications may be necessary in some situations.'' The comment
recommended that FDA clarify its expectations about investigator
qualifications for expanded access programs to reduce the burden for
sponsors and facilitate broader physician participation in expanded
access programs.
    (Response) FDA does not believe the recommended language is
necessary or desirable. Section 312.305(c)(5) requires simply that
sponsors assure themselves that the licensed physicians who will be
participating in an expanded access program are qualified to administer
the drug for the expanded access use. FDA believes the requirement
concerning the qualifications of the licensed physician-investigator is
narrowly focused on the most germane issue--whether the physician is
qualified to administer the drug for the expanded access use. FDA
believes the language proposed in the comment minimizes the
qualifications of the licensed physician to too great an extent because
it eliminates even the cursory inquiry as to whether the physician is
qualified to administer the drug.
    h. Investigator's brochure.
    Proposed Sec.  312.305(c)(5) also requires the sponsor to provide
the licensed physician with information needed to minimize the risk and
maximize the potential benefits of the investigational drug, including
``providing the investigator brochure, if there is one.''
    (Comment 65) One comment requested that this language be revised to
state that the sponsor provide the investigator's brochure ``if
required under Sec.  312.55 (Informing investigators).''
    (Response) FDA does not agree with the proposed change because it
would appear to narrow the circumstances in which a sponsor would be
required to provide an investigator's brochure. It could be interpreted
as requiring that a sponsor make the investigator's brochure available
only if the treatment use is the same use as is being developed (i.e.,
the use for which the investigator's brochure was written). FDA
believes that the investigator's brochure would typically contain
information that would be important for any proposed use of the
investigational drug (e.g., information about adverse events associated
with use of the drug) and, therefore, should be made available by the
sponsor to licensed physicians in an expanded access program whenever
an investigator's brochure exists. To more accurately express this
intent, FDA has revised the provision in the final rule to state as
follows: ``In all expanded access cases, sponsors are responsible for *
* * providing licensed physicians with the information needed to
minimize the risk and maximize the potential benefits of the
investigational drug (the investigator's brochure must be provided if
one exists for the drug) * * *''

    i. Monitoring of expanded access INDs.
    The proposed rule makes the sponsor responsible for monitoring of
expanded access INDs or protocols. Proposed Sec.  312.305(c)(2) states
that an individual or entity that submits an expanded access protocol
or IND is a sponsor for purposes of part 312 and, therefore, must
comply with the responsibilities for sponsors concerning the oversight
of clinical investigations in subpart D of part 312, including
monitoring of ongoing protocols (Sec.  312.56). Proposed Sec.
312.310(c)(3) provides that FDA may require sponsors to monitor an
individual patient expanded access use if the use is for an extended
duration.
    (Comment 66) One comment maintained that the requirement that
sponsors monitor the conduct of individual patient expanded access
protocols is impractical and burdensome and should be eliminated.
Another comment objected to the requirement to monitor individual
expanded access when the use is for an extended duration. The comment
stated that this provision inappropriately interfered with the patient-
physician relationship and implied that the individual physician may be
incapable of monitoring the patient for an extended duration.
    (Response) FDA does not believe the provision that gives FDA the
option to require monitoring for an individual patient access protocol
of extended duration is overly burdensome or impractical. The provision
is intended to provide the option to monitor for relatively long-term
use, such as chronic open-ended use that is likely to continue for many
months. In FDA's experience, the majority of individual patient
treatment uses do not go on for an extended duration, so the number of
instances in which FDA is likely to require monitoring is small.
Moreover, uses that go on for an extended duration are likely to have
greater potential risk and, therefore, warrant higher scrutiny. Also,
the monitoring need not be resource-intensive. Guidance concerning
acceptable monitoring practice in the International Conference on
Harmonisation guidance document entitled ``E6 Good Clinical Practice:
Consolidated Guideline'' provides that the sponsor should determine the
extent and nature of monitoring needed based on considerations such as
the objective, purpose, design, complexity, blinding, size, and
endpoints of the trial. These factors are either absent from an
extended duration individual patient treatment use or favor low-
intensity monitoring (e.g., n = 1), so minimal monitoring would likely
suffice (e.g., may not need onsite monitoring). Therefore, it is
reasonable to require monitoring for individual patient protocols of
extended duration and necessary for appropriate patient protection.
    (Comment 67) Two comments questioned why an industry sponsor should
be required to monitor an individual patient IND when the licensed
physician holds the IND.
    (Response) Where the licensed physician is the IND holder for an
individual patient expanded access IND, as opposed to the entity that
is providing the investigational drug for the expanded access use, the
entity providing the drug is not a sponsor with respect to that IND
and, therefore, has no sponsor responsibilities under part 312.
    Proposed Sec.  312.315(d)(2) provides that the sponsor is
responsible for monitoring the conduct of an intermediate-size patient
population access protocol to ensure that licensed physicians who are
providing the drug to their patients are complying with the protocol
and applicable regulations.
    (Comment 68) One comment requested that FDA eliminate the
requirement for sponsor monitoring of intermediate-size access
programs. The comment urged FDA to replace the monitoring requirement
with additional information about the criteria for selection of
investigators, the method for data collection by investigators, the
circumstances under which a commercial IRB might be used to provide IRB
oversight for investigators who practice in a setting without an IRB
(and also in settings that have an IRB), and the sponsor's prospective
plan for demonstrating due diligence in obtaining data from
investigators.
    (Response) FDA does not believe that the provisions the comment
suggests adding to the intermediate-size patient population IND
submission are adequate to replace real-time monitoring intended to
determine whether investigators are complying with the protocol and
their investigator responsibilities. FDA believes such monitoring is
important to ensure appropriate use of the investigational drug and
patient safety.
6. Issues Specific to Individual Patients, Including Emergency Use
    (Comment 69) One comment recommended that FDA change the name of
this expanded access category from ``individual patients, including for
emergency use'' to ``individually identified patients for treatment
use, including for emergency use'' to make it clear that this expanded
access category is limited to the use of an investigational drug in an
established physician-patient relationship.
    (Response) FDA does not believe the name of the category needs to
be changed. In FDA's experience, individual patient treatment use
arises in the context of an established physician-patient relationship,
so FDA does not think that point needs clarification. Moreover, FDA is
uncertain how the recommended name change would clarify that issue.
    Proposed Sec.  312.310(a)(1) states that a licensed physician
seeking to obtain an investigational drug for treatment use for a
patient must determine that the probable risk to the person from the
investigational drug is not greater than the probable risk from the
disease or condition. FDA must also determine that the potential
patient benefit justifies the potential risks of the treatment use and
those potential risks are not unreasonable in the context of the
disease or condition (proposed Sec.  312.305(a)(2)).
    (Comment 70) Some comments were concerned that the licensed
physician would typically lack sufficient information about an
investigational drug to make an informed decision about the risk to the
patient from the investigational drug versus the risk from the disease
or condition. One comment stated that the very nature of experimental
drugs limits patients' and physicians' abilities to know and fully
understand the risks and benefits of a particular drug. One comment
maintained that it is also unlikely there would be any published
literature or other sources of information available to physicians for
drugs that are early in development. To address this problem, the
comment requested that FDA revise the final rule to include a
requirement that FDA provide information to the medical profession and
patient advocacy organizations about the availability of
investigational drugs for expanded access, including a full accounting
of the scientific evidence supporting expanded access uses.
    (Response) The requirement that the licensed physician determine
that the probable risk to the person from the investigational drug is
not greater than the probable risk from the disease or condition
originates in Congress's mandate in FDAMA to expand access to
investigational drugs for treatment use (section 561(b)(1) of the act)
and is intended to provide greater autonomy to individual patients and
their physicians in decisions about expanded access use. The underlying
premise of the requirement is that physicians know more about the
clinical situations of

their patients than does FDA and, therefore, should have considerable
input into the assessment of risks and benefits. FDA acknowledges that
there is often limited information available to physicians about the
risks and benefits of an investigational drug and no practical way to
provide the physician the information at FDA's disposal (information is
typically proprietary and generally can only be disclosed to a member
of the public on consent of the commercial sponsor).
    That the physician will often have limited information does not,
however, make access to investigational drugs for individual patients
inherently dangerous. In these situations, in addition to the licensed
physician's determination, FDA must determine that the potential
benefit to the patient justifies the potential risks of the treatment
use and that those potential risks are not unreasonable in the context
of the disease or condition to be treated. FDA has access to
considerably more information about the investigational drug and can
evaluate the potential benefits and risks of the therapy in light of
the information provided by the physician about risks and benefits in
relation to the individual patient's condition. FDA believes that its
knowledge of the drug combined with the licensed physician's knowledge
of the patient's clinical condition will lead to expanded access
decisions for individual patients that are in the best interests of
those patients.
    Proposed Sec.  312.310(a)(2) states that FDA must determine that
the individual patient for whom expanded access use is sought cannot
obtain the drug under another type of IND or protocol.
    (Comment 71) One comment recommended that the word ``type'' be
deleted from the language in Sec.  312.310(a)(2) that ``FDA must
determine that the patient cannot obtain the drug under another type of
IND or protocol.''
    (Response) FDA agrees that the intent of Sec.  312.310(a) is
accurately conveyed when the words ``type of'' are omitted and has
revised the provision accordingly.
    Section 312.310(c)(1) of the proposed rule states: ``Treatment is
generally limited to a single course of therapy for a specified
duration unless FDA expressly authorizes multiple courses or chronic
therapy.''
    (Comment 72) One comment recommended that the final rule describe
submission requirements and processes to extend the treatment use in
those instances where the initial authorization was for a single course
of therapy, but additional courses are warranted.
    (Response) FDA does not believe it is necessary to describe in the
regulations specific requirements and processes for submissions to
extend an expanded access treatment for an individual patient. FDA
anticipates that, in most cases, the submission would require a minimal
amount of information to demonstrate that the criteria for the expanded
access use continue to be met and would focus primarily on the response
to treatment to date, including any adverse events.
    (Comment 73) One comment stated that the proposed rule's
requirement that the duration of an individual patient treatment use
generally be limited to a single course of therapy unless FDA expressly
authorizes multiple courses or chronic therapy usurps the physician's
role, restricts access, and therefore should be eliminated.
    (Response) FDA disagrees. This rule provides for treatment use of
an investigational drug in a vulnerable population, often on the basis
of very little information about effectiveness and safety. To fairly
weigh the risks and benefits of an investigational drug for use in this
setting, FDA believes there has to be a clear understanding between the
treating physician and FDA about the planned course of therapy. For
example, to fairly evaluate the risks, it will usually be necessary to
consider the planned dose and duration of therapy in relation to what
is known about the occurrence of toxicity for that dose and duration of
therapy. For the same reason, it will usually be necessary to consider
the extent of prior exposure and the planned duration of subsequent
therapy before authorizing additional courses of an investigational
drug beyond the original treatment plan. Therefore, FDA does not
believe it is reasonable or wise to authorize access of unspecified
duration at the discretion of the treating physician. FDA also does not
believe this provision unreasonably restricts access. FDA believes that
subsequent courses of therapy will routinely be permitted where
appropriate.
    Proposed Sec.  312.310(c)(2) requires, among other things, that
``the licensed physician or sponsor must provide a written summary of
the results of the expanded access use.''
    (Comment 74) One comment stated that the proposed rule should make
clear to whom--presumably FDA--the written summary of the results of
treatment use must be submitted.
    (Response) FDA agrees. The written summary should be submitted to
FDA, specifically to the IND. FDA has revised the language to clarify
who should receive this summary as follows: ``At the conclusion of
treatment, the licensed physician or sponsor must provide FDA with a
written summary of the results of the expanded access use, including
adverse effects.''
    Proposed Sec.  312.310(c)(4) provides that when a significant
number of similar individual patient expanded access requests have been
submitted, FDA may ask the sponsor to submit an IND or protocol for the
use under Sec.  312.315 or Sec.  312.320.
    (Comment 75) One comment objected to this provision because it may
increase the amount of time it takes for an individual to obtain access
and, because there is a higher evidentiary standard for authorizing an
intermediate-size population IND than for an individual patient IND,
may make a drug less accessible for treatment use.
    (Response) FDA does not believe that Sec.  312.310(c)(4) will
increase the amount of time it takes for an individual patient to
obtain access. The intent of this provision is to make access more
efficient at the point it becomes apparent that there will be more than
a few isolated requests for expanded access by individual patients. By
obtaining a submission for an expanded access IND that can enroll
multiple patients, FDA believes this provision will decrease the amount
of time needed to get an investigational drug to any patient seeking
access under the multi-patient IND because it avoids the submission and
review of many individual patient INDs. In addition, even at the point
FDA believes it is appropriate to request a submission of a multi-
patient access IND under Sec.  312.315 or Sec.  312.320, FDA does not
intend to delay responding to individual patient submissions that are
received during the time it takes a sponsor to prepare a submission for
an intermediate-size population expanded access IND.
    FDA agrees that the evidentiary requirement is somewhat higher as
the size of the population to be treated under the access IND increases
(e.g., from individual patient to intermediate-size population IND).
However, FDA does not foresee that this will be an obstacle to
obtaining access. FDA will not request submission of an expanded access
IND that can enroll multiple patients until there has been some volume
of experience under several individual patient INDs. Therefore, at the
time FDA requests submission of a multi-patient expanded access IND
under Sec.  312.315 or Sec.  312.320, FDA will have probably already
concluded that

there is enough patient experience under individual patient INDs and
other evidence to justify broader exposure under an IND that can enroll
multiple patients (e.g., to permit treatment of 10 patients under an
intermediate-size population IND).
    (Comment 76) One comment pointed out an apparent discrepancy
between the codified language in Sec.  312.310(c)(4) of the proposed
rule and the preamble discussion of the section. Section 312.310(c)(4)
states that ``* * * FDA may ask the sponsor to submit an IND or
protocol for use under Sec.  312.315 or Sec.  312.320.'' However, the
preamble states that ``* * * FDA will consider whether to request that
a potential sponsor submit an intermediate-size patient population IND
or protocol for the expanded access use and, possibly, conduct a
clinical trial of the expanded access use.'' The comment stated that it
appears that the preamble goes beyond the language of the regulation
and asks what is meant by ``conduct a clinical trial of expanded access
use'' in the preamble.
    (Response) FDA does not believe there is an inconsistency between
the two statements in the preamble and proposed Sec.  312.310(c)(4). If
FDA asks the sponsor to submit an IND or protocol for use under Sec.
312.315 for a drug being developed, that submission would have to
address why the patients to be treated under the intermediate-size
expanded access IND cannot be enrolled in a clinical trial and under
what circumstances the sponsor would conduct a clinical trial in these
patients. Based on the information submitted, FDA must conclude that
enrollment in a clinical trial is not possible before the intermediate-
size population expanded access protocol can begin. However, FDA might
reasonably conclude, based on that information, that a clinical trial
in the intended treatment population is possible and ask the sponsor to
conduct a clinical trial of the treatment use, either in lieu of, or in
addition to, an intermediate-size population expanded access IND.
    Proposed Sec.  312.310(d) sets out emergency procedures for
expanded access for individual patients. If there is an emergency that
requires a patient to be treated before a written submission can be
made, FDA may authorize the use of the drug without a written
submission. The proposed rule provides that emergency use can be
authorized by telephone.
    (Comment 77) One comment was concerned that emergency use might be
too narrowly defined and thus unnecessarily restrict access in a true
emergency.
    (Response) FDA's intent in articulating criteria for when it is
appropriate to consider authorizing access without a written submission
is intended to differentiate true emergency situations in which
treatment must occur within a fairly narrow time frame from situations
in which there is sufficient time to make a written submission. The
emergency process is, by its exigent nature, not as deliberative and
thorough a consideration of the risks and benefits of a proposed
treatment use in an individual patient as is afforded by a review of a
written submission. Therefore, the emergency procedures may expose
patients to somewhat higher risk than a more deliberative, non-time-
sensitive review and, therefore, should be used only in true
emergencies. FDA is confident, however, that the rule as proposed will
permit evaluation of all true emergency treatment use requests using
the emergency procedures.
    (Comment 78) One comment noted that the proposed regulations on
emergency INDs require that licensed physicians obtaining an IND take
on responsibilities more commonly associated with commercial sponsors
such as monitoring, reporting adverse events, and submitting annual
reports (where applicable). The comment was concerned that these
responsibilities may make physicians less willing to obtain
investigational drugs for their patients.
    (Response) The agency recognizes that the licensed physician who
must obtain his or her own IND to make a drug available for treatment
use to an individual patient, whether or not in an emergency situation,
is subject to regulatory obligations usually applicable to commercial
sponsors and with which the physician may not be familiar. However, the
agency believes that for an individual patient IND, these obligations
will not be too onerous because they closely parallel the type of
monitoring and documentation that are routine in a clinical practice
(e.g., routine patient care, progress notes, discharge summary) and,
therefore, are not a substantial added burden. FDA also believes these
obligations are essential elements of human subject protection. In
addition, FDA can provide assistance to licensed physicians in
complying with their expanded access IND regulatory requirements (e.g.,
FDA's Office of Special Health Issues is a good resource for physicians
concerning expanded access (see http://www.fda.gov/oashi/home.html)).
    Proposed Sec.  312.310(d)(2) requires, as a condition for
authorizing emergency use without a written submission, that the
licensed physician or sponsor explain how the expanded access use will
meet the requirements of Sec. Sec.  312.305(a) and 312.310(a) and,
further, that the licensed physician or sponsor make a written
submission that complies with the requirements of Sec. Sec.  312.205(b)
and 312.310(b) within 5 working days of the onset of the use.
    (Comment 79) Two comments expressed concern about the requirement
to make a written submission within 5 working days in situations in
which a commercial sponsor has agreed to make the drug available under
its own IND (as opposed to making the licensed physician obtain an
IND). These comments stated that in these situations the commercial
sponsor is dependent on the licensed physician to obtain the
information needed to make a written submission and, in their
experience, it takes approximately 30 days to obtain all the
information needed to complete the written submission from the licensed
physician. They ask that FDA provide a longer time period in which to
make a submission.
    (Response) FDA acknowledges that in situations in which a
commercial sponsor makes an investigational drug available for
treatment use under its own IND, it is dependent, to a certain extent,
on the patient's physician to obtain the information needed to make the
submission. Therefore, FDA agrees that the time to make a written
submission should be extended. FDA believes that 15 working days should
be sufficient time to obtain whatever information is needed to make a
written submission. FDA is concerned that providing a longer period of
time, such as 30 days, may reduce compliance with the written
submission requirement and may negatively impact patient safety. FDA
also believes it is inefficient and potentially confusing to have
different time frames for making a written submission for a commercial
sponsor who must obtain information from a patient's physician to
complete a submission and a licensed physician who must complete his or
her own IND submission. Therefore, 15 working days will be the time for
making a written submission for each of these situations. Accordingly,
the Sec.  312.310(d)(2) has been revised to provide 15 working days for
making a written submission following emergency authorization to treat
an individual patient with an investigational drug.
    (Comment 80) One comment stated that there were a number of
administrative steps FDA should take to make expanded access for
individual patients easier to obtain. The comment

stated that different divisions at FDA had different requirements
concerning expanded access. The comment suggested that FDA make its
internal requirements for individual patient expanded access consistent
among the divisions. The comment also stated that FDA should post the
name and contact information of the person in each division who is
responsible for helping physicians submit individual patient expanded
access requests.
    (Response) One of the purposes that will be served by this final
rule is to improve consistency in the way expanded access INDs are
handled within FDA. FDA believes that including clear criteria and
submission requirements in the regulations should help improve
consistency in the individual patient expanded access process. In
addition, FDA intends to educate reviewers and other review division
staff on these new rules. FDA also plans to assess the implementation
of these rules and will determine at a later time whether additional
guidance is needed.
7. Issues Specific to Intermediate-Size Patient Populations
    Proposed Sec.  312.315 provides for expanded access use for
multiple patients under a single IND or protocol for patient
populations smaller than those typical in treatment INDs or treatment
protocols, and sets forth the criteria, submission requirements, and
safeguards specific to expanded access INDs for intermediate-size
patient populations. The primary purpose of the intermediate-size
patient population IND or protocol is to consolidate expanded access
under a single IND to promote better monitoring, oversight, and ease of
administration for an expanded access use compared to multiple
individual patient INDs.
    a. General comments.
    (Comments 81) Several comments expressed approval for the creation
of the intermediate-size patient population IND to formally bridge the
gap between individual patient access and large population access under
treatment INDs late in development. One comment agreed that this
category would promote greater efficiency by aggregating various types
of individual requests. Another comment stated that creation of this
category might diminish the burdens of individual physicians in
complying with the expanded access submission requirements for
individual patient INDs, presumably because individual physicians would
not have to make submissions once the individual patient INDs have been
consolidated under an intermediate-size population IND.
    (Response) FDA agrees that a potential advantage is to reduce the
burdens of individual physicians trying to obtain access for individual
patients. Ideally, only a limited number of physicians would make
submissions for individual patients before patients receiving the
investigational drug for the expanded access use could be consolidated
under an intermediate-size population IND. That consolidation would
ease the burden considerably for subsequent physicians seeking the drug
for treatment use because they would not have to make their own IND
submissions.
    (Comment 82) One comment recommended that this expanded access
category be renamed from ``Intermediate-size patient populations'' to
``Limited patient populations for treatment use.'' The comment
maintained this change would clarify that the intent of this expanded
access category is to provide ``compassionate'' treatment use of the
investigational drug and involves only a limited number of prospective
patients.
    (Response) FDA does not believe it is necessary to further clarify
the intent of this category of expanded access or of expanded access
generally. Section 312.300(a) plainly describes the intent of expanded
access. It states that ``[t]his subpart contains the requirements for
the use of investigational new drugs when the primary purpose is to
diagnose, monitor, or treat a patient's disease or condition.''
Moreover, it is apparent throughout the various requirements set forth
in this subpart that the intent is treatment rather than assessment of
the safety and effectiveness of an investigational drug in a controlled
setting. In addition, FDA believes the term ``intermediate-size
population'' better reflects the intent to describe an expanded access
category intended to accommodate populations in between individual
patients and the large populations that are typical of access to
investigational drugs under treatment INDs or treatment protocols.
    (Comment 83) One comment stated that the proposed rule does not
address the situation in which an investigational drug being made
available under a treatment IND would no longer be available under a
treatment IND because of new information about the drug, but could
still be made available under an intermediate-size patient population
IND. The comment was concerned that, in that situation, the evidentiary
threshold for expanded access would actually be lower than for the
treatment IND.
    (Response) FDA agrees that the proposed rule was not specifically
intended to address a situation in which an investigational drug once
available under a treatment IND would no longer be available under a
treatment IND, but would then become available under an intermediate-
size patient population expanded access IND. FDA believes this would be
an unusual circumstance, but a foreseeable one, and that the rule as
proposed could accommodate that circumstance. For example, clinical
trials of an investigational drug available under a treatment IND might
demonstrate lack of effectiveness on a primary endpoint that is
compatible with the expanded access use under the treatment IND, but
also provide preliminary evidence of effectiveness on secondary
endpoints or in subset analyses, and such evidence could support a
different expanded access use (e.g., a more narrowly defined population
within a disease or a different indication) under an intermediate-size
population expanded access IND. In this circumstance, some of the
patients who were receiving the drug under the treatment IND might be
eligible to receive the drug under the intermediate-size population IND
on the basis of lesser evidence than supported the treatment IND.
However, FDA does not see why this would be a problem (e.g., expose any
patient to unreasonable risk), provided the evidence is adequate to
support the size population to be treated under the intermediate-size
population IND.
    b. Number of patients.
    The preamble to the proposed rule stated that FDA anticipates that
the typical intermediate-size patient population treatment use IND or
protocol will provide access to between 10 and 100 patients.
    (Comments 84) Some comments were concerned that FDA's estimated
range for the number of patients that could be enrolled in an
intermediate-size patient population IND was too narrow. One comment
stated that FDA substantially underestimated the sizes of the potential
populations that would need access to an investigational drug under an
intermediate-size patient population, and that the estimated range
(between 10 and 100 patients) leaves a significant gap between the
intermediate-size population IND and the treatment IND. The comment
recommended the creation of a fourth category of expanded access IND to
bridge this gap. One comment asked FDA to clarify the difference in
size of population between the intermediate category and larger
populations under treatment INDs or protocols because FDA did not
provide any estimate of the lower end of the range for a treatment IND.
Two

comments stated that, although the proposed rule contemplated that
Sec.  312.315(a)(3)(i) and (a)(3)(ii) would be for an intermediate-size
population of 10 to 100 patients, the situations described in these
subsections could easily involve much larger numbers of patients.
    (Response) The population range (10 to 100) for the intermediate-
size patient population IND identified in the preamble to the proposed
rule is simply an estimate and is not intended to exclude the
possibility that more (or fewer) patients could be treated under an
intermediate-size patient population IND. For a drug being developed,
it is possible that more than 100 patients could be treated under an
intermediate-size population IND. However, our experience suggests that
programs substantially larger than this are best administered under a
treatment IND. FDA expects that there would ordinarily be a seamless
transition from intermediate-size population IND to treatment IND at
the point when there was adequate evidence to support the treatment
IND, adequate progress with drug development, a sponsor willing to make
the drug available to a larger population under a treatment IND, and
sufficient numbers of patients who need the drug to justify a treatment
IND.
    For a drug not being developed, there is also the possibility that
greater than 100 patients will need access to an investigational drug
under an intermediate-size patient population IND. Although FDA
anticipates that a relatively small number of patients would be
receiving access at any given point in time under such an IND, it is
foreseeable that, for some drugs in this category, conditions will
never be right for development, and over a period of years the IND will
provide access to more than 100 patients. However, if substantially
more than 100 patients seek or continue to need access under this
category within a fairly narrow time frame, FDA believes there would
likely be an adequate number of potential subjects to initiate a
clinical trial and formal development of the drug.
    When a drug has been withdrawn for safety reasons or in a drug
shortage situation, it is also foreseeable that there will be greater
than 100 patients who may need access to the drug--for patients in whom
the benefits of the withdrawn drug continue to exceed the risks
associated with the drug or patients who need to rely on a drug not
approved for marketing in the United States to substitute for an
approved drug in short supply. In those cases, the intermediate-size
population IND could be used to provide access to greater than 100
patients.
    Because there is a need for flexibility to provide access to
greater than 100 patients under an intermediate-size population IND in
some circumstances, FDA has elected not to provide a specific estimate
of the population range for this category in this final rule. FDA
continues to believe that the population range identified in the
proposed rule--10 to 100 patients--would accommodate most intermediate-
size population INDs. However, FDA believes foremost that the size
population that can be treated under an intermediate-size population
IND should be dictated by the available evidence--the amount of
exposure that the evidence will support--and the circumstances of a
given case, rather than by a somewhat arbitrary estimate of the size of
the upper bound of the population.
    c. Sub-categories of intermediate-size patient population expanded
access.
    Proposed Sec.  312.315 provides for access to an intermediate-size
population in four situations:
     To provide a drug that is not being developed to patients
who may benefit from the drug (typically patients with a rare disease
or condition) (Sec.  312.315(a)(1))
     To make a drug that is being developed available to
patients who cannot participate in clinical trials of the drug (Sec.
312.315(a)(2))
     To provide an approved drug that has been withdrawn for
safety reasons, or cannot be marketed due to failure to meet the
conditions of the approved application (usually a manufacturing
problem) to a limited number of patients who are dependent on the drug
(Sec.  312.315(a)(3)(i))
     To provide a drug that is related to an approved drug, but
is not approved for marketing in the United States, in situations where
there is a shortage of the approved drug or the approved drug is
unavailable due to failure to meet the conditions of the approved
application (Sec.  312.315(a)(3)(ii))
    (Comment 85) One comment objected to the range of situations in
this category, stating that the situations are too diverse to be
accommodated in a single expanded access category.
    (Response) FDA disagrees. Because the amount of evidence needed to
make an investigational drug available under an intermediate-size
population IND is based on the size of population anticipated to be
treated under the IND, the category can accommodate situations with
significant variations in the size of the treatment population (see
also preceding comment response). FDA believes, therefore, that the
criteria set forth in Sec.  312.315 are adequate to ensure that the
risks associated with use of drugs made available in each of these four
situations are minimized and the potential benefits maximized across a
variety of different treatment use situations and size populations.
    (Comment 86) One comment recommended deleting the option to make an
investigational drug available under an intermediate-size population
IND when the drug is not being developed. The comment argued that
because the disease is so rare that it is not possible to recruit
patients for a clinical trial, the sponsor would not ordinarily
maintain an active IND, nor would the sponsor be manufacturing
investigational drug supplies (so, presumably, there is no reason for
the category). The comment stated that the proposed rule also implies
that this situation may be an open-ended commitment to expanded access,
which is likely to further deter commercial sponsors. One comment asked
how FDA would determine that the drug is the only promising therapy for
the people with a rare condition without clinical data to support the
use. The comment stated that this provision of the proposed rule would
further erode the possibility of conducting a controlled clinical trial
in this situation.
    (Response) This category of expanded access use is based on FDA's
experience with situations in which there has been no alternative but
to make a drug not being developed available under an IND to a small
number of patients who could benefit from it. In FDA's experience, it
has not been difficult to determine that a drug is the treatment of
choice for a discrete group of patients with a particular rare disease
or condition. For example, some antivenins and drugs for tropical
diseases are not commercially marketed in the United States because
there is simply not a large enough market to develop the product for
marketing, but these products are nonetheless needed on occasion by
readily identifiable patients. FDA has made other products available to
treat obscure conditions when the population is seemingly too small for
even orphan drug development. For example, thalidomide was made
available for a variety of conditions under several of these types of
INDs before there was sufficient data to approve it. Currently, there
are INDs for products not being actively developed that are ongoing,
and FDA anticipates that it will encounter situations in the future in
which this type of IND is needed. Because these types of INDs exist,
and because one of FDA's goals with this rulemaking to

make the agency's various mechanisms for expanded access transparent
and thereby make investigational drugs more widely available to those
who might benefit, the agency believes it is important to describe this
type of expanded access in the regulations.
    FDA recognizes that a commercial sponsor might not be inclined to
be a sponsor for this type of IND or to make a potentially open-ended
commitment to manufacture products to provide to another sponsor under
this type of IND. In FDA's experience, these types of INDs are not
usually held by commercial sponsors. They are more commonly held by
government agencies and academic institutions. So the fact that this
type of IND is of little interest to a commercial sponsor is no reason
to remove it from the expanded access regulations, particularly when it
meets a demonstrated public health need.
    FDA also recognizes that this type of access could potentially
usurp the entire population that could possibly be enrolled in a
clinical trial of a drug. However, FDA thinks this situation is not
very likely because drugs are rarely developed (at least not in the
United States) for the types of indications for which drugs are made
available under this category. Nonetheless, where appropriate, FDA
intends to make every effort to encourage potential sponsors to study
such a drug in a clinical trial rather than provide it under an
expanded access IND.
    (Comment 87) One comment stated that there was no reason to have an
intermediate-size population expanded access IND for a drug being
developed. The comment stated that there is no justification for
allowing access under such an IND for a disease different from the one
being studied in the clinical trials. For the other situations in which
a patient is unable to participate in the clinical trial (different
disease stage, patient otherwise fails to meet enrollment criteria,
enrollment is closed, or the trial site is not geographically
accessible), the comment stated that the treatment IND would be the
appropriate vehicle for expanded access.
    (Response) FDA believes there is adequate justification for
allowing expanded access under an intermediate-size patient population
IND for a disease different from the one being studied in the clinical
development program. For an oncology drug, for example, the
characteristic of a cancer that is the target of a given
chemotherapeutic agent (e.g., specific receptor or enzyme) may be
present in other types of cancers. In that situation, it may be
appropriate to make an investigational drug being studied for one
cancer available to treat patients with another type of cancer before
there is definitive evidence of effectiveness in the other type of
cancer. As discussed above, FDA also believes it is important to be
able to provide access to multiple patients in a controlled manner
under an intermediate-size patient population IND at a point in time in
which the use for which the drug is being made available would not yet
meet the criteria for a treatment IND. In FDA's experience, it has been
helpful from an administrative, clinical safety, and monitoring
perspective to provide for a multi-patient expanded access IND to
bridge the gap between individual patient INDs and treatment INDs.
    (Comment 88) One comment stated that it is not clear why patients
should receive expanded access to a drug that is no longer marketed for
safety reasons. The comment stated that a clinical trial is the
appropriate setting to identify patients for whom the potential
benefits of a drug outweigh the risks. One comment agreed that, when a
drug is withdrawn from marketing because of safety reasons, there may
be a subset of patients for whom the benefits of treatment would
outweigh the risks. The comment also pointed out that by stating in the
preamble to the proposed rule that those patients for whom the benefits
of treatment are believed to outweigh the risks ``could continue to
receive the drug under an intermediate-size patient population IND,''
FDA implied that only patients who were already receiving the drug when
marketing ceased could obtain the drug under such an IND. The comment
asked FDA to clarify whether this provision is intended to make a drug
available only to patients who were receiving the drug when it was
withdrawn for safety reasons or if it would also be possible to provide
the drug to patients who had not yet received it.
    (Response) In FDA's experience, there are multiple examples of
situations in which a drug has been withdrawn from the market for
safety reasons and there has been a need to make the drug available to
a subset of patients in whom the benefits of treatment outweigh the
risks. Although those who receive the drug will ordinarily be those who
were already receiving the drug at the time of withdrawal and appear to
have benefited, it was not FDA's intent to absolutely foreclose the
possibility that new patients could receive a drug that had been
withdrawn from marketing for safety reasons. It is possible that a
population in whom benefits continue to outweigh risks could be
characterized in a way that would permit access to patients who have
not previously been treated with the drug, even though the drug is
unsafe for marketing. However, a manufacturer may be reluctant to make
an open-ended commitment to provide a drug that has been withdrawn for
safety reasons to a subset of patients when there is no commercial
benefit to the manufacturer. This reluctance could also affect whether
new patients would be able to obtain the drug.
    (Comment 89) One comment recommended that the final rule clarify
that some situations in which a marketed drug is found to benefit only
a subset of the population for which it was approved can be addressed
through a restricted distribution program of the FDA-approved product
in accordance with subpart H of part 314, rather than through
withdrawal of the drug for safety reasons and use of an intermediate-
size patient population IND to make the drug available to the subset
population.
    (Response) FDA agrees that, in situations in which a drug is found
to be beneficial in only a subset of the population in which it was
originally approved, it may be possible to allow continued marketing of
the drug under a restricted distribution program (Lotronex was
originally marketed without restrictions and is now marketed under a
restricted distribution program). In these situations, there would
usually be more compelling data to support the use in the subset
population than would be needed for an expanded access IND (i.e., a
more rigorously defined subset population). The appropriate mechanism
for making a drug available to the subset of patients in whom the
benefits continue to outweigh the risks would depend on the
circumstances of the particular case. FDA is always willing to explore
the full range of options with the manufacturer of such a drug.
    d. Drug shortage.
    (Comment 90) One comment stated that it is not clear that the
expanded access rule would be the right mechanism for access in a drug
shortage situation because the numbers of patients needing access could
be well in excess of the 100 patients that the preamble suggests are
the upper bound of the intermediate-size population IND category.
    (Response) FDA is retracting a statement in the preamble to the
proposed rule suggesting that there is a 100-patient upper bound on the
population for an intermediate-size expanded access IND. FDA agrees
that a drug shortage situation could result in a need for access in
more than 100

patients and more patients than could reasonably be accommodated by an
intermediate-size expanded access IND. In such situations, FDA would be
more likely to exercise its enforcement discretion, the effect of which
would be to permit marketing of a related product that did not meet the
FDA approval requirements to substitute for the drug in short supply
until supply issues for the FDA-approved product were resolved. FDA
included the drug shortage provision in the expanded access regulations
to address a situation in which there is a relatively small, discrete
population affected by a drug shortage. Which mechanism would be
appropriate to make a related drug available in a drug shortage
situation--an intermediate-size population IND or enforcement
discretion--would depend on the circumstances of that situation.
    e. Good manufacturing practices (GMP) issues.
    (Comment 91) One comment suggested that expanded access was not the
appropriate vehicle for providing access to a drug that is approved but
is not being manufactured in a manner consistent with the approval. The
comment stated that because the drug is not investigational, access
should be handled under a different mechanism. The comment added that
there should be assurance of close oversight of the manufacturer to
minimize harm to patients. Another comment asked how it would be
determined that the risk due to manufacturing problems is acceptable.
The comment pointed out that the IND would have to cross-reference the
NDA for CMC information and also describe the good manufacturing
practices (GMP) issues.
    (Response) As in the case of a drug shortage, GMP issues for a
product could create a need for access in a population too large to be
accommodated under an intermediate-size expanded access IND. As with a
drug shortage, in these situations FDA would be more likely to use
enforcement discretion to make the drug available to a very large
number of patients. FDA agrees that, whether enforcement discretion or
an expanded access IND is used, there must be careful consideration of
the safety implications of the manufacturing concerns, including
possible monitoring mechanisms to ensure that patients are not being
harmed by a product that has GMP concerns but is nonetheless being made
available to patients.
8. Issues Specific to Treatment IND and Treatment Protocol
    The proposed rule specifically solicited comment on FDA's decision
to continue to describe the type of expanded access for treatment use
that makes investigational drugs available to large populations as the
``treatment IND'' or ``treatment protocol.''
    (Comment 92) One comment expressed the view that, despite 20 years
of use, these terms are confusing. The comment recommended that the
terminology be changed to ``large-size patient populations'' to be
consistent with the names of the other two categories of expanded
access.
    (Response) FDA continues to believe that it would be preferable to
retain the terms ``treatment IND'' and ``treatment protocol.'' Because
these terms have been in use for more than 20 years, FDA believes they
have become so strongly associated with making investigational drugs
available to large populations that to replace the terms would generate
needless confusion. FDA recognizes that the term ``treatment use'' is
now widely used to refer generically to use of an investigational drug
for treatment purposes outside of a clinical trial, and not just to use
under a treatment IND or protocol. However, FDA believes the confusion
that would result from changing the name of the treatment IND outweighs
any potential confusion resulting from use of the word ``treatment'' in
the title of the large population expanded access IND but not in the
other expanded access categories.
    (Comment 93) One comment noted that FDA's current regulation
concerning the submission requirements for a treatment protocol (Sec.
312.35(a)(ii)) provides that a submission for a treatment protocol must
explain why the use of the investigational drug is preferable to the
use of available marketed treatments. The comment pointed out that
Sec.  312.305(b)(2)(ii) of the proposed rule provides that submissions
for all expanded access uses must explain why the use of the
investigational drug is preferable to the use of available therapeutic
options. The comment interpreted this provision of the proposed rule as
permitting expanded access for a treatment protocol only when the
treatment protocol explains why the use of the investigational drug is
preferable to any approved or unapproved therapies, not just preferable
to any available marketed treatment. The comment contended that this
provision could be interpreted to require companies to show that the
product to be used for treatment use is better than both approved and
unapproved therapies because the preamble states that ``available
therapy'' includes not just FDA-approved products for that indication,
but also includes (1) treatments not FDA-regulated (e.g., surgery) and
(2) off-label use (i.e., not labeled for use for the relevant condition
or disease, but supported by compelling literature reference) (71 FR
75147 at 75151). To avoid this perceived problem, the comment suggested
that FDA take one of three steps: (1) Put the definition of ``available
therapy'' stated in FDA's guidance for industry entitled ``Available
Therapy'' in a formally issued rule, (2) revert back to the requirement
that the investigational new drug must only be measured against other
FDA-approved marketed products, or (3) approve the unapproved therapy
for the new indication so that its use becomes ``on-label.''
    (Response) The Available Therapy guidance (p. 4) states that
``available therapy (and the terms existing treatments and existing
therapy) should be interpreted as therapy that is specified in the
approved labeling of regulated products, with only rare exceptions.''
This guidance was intended to apply to the use of the term in Sec.
312.34(b)(1)(ii) of FDA's current regulations concerning treatment INDs
and treatment protocols. That regulation includes the criterion that
``[t]here is no comparable or satisfactory alternative drug or other
therapy available to treat that stage of the disease in the intended
patient population.'' Section 312.34(b)(1)(ii) is intended to apply
equally to the use of the term in new subpart I. FDA believes this
guidance has effectively addressed confusion associated with use of the
term ``available therapy'' in the varied contexts in which it is used
in FDA's regulations. Therefore, FDA does not believe it is necessary
at this time to promulgate a regulation defining the term or revise the
guidance so that only approved therapies could be considered available
therapy. Nor would it be appropriate to simply approve the unapproved
therapy for the new indication for use, apparently without regard to
the evidence supporting the use, so that its use becomes ``on-label.''
9. Clinical Holds of Expanded Access INDs
    Proposed Sec.  312.42(b)(3) specifies the conditions under which
FDA may place an expanded access IND or protocol on clinical hold.
Proposed Sec.  312.42(b)(3)(i) allows FDA to place a proposed expanded
access use on clinical hold if the pertinent criteria in subpart I for
authorizing the use are not met (e.g., non-serious disease or
condition, satisfactory or comparable therapies are available,
insufficient evidence to support the use) or the IND does not comply
with the pertinent submission

requirements in subpart I. Proposed Sec.  312.42(b)(3)(ii) allows FDA
to place an ongoing expanded access IND on clinical hold if the agency
determines that the pertinent criteria in subpart I are no longer
satisfied.
    (Comment 94) One comment emphasized the importance of providing a
high degree of clarity about the reasons for imposing a clinical hold
on an access program to assure that other studies of the
investigational drug are not unintentionally affected. The comment
stated that lack of clarity could shut down an entire development
program and suggested that in the final rule, FDA cite specific reasons
for imposing a clinical hold on an access program. The comment asserted
that FDA should apply the same level of rigor for imposing holds on
access programs as is applied to clinical holds of clinical trials.
Another comment suggested that FDA propose an approach for supplying
drugs to patients who are clearly benefiting from treatment and are
participating in an expanded access program that is put on clinical
hold.
    (Response) FDA does not believe it is necessary or desirable to
cite in the regulations specific potential reasons for a clinical hold
of an expanded access IND. Section 312.42(b)(3) makes clear that
failure to meet any of the criteria or submission requirements
pertinent to authorizing any of the expanded access IND categories may
be a basis for a clinical hold. It also makes clear that if any of the
criteria that were the basis for authorizing an expanded access IND are
no longer satisfied, FDA may place an ongoing expanded access IND on
clinical hold. If FDA were to cite specific potential reasons for a
hold, it could give the misimpression that failure to meet criteria or
submission requirements not expressly mentioned would not be a basis
for a hold.
    FDA anticipates that clinical holds for expanded access INDs will
be handled in the same manner as for INDs for clinical trials. That is,
the clinical hold letter will cite the relevant regulation and explain
in detail how the criteria that are the basis for the hold are not met.
FDA further anticipates that, in the event that the basis for a
clinical hold is relevant only to an expanded access IND and not to the
clinical development program, the relevant clinical hold documentation
will make this abundantly clear.
    In addition, in situations in which an ongoing expanded access IND
is placed on hold, FDA will carefully consider the needs of patients
already receiving the drug. FDA will not hesitate to use a partial
clinical hold (which permits patients already being treated with a drug
to continue treatment) where appropriate.
10. Comments on Analysis of Impacts
    (Comment 95) Three comments from pharmaceutical companies and a
trade association stated that the rule would likely increase sponsors'
administrative, medical, and regulatory burdens associated with
expanded access. The comments specifically mentioned the costs of
providing the investigational drug, conducting clinical laboratory
tests, and monitoring, collecting, processing, analyzing, and
summarizing data.
    (Response) Based on our analysis, we conclude that the final rule
will not have a substantial economic impact. The final rule clarifies
and expands on regulations in place since 1986 but does not
substantially change those regulations; therefore, the overall economic
impact should be small. Treatment use of investigational drugs is
relatively uncommon and a particular sponsor would be expected to
submit a treatment use request only infrequently. Therefore any
additional regulatory burden is expected to be small and widely
dispersed among affected entities. Most treatment use requests are for
individuals or single patients for which the drug, clinical laboratory
testing, monitoring, data processing, and reporting costs are expected
to be small. The proposed rule does not require sponsors to make
investigational drugs available for treatment use. Such a decision is
the sponsor's alone and will presumably be based on a number of
factors, including cost. If the sponsor can demonstrate that the
clinical trial could not be conducted unless the sponsor is able to
charge for the investigational drug, the sponsor may request permission
to charge patients and recover the direct costs associated with the
treatment use.
    (Comment 96) A comment from an insurance company provided an
estimate of the costs to enrollees in commercial private health plans
associated with the expanded access rule that indicates the costs to be
much larger than those stated in the proposed rule. The comment assumed
that physicians would request access to investigational drugs only when
available therapies have failed or when conventional therapies do not
exist. Additional information related to the comment and submitted to
the docket at FDA's request indicated that ``* * * the grand total
number of patients projected to utilize INDs under these proposals each
year is approximately 67,500.'' The comment also stated its belief that
investigational drugs will be used as first-line therapy, second-line
therapy, monotherapy, and combined therapy with FDA-approved
medications. The comment stated that the aggregate additive cost per
year to all U.S. private-sector payers would be $273,600,000. The
comment maintained that these estimates actually understate the burden
to private-sector payers because they exclude potential annual costs to
Medicare Advantage plans.
    (Response) Based on our analysis, we concluded that the costs of
this final rule should be small. The cost estimate provided in the
comment appears to include costs for investigational drugs under
provisions of the charging final rule published elsewhere in this issue
of the Federal Register. In response to the comment, we have included
estimates of the number of individual patients with access to
investigational drugs under current rules and the number of additional
patients we expect to gain expanded access to investigational drugs
under this final rule. FDA's estimates indicate that, on average, as
many as 53,159 patients per year have access to investigational drugs
under current rules. In addition, we estimate that as many as 3,095
additional patients will gain expanded access to investigational drugs
under this final rule. These estimates are based on assumptions used in
our Analysis of Impacts for the proposed rule that were not
substantively challenged in any comments received. It appears that the
estimate of 67,500 patients per year in the comment draws no
distinction between patients receiving investigational drugs under
current rules and the additional patients who will have expanded access
under this final rule. In assessing the impact of the final rule, it is
the incremental effect, or additional patients that will gain expanded
access, that must be considered. Patients with access to
investigational drugs under current rules are not relevant to an
analysis of impacts for this final rule. The only direct costs that are
relevant to this final rule are the costs to drug sponsors to prepare
and submit expanded access requests. The comment did not provide an
estimate of these costs.
    (Comment 97) A comment from a capital fund disagreed with the
proposed rule's assertion that the rule would not have a significant
economic impact on a substantial number of small entities. The comment
stated that FDA had overlooked the extensive role of small biotech
companies in developing novel kinds of investigational drugs that are
often the most sought-after therapies for expanded access. The comment
also

stated that small biotech companies severely lack funding and also face
special difficulties in getting their therapies to the stage where they
are able to obtain significant partnering arrangements. The comment
stated that such companies could be substantially helped by expanded
access programs by permitting them to reach larger numbers of patients
sooner and to generate larger amounts of supporting data sooner. The
comment stated that the most powerful boost for small biotech companies
and the patients seeking their new therapies would come from combining
expanded access programs with policies allowing cost recovery and
reimbursement (the subject of the charging proposed rule). The comment
also advocated minimal efficacy requirements for expanded access and
stated that such a policy would not impose substantial costs on society
or the healthcare system because sponsors would be paying for the costs
of producing and supplying the therapy in most expanded access
programs. The comment added that if such programs enable a product to
reach marketing approval sooner than otherwise, that would greatly
reduce the costs that sponsors must recoup in pricing products for
commercial sale.
    (Response) The comment suggests that investigational drugs produced
by small biotech companies are often the most sought-after therapies
for expanded access, but provides no examples. While small biotech
companies may face a number of difficulties--including a lack of
funding and partnering opportunities--such obstacles are neither the
subject of this final rule nor the responsibility of FDA. The purpose
of the proposed expanded access rule is not to help sponsors reach
larger numbers of patients and generate larger amounts of supporting
data sooner. The agency believes that these goals are best pursued
through the normal drug development process. FDA believes that cost
recovery for expanded access--the subject of the charging proposed
rule--is appropriate only in limited circumstances. Further, the agency
has determined that the amount to be charged should be limited to the
direct costs of providing the investigational drug for the treatment
use. Cost recovery through charging is not intended as a mechanism
through which sponsors may generate funds to support drug development
generally. The agency agrees with the comment that the proposed rule
would not impose substantial costs on society or the healthcare system.
    (Comment 98) One comment stated that the estimates of increased
expanded use in the Analysis of Impacts appeared overly optimistic
because Federal Register notices are not the best way of disseminating
information to the lay public or their physicians and the proposed rule
did not mention any additional efforts to disseminate information about
expanded access.
    (Response) Issuance of the final rule is not the only way FDA plans
to disseminate information on expanded access programs to the lay
public and physicians. FDA intends to develop and engage in a broad
range of publicity and educational efforts in a variety of forums and
media to increase awareness of the mechanisms for obtaining
investigational drugs for treatment use.

IV. Legal Authority

    The agency believes it has the authority to impose requirements
regarding expanded access to investigational drugs under various
sections of the act, including sections 505(i), 561, 701(a) (21 U.S.C.
371(a)), and 505-1(f)(6).
    Section 505(i) of the act directs the agency\1\ to issue
regulations exempting from the operation of the new drug approval
requirements drugs intended solely for investigational use by experts
qualified by scientific training and expertise to investigate the
safety and effectiveness of drugs. The final rule explains procedures
for obtaining FDA authorization for expanded access uses of
investigational drugs and factors relevant to making necessary
determinations.
---------------------------------------------------------------------------

    \1\ In light of section 903(d) of the act (21 U.S.C. 393(d)) and
the Secretary's delegations to the Commissioner of Food and Drugs,
statutory references to ``the Secretary'' in the discussion of legal
authority have been changed to ``FDA'' or ``the agency.''
---------------------------------------------------------------------------

    Section 561 of the act, added by FDAMA, provides significant
additional authority for this final rule. Section 561(a) of the act
states that FDA may, under appropriate conditions determined by the
agency, authorize the shipment of investigational drugs for the
diagnosis, monitoring, or treatment of a serious disease or condition
in emergency situations. This final rule sets forth factors that the
agency will consider in determining whether to authorize shipment of
investigational drugs in emergency situations.
    Section 561(b) of the act allows any person, acting through a
physician licensed in accordance with State law, to request from a
manufacturer or distributor an investigational drug for the diagnosis,
monitoring, or treatment of a serious disease or condition if four
conditions are met: (1) The physician must determine that the person
has no comparable or satisfactory alternative therapy available and the
probable risk to the person from the investigational drug is not
greater than the probable risk from the disease or condition; (2) FDA
must determine that there is sufficient evidence of safety and
effectiveness to support the use of the investigational drug in the
particular case; (3) FDA must determine that provision of the
investigational drug will not interfere with the initiation, conduct,
or completion of clinical investigations to support marketing approval;
and (4) the sponsor or clinical investigator of the investigational
drug must submit a clinical protocol consistent with the provisions of
section 505 of the act (21 U.S.C. 355) describing the use of the
investigational drug in a single patient or a small group of patients.
The final rule sets forth factors that FDA will consider in making the
necessary determinations and explains the procedures and criteria for
physicians, sponsors, and/or investigators to make the necessary
representations and submissions to FDA.
    Section 561(c) of the act specifically authorizes expanded access
under a treatment IND if FDA makes the following determinations: (1)
Under the treatment IND, the investigational drug is intended for use
in diagnosing, monitoring, or treating a serious or immediately life-
threatening disease or condition; (2) there is no comparable or
satisfactory alternative therapy available to diagnose, monitor, or
treat that stage of the disease or condition in the population of
patients to which the investigational drug is intended to be
administered; (3) the investigational drug is already under
investigation in a controlled clinical trial for the same use under an
IND under section 505(i) of the act, or all clinical trials necessary
for approval of that use of the investigational drug have been
completed; (4) the sponsor of the controlled clinical trials is
actively pursuing marketing approval of the investigational drug, with
due diligence, for the same intended use; (5) provision of the
investigational drug will not interfere with the enrollment of patients
in ongoing clinical investigations under section 505(i) of the act; (6)
in the case of serious diseases, there is sufficient evidence of safety
and effectiveness to support the intended use; and (7) in the case of
immediately life-threatening diseases, the available scientific
evidence, taken as a whole, provides a reasonable basis to conclude
that the investigational drug may be effective for its intended use and
will not expose patients to an unreasonable and significant risk of
illness and injury. The

final rule sets forth factors that FDA will consider in making the
necessary determinations.
    Section 561 of the act further requires that protocols submitted
under section 561 be subject to section 505(i) of the act including
regulations issued under section 505(i). Section 561(d) of the act
permits the agency to terminate expanded access for failure to comply
with the requirements of section 561 of the act. The final rule sets
forth the conditions under which FDA will place an expanded access use
on clinical hold.
    This final rule establishes three categories of expanded access.
While authority for individual patient access is based on section
561(b) of the act, and authority for treatment INDs and treatment
protocols is based on section 561(c) of the act, there is also
authority in the statute for FDA to issue regulations for intermediate-
size patient populations. Section 561(b)(4) of the act requires
submission of a protocol for the expanded access use that is consistent
with the requirements of the IND regulations describing the use of the
investigational drug in a single patient or a small group of patients.
The provisions of the final rule concerning expanded access for
intermediate-size patient populations address the use of the
investigational drug in the small groups of patients mentioned in the
statute.
    Section 701(a) of the act provides general authority to issue
regulations for the efficient enforcement of the act. By clarifying the
criteria and procedures relating to expanded access to investigational
products, this final rule is expected to aid in the efficient
enforcement of the act.
    Finally, section 505-1(f)(6) of the act, added by FDAAA, states
that ``[t]he mechanisms under section 561 to provide for expanded
access for patients with serious or life-threatening diseases or
conditions may be used to provide access for patients with a serious or
life-threatening disease or condition, the treatment of which is not an
approved use for the drug, to a drug that is subject to elements to
assure safe use under this subsection.'' FDA ``shall promulgate
regulations for how a physician may provide the drug under the
mechanisms of section 561.'' Because the expanded access mechanisms in
this final rule may be used by patients seeking access to a drug that
is subject to elements to assure safe use, this rule fulfills the FDAAA
requirement.

V. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VI. Analysis of Economic Impacts

    FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is not an economically significant regulatory action
under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Our economic analysis for the proposed rule did not
indicate any significant new regulatory burden, and we did not receive
any comments that would cause us to reconsider this determination.
Therefore, the agency certifies that the final rule will not have a
significant economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in an expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $133 million, using the most current (2008) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that will meet or exceed
this amount.
    The agency estimates that the total costs to drug sponsors and
physicians to submit the additional expanded access submissions
expected under this final rule will be between $1.5 million and $3.0
million per year. Because a typical sponsor will submit an expanded
access use request only infrequently, these costs are expected to be
widely dispersed among affected entities. The benefits of the final
rule are expected to result from increased patient access to
investigational drugs generally and from expanded access being made
available for a broader variety of disease conditions and treatment
settings. Private benefits will accrue to individual patients receiving
drugs for expanded access use, whereas social benefits will accrue if
information obtained contributes to the development of new therapies
generally. Due to uncertainty with respect to the potential magnitude
of such benefits, and a lack of necessary data, FDA did not generate
quantitative estimates of expected benefits.

A. Objectives of the Final Action

    FDA is proposing this action to describe in greater detail all of
the ways patients may obtain expanded access to investigational drugs
for treatment use. Specifically, the final rule establishes eligibility
criteria, submission requirements, and safeguards for the expanded
access use of investigational drugs by individual patients, including
in emergencies; intermediate-size patient populations; and larger
populations under a treatment protocol or treatment IND. The proposal
is also intended to increase public knowledge and awareness of expanded
access and, thus, to make investigational drugs more widely available.
In addition, by establishing clear eligibility criteria and submission
requirements, the final rule will ease administrative burdens on
physicians seeking investigational drugs for their patients and on
sponsors who are willing to make promising unapproved therapies
available for treatment use.

B. Nature of the Problem Being Addressed

    The fundamental problem addressed by the final rule is one of
incomplete information. In some circumstances, a lack of clearly
defined eligibility criteria and submission requirements has created
inefficiencies that limit patient access to potentially beneficial
investigational drugs. The final rule is also intended to address
concerns that, historically, cancer and Acquired Immunodeficiency
Syndrome (AIDS) patients have had better access to investigational
drugs than patients with other serious diseases or conditions, and that
patients under the care of physicians based in academic medical centers
are more likely to obtain such access than patients whose physicians
practice outside such centers. In addition, the lack of clearly defined
eligibility criteria and submission requirements has led some
physicians and drug sponsors to devote more

resources than necessary to the preparation of expanded access
submissions. Through this final rule, the agency seeks to correct these
shortcomings.
    The final rule establishes general eligibility criteria, submission
requirements, and safeguards for the expanded access use of
investigational drugs. The requirements that apply to all types of
expanded access use are discussed in section III.C.3 of this document.
The final rule also describes more specific eligibility criteria,
submission requirements, and safeguards for three specific categories
of expanded access: (1) Expanded access for individual patients, (2)
expanded access for intermediate-size patient populations, and (3)
expanded access under a treatment protocol or treatment IND.

C. Baseline for the Analysis

    During the period 1997 through 2005, FDA received an average of
2,046.6 INDs per year. Of this number, on average, approximately 659,
or 32.2 percent (0.322 = 659 / 2,046.6) were individual patient or
emergency INDs. In addition, FDA received approximately 4.6 treatment
IND or treatment protocol submissions per year during this time period.
Thus, treatment IND or treatment protocol submissions represent about
0.2 percent (0.0022 = 4.6 / 2,046.6) of all INDs received by the agency
each year. Because expanded access for intermediate-size patient
populations is not currently established in the regulations, FDA does
not have a record of the number of submissions in this category.
However, based on an internal survey of drug review divisions, FDA
estimates that approximately 55 other expanded access submissions were
received each year between 2000 and 2002. While it is not possible to
determine the precise number that will be considered intermediate-size
patient population expanded access submissions, FDA experts believe
that most of the 55 other submissions each year will fall under this
category.
    Thus, approximately 2.7 percent (0.0269 = 55 / 2,046.6) of all INDs
received by FDA each year may be associated with intermediate-size
patient population expanded access requests. The information presented
previously is summarized in table 1 of this document.

              Table 1.--Baseline Data for the No. of INDs and Expanded Access Requests by Category
----------------------------------------------------------------------------------------------------------------
                                                 Individual Patient     Treatment IND  or
        Category               Total INDs         or  Emergency IND         Protocol                Other
----------------------------------------------------------------------------------------------------------------
Number                                  2046.6                   659                   4.6                    55
----------------------------------------------------------------------------------------------------------------
Percent of all INDs                        100                  32.2                   0.2                   2.7
----------------------------------------------------------------------------------------------------------------

    One comment submitted in response to the proposed rule provided an
estimate of the number of patients that might be affected by this rule.
As part of our response, we have generated estimates of the number
receiving investigational drugs under current expanded access programs,
in place since 1986.
    Based on the information presented previously, FDA currently
receives an average of 659 individual patient or emergency INDs per
year. Thus, approximately 659 individuals per year currently receive
investigational drugs under single patient or emergency INDs. FDA
believes that it is reasonable to assume that a typical expanded access
submission for an intermediate-size patient population will affect
between 10 and 100 individuals. Given that FDA currently receives an
average of 55 such submissions per year, we estimate that between 550
and 5,500 individuals currently receive investigational drugs under
intermediate-size patient population or other expanded access programs.
A treatment IND or protocol can vary significantly in size and may
include between 100 and 10,000 patients. Thus, an average of 4.6
treatment IND or protocol submissions could affect between 460 and
46,000 individuals. Based on this information, FDA estimates that
between 1,669 and 52,159 individuals currently receive investigational
drugs through expanded access programs. The wide range of these
estimates reflects significant variation in the number of patients in
intermediate-size patient populations, and treatment INDs or protocols.
These estimates are summarized in table 2 of this document.

        Table 2.--Approximate No. of Individuals Affected by Expanded Access Programs in Place Since 1986
----------------------------------------------------------------------------------------------------------------
                             Average No.  of                             Minimum No.  of       Maximum No.  of
        Category               Submissions        No. of  Patients         Individuals           Individuals
----------------------------------------------------------------------------------------------------------------
Individual Patient or                      659                     1                   659                   659
 Emergency IND
----------------------------------------------------------------------------------------------------------------
Small Patient Population/                   55             10 to 100                   550                 5,500
 Other
----------------------------------------------------------------------------------------------------------------
Treatment IND or                           4.6         100 to 10,000                   460                46,000
 Protocol
----------------------------------------------------------------------------------------------------------------
Total                                                                                1,669                52,159
----------------------------------------------------------------------------------------------------------------

D. Nature of the Impact

    The final rule will affect patients who lack effective therapeutic
alternatives and may benefit from access to investigational drugs,
physicians attempting to obtain investigational drugs for their
patients, drug sponsors who make investigational drugs available to
patients, and FDA in its oversight role in the process for making
investigational drugs available for expanded access use. As discussed
in the preamble of the proposed rule (71 FR 75147 at 75149 to 75150), a