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[Federal Register Volume 74, Number 155 (Thursday, August 13, 2009)]
[Rules and Regulations]
[Pages 40900-40945]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-19005]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 312 and 316

[Docket No. FDA-2006-N-0238] (formerly Docket No. 2006N-0062)
RIN 0910-AF14

Expanded Access to Investigational Drugs for Treatment Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations on access to investigational new drugs for the treatment of 
patients. The final rule clarifies existing regulations and adds new 
types of expanded access for treatment use. Under the final rule, 
expanded access to investigational drugs for treatment use is available 
to individual patients, including in emergencies; intermediate-size 
patient populations; and larger populations under a treatment protocol 
or treatment investigational new drug application (IND). The final rule 
is intended to improve access to investigational drugs for patients 
with serious or immediately life-threatening diseases or conditions who 
lack other therapeutic options and who may benefit from such therapies. 
Elsewhere in this issue of the Federal Register, FDA is publishing the 
final rule on Charging for Investigational Drugs Under an 
Investigational New Drug Application which clarifies the circumstances 
in which charging for an investigational drug in a clinical trial is 
appropriate, sets forth criteria for charging for an investigational 
drug for the different types of expanded access for treatment use 
described in this final rule, and clarifies what costs can be recovered 
for an investigational drug.

DATES: This rule is effective October 13, 2009.

FOR FURTHER INFORMATION CONTACT:
    Colleen L. Locicero, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 4200, 
Silver Spring, MD 20993-0002, 301-796-2270; or
    Stephen M. Ripley, Center for Biologics Evaluation and Research 
(HFM-17), Food and Drug Administration, 1401 Rockville Pike, Rockville, 
MD 20852, 301-827-6210.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Overview of the Final Rule Including Changes to the Proposed 
Rule
    A. Overview
    B. Changes to the Proposed Rule
III. Comments on the Proposed Rule
    A. General Comments on the Proposed Rule
    B. Comments Related to Proposed Rule as a Whole
    C. Comments on Specific Provisions of the Proposed Rule
IV. Legal Authority
V. Environmental Impact
VI. Analysis of Economic Impacts
    A. Objectives of the Final Action
    B. Nature of the Problem Being Addressed
    C. Baseline for the Analysis
    D. Nature of the Impact
    E. Benefits of the Final Rule
    F. Costs of the Final Rule
    G. Minimizing the Impact on Small Entities
    H. Alternatives
VII. Paperwork Reduction Act of 1995
    A. The Final Rule
    B. Estimates of Reporting Burden
VIII. Federalism

I. Background

    In the Federal Register of December 14, 2006 (71 FR 75147), FDA 
proposed to amend its regulations permitting access to investigational 
drugs to treat patients with serious or immediately life-threatening 
diseases or conditions when there is no comparable or satisfactory 
alternative therapy to diagnose, monitor, or treat the patient's 
disease or condition.
    As discussed in greater detail in the preamble to the proposed rule 
(71 FR 75147 at 75148 to 75149), there have been several statutory and 
regulatory efforts to expand access to investigational drugs for 
treatment use. Before 1987, there was no formal recognition of 
treatment use in FDA's regulations concerning INDs, but investigational 
drugs were made available for treatment use informally. In 1987, FDA 
revised the IND regulations in part 312 (21 CFR part 312) to explicitly 
provide for one specific kind of treatment use of investigational drugs 
(52 FR 19466, May 22, 1987). Section 312.34 authorized access to 
investigational drugs for a broad population under a treatment protocol 
or treatment IND when certain criteria were met. Section 312.35 
described the submission requirements for such treatment use. The 1987 
IND regulations also implicitly acknowledged the existence of other 
kinds of treatment use, notably use in individual patients, by adding a 
provision for obtaining an investigational drug for treatment use in an 
emergency situation (Sec.  312.36). However, Sec.  312.36 did not 
describe criteria or requirements that must be met to authorize 
individual patient treatment use.
    In response to criticisms that this lack of criteria and submission 
requirements resulted in inconsistent policies, inequitable access, and 
preferential access for certain categories of patients, Congress 
included in the Food and Drug Administration Modernization Act of 1997 
(FDAMA) (Public Law 105-115), which amended the Federal Food, Drug, and 
Cosmetic Act (the act), specific provisions concerning expanded access 
to investigational drugs for treatment use (Expanded Access to 
Unapproved Therapies and Diagnostics, section 561 of the act (21 U.S.C. 
360bbb)).
    FDA proposed this rule in December 2006 to further address the 
concerns that motivated the FDAMA changes, including problems of 
inconsistent application of access policies and programs and inequities 
in access based on the relative sophistication of the setting in which 
a patient is treated or on the patient's disease or condition. By 
describing in detail in the final rule the criteria, submission 
requirements, and safeguards for the different types of expanded access 
for treatment use of investigational drugs, FDA hopes to increase 
awareness and knowledge of expanded access programs and the procedures 
for obtaining investigational drugs for treatment use. The agency 
believes that the final rule appropriately authorizes access to 
promising drugs for treatment use, while protecting patient safety and 
avoiding interference with the development of investigational

[[Page 40901]]

drugs for marketing under approved applications.
    In 2007, after the proposed rule on expanded access was published, 
Congress passed the Food and Drug Administration Amendments Act of 2007 
(FDAAA) (Public Law 110-85). One provision, codified in 505-1(f)(6) of 
the act (21 U.S.C. 355-1(f)(6)), requires the Secretary of Health of 
Human Services (the Secretary) to promulgate regulations concerning how 
a physician may provide a drug under the mechanisms of section 561 when 
the drug is subject to elements to assure safe use under a risk 
evaluation and mitigation strategy (REMS). The expanded access 
mechanisms described in this final rule can be used by a patient 
seeking access to a drug with a REMS in the event that the drug is not 
available to the patient under the criteria of the REMS, provided the 
drug and the patient meet the criteria for an expanded access program. 
Therefore, this rule fulfills the FDAAA requirement.
    This final rule applies both to drug products that are subject to 
section 505 of the act (21 U.S.C. 355) and biological products subject 
to the licensing provisions of the Public Health Service Act (42 U.S.C. 
201 et seq.) and 21 CFR part 601. This is consistent with the previous 
regulations on treatment use, which applied to both drug and biological 
products.

II. Overview of the Final Rule Including Changes to the Proposed Rule

A. Overview

    The final rule amends FDA regulations by removing the current 
sections on treatment use of investigational drugs (Sec. Sec.  312.34, 
312.35, and 312.36), revising Sec.  312.42 on clinical holds, and 
adding subpart I of part 312 on expanded access. Subpart I describes 
the following ways that expanded access to treatment use of 
investigational drugs are available:
     Expanded access for individual patients, including in 
emergencies;
     Expanded access for intermediate-size patient populations 
(smaller than those typical of a treatment IND or treatment protocol); 
and
     Expanded access treatment IND or treatment protocol 
(described in previous Sec. Sec.  312.34 and 312.35).
    The final rule provides the following: (1) Criteria that must be 
met to authorize the expanded access use, (2) requirements for expanded 
access submissions, and (3) safeguards to protect patients and preserve 
the ability to develop meaningful data about treatment use.

B. Changes to the Proposed Rule

    The final rule has been revised in response to comments received on 
the proposed rule. The responses are discussed in section III of this 
document. The final rule:
     Revises proposed Sec.  312.300(a) to clarify that subpart 
I is intended to apply not only to the use of investigational new drugs 
but also to approved drugs whose availability is limited because the 
drugs are subject to a risk evaluation and mitigation strategy (REMS) 
in accordance with section 505-1(f)(6) of the act.
     Also revises proposed Sec.  312.300(a) to clarify that 
subpart I is intended to apply to all those with a serious disease or 
condition, regardless of whether the patient would currently be 
considered seriously ill with that disease or condition.
     Revises proposed Sec.  312.300(b) to include a definition 
of ``serious disease or condition.''
     Revises proposed Sec.  312.305(c)(5) to clarify that a 
sponsor should make an investigator's brochure available to licensed 
physicians in an expanded access program whenever such a brochure 
exists.
     Revises proposed Sec.  312.310(a)(2) to omit the words 
``type of.''
     Revises proposed Sec.  312.310(c)(2) to clarify that the 
summary of the expanded access use should include all adverse effects, 
not merely unexpected ones, and that the summary should be submitted to 
FDA.
     Revises proposed Sec.  312.310(d)(2) to extend the time in 
which to make written submissions to 15 working days after FDA's 
authorization of emergency use.
    The agency did not propose to amend the text of Sec.  316.40. 
However, because Sec.  316.40 references the requirements of Sec.  
312.34, which is being withdrawn, FDA has revised Sec.  316.40 to 
remove the reference to Sec.  312.34.

III. Comments on the Proposed Rule

    The agency received 119 comments on the proposed rule. Comments 
were received from individuals (persons with serious or immediately 
life-threatening diseases or conditions, persons with family members 
with such diseases or conditions, and other interested persons), 
healthcare and consumer advocacy organizations, healthcare 
professionals (physicians and pharmacists), pharmaceutical and 
biotechnology companies, trade organizations representing 
pharmaceutical and biotechnology companies, health insurance companies, 
a trade organization representing health insurance companies, 
hospitals, a trade organization representing hospitals, and a 
professional society representing oncologists.

A. General Comments on the Proposed Rule

    Most of the comments strongly supported the goal of expanding 
access to investigational drugs for treatment use. The vast majority of 
these comments expressed strong support for the proposed rule as a way 
to expand access. As a category, the largest volume of comments came 
from individuals, and the vast majority of those supported the proposed 
rule. Healthcare and consumer advocacy organizations provided the next 
largest volume of comments. Comments from these organizations spanned 
the spectrum from strongly supportive to strongly negative. Many 
healthcare and consumer advocacy organizations commented that they 
believe the rule strikes the appropriate balance between increased 
access and patient safety without impeding enrollment in clinical 
trials or otherwise jeopardizing the development of new drugs for 
marketing approval.
    Healthcare and consumer advocacy organizations who opposed the 
proposed rule had widely divergent views. Some of these commenters 
expressed the view that the rule did not go far enough in removing the 
obstacles to patient access to investigational drugs for treatment use 
and argued that, after phase 1 safety testing, there should be largely 
unfettered access to investigational drugs for patients with serious or 
immediately life-threatening diseases or conditions and no alternative 
therapies. One of these organizations urged that the rule be withdrawn 
and a substantially more permissive access policy (one that affords 
individual patients greater autonomy) be developed and implemented.
    Some healthcare and consumer advocacy organizations expressed the 
view that the proposed rule went much too far in making investigational 
drugs available to patients for treatment use. One comment argued that 
expanded access as described in the proposed rule would eliminate the 
incentive for patients to enroll in clinical trials that provide the 
evidence necessary to make effective use of new therapies, would be 
harmful to patients exposed to therapies for which there is limited 
safety and effectiveness information, and raises issues of fairness 
because of the potential that the supply of the drug may not be 
adequate to make it available to all those seeking access. Some

[[Page 40902]]

comments argued that there should be access only in the very late 
stages of clinical development, ideally not until phase 3 testing had 
been completed.
    Comments from pharmaceutical and biotechnology companies and their 
trade organizations were the next largest category of comments. These 
comments were generally supportive of the goal of expanding access, but 
expressed concern about the potential for expanded access, as described 
in the proposed rule, to impede drug development and add new 
administrative burdens or expense for companies.
    FDA's response to these general comments is that we believe the 
final rule appropriately addresses the competing concerns surrounding 
expanded access. As discussed in detail in the preamble to the proposed 
rule (71 FR 75147 at 75160), the key question in making investigational 
drugs available for treatment use is how to address the various 
interests--individual patients' desires to make their own decisions 
about their healthcare, including decisions about using experimental 
therapies in advance of such treatments being approved for marketing, 
society's interest in the efficient development of new therapies to 
treat serious and immediately life-threatening diseases or conditions, 
and the need to protect vulnerable patients from unnecessary and 
unacceptable risks. FDA recognizes that these issues are complex and 
can have life-or-death implications, both for individuals seeking 
access to investigational drugs and for large populations of patients 
with a given disease or condition who desire that innovative therapies 
for their disease or condition be developed and marketed as quickly as 
possible. Therefore, it is not surprising that there are a range of 
perspectives about how best to reconcile these competing interests and 
highly impassioned defenses of the various perspectives.
    FDA's perspective in attempting to address and, where possible, 
reconcile these different views, is intended to be consistent with its 
statutory mandate to ensure that drug therapies developed and marketed 
for serious and immediately life-threatening diseases or conditions are 
safe and effective (which requires substantial evidence from clinical 
trials) and that individuals exposed to investigational therapies under 
an IND, whether in a clinical trial or for an expanded access use, are 
not subject to unnecessary and unacceptable risks. FDA acknowledges the 
varied positions expressed on access to investigational drugs for 
treatment use. The agency recognizes that this rule may not be 
satisfactory to all; sometimes it is not possible to reconcile the more 
disparate views. FDA has made its best effort to set forth a regulatory 
policy that is consistent with its statutory mandate, taking into 
account the views of those who commented. FDA believes it has addressed 
these competing issues in a way that affords patients a meaningful and 
reasonable measure of autonomy over their own healthcare decisions 
while preserving the integrity of the drug approval process and 
protecting patient safety.
    Specific issues raised by the comments and the agency's responses 
follow.

B. Comments Related to the Proposed Rule as a Whole

1. Public Awareness and Physician and Patient Education Programs
    (Comment 1) In the preamble to the proposed rule (71 FR 75147 at 
75149), FDA stated that the major goals of this rulemaking are to 
broaden the scope of expanded access and to address concerns about 
inequities in access to investigational drugs under expanded access 
programs. FDA explained that by describing in detail in regulation the 
criteria, submission requirements, and safeguards for the different 
types of expanded access programs, FDA hoped to increase knowledge and 
awareness of expanded access programs and the procedures for obtaining 
investigational drugs under such programs and, as a result, facilitate 
wider availability of investigational drugs in appropriate 
circumstances. FDA also explained that it wished to address concerns 
that in the past, access to investigational drugs has been primarily 
available to patients with certain serious or immediately life-
threatening diseases or condition--particularly cancers, Human 
Immunodeficiency Virus (HIV) disease, and HIV-related conditions--and 
hoped that the greater awareness and clarity fostered by this 
rulemaking would facilitate access to investigational drugs for 
patients with serious or immediately life-threatening diseases or 
conditions who may have been underserved in the past.
    Several comments expressed the view that this rulemaking alone 
would not be sufficient to accomplish these goals. One comment argued 
that promulgating expanded access regulations is an ineffective vehicle 
to increase knowledge and awareness of expanded access programs because 
FDA regulations are not widely read by healthcare providers and 
consumers. Another comment stated that Federal Register notices are not 
the best way of disseminating information to the lay public or their 
healthcare providers and complained that the proposed rule did not 
mention any additional efforts to disseminate the new policies.
    Several comments recommended that FDA do more to publicize its 
expanded access regulations, educate and train physicians, and/or 
improve communications with patients and patient advocacy 
organizations. One comment stated that patients are sometimes confused 
about the reasons they are not able to enroll in an expanded access 
program or obtain individual access and urged FDA to consider ways to 
improve communication to patients about the standards for expanded 
access to minimize this confusion. One comment recommended that 
training materials and information be made available to the general 
public in an easily accessible format and medium, such as on FDA's Web 
site, so that patients and patient advocates can obtain the 
instructions for submitting an expanded access request. Another comment 
from a patient advocacy group recommended that FDA provide guidance on 
each of the specific types of expanded access. The comment stated that 
not all physicians will have the time or inclination to inform 
themselves about the expanded access mechanisms and processes and, 
therefore, it is important that patients and patient advocates be 
informed about expanded access and FDA's requirements for expanded 
access so that they can inform their physicians.
    (Response) FDA believes that clearly specifying in regulations the 
mechanisms and processes for obtaining investigational drugs for 
treatment use is the essential and fundamental platform on which to 
build awareness of, and accessibility to, expanded access programs. FDA 
agrees, however, that new expanded access regulations alone will not be 
sufficient to increase knowledge and awareness about expanded access to 
an extent that will meet FDA's goals for broader and more equitable 
access. Therefore, in conjunction with publication of this final rule, 
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.
    (Comment 2) Some comments stated that additional steps would be 
needed to address complaints that access to investigational drugs was 
biased toward cancer and HIV disease patients. One comment recommended 
that FDA work more closely on early access programs with disease-
specific institutes at the

[[Page 40903]]

National Institutes of Health (NIH) in addition to the National Cancer 
Institute and the Office of AIDS Research in the National Institute for 
Allergy and Infectious Disease. One comment recommended outreach to 
better inform minorities about access to investigational drugs for 
treatment use. The comment suggested a program specifically directed at 
African-American women because of their low rates of cancer survival 
relative to white women.
    FDA's Office of Special Health Issues (OSHI) works closely with 
individual patients and patient organizations, including minority and 
special disease groups, and with the healthcare provider community and 
organizations. The office responds to questions about expanded access 
and directs inquiries for specific treatment uses of investigational 
products to the appropriate staff within FDA. The office maintains a 
Web site with general information about expanded access and other ways 
of getting promising therapies to seriously ill patients (see http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/SpeedingAccesstoImportantNewTherapies/default.htm).
    (Comment 3) Some comments urged that all expanded access INDs and 
protocols be listed on ClinicalTrials.gov (http://www.clinicaltrials.gov), the Web site maintained by NIH that is 
intended to include a listing of controlled clinical trials for drugs 
in development. One comment asked that FDA clarify whether the public 
notification provision (the provision that describes what should be 
listed on ClinicalTrials.gov) applies to access programs for 
intermediate-size patient populations.
    (Response) ClinicalTrials.gov is governed by section 402(j) of the 
Public Health Service Act (PHS Act) (42 U.S.C. 282(j)). The law, as 
amended by FDAAA, requires the registration of certain controlled 
clinical trials on ClinicalTrials.gov and specifically requires 
information to be included about whether expanded access to an 
investigational drug under section 561 of the act is available for 
those who do not qualify for enrollment in the clinical trial and how 
to obtain information about such access (section 
402(j)(2)(A)(ii)(II)(gg) of the PHS Act). The ClinicalTrials.gov 
provisions only apply to certain controlled clinical trials (see 
definition of ``applicable drug clinical trial'' in section 
402(j)(1)(iii) of the PHS Act). Thus, information about expanded access 
is required to appear in ClinicalTrials.gov when the drug at issue is 
the subject of certain controlled clinical trials (i.e., other than 
phase 1 trials in which one group of participants is given an 
investigational drug subject to FDA's jurisdiction, while the control 
group receives either a standard treatment for the disease or a 
placebo). If expanded access is for an investigational drug that is not 
the subject of certain controlled clinical trials, the statute does not 
require information about the expanded access in ClinicalTrials.gov. 
Thus, for example, information about an expanded access program for an 
intermediate-size patient population for a drug that is being developed 
(see Sec.  312.315(a)(2)) would be included in ClinicalTrials.gov as 
long as the other requirements for inclusion are met. However, 
information about an expanded access program for an intermediate-size 
patient population for a drug that is not being developed under a 
clinical trial (see Sec.  312.315(a)(1)) and therefore is not subject 
to the mandatory registration provisions in section 402(j) of the PHS 
Act would not be required to be included in ClinicalTrials.gov.
2. Administrative Burdens Associated With Obtaining Expanded Access
    (Comment 4) A number of comments, particularly from patient 
advocacy groups, stated that the administrative burdens associated with 
expanded access could undermine FDA's efforts to broaden access. The 
general concern was that the requirements, particularly for physicians 
seeking individual patient INDs, are too onerous and, therefore, 
physicians will be reluctant or unwilling to seek investigational drugs 
for treatment use for their patients. Two comments argued that the 
burden would be greatest in nonacademic settings because physicians in 
those settings are typically not as familiar with IND regulations and 
Institutional Review Board (IRB) requirements. The comments recommended 
that the requirements for expanded access for individual patients be 
simplified and disconnected from compliance with other sections of part 
312 (e.g., investigator and sponsor responsibilities in subpart D 
(Responsibilities of Sponsors and Investigators)). Another comment 
stated that administrative burdens are a particular problem in the 
academic research setting, where intensive IRB approval and oversight, 
combined with the data collection requirements of the protocols, have 
forced some centers to forego participation in expanded access programs 
until they can find a source of funding.
    (Response) FDA shares the concern that the requirements for 
obtaining access to investigational drugs, if perceived as burdensome, 
may be a deterrent to obtaining access to investigational drugs for 
treatment use. However, FDA believes the evidentiary, submission, and 
data collection requirements are generally non-labor intensive, 
straightforward, and appropriate to the kind of assurances needed to 
permit treatment use of investigational drugs. We acknowledge that 
compliance with the expanded access requirements might pose particular 
challenges for physicians (whether in academic or nonacademic settings) 
who are not very familiar with IND and IRB regulations, as well as for 
medical centers in which existing administrative burdens already test 
the limits of available resources. However, we believe that the burdens 
associated with IND compliance and IRB review under expanded access 
programs have been minimized to the extent possible while still 
ensuring patient safety.
    The majority of the data necessary to satisfy the IND submission 
requirements for a licensed physician obtaining an IND for an 
individual patient will, in most cases, be provided by reference to the 
content of an IND held by a sponsor who is developing the 
investigational drug for marketing. (In the case of treatment access to 
an approved drug that is subject to a REMS, reference to a sponsor's 
IND may not be necessary.) Therefore, in making an IND submission, the 
physician will ordinarily only be required to provide a narrative 
explaining the rationale for the intended use and dose, why there are 
no comparable or satisfactory therapeutic alternatives, a description 
of the patient's disease or condition (including recent medical history 
and previous treatments), and the monitoring, testing, or other 
procedures needed to minimize the risks of the drug to the patient. For 
the post-treatment submission, the physician must provide a written 
summary of the results of the expanded access use, including adverse 
effects. The information needed for each of these submissions is the 
same kind of information that is captured during routine patient care 
and, consequently, is already known to the physician or can be readily 
accessed. Therefore, FDA does not consider these submission 
requirements to be a burden that is out of proportion with the risks 
inherent in using an investigational product for treatment use (see 
response to comment 60 for discussion of IRB review issues). FDA 
intends to engage in educational efforts to help physicians understand 
the individual patient requirements and how to navigate those 
requirements in a way that minimizes the administrative

[[Page 40904]]

burdens. These efforts will be directed at physicians in both academic 
and nonacademic settings.
    For multi-patient expanded access INDs, FDA agrees that there are 
steps that could be taken to minimize administrative burdens at 
participating sites. As with any use of investigational agents, FDA 
encourages the use of centralized IRBs and standardized data collection 
documentation across expanded access IND sites when there are multiple 
sites. As part of its ongoing outreach efforts on expanded access, FDA 
intends to work with constituents in patient advocacy, clinical 
settings, and the pharmaceutical industry to minimize the burdens 
associated with multi-patient expanded access programs generally, as 
well as the burdens associated with specific multi-patient access 
programs as they arise.
    FDA does not believe that licensed physicians and sponsors should 
be exempt from compliance with the sponsor and investigator 
requirements in subpart D of part 312. It is crucial to keep in mind 
that expanded access involves use of an investigational therapy in a 
vulnerable population, so the rationale for oversight, monitoring, 
recordkeeping and human subject protections applicable to clinical 
trials is equally applicable in the treatment use context. Accordingly, 
Sec.  312.305(c) of the final rule provides that investigators, 
sponsors, and sponsor-investigators must comply with the 
responsibilities for sponsors and investigators set forth in subpart D 
of part 312 to the extent they are applicable to the expanded access 
use. Section 312.305(c)(1) provides that a licensed physician under 
whose immediate direction an investigational drug is administered or 
dispensed for an expanded access use is considered an investigator. 
Section 312.305(c)(2) provides that an individual or entity that 
submits an expanded access IND or protocol is considered a sponsor. 
Section 312.305(c)(3) provides that a licensed physician under whose 
immediate direction an investigational drug is administered or 
dispensed, and who submits an IND for expanded access use, is 
considered a sponsor-investigator.
3. Equitable Access
    The preamble to the proposed rule (71 FR 75147 at 75149) explains 
that, by describing in detail the categories of expanded access use and 
the criteria and submission requirements for such use, and otherwise 
increasing awareness of the mechanisms and processes for obtaining 
investigational drugs for treatment use, FDA hopes to make 
investigational drugs for treatment use more accessible for diseases 
and conditions and in clinical settings that have purportedly been 
underserved by expanded access programs.
    (Comment 5) Several comments agreed that certain diseases, 
conditions, and regions have been underserved by expanded access 
programs. Some comments maintained that minority populations, in 
particular African-Americans and women, have been underserved by 
expanded access programs and that these populations should be the focus 
of efforts to make access to investigational drugs for treatment use 
more equitable.
    (Response) FDA agrees that regions, diseases, or populations that 
have been underserved by expanded access programs should be the focus 
of efforts to ensure more equitable access. FDA's OSHI is committed to 
working with any underserved constituencies to help address inequities 
in the access to investigational drugs for treatment use.
    (Comment 6) One comment expressed concern that the implications of 
one of FDA's stated goals--to improve access to investigational 
therapies outside academic medical centers--are unknown and may be 
harmful. The comment suggested that a possible reason that access to 
investigational drugs for treatment use is more likely in academic 
medical centers is that these centers tend to treat more patients with 
serious and immediately life-threatening diseases or conditions who 
have exhausted all available conventional treatment options. The 
comment noted that there is a lack of information in the proposed rule 
concerning differences in patient outcomes between patients treated 
with investigational drugs in academic medical centers and those 
treated elsewhere and suggested that, absent such data, it is not 
necessarily desirable for the use of investigational drugs for 
treatment use to become significantly more prevalent outside academic 
medical centers.
    (Response) FDA acknowledges that patients who have the diseases or 
conditions for which treatment use of investigational drugs is 
generally sought may be found in greater numbers in academic medical 
centers specializing in the treatment of serious and immediately life-
threatening conditions. FDA does not agree, however, that the intent to 
facilitate access in all settings requires data on comparative quality 
of care across different settings, any more than it would require such 
a comparison among academic centers in geographic regions. FDA believes 
it is important to foster use of investigational drugs for treatment 
use in all settings in which eligible patients receive care, provided 
there are appropriate controls and oversight, as set forth in this 
final rule.
4. Supplies of Investigational Drugs
    (Comment 7) Several comments were concerned that there seemed to be 
an implicit assumption in the proposed rule that there will be an 
adequate supply of an investigational drug to meet the demand for the 
drug generated by potentially broader access over an indefinite period 
of time. Some comments pointed out that increasing demand for an 
investigational drug could create supply constraints, which could make 
it impossible to provide a drug for treatment use to all those who seek 
it and could also threaten the completion of clinical studies of the 
drug. One comment argued that expanded access programs should focus on 
investigational drugs with an adequate supply to meet the potential 
demand. Two comments stated that access should be fair and equitable in 
situations in which the supply cannot meet the demand. One comment 
recommended that the treatment IND provisions in the final rule include 
a way to ensure fair and equitable access in situations in which there 
is not enough supply of a drug to meet the demand.
    (Response) FDA agrees that, in cases when there is not sufficient 
supply of an investigational drug to make it available to all patients 
who seek it, access to the drug for treatment use should be as 
equitable as reasonably possible. FDA does not agree that expanded 
access programs should be limited to only those situations in which 
there is an adequate drug supply for all potential subjects. Mechanisms 
to fairly allocate limited drug supply (e.g., lotteries) have been used 
in the past to provide drugs to at least some of the patients who could 
benefit. FDA supports the use of these mechanisms where they are 
needed.
    However, FDA does not believe that it is necessary to include in 
the final rule a requirement that fair and equitable distribution 
mechanisms be used to allocate an investigational drug in the event of 
insufficient supply. Current IRB regulations require an IRB to 
determine that selection of subjects, in this case patients to be 
treated, is equitable (21 CFR 56.111(a)(3)). FDA believes that 
provision is adequate to ensure equitable access in cases in which the 
drug supply is not adequate to meet the demand.
    FDA anticipates that the most appropriate distribution mechanism 
for a drug with limited supply will be very case specific, for example, 
requiring

[[Page 40905]]

identification of threshold clinical parameters for possible access and 
a mechanism to randomly select from those who meet the parameters. 
Therefore, FDA believes it is advisable for the sponsor to work with 
the relevant patient or disease advocacy organizations, professional 
societies, and other affected constituencies to devise the most 
appropriate mechanism for allocating a limited drug supply in a 
specific situation. However, it should be noted that FDA has no 
authority to compel sponsors to participate in that collaboration or to 
make their investigational products available for treatment use.
5. Industry Support or Incentives to Broaden Expanded Access
    (Comment 8) Some comments argued that the proposed rule would not 
increase expanded access because a substantial increase in access would 
require industry support. Some comments suggested that FDA offer 
financial incentives to industry, such as extending periods of 
exclusivity or expediting drug review, to encourage drug companies to 
make drugs available for treatment use.
    (Response) FDA is aware that, for a variety of reasons, there may 
be reluctance among pharmaceutical and biotechnology companies to make 
investigational drugs available under expanded access programs. FDA's 
charging rule, published elsewhere in this issue of the Federal 
Register, is intended to address concerns about financial barriers to 
providing access by allowing companies to charge an amount for an 
investigational drug that enables them to recover the costs associated 
with making the drug available. Other financial incentives are beyond 
the scope of this regulation and FDA's statutory authority. For 
example, FDA's existing authority to extend marketing exclusivity to 
induce certain behavior derives from congressional mandates.
    FDA also does not believe that a promise to expedite review of new 
drug applications (NDAs) is a reasonable option to encourage broader 
access to investigational drugs for treatment use. The types of drug 
products that meet the requirements for treatment use--investigational 
therapies to treat serious and immediately life-threatening diseases or 
conditions--are likely to already be eligible for the shortest review 
times currently available (6 months). Given the complexity of NDAs, FDA 
does not believe it can routinely review applications in less time 
while maintaining the integrity of the review process.
6. Data Obtained from Expanded Access Use
    (Comment 9) One comment asked whether data generated in expanded 
access programs must be submitted to the NDA for the drug product and, 
if so, how FDA evaluates this information when determining the safety 
and efficacy of the drug for the proposed indication and patient 
population. Another comment stated that FDA's historical reluctance to 
consider efficacy information from expanded access uses as evidence of 
efficacy in an NDA or supplemental NDA has been a disincentive for some 
companies to make a product available for expanded access. The comment 
maintained that it would be appropriate to consider safety and efficacy 
information from an expanded access IND or protocol in assessing the 
safety and effectiveness of a drug when the use and patient population 
in the expanded access IND or protocol are similar to the use and 
population for which approval is sought. The comment asked that FDA 
revise the proposed rule to explicitly inform sponsors, investigators, 
patients, and patient representatives that any safety and efficacy data 
collected in expanded access are expected to be reported in the initial 
NDA seeking approval for the drug or biological product. One comment 
argued that a company that makes a drug available for treatment use 
under an expanded access IND or protocol runs the risk of being 
adversely affected by unfavorable safety observations from use in the 
expanded access population, notwithstanding that the patients receiving 
the drug under an expanded access IND or protocol are often sicker, 
nonresponders to prior treatments, and otherwise not representative of 
the population evaluated in controlled clinical trials, but there is no 
commensurate benefit to the company from favorable efficacy 
observations in the expanded access population.
    (Response) As with any IND, sponsors of expanded access INDs must 
provide FDA with information on patient outcomes and adverse events 
observed during an expanded access use. This information must be 
included in IND annual reports (Sec.  312.33) and/or IND safety reports 
(Sec.  312.32) and, typically, an NDA must also contain at least a 
summary of the expanded access experience with a drug. The information 
obtained from an expanded access use can be useful to a drug's safety 
assessment. For example, a relatively rare adverse event might be 
detected during expanded access use, or such use might contribute 
safety information for a population not exposed to the drug in clinical 
trials. However, a control group is more important to the utility of 
effectiveness data than safety data. Because expanded access programs 
are typically uncontrolled exposure (with limited data collection), it 
is very unlikely that an expanded access IND would yield effectiveness 
information that would be useful to FDA in considering a drug's 
effectiveness. However, if a sponsor believes that effectiveness 
information from expanded access use can contribute to a determination 
that there is substantial evidence of effectiveness, it should submit 
the information and an explanation of its relevance to FDA.
    There are examples in which FDA has made use of adverse events 
information from expanded access use in the safety assessment of a 
drug. There are a small number of cases in which an important adverse 
event was first identified during expanded access use and those adverse 
events were included in product labeling. This is not a negative from a 
public health perspective--the sooner important adverse events are 
identified the better. Even from the sponsor's viewpoint, early 
discovery of a rare adverse event is, on the whole, a benefit. Although 
adverse events first identified during expanded access use of certain 
drugs have been included in the drugs' approved product labeling, we 
are unaware of any cases in which adverse event information obtained 
from expanded access use has resulted in denial of approval for a 
product.
    (Comment 10) One comment observed that data from expanded access 
might provide helpful information about use of a drug in patients who 
are sicker than those patients enrolled in clinical trials.
    (Response) FDA agrees that expanded access use in a population with 
a particular disease or condition that is sicker than the population in 
the clinical trials might yield some helpful insights into the 
tolerability profile, but typically would not provide insight into the 
response to the drug (effectiveness) because of the uncontrolled nature 
of the access program and limited data collection.
    (Comment 11) Some comments recommended that investigational drugs 
be made available for expanded access only under protocols that are 
designed to capture some scientific knowledge. One comment recommended 
that the final rule require all categories of expanded access to be 
conducted under a clearly defined research protocol. The comment 
recommended that the final rule require that: (1) An appropriate 
sponsor be responsible for collecting patient outcomes data, (2) 
reports be

[[Page 40906]]

submitted in a timely fashion to FDA, and (3) patients be required by 
FDA to participate in official data-gathering processes within a formal 
cohort study or patient registry.
    (Response) FDA does not agree that investigational drugs should be 
made available only under expanded access protocols designed to obtain 
meaningful scientific data, or contingent on enrolling patients in a 
formal cohort study or registry. As explained in Sec.  312.300(a) of 
this final rule, the primary purpose of expanded access is to diagnose, 
monitor, or treat a patient's disease or condition, not to generate 
scientific data intended to characterize the drug. However, FDA agrees 
that there should be efforts to optimize the information obtained from 
expanded access exposures with an eye toward detecting any unexpected 
outcomes or events.
    (Comment 12) FDA received several comments advocating more 
systematic collection of data on outcomes of expanded access programs, 
including adverse events. One comment maintained that current data 
collection practices for expanded access programs rarely yield useful 
information and that better collection of safety data might identify 
previously unknown safety concerns. One comment stated that data 
collection should focus on elements such as drug start and stop dates, 
dose, patient treatment outcomes, and significant adverse events, and 
that collection of adverse events could use standardized reporting 
forms (e.g., MedWatch), which might promote more consistent collection 
of reliable information. One comment also stated that FDA should 
consider compiling a database of evidence derived from expanded access 
uses for use by patients, clinicians, manufacturers, and researchers to 
help identify areas that researchers might pursue for new treatments 
and therapies.
    (Response) FDA agrees that more standardized data collection 
methods and forms could ease some of the documentation burdens 
associated with expanded access. However, FDA does not believe it is in 
a position, at this time, to be able to describe in regulation or 
guidance the form and content of data collection programs specific to 
expanded access uses. FDA is willing to participate in collaborative 
efforts with interested constituents to develop better data collection 
methods. FDA does not believe that data collected from expanded access 
use would, in most cases, be in a form that would be useful for 
hypothesis generation. It is important to note, however, that 
information about some expanded access uses (those involving applicable 
drug clinical trials) will be included in the ClinicalTrials.gov 
results database (see response to comment 3 and http://www.clinicaltrials.gov).
7. Assessing the Impact of Expanded Access
    (Comment 13) One comment encouraged FDA to develop a tracking 
system to evaluate how well the expanded access program is working and 
to identify factors, such as economic obstacles, that might be impeding 
access to investigational drugs for treatment use. The comment 
recommended that the system include information on patients and 
investigators, whether or not requests for expanded access are granted, 
and if not, the reason for not granting such requests, the outcomes of 
the treatments, and costs, if any, to patients who pay for their 
treatments.
    (Response) FDA believes this final rule, in conjunction with 
implementation of electronic format INDs and the expanded 
ClinicalTrials.gov information, will make it easier for the agency to 
compile information about the types of diseases or conditions that are 
or are not being treated under expanded access INDs. That information 
could, for example, identify disease categories that appear to be 
underserved by expanded access INDs. FDA does not foresee that such 
information would be able to specifically identify economic or other 
obstacles to obtaining access for certain diseases or conditions, but 
it could be used to initiate discussions among patient and disease 
advocacy organizations, the relevant medical specialty professional 
society, pharmaceutical companies with products that could possibly be 
made available for expanded access, FDA, and other interested parties 
to help identify barriers to access. As to the comment's specific 
recommendation that a tracking system include information on patients 
and investigators, whether or not requests for expanded access are 
granted, and if not, the reason for not granting such requests, the 
outcomes of the treatments, and costs, if any, to patients who pay for 
their treatments, FDA does not believe that such a system is necessary 
at this time, nor do resources permit establishment of such a system.
8. Open-Label Safety Studies
    In the preamble to the proposed rule (71 FR 75147 at 75155), FDA 
expressed concern that sponsors have used programs other than treatment 
INDs or treatment protocols to make investigational drugs available to 
large populations for treatment use, particularly by identifying such 
programs as ``open-label safety studies.'' The goal of an open-label 
safety study is to better characterize the safety of a drug late in its 
development. However, in practice, many studies that are described as 
open-label safety studies have characteristics that appear to be more 
consistent with treatment INDs or treatment protocols. FDA stated that, 
in the future, it intends to evaluate submissions identified as open-
label safety studies to determine whether those studies are more 
characteristic of treatment INDs or treatment protocols. The proposed 
rule stated that a study described as an open-label safety study that 
provides broad access to an investigational drug in the later stages of 
development, but lacks planned, systematic data collection and a design 
appropriate to evaluation of a safety issue, is likely to be considered 
a treatment IND or treatment protocol.
    (Comment 14) Several comments expressed support for FDA's position 
that programs that make investigational drugs available to large 
populations for treatment use should be treatment INDs or treatment 
protocols, not open-label safety studies. One comment stated that 
mischaracterizing a treatment IND as an open-label safety study 
afforded the study more credibility than it deserved. Several comments 
opposed FDA's position, stating that open-label safety studies are 
important in elucidating the safety profile of investigational drugs 
prior to approval, the time required for formal review could affect 
expediting drug development, and FDA's plan would result in fewer 
expanded access programs.
    (Response) In enunciating this policy, FDA did not intend to limit 
the conduct of open-label safety studies intended to evaluate 
particular safety concerns, such as long-term followup of subjects 
initially enrolled in a randomized trial, safety studies in pediatric 
development programs, and other safety studies. These types of studies 
are legitimate open-label protocols and are an integral part of a drug 
development program. FDA will continue to encourage such studies as 
appropriate.
    However, FDA continues to believe that the treatment IND process is 
a more appropriate vehicle for providing access to investigational 
drugs for treatment use to large populations outside controlled 
clinical trials late in a drug's development. The treatment IND 
provides appropriate patient safeguards and permits FDA the necessary 
oversight over the development program. And as FDA explained in the

[[Page 40907]]

preamble to the proposed rule (71 FR 75147 at 75155), authorization of 
expanded access use is subject to a more formal review process that 
explicitly considers the impact of expanded access on enrollment in any 
ongoing clinical trials and the progress of drug development generally. 
The time for review of a treatment use program should not affect the 
timing of drug development because the need for such an expanded access 
program and the protocol for the program can be considered in advance 
and put in place when needed. Therefore, FDA does not believe this 
policy will result in fewer expanded access programs.
    (Comment 15) One comment asked whether only patients with a serious 
disease or condition could be enrolled in open-label studies that FDA 
would consider to be treatment INDs.
    (Response) One of the threshold criteria for a treatment IND is 
that the population to be enrolled has a serious or immediately life-
threatening disease or condition. Therefore, only protocols intended to 
treat patients with serious or life-threatening diseases or conditions 
are subject to this requirement.
    It should be noted that FDA has not taken the position that the 
agency will consider all open-label safety studies to be treatment 
INDs. FDA will not consider an open-label safety study to be a 
treatment IND when the purpose of the study is actually to study the 
safety profile of the drug.
9. Insurance Coverage for Investigational Drugs and Related Patient 
Care Drug Coverage
    (Comment 16) Several comments were concerned about the potential 
implications of the proposed rule on coverage decisions by health 
insurers and other third-party payers. Some comments were concerned 
that, because the drug made available is investigational, third-party 
payers would deny coverage for the drug and may also deny coverage for 
patient care necessitated by use of the drug. One comment noted an 
example of a patient seeking expanded access to an investigational drug 
who would be required to have frequent, expensive monitoring, including 
electrocardiograms (EKGs) and monthly Computed Tomography (CT) scans, 
and who might not be able to obtain access if health insurance did not 
reimburse for the required monitoring. One comment argued that the 
goals of expanded access are illusory if third-party payers do not 
reimburse for drug costs (if any) and routine patient care necessitated 
by administration of the investigational drug.
    One comment from a health insurance company stated that the design 
of insurance benefits already recognizes that some patients should 
receive benefit coverage for treatments that are not yet supported by 
clinical evidence, both in clinical trials and as treatment for 
promising but unproven treatments for life-threatening illnesses 
outside of clinical trials. The comment asked FDA to clarify in the 
rule that therapies provided under expanded access programs are 
experimental and not FDA-approved and that making these therapies 
available for treatment use does not provide evidence that such 
treatments are ``reasonable,'' ``necessary'' or ``medically 
necessary,'' as defined in benefit documents. The comment stated that 
third-party payers would welcome a more standardized approach to the 
treatment of diseases without established therapies, particularly 
because these rules raise questions about responsibility for routine 
costs associated with otherwise excluded care.
    (Response) FDA's intent in promulgating the expanded access 
regulation is to foster the availability of investigational drugs for 
treatment use to as many patients with serious and life-threatening 
diseases as possible who lack known effective therapies for their 
disease or condition. FDA recognizes that determinations that 
investigational drugs made available under expanded access programs, 
and patient care related to administration of those drugs, are not 
reimbursable would be likely to limit access to such therapies for some 
patients (e.g., those who lack the financial resources to pay out-of-
pocket). It is FDA's hope, therefore, that health insurers and other 
third-party payers will make well-reasoned reimbursement decisions that 
will not impinge on the availability of investigational drugs for 
treatment use. To the extent that it is an insurer's policy that care 
necessitated by administration of an investigational drug in a clinical 
trial is reimbursable, FDA believes that care associated with 
administration of an investigational drug in an expanded access program 
should be treated similarly for reimbursement purposes. However, FDA 
recognizes it has no inherent authority to dictate reimbursement 
policy.
    FDA also recognizes that this final rule may have implications for 
health insurance coverage decisions because of existing language in 
health insurance contracts and how that language is interpreted with 
respect to costs associated with investigational drugs and ancillary 
care provided under expanded access programs. FDA agrees that drugs 
made available under expanded access programs are typically 
investigational and not approved for marketing. However, FDA takes no 
position on how the terms ``reasonable,'' ``necessary,'' or ``medically 
necessary'' in health insurance contracts should be interpreted.
10. Waiver of Liability for Harm Related to Expanded Access
    (Comment 17) One comment from a pharmaceutical company stated that 
the proposed rule does not address the significant liability issues for 
sponsors and investigators arising from making investigational drugs 
available for expanded access. Many comments from individuals stated 
that receiving investigational drugs under expanded access programs 
should be premised on a patient's waiver of liability for harm 
resulting from treatment with the investigational drug. These comments 
maintained that liability should be waived for doctors, hospitals, drug 
manufacturers, and FDA.
    (Response) FDA does not believe it is appropriate to insulate 
investigators or sponsors, whether they are treating physicians, 
hospitals or other clinical settings, or drug manufacturers, from 
potential liability arising from the administration or provision of 
investigational drugs for treatment use. In fact, FDA's informed 
consent regulation, 21 CFR 50.20, states, ``No informed consent, 
whether oral or written, may include any exculpatory language through 
which the subject or the representative is made to waive or appear to 
waive any of the subject's legal rights, or releases or appears to 
release the investigator, the sponsor, the institution, or its agents 
from liability for negligence.'' The scope of FDA's liability, if any, 
for any harm resulting from decisions concerning expanded access to 
investigational drugs for treatment use is determined by statute and 
cannot be modified by a waiver provision in a regulation.
11. Inconsistency Between Subpart I and Subpart E
    The expanded access regulations use the terms ``immediately life 
threatening disease or condition'' and ``serious disease or 
condition.''
    (Comment 18) One comment suggested that there was a discrepancy 
between terminology used in the proposed rule (subpart I of part 312) 
and terminology used in subpart E of part 312. The proposed rule uses 
the term ``immediately life-threatening,'' while

[[Page 40908]]

subpart E uses the term ``life-threatening.'' The proposed rule uses 
the term ``serious,'' while subpart E uses the term ``severely 
debilitating.'' The comment recommended that this final rule clear up 
the confusion arising from the use of similar but different terms in 
FDA regulations.
    (Response) The subpart I regulations are being issued in response 
to a provision of FDAMA, now codified in section 561 of the act (21 
U.S.C. 360bbb). The terms used in this final rule are consistent with 
and drawn from the terminology in section 561. Accordingly, any change 
to make the terms consistent would require revision to subpart E. This 
final rule deals only with subpart I, and thus the comment asks for a 
remedy that is outside the scope of this rule.
    Moreover, we note that subpart E and subpart I have different 
purposes. Subpart E provides procedures to expedite the development, 
evaluation, and marketing of new therapies. Subpart I provides 
procedures for making investigational drugs available when the primary 
purpose is to diagnose, monitor, or treat a patient's disease or 
condition. Nonetheless, if subpart E were to be amended, FDA would then 
consider the propriety of the terminology used in subpart E.

C. Comments on Specific Provisions of the Proposed Rule

1. Scope (Sec.  312.300 and 312.300(a))
    Proposed Sec.  312.300(a) describes the intended scope of subpart I 
of part 312. It makes clear that the purpose of subpart I is to 
describe processes for making investigational drugs available in 
situations in which the primary purpose is to diagnose, monitor, or 
treat a serious or immediately life-threatening disease or condition in 
a patient who has no comparable or satisfactory alternative therapeutic 
options.
    (Comment 19) Three comments asked that FDA clarify whether it 
intended that an expanded access IND be used to make an approved drug 
available for an unapproved indication in a situation in which a 
sponsor is conducting a clinical trial of the approved drug under an 
IND for a new indication to treat a serious disease or condition. Two 
of these comments urged that FDA modify the proposed rule to make clear 
that it applies to unapproved uses of approved drugs. The comments 
believed that such modification would make it more likely that health 
insurance companies would reimburse for unapproved use of approved 
drugs.
    (Response) In general, for an already approved drug that is not 
subject to a REMS, FDA did not intend that an expanded access IND under 
subpart I be used to provide the approved drug to patients with a 
serious disease or condition when the approved drug is being used for 
an unapproved indication. Regardless of whether an approved drug is 
being tested in a clinical trial to treat a serious disease or 
condition that is not part of the current approved indication, use of 
an approved drug off-label for an unapproved indication within the 
practice of medicine (i.e., to treat a patient in a clinical setting) 
is not subject to part 312 (the IND regulations), including subpart I. 
By definition, in such a case, the drug is already being legally 
marketed.
    However, in at least two situations, expanded access under subpart 
I may be appropriate for drugs that are already approved: First, it is 
conceivable that a sponsor developing an approved drug for a new 
indication for treatment of a serious or immediately life-threatening 
disease or condition may want to make the approved drug available for 
the new indication under a treatment IND. For example, if the new 
indication involves a different route of administration or dosage form, 
the sponsor may prefer to provide the new dosage form under a treatment 
IND if it believes that failure to make the drug available under a 
treatment IND could lead to compounding of the drug (e.g., preparation 
of a new dosage form of a drug by a compounding pharmacist using the 
active ingredient of an approved drug product) and that such 
compounding could expose patients to unnecessary risks. FDA would be 
amenable to receiving treatment INDs for unapproved uses of approved 
drugs in situations in which the sponsor would prefer the use of a 
treatment IND to make the drug available for treatment use outside the 
ongoing or completed controlled trials of the unapproved use.
    Second, for drugs that are subject to a REMS, expanded access under 
subpart I may be available to allow treatment of patients who do not 
otherwise meet the criteria under the REMS to receive the drug.
    For these reasons, we have revised Sec.  312.300(a) to state that 
subpart I contains the requirements for the use of investigational new 
drugs and approved drugs where availability is limited by a REMS when 
the primary purpose is to diagnose, monitor, or treat a patient's 
disease or condition. This fulfills the mandate, codified in 505-
1(f)(6) of the act, for the Secretary of Health of Human Services to 
promulgate regulations concerning how a physician may provide a drug 
under the mechanisms of section 561 of the act when the drug is subject 
to elements to assure safe use under a REMS. We will assess the impact 
of this rule on expanded access to drugs subject to a REMS and, if 
appropriate, will consider issuing a guidance on this matter.
    In response to the comment on insurance reimbursement, we note that 
FDA does not have jurisdiction over coverage decisions by health 
insurance companies and, in any case, is not aware that allowing 
expanded access to an already approved drug under subpart I would 
influence coverage decisions by health insurance companies.
    (Comment 20) One comment notes that Sec.  312.300(a) states that 
the intent is to make investigational drugs available to ``seriously 
ill patients,'' while the general criteria in Sec.  312.305(a) require 
that patients to be treated with an investigational drug have ``a 
serious or immediately life-threatening disease or condition.'' The 
comment pointed out that a patient can have a serious disease or 
condition and not be seriously ill, for example, in the early stages of 
a progressive disease.
    (Response) FDA acknowledges that the use of the term ``seriously 
ill'' in the provision describing the intended scope of the access 
provision could be interpreted as narrower in scope than was intended, 
and thus inconsistent with the term ``serious or immediately life-
threatening disease or condition.'' Therefore, FDA has changed Sec.  
312.300(a) to make clear that subpart I is intended to apply to all 
those with a serious disease or condition, whether or not the patient 
would currently be considered seriously ill with that disease or 
condition.
2. Definitions (Sec.  312.300(b))
    a. Immediately life-threatening disease or condition.
    Proposed section 312.300(b) defines the term ``immediately life-
threatening disease'' as a stage of disease in which there is a 
reasonable likelihood that death will occur within a matter of months 
or in which premature death is likely without early treatment.
    (Comment 21) One comment expressed support for the proposed rule's 
definition of the term ``immediately life-threatening disease'' and 
encouraged FDA to include this definition in the final rule. One 
comment maintained that the proposed definition of immediately life-
threatening was unnecessary because immediately life-threatening 
conditions are a subset of serious conditions and thus need not be 
defined.
    (Response) The proposed rule defined the term ``immediately life-
threatening disease'' because the evidentiary criteria

[[Page 40909]]

for authorizing a treatment IND under proposed Sec.  312.320 vary 
depending on whether the disease or condition is merely serious or is 
also immediately life-threatening. There is a lower evidentiary 
threshold for a treatment IND for an immediately life-threatening 
condition. The evidentiary distinction and definition are carried over 
from the previous treatment IND regulation and reflect the distinction 
between section 561(c)(6) and (c)(7) of the act. Because the final rule 
retains the lower evidentiary standard for authorizing a treatment IND 
for an immediately life-threatening condition, FDA believes it is 
necessary to retain the definition.
    (Comment 22) One comment from an organization representing epilepsy 
centers asked the agency to define immediately life-threatening in such 
a way that it would include status epilepticus and pointed out that the 
mortality rate from status epilepticus is up to 6 percent.
    (Response) A disease or condition with an acute mortality rate of 
six percent would be considered an immediately life-threatening 
condition for purposes of subpart I.
    b. Serious disease or condition.
    In the preamble to the proposed rule (71 FR 75147 at 75151), the 
agency explained that, because of the difficulty in specifically 
describing regulatory criteria that characterize a ``serious disease or 
condition,'' the proposed rule does not provide a definition for the 
term. Because it is difficult to define ``serious disease or 
condition'' without appearing to exclude diseases or conditions that 
should be considered serious or include those that should not, FDA in 
the proposed rule elected to describe and illustrate by example what is 
meant by serious disease or condition in other regulatory settings 
where the seriousness of a disease or condition is an issue (e.g., Fast 
Track, Accelerated Approval) (see FDA's guidance for industry entitled 
``Fast Track Drug Development Programs--Designation, Development, and 
Application Review'' (Fast Track guidance) (63 FR 64093, November 18, 
1998)). The preamble solicited comment on this approach for purposes of 
expanded access--implicitly asking whether the term should be defined 
or the agency's previous practice of describing the concept and 
illustrating by example was acceptable.
    (Comment 23) Several comments stated that FDA should define 
``serious disease or condition.'' No comments recommended not defining 
the term. Three comments stated that not defining the term and relying 
on existing descriptions and illustrations of what is meant by the term 
would make access to investigational drugs for treatment use overly 
broad. One of those comments argued that a definition would promote 
more consistent application of the rule. One comment recommended that 
the definition err on the side of inclusiveness. One comment asked for 
clarification of what is meant by serious disease or condition because 
it is unclear what serious conditions would have an important effect on 
functioning or other aspects of quality of life as well as persistent 
or recurrent morbidity.
    Some comments provided recommendations or specific language on how 
to define serious disease or condition. Two comments recommended 
relying on existing language in the Fast Track guidance (pp. 3 to 4). 
One comment recommended defining serious disease or condition based on 
the following criteria in a 1999 Institute of Medicine (IOM) Report 
entitled ``Definition of Serious and Complex Medical Conditions.'' The 
IOM report gave the following examples of descriptive criteria for 
serious and complex medical conditions:
     Conditions that cause serious disability, such as stroke 
or closed head or spinal cord injuries.
     Conditions that cause significant pain or discomfort that 
can cause serious interruptions to life activities, such as arthritis 
and sickle cell disease.
     Conditions that may require frequent monitoring, such as 
schizophrenia and other psychotic illnesses.
     Conditions whose treatment carries the risk of serious 
complications, such as most cancers or conditions requiring complex 
surgery.
    Another comment recommended that the definition of serious disease 
or condition be made consistent with the definition of serious adverse 
drug experience in Sec.  312.32(a) (the definition used for the IND 
safety reporting requirements), which defines a serious adverse drug 
experience as including inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/
incapacity, or a congenital anomaly/birth defect.
    (Response) Because of the support for defining the term ``serious 
disease or condition'' in the comments, FDA is providing a definition 
in the final rule. As recommended by some comments, FDA is basing the 
definition on the description of a serious disease or condition in the 
Fast Track guidance. That description and illustration of serious 
disease or condition was the result of prolonged and careful 
deliberations concerning what should be considered a serious disease or 
condition and has served the agency well in its implementation of the 
Fast Track legislation. The Fast Track guidance (p. 4) states that 
whether a disease or condition is serious ``is a matter of judgment, 
but generally is based on its impact on such factors as survival, day-
to-day functioning, or the likelihood that the disease, if left 
untreated, will progress from a less severe condition to a more serious 
one. * * * For a condition to be serious, the condition should be 
associated with morbidity that has substantial impact on day-to-day 
functioning. Short-lived and self-limiting morbidity will usually not 
be sufficient but the morbidity need not be irreversible, provided it 
is persistent or recurrent.'' FDA believes this definition is also 
conceptually consistent with the criteria identified in the IOM report, 
the definition of serious adverse drug experience in the IND safety 
reporting regulation, and the description of serious disease or 
condition in the preamble to 21 CFR part 314, subpart H (Accelerated 
Approval of New Drugs for Serious or Life-Threatening Illnesses). 
Therefore, we have adopted this definition of serious disease or 
condition in Sec.  312.300(b).
    FDA recognizes, based on its own experience in trying to define and 
describe what is meant by serious disease or condition, that this 
definition will be subject to various interpretations. FDA intends to 
be flexible in its interpretation of the term to ensure that the 
definition does not thwart access to an investigational drug in a 
situation where access would be desirable. It is foreseeable that there 
might even be situations in which a serious health risk in the absence 
of active serious disease should be considered a serious condition. For 
example, it may be desirable to make an experimental vaccine available 
as a prophylactic measure to laboratory workers who have been 
inadvertently exposed to a deadly pathogen but have not yet contracted 
the disease. Notwithstanding the potential pitfalls in defining serious 
disease or condition, based on the views expressed in the comments 
received, FDA believes that stating a definition is preferable to 
providing only an explanation and illustration of the concept of 
serious disease or condition and will facilitate more consistent and 
equitable application of the expanded access regulations.
    (Comment 24) One comment stated that intractable epilepsy should be 
considered a serious disease or

[[Page 40910]]

condition. Another comment was concerned that in situ breast cancer 
would not be considered a serious disease or condition for purposes of 
the expanded access regulations.
    (Response) FDA agrees that intractable epilepsy and in situ breast 
cancer would be considered serious conditions for purposes of the 
expanded access regulations as each would unquestionably cause 
morbidity and potentially premature mortality if left untreated.
3. Requirements for All Expanded Access (Sec.  312.305)
    Proposed Sec.  312.305 contains the general criteria for 
determining whether access to investigational drugs for treatment use 
is appropriate under the expanded access uses described in subpart I 
(Sec.  312.305(a)), the general submission requirements for the 
expanded access INDs described in subpart I (Sec.  312.305(b)), and 
safeguards applicable to those expanded access uses (Sec.  312.305(c)).
    Proposed Sec.  312.305(a)(1) states that FDA must determine that 
the patient or population to be treated has a serious or immediately 
life-threatening disease or condition and there is no comparable or 
satisfactory alternative therapy to diagnose, monitor, or treat the 
disease or condition.
    a. Comparable or satisfactory alternative therapy.
    (Comment 25) One comment from a cancer patient appeared to assert 
that there should be more flexibility in assessing whether there are 
comparable satisfactory or alternative therapies. The comment stated 
that certain comparable alternative therapies may be more toxic and 
patients exposed to those therapies may become too sick to survive any 
subsequent treatment, thus barring them from access to a promising 
experimental treatment.
    (Response) FDA shares the comment's concern that existing 
alternative therapies may have greater toxicity than an experimental 
treatment option, especially in the oncology setting. FDA believes that 
the relative toxicity of potential alternative therapies is clearly an 
element to be considered in whether there are comparable or 
satisfactory alternative therapies for a given patient. The potential 
lower toxicity of an experimental therapy would be considered in light 
of the more established effectiveness profile of the approved therapy, 
the patient's ability to tolerate the approved therapy, and other 
clinical factors in assessing whether the approved therapy is a 
satisfactory alternative therapy.
    b. Risk/benefit assessment--evidentiary standards.
    Proposed Sec.  312.305(a)(2) provides that FDA must determine that 
the potential patient benefit justifies the potential risks of the 
treatment use and that those risks are reasonable in the context of the 
disease or condition to be treated. For individual patients, proposed 
Sec.  312.310(a)(1) further provides that the physician seeking access 
for a patient must also determine that the probable risk to the person 
from the investigational drug is not greater than the probable risk 
from the disease or condition. For intermediate-size patient 
populations, proposed Sec.  312.315(b)(1) further provides that FDA 
must determine that there is enough evidence that the drug is safe at 
the dose and duration proposed for expanded access use to justify a 
clinical trial of the drug in the approximate number of patients 
expected to receive the drug under expanded access, and proposed Sec.  
312.315(b)(2) provides that FDA must determine that there is at least 
preliminary clinical evidence of effectiveness, or of a plausible 
pharmacologic effect of the drug, to make expanded access use a 
reasonable therapeutic option in the anticipated patient population. 
For treatment INDs or treatment protocols, Sec.  312.320(a)(3)(i) 
further provides that for a serious disease or condition, there must be 
sufficient evidence of safety and effectiveness to support the use, 
which would ordinarily consist of data from phase 3 trials but could 
consist of compelling data from completed phase 2 trials. Section 
312.320(a)(3)(ii) requires that, for an immediately life-threatening 
disease or condition, the available scientific evidence taken as whole 
must provide a reasonable basis to conclude that the investigational 
drug may be effective for the expanded access use and would not expose 
patients to an unreasonable and significant risk of illness or injury. 
Such evidence would ordinarily consist of clinical data from phase 3 or 
phase 2 trials, but could be based on more preliminary clinical 
evidence.
    (Comment 26) One comment from a physician with investigational drug 
experience asked that FDA remove the requirement that the agency must 
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 to be treated. 
The comment maintained that the seriously ill patient and his/her 
physician should be the ones to decide whether or not to accept the 
risks of the treatment and that the decision should not be made by FDA 
reviewers. The comment also stated that this provision ``represents a 
sea change'' in FDA's policy because it would regulate the practice of 
medicine.
    Another comment stated that the risk-benefit decision to be made 
for individual patient expanded access should be made only by the 
patient's physician, not also by FDA. The comment objected to the 
proposed criterion that FDA determine that the potential patient 
benefit 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 (Sec.  312.305(a)(2)). The comment 
argued that, in interposing itself into the risk-benefit decision, FDA 
had impermissibly changed the statutory standard for deciding whether 
to grant individual patient expanded access. The comment recognized 
that section 561(b)(2) of the act requires the Secretary to determine 
that there is sufficient evidence of safety and effectiveness to 
support the use of the investigational drug in an individual patient. 
However, the comment stated that this provision does not empower FDA to 
make a risk determination.
    (Response) FDA disagrees with the recommendation to remove the 
requirement that the agency determine whether the potential patient 
benefit justifies the potential risks and whether those risks are 
reasonable in the context of the disease or condition to be treated. 
FDA also rejects the characterization of this policy as a ``sea 
change.'' This policy reflects the essence of FDA's long-standing 
approach to using investigational drugs for treatment use, whether 
under individual patient INDs or multi-patient INDs, and reflects the 
act's requirement of FDA involvement in a determination of the 
propriety of the expanded access use (see section 561(b)(2), (b)(3), 
(c)(6), and (c)(7) of the act). The practice-of-medicine exemption in 
the IND regulations applies to use of an approved drug for an 
unapproved use in a clinical setting, not to the use of an unapproved 
drug. With regard to treatment access to an approved drug subject to a 
REMS, because the risk profile of such a drug means that it is not 
available for unrestricted use, FDA maintains a role, consistent with 
sections 505-1(f)(6) and 561 of the act, in assessing the 
appropriateness of the drug for treatment use analogous to its role 
regarding treatment access to investigational drugs.
    As to the comment that FDA has impermissibly aggregated to itself 
the risk benefit decision to be made for

[[Page 40911]]

individual patient expanded access, the comment itself acknowledges 
that section 561(b)(2) of the act states that the criteria for 
individual patient expanded access include that the Secretary 
determines that there is ``sufficient evidence of safety and 
effectiveness to support the use of the investigational drug.'' If FDA 
were to accede to the comment's interpretation that the risk 
determination belongs solely to the physician, it would effectively 
read out of existence section 561(b)(2) of the act. In that section, 
Congress expressly directed FDA to make a determination regarding the 
sufficiency of the evidence of both safety and effectiveness to justify 
treatment use of an investigational product. While section 561(b)(1) of 
the act requires a physician to make a determination that the probable 
risk to the patient is not greater than the probable risk from the 
disease or condition, this finding is a necessary, but not in itself 
sufficient, prerequisite to providing a drug for individual treatment 
use. Section 561(b)(2) of the act clearly contemplates a determination 
by FDA regarding safety and effectiveness, and the agency cannot choose 
to ignore that responsibility.
    (Comment 27) Some comments were concerned that the proposed rule 
did not provide an adequate balance between risks and benefits and, in 
particular, did not provide a sufficiently high evidentiary standard 
for providing access, and as a result would expose patients to 
unnecessary risks. One comment stated that because many of the drugs 
that would be made available under access programs are highly likely to 
prove ineffective in further clinical testing, exposure to such drugs 
may not improve patients' conditions and, in some cases, may increase 
patient suffering and hasten death. One comment provided an apparent 
illustration of the potential harm. The comment pointed out that 
autologous bone marrow transplants were performed on approximately 
30,000 women with advanced breast cancer before it was established that 
such treatment did more harm than good and that, as a result, some of 
the women who received this treatment had increased suffering and 
shortened lives. One comment stated that a patient should have some 
assurance that an investigational drug may be potentially life-saving 
that would outweigh any potential negative risks of using the drug. 
Some comments maintained that, until there is a certain threshold of 
data available, there should be no access whatsoever. One comment 
argued that there should no expanded access until the completion of 
phase 2 testing, and then only if the phase 2 data are compelling. 
Another comment recommended that there be no expanded access until 
evidence of a drug's safety and effectiveness has been demonstrated in 
clinical trials that will be submitted for approval, which would 
usually be data from phase 3 trials but may include phase 2 data. Other 
comments were concerned that the proposed rule required too much 
evidence to obtain an investigational drug for treatment use. Those 
comments believe that the evidentiary standards would inappropriately 
deny access to investigational drugs to some patients.
    (Response) The assessment of the risks and benefits of 
investigational therapies in the absence of complete data about the 
safety and effectiveness of those therapies is challenging and subject 
to varied interpretations and viewpoints. FDA believes the proposed 
rule strikes an appropriate balance and sets forth a reasonable 
approach to balancing risks and benefits. That approach, as outlined in 
the discussion above, requires an assessment of risk and benefit based 
on the relative seriousness of the disease or condition and the size of 
the population to be treated under the expanded access IND or 
protocol--with the evidentiary requirements decreasing as seriousness 
increases and the size of the population decreases. Increasing the 
amount of evidence needed as the size of the population exposed 
increases is based on FDA's considerable experience with the clinical 
development of drugs that demonstrates the need to cautiously increase 
the size of exposure in order to detect serious toxicities that occur 
in small percentages of those exposed (and are thus not likely to be 
detected in a small population exposure). Decreasing the amount of 
evidence needed as the seriousness of the disease or condition 
increases simply acknowledges that patients in greater peril are 
willing to assume greater risks.
    FDA recognizes that investigational drugs have risks, including 
unknown risks, and that it is likely that some drugs made available for 
treatment use will ultimately be shown to have no benefit, and in fact 
cause harm. As a result, there is the potential for some patients to be 
harmed by such drugs. However, FDA believes that, on balance, more 
patients are likely to gain some benefit from investigational drugs 
than be harmed by them and, therefore, patient interests are best 
served by making such drugs available under appropriate programs. FDA 
does not believe that a lesser evidentiary standard is warranted. FDA 
believes that to require less evidence would significantly increase the 
likelihood that patients would be more harmed than benefited by use of 
experimental therapies.
    Conversely, FDA does not believe that there should categorically be 
a specified minimum amount of data, such as data from completed phase 2 
or 3 trials, before any expanded access is permitted. As detailed in 
the preamble to the proposed rule (71 FR 75147 at 75168), FDA believes 
there needs to be flexibility in the evidentiary standards to be 
applied to the varied types of expanded access INDs and expanded access 
protocols that the agency is likely to receive. Moreover, even if a 
specified minimum amount of data for expanded access were desirable, 
FDA believes that completion of phase 2 or 3 testing is more than 
should be required for certain types of expanded access INDs and 
expanded access protocols.
    (Comment 28) One comment argued that access has the potential to 
increase the risk to patients with the possibility of no commensurate 
benefit. The comment maintained that safety issues related to exposure 
to an investigational drug are best addressed in the context of 
clinical trials and asked FDA to require that access be provided only 
under a defined protocol, by a qualified investigator, with defined 
dosage range and adverse event monitoring procedures, and with 
specified time intervals for assessing response.
    (Response) FDA agrees that access protocols should provide a 
detailed plan for the conduct of the protocol, including plans for data 
collection and patient monitoring commensurate with the size of the 
population to be treated and the nature of the use (e.g., short-term 
versus long-term). However, because of the broad range of potential 
populations for which access may be provided under an expanded access 
protocol--from an individual patient to many thousands of patients--and 
the wide range of potential risks and resulting need for variations in 
the intensity of monitoring, it would not be good policy to require the 
same level of detail and specificity for each protocol. The amount of 
detail and specificity required will increase with increasing size of 
the population, increasing complexity of the disease being treated, and 
greater risks associated with the use of the drug. For the same 
reasons, the amount of data to be collected and the potential utility 
of that data might vary. Accordingly, FDA believes it would not be 
useful to promulgate specific and uniform data collection and monitor

[[Page 40912]]

requirements for all expanded access protocols.
    i. Individual Patient Evidentiary Standard
    Proposed Sec.  312.310(a)(1) provides that the physician seeking 
access 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. Concerning the evidence needed 
before treating an individual patient with an immediately life-
threatening illness or disease or condition, the preamble to the 
proposed rule stated that to support expanded access for an individual 
patient when the patient has an immediately life-threatening condition 
that is not responsive to available therapy, ordinarily, completed 
phase 1 safety testing in humans at doses similar to those to be used 
in the treatment use, together with preliminary evidence suggesting 
possible effectiveness, would be sufficient to support such a use. 
However, the preamble further stated that in some cases, there may be 
no relevant clinical experience, and the case for the potential benefit 
may be based on preclinical data or on the mechanism of action (71 FR 
75147 at 75151).
    (Comment 29) Several comments were concerned that the evidentiary 
standards applicable to individual patient expanded access allow for 
the possibility of making a drug available to a patient without 
evidence from clinical experience. One comment stated that ``it is 
wrong to permit use in the absence of evidence in humans and to present 
this scenario as `treatment' even for desperately ill patients.'' 
Another comment stated that ``it seems inappropriate and possibly 
dangerous to permit this relatively uncontrolled access to an 
investigational drug to represent the first human exposure to a drug.'' 
Another comment recommended that there be at least preliminary clinical 
evidence (such as phase 1 safety testing) before there be any expanded 
access use regardless of the number of patients. One comment 
recommended that the final rule state that proceeding with treatment 
use in an individual patient should be a rare circumstance that 
requires, at a minimum, submission to FDA of robust evidence from 
nonclinical studies to show that it is reasonably safe to proceed with 
the proposed treatment use, and information forming the basis from 
nonclinical toxicokinetic studies and nonclinical pharmacology studies 
for selecting dosage, dosage interval, and duration of treatment for 
use in patients. One comment recommended that the evidentiary threshold 
for individual patient expanded access be evidence from the clinical 
trials intended to demonstrate safety and effectiveness for marketing 
approval (which would ordinarily be phase 3 studies but could include 
phase 2 studies that support approval). The comment added, however, 
that this category could be used to provide continuity of care for a 
patient who appeared to benefit from a drug during participation in an 
earlier clinical trial.
    (Response) FDA agrees that making an investigational drug available 
to an individual patient in the absence of any clinical data to support 
the use may carry substantial risk. FDA does not believe, however, that 
access under such circumstances should be entirely foreclosed by the 
expanded access provisions. FDA believes--and our experience has 
demonstrated--that there are circumstances in which such use may be 
appropriate. These circumstances might involve a patient with an 
imminently life-threatening disease or condition, a novel therapy that 
has a plausible pharmacologic rationale suggesting it may potentially 
be beneficial for that disease or condition, and robust nonclinical 
safety data to support the use. FDA does agree that use of an 
investigational drug for treatment purposes in an individual patient in 
the absence of any clinical data should be extremely rare. FDA 
anticipates that authorizing an individual patient treatment use of a 
drug in the absence of clinical data on use of the drug for that 
indication would be more likely to occur when there was some clinical 
data on the drug (e.g., from a study for another use) but no clinical 
data in the population or disease for which treatment use is sought.
    However, FDA does not agree that there should be no expanded access 
to an investigational drug for anyone until the evidence needed to 
support approval is developed, which ordinarily would not occur until 
the completion of phase 3 clinical testing. In addition, FDA does not 
believe the expanded access provisions in subpart I are necessary to 
provide continuity of care for patients who seemed to have responded to 
an investigational therapy during a clinical trial. A protocol 
amendment adding a continuation phase to the clinical trial would 
ordinarily be the preferred mechanism for providing an investigational 
therapy to clinical trial participants who wish to continue to receive 
the drug after the completion of the controlled phase of the clinical 
trial.
    (Comment 30) Two comments recommended that FDA have different 
evidentiary standards for individual patient expanded access for 
patients with a serious disease or condition and the subset of those 
patients with an immediately life-threatening disease or condition. For 
immediately life-threatening diseases or conditions, one comment 
recommended that there be data from completed phase 1 testing at doses 
similar to those to be used in the treatment use and preliminary 
evidence suggesting possible effectiveness. The other comment 
recommended that the evidentiary standard that applies to treatment 
INDs for immediately life-threatening diseases or conditions apply to 
individual patient treatment use for such conditions (i.e., the 
available scientific evidence taken as whole provides a reasonable 
basis to conclude that the investigational drug may be effective for 
the expanded access use and would not expose patients to an 
unreasonable and significant risk of illness or injury). Such evidence 
would ordinarily consist of clinical data from phase 3 or phase 2 
trials, but could be based on more preliminary clinical evidence. For 
individual patient treatment use for serious diseases or conditions, 
both comments recommended that there be evidence of safety and 
effectiveness from phase 3 trials, although in some circumstances 
compelling data from phase 2 trials may be sufficient (the same 
standard that applies to treatment INDs for serious diseases or 
conditions).
    (Response) As discussed in the previous response, FDA believes that 
the suggested evidentiary requirements are too high a barrier to access 
for individual patient treatment use. Where the population exposed to 
an experimental therapy is small (in this case, a single individual), 
the amount of safety and effectiveness evidence needed to support the 
use is less than would be needed to allow exposure in the size 
population that might be treated under a treatment IND (often more than 
1,000 patients).
    In contrast to treatment INDs, which usually occur very late in a 
drug's development, individual patient treatment use may be sought 
quite early in a drug's development, and at any point during the 
development. Therefore, FDA also believes it is important to have 
flexibility in the evidentiary standards to permit it to respond 
appropriately to wide variations in the amount and nature of evidence 
that might be presented in support of an individual patient IND. Thus, 
FDA would prefer to avoid evidentiary standards pegged to data

[[Page 40913]]

from specific phases of drug development. FDA also believes a two-
tiered evidentiary standard--one standard for serious diseases and 
conditions and a lower standard for immediately life-threatening 
diseases or conditions--is unnecessary for individual patient INDs 
because the relative seriousness of the disease or condition is an 
implicit component of the risk-benefit assessment for individual 
patient INDs, and the current evidentiary standard allows for 
considerable flexibility in the amount and nature of evidence needed to 
support an individual patient IND.
    ii. Intermediate-size patient population evidentiary requirements.
    Proposed Sec.  312.315(b)(1) provides that, for expanded access 
under intermediate-size population INDs or protocols, FDA must 
determine that there is enough evidence that the drug is safe at the 
dose and duration proposed for expanded access use to justify a 
clinical trial of the drug in the approximate number of patients 
expected to receive the drug under expanded access. Proposed Sec.  
312.315(b)(2) provides that FDA must determine that there is at least 
preliminary clinical evidence of effectiveness or of a plausible 
pharmacologic effect of the drug to make expanded access use a 
reasonable therapeutic option in the anticipated patient population.
    (Comment 31) One comment recommended that FDA have different 
evidentiary standards for intermediate-size expanded access for serious 
diseases or conditions and intermediate-size expanded access for 
immediately life-threatening diseases or conditions. For INDs for 
immediately life-threatening diseases or conditions, the comment stated 
that there should be some preliminary evidence of clinical 
effectiveness. For INDs for serious diseases or conditions, the comment 
recommended that there be evidence of safety data from completed phase 
1 testing at doses similar to those to be used in the treatment use and 
preliminary evidence suggesting possible effectiveness.
    (Response) Because intermediate-size population INDs can occur 
earlier in drug development than treatment INDs and because there are 
three different intermediate-size population access scenarios (for a 
drug being developed, for a drug not being developed, and for an 
approved or related drug that is not available through marketing 
channels), FDA must have flexibility in the evidentiary standards to 
permit it to respond appropriately to variations in the amount and 
nature of evidence that might be presented in support of an 
intermediate-size population IND. Thus, FDA rejects the recommendation 
to have evidentiary standards pegged to data from a specific phase or 
phases of drug development. Again, because of the flexibility inherent 
in the evidentiary standards for intermediate-size patient population 
INDs, FDA does not believe it is necessary or useful to have different 
standards for serious diseases or conditions than for immediately life-
threatening diseases or conditions.
    iii. Treatment IND or treatment protocol evidentiary standards.
    Proposed Sec.  312.320(a)(3)(i) provides that for a treatment IND 
or treatment protocol for a serious disease or condition, there must be 
sufficient evidence of safety and effectiveness to support the use, 
which would ordinarily consist of data from phase 3 trials, but could 
consist of compelling data from completed phase 2 trials. Section 
312.320(a)(3)(ii) provides that, for an immediately life-threatening 
disease or condition, the available scientific evidence taken as whole 
must provide a reasonable basis to conclude that the investigational 
drug may be effective for the expanded access use and would not expose 
patients to an unreasonable and significant risk of illness or injury. 
Such evidence would ordinarily consist of clinical data from phase 3 or 
phase 2 trials, but could be based on more preliminary clinical 
evidence.
    (Comment 32) Two comments were concerned that the proposed 
evidentiary standards for authorizing a treatment IND or treatment 
protocol were not sufficiently rigorous to protect patients. One 
comment recommended that, for treatment INDs or treatment protocols for 
serious diseases or conditions, only data from phase 3 clinical trials 
should be used to assess the potential benefits and risks of the drug. 
The comment also recommended that for a treatment IND or treatment 
protocol for immediately-life threatening diseases or conditions, only 
data from phase 3 clinical trials or compelling data from phase 2 
trials should be considered. One comment objected to the proposed 
evidentiary standard for a treatment IND or a treatment protocol for an 
immediately life-threatening disease or condition because it would 
permit authorization of expanded access on the basis of clinical data 
more preliminary than phase 2 or 3 data.
    Two comments were concerned that the evidentiary standards for a 
treatment IND were overly rigorous. One comment stated that requiring 
safety and effectiveness data from phase 3 or phase 2 studies limits 
the use of expanded access under treatment INDs to programs initiated 
very late in the drug development process. The comment noted that if 
phase 3 data are required, a treatment IND would typically only provide 
access to the investigational drug for a matter of months (i.e., the 
time between the initiation of a treatment IND and approval of a drug 
for marketing would be relatively short) and thus would not meet the 
needs of patients or substantially help small biotech companies. The 
comment argued that to be truly useful, either treatment INDs or 
treatment protocols need to be available based upon phase 1 data (at 
least in cases where appropriate because of the severity of the disease 
and a relatively benign safety profile for the drug), the intermediate 
population programs need to be able to go well above 100 patients 
(i.e., up to 500 or 1,000 patients), or there needs to a fourth 
category between the intermediate and the large populations programs. 
Another comment stated that the proposed rule's evidentiary 
requirements for a treatment IND raise the bar to a level effectively 
equivalent to the amount of data required to obtain marketing approval.
    (Response) FDA believes that the proposed evidentiary requirements 
for authorizing treatment use under a treatment IND effectively balance 
making an investigational drug available to a substantial number of 
patients who might benefit from the drug with simultaneously protecting 
those patients from unreasonable risks associated with the drug. Our 
experience with this standard--spanning more than two decades--supports 
this assessment. Moreover, the evidentiary standards provide a certain 
amount of flexibility, particularly in the case of a treatment IND to 
treat an immediately life-threatening disease or condition, so that FDA 
can make investigational therapies available to substantial numbers of 
patients as early in the development process as is reasonably possible. 
FDA believes that more rigorous or inflexible standards would present 
an inappropriate barrier to obtaining a treatment IND in some cases. 
FDA also believes that relaxing these standards could potentially 
expose significant numbers of patients receiving investigational drugs 
under a treatment IND to unnecessary harm. A key tenet of drug 
development is to gradually increase the size of the population exposed 
to an investigational drug so as to be able to detect relatively low-
frequency, serious toxicity as early as possible, and before very large 
numbers of patients have been exposed. This

[[Page 40914]]

principle applies with equal force to the use of investigational drugs 
for treatment use.
    FDA wishes to emphasize that the evidentiary standards for a 
treatment IND are not the functional equivalent of the amount and type 
of data needed for marketing approval. The standards provide a degree 
of flexibility that enables FDA to authorize a treatment IND on the 
basis of data often well short of that needed to obtain marketing 
approval. FDA also does not believe that there needs to be a fourth 
category of treatment use in between an intermediate-size patient 
population IND and a treatment IND. As discussed elsewhere in this 
preamble, FDA intends that there be sufficient flexibility in the size 
of the population that might be treated under an intermediate-size 
population IND to enable treatment of as many patients as is supported 
by the available evidence of safety and effectiveness.
    (Comment 33) One comment objected to the proposed rule's 
evidentiary standard for a treatment IND or treatment protocol for a 
serious disease, asserting that it was higher than both the statutory 
and current regulatory standards and thus further restricted access. 
The comment noted that section 561(c)(1) of the act only requires 
``sufficient'' evidence of safety and effectiveness. The comment also 
noted that Sec.  312.34(a) of FDA's current regulations allows drugs to 
be made available during Phase 2 ``in appropriate circumstances.'' The 
comment pointed out that Sec.  312.320(a)(3) of the proposed rule 
provides that the evidence needed for a treatment IND or treatment 
protocol would ordinarily consist of data from phase 3 trials, but 
could consist of compelling data from completed phase 2 trials. The 
comment stated that, under the proposed rule, phase 2 trials would have 
to be completed, not merely ongoing, thus raising the standard for 
expanded access for treatment INDs and treatment protocols. The comment 
also stated that FDA has also raised the standard because the data 
would have to be ``compelling'' The comment suggested that because of 
design limitations, many phase 2 trials could be considered not 
compelling. The comment suggested that the proposed rule may result in 
treatment INDs and treatment protocols being less frequent than under 
FDA's current regulations. The comment stated that the final rule 
should use the language in Sec.  312.34(a) of FDA's current regulation 
instead of the new proposed language in Sec.  312.320(a)(3).
    (Response) FDA does not agree that the proposed rule articulates a 
more stringent evidentiary standard for a treatment IND or treatment 
protocol for a serious disease or condition than was contained in FDA's 
previous regulation in Sec.  312.34. Section 312.34 was not specific 
about the nature of the evidence that would be needed to support a 
treatment IND for a serious, as opposed to immediately life-
threatening, disease or condition. Rather, the general discussion in 
Sec.  312.34(a) suggested an earliest point in time at which such a 
treatment IND could be allowed to proceed (``in appropriate 
circumstances, a drug may be made available during phase 2''). FDA has 
always interpreted that requirement to mean that a treatment IND for a 
serious, but non-life-threatening, disease or condition would have to 
be supported by some phase 2 data (controlled trial data on the disease 
of interest), but that phase 2 did not have to be completed. Or, to put 
it another way, at least one phase 2 trial would have to have been 
completed, but others could be ongoing. FDA has never interpreted this 
provision to mean that a treatment IND for a serious disease or 
condition could proceed without any phase 2 data. Therefore, FDA 
believes that stating in this final rule that data needed to support 
for a treatment IND for a serious disease or condition could consist of 
compelling data from phase 2 trials is consistent with the statement 
that a drug may be made available for treatment use during phase 2.
    FDA also does not agree that characterizing the phase 2 data needed 
to support an treatment IND for a serious disease or condition as 
compelling raises the bar compared to that in Sec.  312.34. That 
provision made clear that a treatment IND for a serious disease or 
condition would ordinarily not be permitted until some point during 
phase 3 or at a point when all controlled trials were completed. To 
permit a treatment IND to proceed during phase 2 was plainly intended 
to be an exceptional circumstance. FDA does not believe that ambiguous, 
inconclusive, or marginally statistically significant phase 2 data 
would justify the exceptional circumstance of permitting a treatment 
IND for a serious disease or condition based on phase 2 data. 
Therefore, FDA believes it is reasonable to characterize the phase 2 
data needed as compelling. FDA also disputes the contention that the 
design of a typical phase 2 could not yield compelling data.
    For the reasons stated previously, FDA also does not agree that 
there will be fewer treatment INDs and treatment protocols for serious 
disease or conditions because of the way FDA articulated the 
evidentiary standard for a treatment IND for a serious disease or 
condition in Sec.  312.320(a)(3) of this final rule.
    c. Non-interference with drug development.
    Proposed Sec.  312.305(a)(3) states that, for all expanded access 
uses, FDA must determine that providing the investigational drug for 
the requested use will not interfere with the initiation, conduct, or 
completion of clinical investigations that could support marketing 
approval of the expanded access use or otherwise compromise the 
potential development of the expanded access use. For a treatment IND, 
proposed Sec.  312.320(a)(1) also requires FDA to determine that the 
drug is being investigated in a controlled trial under an IND designed 
to support a marketing application for the expanded access use, or that 
all clinical trials of the drug have been completed, and that the 
sponsor is actively pursuing marketing approval of the drug for the 
expanded access use with due diligence.
    (Comment 34) Several comments expressed concern that the proposed 
rule would seriously impede the initiation and completion of clinical 
trials and drug development generally. A number of comments stated 
that, given a choice, patients would be more likely to try to obtain an 
investigational drug under an expanded access IND or protocol than to 
participate in a clinical trial of the drug (and, for example, risk 
randomization to another treatment). Two comments argued that making 
drugs more widely available under expanded access INDs would have a 
domino effect in which decreased enrollment in clinical trials would 
lead to less rigorous trial protocols, less useful data, and ultimately 
decrease the amount of safety and efficacy information on approved 
drugs.
    (Response) FDA believes that the provisions in the proposed rule 
requiring that expanded access programs not impede clinical development 
of the investigational drug that is being made available for treatment 
use are adequate to mitigate the impact of expanded access on clinical 
development. In the case of individual patient expanded access INDs, an 
individual patient is not eligible to obtain access under an individual 
patient expanded access IND if the patient can participate in a 
clinical trial of the drug or obtain the drug under a larger access 
IND. In the case of an intermediate-size patient population IND for a 
drug being developed, the intent of such an IND is to make a drug 
available to patients who cannot enroll in a clinical trial; therefore, 
there would be no effect on

[[Page 40915]]

drug development. The other two intermediate-size patient population 
IND scenarios do not involve drugs that are being actively developed. 
In the case of a treatment IND, in FDA's experience, sponsors usually 
do not initiate treatment INDs until the clinical studies needed to 
support approval are completed or fully enrolled. However, it is 
possible to authorize a treatment IND before clinical trials needed to 
support marketing approval are fully enrolled. In such cases, it would 
be important for FDA to closely monitor the implications of the 
treatment IND on the rate of accrual of subjects into the clinical 
trial and other clinical development milestones.
    (Comment 35) Some comments asked FDA to specify how it will 
determine that making an investigational drug available for treatment 
use will not interfere with clinical trials or drug development 
generally. One comment stated that the expanded access rule should 
contain more explicit criteria for determining that expanded access 
does not detrimentally affect clinical trials.
    (Response) FDA believes the criteria are sufficiently explicit to 
enable FDA to meaningfully assess the impact of an expanded access 
program on development, and also provide FDA the flexibility to ask for 
varied types of assurances that access will not impede development, 
depending on the particular situation. For example, before authorizing 
a treatment IND for an investigational drug for which clinical trials 
are ongoing, FDA could seek specific assurances from the sponsor that 
the treatment IND would not interfere with accrual of patients in the 
clinical trial. FDA would likely request that the sponsor submit a 
comprehensive investigational plan with a timetable and milestones to 
its IND (if it had not done so already), so that FDA could periodically 
assess whether the treatment IND is having an effect on accrual or 
other parameters related to the pace of clinical development. If FDA 
determines that the treatment IND is slowing the pace of drug 
development or the sponsor is not actively pursuing marketing approval 
with due diligence, FDA can place the treatment IND on clinical hold. 
It is also worth noting that it is likely not in the sponsor's interest 
to delay development because it delays marketing approval and 
commercial sale of the drug. Therefore, sponsors are unlikely to 
provide expanded access in situations in which drug development would 
be impeded.
    (Comment 36) One comment raised two objections to the provisions of 
the proposed rule relating to FDA's finding of noninterference with 
clinical trials. First, the comment asserted that with regard to 
``widespread'' treatment INDs, the criteria imposed by Sec.  
312.305(a)(3) were broader than the authority in section 561(c)(5) of 
the act and impermissibly permitted FDA to refuse to approve requests 
for expanded access for reasons other than the proposed treatment use's 
effect on enrollment of clinical trials. The comment referred to the 
proposed rule's criterion that providing expanded access will not 
interfere with the initiation, conduct, or completion of clinical 
investigations that could support marketing approval of the expanded 
access use or otherwise compromise the potential development of the 
expanded access use (Sec.  312.305(a)(3)), and urged that the final 
rule use statutory language rather than that used in the proposed rule.
    Second, in a section related to individual patient access to 
investigational drugs, the comment argued that FDA lacks statutory 
authority for the proposed rule's product development criteria. 
Specifically, the comment noted that in the case of the single patient 
IND, Congress gave FDA authority to authorize a single patient IND if 
the Secretary determines that ``provision of the investigational drug * 
* * will not interfere with the initiation, conduct, or completion of 
clinical investigations to support marketing approval.'' The comment 
objected to the phrase ``or otherwise compromise the potential 
development of the expanded access use'' in proposed Sec.  
312.305(a)(3).
    (Response) FDA disagrees with the comment. Regarding the first 
assertion, that FDA has applied a more stringent provision on 
noninterference with clinical trials than is called for in the section 
of the act relating to expanded access for treatment INDs, FDA 
disagrees that the language in Sec.  312.305(a)(3) impermissibly 
expands the grounds on which FDA may reject a proposed treatment IND. 
Section 312.305(a)(3) provides that, for all types of expanded access, 
FDA must determine that providing the investigational drug for the 
requested use ``will not interfere with the initiation, conduct, or 
completion of clinical investigations that could support marketing 
approval of the expanded access use or otherwise compromise the 
potential development of the expanded access use.'' While admittedly 
much of this language matches terminology found in section 561(b)(3) of 
the act, which applies to individual patient treatment access and 
access by small groups of patients, it also generally describes the 
type of finding that FDA must make under section 561(c) of the act, 
which applies to treatment INDs.
    The comment seems to be based on the mistaken assumption that under 
section 561(c)(5), the only determination that FDA must make is whether 
an investigational drug will ``interfere with the enrollment of 
patients in ongoing clinical investigations.'' However, under section 
561(c)(4) of the act, FDA also must determine that the sponsor of the 
controlled clinical trial is actively pursuing marketing approval of 
the investigational drug with due diligence. Such active pursuit of 
marketing approval with due diligence implicitly includes a 
determination that the treatment use will not interfere with the 
initiation, conduct, or completion of clinical investigations that 
could support marketing approval for the investigational drug, which is 
why FDA included those particular terms in the regulation. FDA could 
have simply restated the statutory language in the regulation, but 
since the regulation implementing the statute is aimed, in part, at 
shedding light on how FDA interprets the statute, the agency believes 
the proposed language provides more helpful guidance than merely 
restating the terms from the statute without more.
    Regarding the argument that the statutory language does not allow 
FDA to require a determination that provision of the investigational 
drug for treatment use will not ``otherwise compromise the potential 
development of the expanded access use,'' FDA disagrees for reasons 
similar to those explained previously. In Sec.  312.305(a)(3), which is 
applicable to all treatment uses, FDA included this term to generically 
address other criteria required under different sections of section 
561, including section 561(b)(4), (c)(3) and (c)(4). FDA does not 
intend to use this catchall language as a limitless means to deny 
treatment use of investigational drugs. Rather, the intent is to endow 
the implementing regulation with sufficient flexibility to allow FDA to 
address situations where potential development of the treatment use 
would be compromised by a particular treatment proposal, for instance, 
where a proposed use would usurp the entire population of patients who 
might be studied in controlled clinical trials. This particular 
regulatory language is motivated by one of the core notions underlying 
the act--namely, recognition that the best form of access to a drug is 
full marketing approval.
    d. Impeding development of related drug products.

[[Page 40916]]

    (Comment 37) One comment expressed concern about the potential for 
expanded access to impede development of other drug products being 
developed for the same or a similar indication as the investigational 
drug being sought for treatment use. The comment recommended that 
requests for expanded access include a statement that the public list 
of clinical trials has been reviewed and the patient is not eligible or 
is otherwise unable to participate (e.g., because of distance) in 
available studies. Another comment cited an example of a situation in 
which enrollment in a clinical trial had decreased following 
accelerated approval of drugs for the same use under subpart H.
    (Response) FDA acknowledges the possibility that a large expanded 
access IND for a given product could impede concurrent development of 
other products for the same or a similar indication because trials for 
those products would be competing with the access program for the same 
patient population. However, requiring that the sponsor of a proposed 
expanded access IND demonstrate that the expanded access use will not 
impede development of not only its drug but of any other drug in 
clinical development for the same use would seem to present an 
unreasonable obstacle to access. For example, it is not clear how a 
sponsor would be able to demonstrate no effect on the development of a 
related therapy absent some proprietary knowledge about the development 
plans of the related therapy. Because there is no obvious way that the 
sponsor of a proposed expanded access plan could provide proof that the 
plan would have no effect on another company's development program, 
such determinations would have to rely primarily on conjecture. For 
that reason, such a requirement would likely be applied inconsistently 
and, as a result, could unnecessarily deny access to patients in 
desperate circumstances. FDA also does not believe that the sponsor of 
a competing therapy under development should have the ability to cause 
an ongoing expanded access IND to be put on hold, as would be the case 
if FDA were to require a sponsor to show that the expanded access IND 
would not interfere with another company's development program, and the 
other company were to demonstrate such interference.
    FDA also acknowledges the potential for marketing approval of a 
related product for the same or a similar indication to impede 
development of drugs for that indication. However, denial or delay of 
marketing approval because such approval would impede development of a 
competing product is clearly not in the best interests of the public 
health because it would deny patients access to a proven effective 
therapy. There do not appear to be any other regulatory options that 
could mitigate the impact on development or approval of a related drug.
    (Comment 38) One comment stated that expanded access would be more 
likely to impede development in the early stages of drug development 
and the development of orphan drugs.
    (Response) FDA agrees that expanded access has greater potential to 
impede development when a drug is available under an access IND early 
in development, particularly if the access is widespread. For this 
reason, FDA must determine that a patient seeking access to an 
investigational drug under an individual patient expanded access IND 
cannot participate in a clinical trial of the drug or obtain the drug 
under a larger expanded access IND or protocol (Sec.  312.310(a)(2)). 
Similarly, an intermediate-size patient population IND intended for a 
drug being developed is intended to make the drug available only to 
those who cannot participate in a clinical trial of the drug (Sec.  
312.315(a)(2)). FDA believes that these provisions should minimize the 
potential for these types of expanded access INDs to impede drug 
development.
    FDA also agrees that expanded access for drugs for orphan diseases 
has added potential to impede drug development due to the relatively 
smaller population from which clinical trial subjects can be drawn. FDA 
will carefully evaluate any expanded access submission for an orphan 
drug to ensure that the data needed to support approval of the orphan 
product will not be compromised by the expanded access use.
    (Comment 39) One comment maintained that expanded access would be 
more likely to decrease clinical trial participation in more rural 
communities and that even if clinical trials were still able to accrue 
adequate numbers of subjects, the demographics of participation in 
clinical trials could be skewed toward more urban populations.
    (Response) FDA disagrees. The agency believes that expanded access 
programs would have a neutral effect on clinical trial enrollment in 
rural areas because the same criteria apply in rural and more urban 
settings. Admittedly, patients in rural areas are more likely to be 
unable to enroll in a clinical trial because of geographical 
constraints, but providing access to those patients would have no 
effect on clinical trial enrollment or the demographics of the trial 
because those patients would not have been able to participate in the 
clinical trial because of geographical constraints.
    (Comment 40) One comment asked whether there have ever been any 
investigational drugs made available through a treatment IND that were 
not subsequently approved for marketing.
    (Response) Yes, there have been drugs that were made available 
under a treatment IND that did not obtain marketing approval. However, 
for these drugs, the failure to obtain marketing approved was not due 
to the treatment IND interfering with the clinical development program.
4. Expanded Access IND Submission Requirements
    Section 312.305(b) describes the content of an IND submission or 
protocol amendment for expanded access. In the event that a licensed 
physician, as opposed to a commercial sponsor, is making the IND 
submission, it provides that the licensed physician may provide some of 
the required information by obtaining a right of reference to the 
content of the existing IND. Proposed Sec.  312.305(b)(2) requires that 
an expanded access submission include:
     A cover sheet (Form FDA 1571) meeting the requirements of 
Sec.  312.23(a);
     The rationale for the intended use of the drug, including 
a list of therapeutic options that would ordinarily be tried before 
resorting to the investigational drug or an explanation of why the use 
of the investigational drug is preferable to the use of available 
therapeutic options;
     The criteria for patient selection or, for an individual 
patient, a description of the patient's disease or condition, including 
recent medical history and previous treatments of the disease or 
condition;
     The method of administration of the drug, dose, and 
duration of therapy;
     A description of the facility where the drug will be 
manufactured;
     Chemistry, manufacturing, and controls information 
adequate to ensure proper identification, quality, purity, and strength 
of the investigational drug;
     Pharmacology and toxicology information adequate to 
conclude that the drug is reasonably safe at the dose and duration 
proposed for the treatment use (ordinarily, information that would be 
adequate to permit clinical testing of the drug in a population of the 
size expected to be treated); and
     A description of clinical procedures, laboratory tests, or 
other monitoring necessary to evaluate the

[[Page 40917]]

effects of the drug and minimize its risks.
    (Comment 41) One comment asked whether the proposed submission 
requirements for expanded access apply to both sponsors and sponsor-
investigators. The comment also asked whether some of the required 
information could be incorporated into the protocol rather than 
provided as separate documents in the IND submission, including the 
rationale for the intended use of the investigational drug with a list 
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

[[Page 40918]]

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

[[Page 40919]]

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

[[Page 40920]]

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

[[Page 40921]]

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

[[Page 40922]]

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) * * *''

[[Page 40923]]

    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

[[Page 40924]]

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

[[Page 40925]]

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

[[Page 40926]]

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

[[Page 40927]]

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

[[Page 40928]]

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

[[Page 40929]]

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

[[Page 40930]]

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

[[Page 40931]]

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

[[Page 40932]]

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

[[Page 40933]]

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 
major purpose of this rule is to expand access to investigational drugs 
for patients with serious and immediately life-threatening conditions 
who lack satisfactory therapeutic alternatives. Therefore, FDA 
anticipates that the final rule will increase the number of patients 
who obtain access to investigational drugs for treatment use. This 
increase in volume will lead to more expanded access

[[Page 40934]]

submissions from sponsors and physicians seeking investigational drugs 
for their patients and, as a consequence, will require FDA to review 
more submissions. Given the relatively small burden associated with 
expanded access use submissions under the previous regulations 
(although such submissions are approximately one-third of all IND 
submissions, the vast majority of those are for individual patients and 
do not typically require substantial agency resources to review), and 
the small additional burden associated with the expanded access 
provisions in this final rule, FDA expects that the economic impact of 
the final rule will be small.
    The final rule also attempts to minimize the potential 
administrative burdens for physicians, sponsors, and FDA that will 
result from an increased volume of patients obtaining investigational 
drugs for expanded access use. The final rule encourages the 
consolidation of multiple individual patient INDs or protocols for a 
given use under an intermediate-size patient population IND or 
protocol. By reducing the total volume of submissions that will have 
been prepared if all patients were to obtain a drug under individual 
patient INDs or protocols, consolidation will limit the additional 
administrative burdens from increased patient access. In addition, by 
explicitly clarifying the eligibility criteria and submission 
requirements for expanded access, the final rule should make the 
process of obtaining access to investigational drugs more efficient for 
all affected parties.
    It is expected that any increase in the volume of submissions will 
result primarily from greater numbers of patients obtaining 
investigational drugs under expanded access INDs or protocols for 
individual patients and intermediate-size patient populations. Because 
this final rule does not significantly change the existing regulations 
concerning treatment INDs or treatment protocols, the number of 
patients receiving investigational drugs under these mechanisms should 
be largely unaffected.
1. Individual Patient Expanded Access Submissions
    By increasing awareness of the ways individual patients can obtain 
expanded access to investigational drugs for treatment use, and 
decreasing the perceived difficulty of obtaining such access, the final 
rule should increase the number of individual patients seeking access 
to investigational drugs. FDA anticipates that this increase in 
individual patient expanded access submissions will be greatest in the 
years immediately following implementation of the final rule and will 
at some point level off or possibly even decline. This leveling off or 
decline will occur when a significant volume of individual patient 
expanded access has accumulated for a variety of drugs, and the 
individual patient expanded access INDs or protocols for those drugs 
are then replaced with intermediate-size patient population INDs or 
protocols that enroll multiple subjects. Making the transition from 
multiple individual patient INDs or protocols to a single intermediate-
size patient population IND or protocol should reduce the overall 
administrative burden associated with making a particular 
investigational drug available for treatment use.
    From 1997 to 2005, FDA received, on average, approximately 659 
individual patient and emergency IND submissions per year. Although FDA 
is confident this final rule will increase this volume, it is difficult 
to predict with precision the extent of the increase. There is 
uncertainty concerning the extent to which patients who desire expanded 
access to investigational drugs are unable to obtain them; the extent 
to which better information about the mechanisms and processes for 
obtaining access to investigational drugs will stimulate more patients, 
or their physicians, to seek investigational drugs for expanded access 
use; and the extent to which drug manufacturers will be willing to make 
investigational drugs more broadly available for expanded access use. 
Although FDA is confident there will be an increase in the volume of 
individual patient expanded access use following issuance of this final 
rule, because of these uncertainties the agency can provide only an 
estimate of the range of potential increase. FDA believes that, after 
publication of the final rule, it is reasonable to anticipate a 40 to 
60 percent increase in the volume of individual patient expanded access 
submissions by year 3. As discussed previously in this document, we 
anticipate that growth will be most rapid in the years immediately 
following publication of the final rule and will eventually plateau or 
possibly even decline. The implications of these assumptions for the 
total number of individual patient expanded access submissions are 
summarized in table 3 of this document.

   Table 3.--Expected Percent Increase and Estimated No. of Individual
                   Patient Expanded Access Submissions
------------------------------------------------------------------------
       Year After            Expected Percent         Expected No. of
 Implementation of Final  Increase in Individual    Individual Patient
          Rule              Patient Submissions       Submissions\1\
------------------------------------------------------------------------
1                         20 to 40                791 to 923
------------------------------------------------------------------------
2                         30 to 50                857 to 988
------------------------------------------------------------------------
3                         40 to 60                923 to 1054
------------------------------------------------------------------------
4                         0                       923 to 1054
------------------------------------------------------------------------
5                         0                       923 to 1054
------------------------------------------------------------------------
\1\ Based on the current average of 659 individual patient treatment use
  submissions per year and the estimated percent increases in column 2.

2. Intermediate-Size Patient Population Expanded Access Submissions
    Although intermediate-size patient population expanded access has 
not previously been described in the regulations, this general type of 
mechanism has been used informally to make investigational drugs 
available for treatment use. Based on an internal survey of review 
divisions, FDA estimates that for the period 2000 through 2002 it 
received approximately 55 submissions per year that would be considered 
intermediate- size patient population expanded access submissions under 
the final rule. The agency anticipates that this final rule will 
increase the number of such submissions. Because this previously 
informal mechanism will be described in the regulations for the first 
time, there will be greater awareness, which is likely to stimulate 
submissions. In addition, the anticipated increase in

[[Page 40935]]

volume of individual patient expanded access submissions discussed 
previously in this document is expected to increase the number of 
intermediate-size patient population expanded access submissions 
because the final rule encourages the consolidation of multiple 
individual patient INDs or protocols for a given expanded access use.
    The extent to which submissions for expanded access for 
intermediate-size patient populations will increase is uncertain. 
Section 312.315 of the final rule concerns expanded access for 
intermediate-size patient populations. This section provides that FDA 
may ask a sponsor to consolidate expanded access under this section 
when the agency has received a significant number of requests for 
individual patient expanded access to an investigational drug for the 
same use. FDA does not have historical information that will permit us 
to accurately predict what portion of individual patient expanded 
access submissions are likely to be appropriate for consolidation.
    Based on our experience, we believe that many of the individual 
patient expanded access submissions we receive will be appropriate for 
consolidation. However, some individual patient expanded access 
submissions will be for expanded access uses that are sufficiently rare 
that it is unlikely that there will be enough similar uses to 
consolidate them under an intermediate-size patient population IND or 
protocol. There is also uncertainty about the extent to which sponsors 
will be willing to make investigational drugs available for expanded 
access use under intermediate-size patient population INDs or 
protocols. Although FDA is confident that there will be growth in the 
volume of intermediate-size patient population expanded access INDs or 
protocols, because of the uncertainties identified, we can provide only 
an estimate of the range of potential increase. FDA believes it is 
reasonable to anticipate a 25 to 50 percent growth in the volume of 
submissions for intermediate-size population expanded access INDs or 
protocols over a 5-year period.
    Compared with the growth in individual patient expanded access 
submissions, this increase is likely to be more gradual in the years 
immediately following implementation of a final rule, and will increase 
more sharply after 2 to 3 years as some of the increase in volume of 
individual patient expanded access submissions is shifted to 
intermediate-size population INDs or protocols. As in the case of 
expanded access for individual patients, growth in the number of 
submissions is expected to plateau or even decline after a few years. 
The implications of these assumptions for the number of individual 
patient expanded access submissions are summarized in table 4 of this 
document.

 Table 4.--Expected Percent Increase and Estimated No. of Intermediate-
           Size Patient Population Expanded Access Submissions
------------------------------------------------------------------------
                             Expected Percent
       Year After               Increase in           Expected No. of
 Implementation of Final     Intermediate-Size       Intermediate-Size
          Rule              Patient Population      Patient Population
                                Submissions           Submissions\1\
------------------------------------------------------------------------
1                         5 to 10                 58 to 61
------------------------------------------------------------------------
2                         10 to 20                61 to 66
------------------------------------------------------------------------
3                         20 to 40                66 to 77
------------------------------------------------------------------------
4                         25 to 50                69 to 82
------------------------------------------------------------------------
5                         0                       69 to 82
------------------------------------------------------------------------
\1\ Based on the current average of 55 intermediate-size patient
  population submissions per year and the estimated percent increases in
  column 2.

3. Expanded Access under Treatment INDs and Treatment Protocols
    The number of treatment INDs and treatment protocols should be 
largely unaffected by the final rule. The concept of large access 
programs is well established and most drugs that meet an unmet medical 
need for a serious or immediately life-threatening condition have had 
some kind of large access program late in their development. Therefore, 
the number of large access programs is primarily a function of the 
number of new drugs to treat serious and immediately life-threatening 
conditions that reach the latter stages of drug development (e.g., 
become NDA submissions). This rule is unlikely to influence that 
number.
    As stated in the preamble of the proposed rule (71 FR 75147 at 
75155), sponsors have instituted large expanded access programs under 
treatment INDs or treatment protocols or under less formal open-label 
(also referred to as open-access) protocols. The agency intends to be 
more vigilant in ensuring that a use of an investigational drug that 
has the characteristics of a treatment IND or treatment protocol is 
submitted and authorized as such, rather than as an open-label 
protocol. While this increased vigilance may increase the number of 
treatment INDs or treatment protocols, any increase will be primarily 
attributable to reclassifying open-label safety studies as treatment 
INDs or treatment protocols rather than a net increase in the overall 
number of large access programs. This reclassification should also 
improve safety monitoring of large access programs without 
significantly increasing administrative costs, because the costs for a 
treatment IND or treatment protocol and an open-label protocol are 
similar.
    Reclassification of an open-label protocol as a treatment IND or 
treatment protocol may also increase publicity for, and awareness of, 
the access program. Sponsors of treatment INDs or treatment protocols 
may, in certain circumstances, be required to list those programs at 
http://www.clinicaltrials.gov, a Web site maintained by the NIH as a 
resource for patients seeking to enroll in clinical trials or obtain 
access to investigational drugs for treatment use. The additional 
exposure generated by this site may attract more patients than will 
have had access under an open-label protocol. As a result, any given 
treatment IND or treatment protocol may be somewhat more costly than a 
less-publicized open-label protocol due to the volume of patients 
enrolled. FDA is not able to predict the impact on patient volume as a 
result of reclassifying open-label or open-access protocols as 
treatment INDs or treatment protocols. However, FDA

[[Page 40936]]

anticipates that there will be some economies of scale, so that the 
incremental costs will be relatively small on a per-patient basis. FDA 
believes any added costs will be justified by the potentially greater 
number of patients who will benefit from access to investigational 
drugs.

E. Benefits of the Final Rule

    Because FDA currently has no data that will allow us to predict the 
extent to which the amendments to existing IND regulations will 
generate direct benefits for consumers, it is not possible to 
accurately quantify the magnitude of any expected incremental benefits 
at this time. The number of patients obtaining expanded access to 
investigational drugs is expected to increase. However, because 
eligible patients will have serious or immediately life-threatening 
conditions that have failed to respond to available therapies, and 
because the investigational drugs are unproven, FDA cannot predict the 
extent to which individual patients will benefit from access to these 
drugs. Thus, the following discussion describes, in general terms, the 
nature of the potential benefits associated with the final rule.
    The benefits of the final rule are expected to result from improved 
patient access to investigational drugs generally and from expanded 
access being made available for a broader variety of disease conditions 
and treatment settings. In particular, the clarification of eligibility 
criteria and submission requirements will enhance patient access by 
easing the administrative burdens on individual physicians seeking 
investigational drugs for their patients and on sponsors who make 
investigational drugs available for expanded access use. Expanded 
access to investigational drugs may generate both private and social 
benefits. Private benefits will accrue to individual patients receiving 
drugs for expanded access use, whereas social benefits will accrue if 
these private benefits are also valued by society at large, or if any 
information obtained contributes to the development of new therapies 
generally.
    The final rule is also designed to address concerns that many 
physicians and their patients, particularly those outside of academic 
medical centers, are unaware of the availability of investigational 
drugs for expanded access use. In FDAMA, Congress included language in 
section 561(c) of the act to authorize the Secretary to inform medical 
associations, medical societies, and other appropriate persons of the 
availability of investigational drugs under treatment INDs or treatment 
protocols. FDA believes that this action, along with detailed 
eligibility criteria and submission requirements established in the 
final rule, will improve access to investigational drugs and result in 
making expanded access use more widely available to patients regardless 
of treatment setting.
    In formulating the final rule, FDA considered its statutory mandate 
and the interests of individuals and special patient populations, drug 
sponsors, and the general public. The agency found that in many 
situations, individuals or special patient populations have benefited 
from increased access to a drug that has not yet been approved for 
marketing (e.g., in the case of cancer or HIV therapies). These 
individuals or patient groups generally have serious or immediately 
life-threatening conditions and have not responded to available 
therapies or cannot participate in ongoing clinical trials for some 
reason.
    On the other hand, unrestricted access to investigational drugs for 
treatment use could reduce the patient population available for 
enrollment in the clinical trials required to demonstrate safety and 
efficacy in support of new drug marketing applications. If expanded 
access to investigational drugs were to adversely affect the marketing 
approval process, the general population will experience diminished 
social benefits due to the reduced or delayed availability of new 
therapies approved for marketing by FDA.
    The final rule addresses these competing interests by allowing 
investigational drugs to be made available for expanded access use only 
if providing the drug for the requested use will not interfere with the 
initiation, conduct, or completion of clinical investigations that 
could support marketing approval, or otherwise compromise the potential 
development of the expanded access use. In this way, the final rule 
effectively balances the interests of those patient populations who 
will benefit from having greater access to investigational drugs with 
the broader interests of society in having safe and effective new 
therapies approved for marketing and widely available.
    The agency is also aware that allowing expanded access to 
investigational drugs before they are fully evaluated for safety may 
have adverse consequences for the seriously ill patients who receive 
them. The safeguards in the final rule are also designed with this 
concern in mind. Authorization of a particular expanded access use is 
generally contingent upon a number of factors, including some evidence 
of the drug's safety and effectiveness, obtaining the informed consent 
of the patient, approval of an IRB, and a careful assessment of the 
potential risks and benefits to the patient. In addition, the final 
rule will place limits on the scope and duration of certain types of 
expanded access use, require that sponsors of such INDs or protocols 
monitor the expanded access use and comply with safety and annual 
reporting requirements for INDs, and subject ongoing INDs or protocols 
to periodic reassessment. The agency believes these safeguards will 
adequately protect the safety and welfare of patients who will seek, 
and may benefit from, expanded access to investigational drugs.

F. Costs of the Final Rule

    To the extent that the final rule results in an increase in the 
number of expanded access submissions, drug sponsors and physicians 
requesting investigational drugs on behalf of their patients will incur 
some additional costs. Because the final rule does not include any new, 
mandatory reporting requirements, the agency believes that the one-time 
costs associated with this rule will be negligible. Thus, the 
incremental burden imposed by this final rule will be in the form of 
additional annual or recurring costs associated with the increased 
number of expanded access submissions estimated previously in this 
document.
    The agency estimates that preparation and submission of an 
individual patient expanded access submission will require a total of 
approximately 8 hours. This time burden will be divided among 
physicians (approximately 15 percent or 1.2 hours) and nurses, nurse 
practitioners, or medical administrators (approximately 85 percent or 
6.8 hours). According to the U.S. Department of Labor, Bureau of Labor 
Statistics,\2\ total employer costs per hour worked for employee 
compensation for registered nurses in the health care and social 
assistance sector was $44.21 as of March 2008. Thus, the cost of the 
estimated 6.8 hours of nurse time required to prepare and submit an 
individual patient expanded access submission will be approximately 
$301 ($300.62 = $44.21 per hour x 6.8 hours).
---------------------------------------------------------------------------

    \2\ See http://www.bls.gov/news.release/ecec.toc.htm, last 
viewed July 11, 2008. (FDA has verified the Web site address, but 
FDA is not responsible for any subsequent changes to the Web site 
after this document publishes in the Federal Register.)
---------------------------------------------------------------------------

    Historically, most of the treatment use requests submitted to the 
agency have been prepared by physicians in the hematology/oncology 
specialty category. Data available on the Internet indicate

[[Page 40937]]

that the median expected total compensation for a physician in the 
hematology/oncology specialty category was $387,739 as of March 
2008.\3\ This median total compensation figure corresponds to 
approximately $186 per hour ($186.41 = $387,739 / 2,080 hours). Thus 
the cost for the 1.2 hours of physician time required to prepare and 
submit an individual patient expanded access submission is about $224 
($223.69 = $186.41 per hour x 1.2 hours). Therefore, the agency 
estimates that the total cost to prepare and submit an individual 
patient expanded access submission will be about $525 ($525 = $301 + 
$224). Applying this cost figure to the number of additional individual 
patient expanded access submissions estimated previously in this 
document suggests the pattern of incremental annual costs summarized in 
table 5 of this document.
---------------------------------------------------------------------------

    \3\ See http://swz.salary.com/salarywizard/layoutscripts/swzl_newsearch.asp, last viewed July 11, 2008. (FDA has verified the Web 
site address, but FDA is not responsible for any subsequent changes 
to the Web site after this document publishes in the Federal 
Register).

     Table 5.--No. of Additional Individual Patient Expanded Access
                 Submissions and Estimated Annual Costs
------------------------------------------------------------------------
       Year After          Expected Increase in      Expected Cost of
 Implementation of Final   the No. of Individual   Additional Individual
          Rule            Patient Submissions\1\  Patient Submissions\2\
------------------------------------------------------------------------
1                         132-264                 $69,300 to $138,600
------------------------------------------------------------------------
2                         198-329                 $103,950 to $172,725
------------------------------------------------------------------------
3                         264-395                 $138,600 to $207,375
------------------------------------------------------------------------
4                         264-395                 $138,600 to $207,375
------------------------------------------------------------------------
5                         264-395                 $138,600 to $207,375
------------------------------------------------------------------------
\1\ Based on increases in the number of individual patient expanded
  access submissions implied by the estimates presented in table 2 of
  this document.
\2\ Based on an estimated cost of $525 per individual patient expanded
  access submission.

    Preparation and submission of an intermediate-size patient 
population expanded access IND or protocol is expected to require a 
total of about 120 hours of staff time. This time burden will be 
divided between a Medical Director or Director of Clinical Research, 
typically a medical doctor (approximately 50 percent or 60 hours), a 
Regulatory Affairs Director (approximately 20 percent or 24 hours), and 
a Clinical Research Associate (approximately 30 percent or 36 hours).
    Information available on the Internet suggests that the median 
total compensation for a physician serving as a Medical Director is 
about $316,134 per year.\4\ This translates into an estimated hourly 
total compensation figure of about $152 ($151.98 = $316,134 / 2,080 
hours). Thus, the cost associated with the 60 hours of Medical Director 
time required to prepare and submit an intermediate-size patient 
population expanded access submission is approximately $9,120 ($9,120 = 
60 hours x $152).
---------------------------------------------------------------------------

    \4\ See http://swz.salary.com/salarywizard/layoutscripts/swzl_newsearch.asp, last viewed July 11, 2008. (FDA has verified the Web 
site address, but FDA is not responsible for any subsequent changes 
to the Web site after this document publishes in the Federal 
Register.)
---------------------------------------------------------------------------

    Information available on the Internet also indicates that the 
median total compensation for a Regulatory Affairs Director is 
approximately $235,149 per year.\5\ This translates into an estimated 
hourly total compensation figure of about $113 ($113.05 = $235,149 / 
2,080 hours). Thus, the cost associated with the 24 hours of Regulatory 
Affairs Director time required to prepare and submit an intermediate-
size patient population expanded access submission is approximately 
$2,712 ($2,712 = 24 hours x $113).
---------------------------------------------------------------------------

    \5\ See footnote 4 of this document.
---------------------------------------------------------------------------

    Finally, information available on the Internet indicates that the 
median total compensation for a Clinical Research Associate is 
approximately $86,890 per year.\6\ This translates into an estimated 
hourly total compensation figure of about $42 ($41.77 = $86,890 / 2,080 
hours). Thus, the cost associated with the 36 hours of Clinical 
Research Associate time required to prepare and submit an intermediate-
size patient population expanded access submission is approximately 
$1,512 ($1,512 = 36 hours x $42).
---------------------------------------------------------------------------

    \6\ See footnote 4 of this document.
---------------------------------------------------------------------------

    Based on the information presented, the agency estimates that the 
total cost to prepare and submit an intermediate-size patient 
population expanded access submission will be approximately $13,350 
($13,344 = $9,120 + $2,712 + $1,512). Applying this figure to the 
increases in the number of intermediate-size patient population 
expanded access submissions estimated previously in this document 
suggests the pattern of annual cost increases summarized in table 6 of 
this document.

    Table 6.--No. of Additional Intermediate-Size Patient Population
         Expanded Access Submissions and Estimated Annual Costs
------------------------------------------------------------------------
                           Expected Increase in      Expected Cost of
       Year After               the No. of              Additional
  Implementation After       Intermediate-Size       Intermediate-Size
       Final Rule           Patient Population      Patient Population
                              Submissions\1\          Submissions\2\
------------------------------------------------------------------------
1                         3 to 6                  $40,050 to $80,100
------------------------------------------------------------------------
2                         5 to 11                 $66,750 to $146,850
------------------------------------------------------------------------
3                         11 to 22                $146,850 to $293,700
------------------------------------------------------------------------

[[Page 40938]]

 
4                         14 to 27                $186,900 to $360,450
------------------------------------------------------------------------
5                         14 to 27                $186,900 to $360,450
------------------------------------------------------------------------
\1\ Based on increases in the number of intermediate-size patient
  population expanded access submissions implied by the estimates
  presented in table 3 of this document
\2\ Based on an estimated cost of $11,000 per intermediate-size patient
  population expanded access submission.

    For reasons discussed previously in this document, the agency does 
not expect that the final rule will have an impact on the overall 
number of treatment INDs or treatment protocols. Therefore, FDA does 
not expect the provisions of this final rule regarding treatment INDs 
or treatment protocols to impose any incremental cost burden. The total 
estimated variable and annual cost burdens associated with this final 
rule are summarized in table 7 of this document.

                         Table 7.--Cost Summary
------------------------------------------------------------------------
     Year After
 Implementation of     One-Time      Variable Cost      Annual Cost\1\
     Final Rule       Fixed Cost
------------------------------------------------------------------------
1                    $0           $109,350 to         $109,350 to
                                   $218,700            $218,700
------------------------------------------------------------------------
2                    $0           $170,700 to         $170,700 to
                                   $319,575            $319,575
------------------------------------------------------------------------
3                    $0           $285,450 to         $285,450 to
                                   $501,075            $501,075
------------------------------------------------------------------------
4                    $0           $325,500 to         $325,500 to
                                   $567,825            $567,825
------------------------------------------------------------------------
5                    $0           $325,500 to         $325,500 to
                                   $567,825            $567,825
------------------------------------------------------------------------
\1\ Since estimated one-time fixed costs are negligible, annual costs
  equal variable costs.

    For reasons discussed previously in this document, the agency 
expects that the total one-time costs of the final rule will be 
negligible. FDA expects that the annual costs of this final rule will 
range from a low of about $109,000 to $219,000 in the first year 
following publication of the final rule, to a high of about $325,000 to 
$568,000 in the fourth and fifth years. These estimates suggest total 
annual costs for the final rule of between $1.2 and $2.2 million for 
the 5-year period following implementation of the final rule.
    The agency expects that the estimated incremental cost burdens 
associated with this final rule are likely to be widely dispersed among 
affected entities for several reasons. First, given the historical 
volume of various types of treatment use submissions, the agency 
believes that a particular drug sponsor--or a physician acting on 
behalf of a patient--will submit a request for expanded access to 
investigational drugs fairly infrequently. Second, as noted previously, 
the final rule encourages the consolidation of multiple expanded access 
INDs or protocols for individual patients for a particular expanded 
access use under an intermediate-size patient population expanded 
access IND or protocol. Such consolidation should, to some extent, 
offset incremental administrative burdens caused by increased patient 
access. Making the transition from multiple individual patient expanded 
access INDs or protocols to a single IND or protocol for an 
intermediate-size patient population should reduce for sponsors the 
administrative burdens associated with making a drug available for 
expanded access use. In addition, provisions of the final rule are 
designed to minimize the amount of information and paperwork required 
to support a particular expanded access request. Physicians and drug 
sponsors will need to review the rule to become familiar with its 
provisions and to gather the evidence and information necessary to 
support an expanded access submission. However, in instances where a 
current IND already exists, a sponsor need only submit an amendment 
describing the information relevant to the expanded access protocol. 
Also, another sponsor or individual physician acting on behalf of a 
patient may, with the written permission of the original sponsor, 
reference information in the current IND already on file. The agency 
believes that a majority of expanded access submissions will have such 
a right of reference, either because the sponsor is also the drug 
developer or the developer will generally be willing to grant the 
request. To the extent that these provisions minimize the informational 
burden on potential sponsors or physicians, the final rule will enhance 
both efficiency and cost effectiveness.
    One comment submitted in response to the proposed rule provided an 
estimate of the number of patients that might be affected by this final 
rule. As part of our response, we have generated estimates of the 
number additional individuals that will gain access to investigational 
drugs as a result of the final rule.
    Information presented in table 5 of this document indicates that 
FDA expects this final rule to generate between 132 and 395 additional 
individual patient or emergency INDs per year. Thus, we estimate that 
between 132 and 395 additional individuals per year will have expanded 
access to investigational drugs under single patient or emergency INDs 
as a result of this final rule. Information presented in table 6 of 
this document indicates that FDA expects this final rule to generate 
between 3 and 27 additional expanded access submissions for 
intermediate-size patient populations. As discussed previously,

[[Page 40939]]

we believe that an intermediate-size patient population or other 
expanded access program will generally include between 10 and 100 
individuals. Therefore, we estimate that between 30 (30 = 3 x 10) and 
2,700 (2,700 = 27 x 100) additional individuals per year will have 
expanded access to investigational drugs under intermediate-size 
patient populations. Finally, because FDA expects this final rule to 
have no impact on the number of treatment INDs or protocols, the number 
of patients with access to investigational drugs will be unaffected. 
Based on this information, FDA estimates that between 162 (162 = 132 + 
30) and 3,095 (3,095 = 395 + 2,700) additional individuals will receive 
investigational drugs through expanded access programs as a result of 
this final rule. The range of these estimates reflects significant 
variation in the number of patients in intermediate-size patient 
populations. These estimates are summarized in table 8 of this 
document.

Table 8.--Approximate No. of Additional Individuals Affected by Expanded
                  Access Programs Under the Final Rule
------------------------------------------------------------------------
                   Expected No.                 Minimum No.  Maximum No.
                        of          No. of          of            of
     Category       Additional     Patients     Additional    Additional
                    Submissions                 Individuals  Individuals
------------------------------------------------------------------------
Individual         132 to 395    1             132           395
 Patient or
 Emergency IND
------------------------------------------------------------------------
Small Patient      3 to 27       10 to 100     30            2,700
 Population/Other
------------------------------------------------------------------------
Treatment IND or   0             100 to        0             0
 Protocol                         10,000
------------------------------------------------------------------------
Total                                          162           3,095
------------------------------------------------------------------------

G. Minimizing the Impact on Small Entities

    The agency does not believe the final rule will have a significant 
economic impact on a substantial number of small entities. 
Nevertheless, in the proposed rule, we recognized our uncertainty 
regarding the number and size distribution of affected entities, as 
well as the economic impact of the final rule on those entities, and 
requested detailed comment on these important issues. We received no 
comments that would cause us to change our determination that the final 
rule will not have a significant economic impact on a substantial 
number of small entities.
    Agency records indicate that the majority of submissions for 
treatment use of investigational drugs (about 78 percent) are submitted 
by commercial drug sponsors. Other entities making treatment use 
submissions include government agencies (approximately 14 percent), 
individual physicians (7 percent), and academic institutions (1 
percent). Thus, the agency believes that the vast majority (92 percent) 
of sponsors of expanded access INDs or protocols (consisting of 
commercial drug sponsors or government agencies) will not be considered 
small entities. The remaining 8 percent of treatment use submissions 
are made by individual physicians and academic institutions that the 
agency believes will meet Small Business Administration small business 
criteria.
    Of the average of 659 individual patient treatment use submissions 
submitted annually, very few are associated with commercial sponsors. 
The vast majority are submitted by individual physicians and various 
other unidentified sponsors for research purposes. Because nearly all 
individual patient treatment use submissions are made by various types 
of entities for research purposes, the agency believes that most of 
these entities will be classified as small entities.
    Because there is currently no formal mechanism in place for 
tracking the other types of expanded access (e.g., intermediate-size 
patient population submissions), no data exist that will allow the 
agency to identify the number of sponsors in this category that will 
qualify as small entities.
    Thus, while highly uncertain, the agency believes that at least 
some of the entities submitting expanded access requests will qualify 
as small entities. As discussed in section VI.F of this document, the 
agency expects that any incremental burden associated with the final 
rule will be small and widely dispersed among affected entities.

H. Alternatives

    FDA considered several alternatives to the final rule. They are 
discussed in the following paragraphs.
1. Do Not Propose Implementing Regulations for the Expanded Access 
Provisions of FDAMA
    FDAMA revised the act to specifically authorize the use of 
investigational new drugs by licensed physicians to diagnose, monitor, 
or treat individual patients who have a serious disease or condition 
if, among other things, the physician determines that the person has no 
comparable or satisfactory alternative therapy to diagnose, monitor, or 
treat the disease or condition, and that the probable risk from the 
investigational drug is not greater than the probable risk from the 
disease or condition; and FDA determines that there is sufficient 
evidence of safety and effectiveness to support the use of the 
investigational drug. FDAMA also largely incorporated into the act 
FDA's current regulation concerning treatment INDs or treatment 
protocols under which large populations currently receive 
investigational drugs for treatment use. Because FDAMA did not require 
that FDA adopt implementing regulations, the agency could have chosen 
not to do so.
    However, the agency believes that implementing regulations will 
further improve expanded access to investigational drugs for treatment 
use. One of the major criticisms about access to investigational drugs 
is that the criteria for authorizing access are unclear and that there 
is not broad knowledge among affected, or potentially affected, parties 
about the mechanisms or procedures to obtain access. FDA believes the 
final regulations are needed to address these concerns. The regulations 
provide to sponsors, patients, and licensed physicians who will be 
seeking investigational drugs for their patients clear direction about 
the criteria for authorizing expanded access and what information must 
be submitted to the agency to enable it to evaluate a proposed expanded 
access submission. Clearer direction and greater knowledge of the 
mechanisms and procedures for obtaining investigational drugs for 
expanded access use should reduce barriers to access.

[[Page 40940]]

2. Propose a Regulation Describing Only Individual Patient Expanded 
Access and the Treatment IND or Treatment Protocol
    As discussed in the previous paragraphs, FDAMA specifically 
authorized the use of investigational new drugs by licensed physicians 
to diagnose, monitor, or treat individual patients in certain 
circumstances. FDAMA also essentially repeated FDA's current regulation 
concerning treatment INDs or treatment protocols under which large 
populations currently receive investigational drugs for treatment use.
    FDA could have chosen to adopt regulations that described only 
these two categories of expanded access. However, FDA has had a long 
history of using an informal mechanism to make investigational drugs 
available to intermediate-size patient populations. This mechanism has 
been used in situations in which both: (1) The expanded access use did 
not meet the criteria for a treatment IND under the previous regulation 
and (2) it would have been excessively burdensome for sponsors and FDA 
to require large numbers of individual patient INDs for the same use. 
The agency concluded that, consistent with the terminology of section 
561(b)(4) of the act, it is preferable to establish an intermediate 
category for expanded access, with additional criteria and monitoring 
requirements, that will be used for more than an individual patient, 
but fewer than the large numbers of patients in treatment INDs or 
treatment protocols.
    In FDA's experience, there is often a need for a middle ground 
between an individual patient IND or protocol and a treatment IND or 
treatment protocol. For some drugs in development, there is 
considerable demand for expanded access before the use meets the 
criteria for a treatment IND or treatment protocol. There are also 
situations in which investigational drugs that are not being actively 
developed are the best available therapy for a significant number of 
patients and should be made available to patients under an expanded 
access process. In these situations, making the drug available under a 
series of individual patient expanded access INDs or protocols is 
burdensome on physicians, sponsors, and FDA, and makes it difficult to 
monitor the expanded access use to identify significant safety concerns 
such as serious adverse events.
    Describing this intermediate category in the regulations is also 
consistent with FDA's goal of maximizing awareness of expanded access 
programs by being more transparent about the processes for making drugs 
available for expanded access. As stated previously, FDA has used this 
intermediate category informally in the past and believes it will have 
reason to use this category in the future. Therefore, FDA believes it 
is appropriate to formalize and fully describe in the regulations the 
intermediate expanded access category, as well as the two other 
categories of expanded access.
3. Propose a Regulation Describing More Than Three Expanded Access 
Categories
    FDA also considered proposing a rule that will include more than 
three expanded access categories, but rejected this alternative. In 
internal discussions, FDA found that the distinctions between the 
proposed categories and the additional categories it considered were 
unclear. FDA was concerned that the additional categories would create 
confusion rather than provide the clarity that is the goal of the final 
regulations. FDA concluded that the additional categories could be 
merged into the three proposed categories and that these categories 
will be able to provide access to investigational drugs in all 
situations FDA is likely to encounter.

VII. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520) (the 
PRA). The title, description, and respondent description of the 
information collection provisions are shown below with an estimate of 
the annual reporting burden. Our estimate includes the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Expanded Access to Investigational Drugs for Treatment Use
    Description: The final rule clarifies existing regulations and 
revises them by adding new types of expanded access for treatment use. 
Under the final rule, expanded access to investigational drugs will be 
available to individual patients, including in emergencies; to 
intermediate-size patient populations; and to larger populations under 
a treatment protocol or IND. The final rule is intended to improve 
access to investigational drugs for patients with serious or 
immediately life-threatening diseases or conditions who lack other 
therapeutic options and may benefit from such therapies.

A. The Final Rule

1. Submission Requirements for All Expanded Access Uses
    Section 312.305(b) describes the submission requirements applicable 
to all types of expanded access.
    Section 312.305(b)(1) states that an expanded access submission is 
required for each type of expanded access. The submission may be a new 
IND or a protocol amendment to an existing IND. Information required 
for a submission may be supplied by referring to pertinent information 
contained in an existing IND if the sponsor of the existing IND grants 
a right of reference to the IND.
    Section 312.305(b)(2) describes the expanded access submission 
requirements. The following items must be included:
     A cover sheet (Form FDA 1571) meeting the requirements of 
Sec.  312.23(a);
     The rationale for the intended use of the drug, including 
a list of available therapeutic options that will ordinarily be tried 
before resorting to the investigational drug or an explanation of why 
the use of the investigational drug is preferable to the use of 
available therapeutic options;
     The criteria for patient selection; or, for an individual 
patient, a description of the patient's disease or condition, including 
recent medical history and previous treatments used for the disease or 
condition;
     The method of administration of the drug, dose, and 
duration of therapy;
     A description of the facility where the drug will be 
manufactured;
     Chemistry, manufacturing, and controls information 
adequate to ensure the proper identification, quality, purity, and 
strength of the investigational drug;
     Pharmacology and toxicology information adequate to 
conclude that the drug is reasonably safe at the dose and duration for 
expanded access use (ordinarily, information that will be adequate to 
permit clinical testing of the drug in a population of the size 
expected to be treated); and
     A description of clinical procedures, laboratory tests, or 
other monitoring necessary to evaluate the effects of the drug and 
minimize its risks.
2. Individual Patient Expanded Access
    Section 312.310(b) contains additional submission requirements that 
apply to use of an investigational drug for the treatment of an 
individual patient by a licensed physician. The expanded access 
submission must include information adequate to satisfy

[[Page 40941]]

FDA that the criteria for all expanded access uses and those specific 
to individual patient expanded access have been met. The individual 
patient expanded access criteria are:
     The physician 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, and
     FDA must determine that the patient cannot obtain the drug 
under another type of IND.
    Section 312.310(b)(1) states that if the drug is the subject of an 
existing IND, the expanded access submission may be made by a 
commercial sponsor or by a licensed physician.
    Section 312.310(b)(2) states that a sponsor may satisfy the 
submission requirements by amending its existing IND to include an 
individual patient expanded access protocol.
    Section 312.310(b)(3) states that a licensed physician may satisfy 
the submission requirements by obtaining a right of reference to 
pertinent information in the IND and providing any other required 
information not contained in the IND (usually only the information 
specific to the individual patient).
3. Intermediate-Size Patient Populations
    Section 312.315(c) states that an expanded access submission for an 
intermediate-size patient population must include information adequate 
to satisfy FDA that the criteria for all expanded access uses and those 
specific to intermediate-size patient populations have been met. The 
intermediate-size patient population criteria are: (1) There is enough 
evidence that the drug is safe at the dose and duration proposed for 
treatment use to justify a clinical trial of the drug in the 
approximate number of patients expected to receive the drug for 
treatment use; and (2) there is at least preliminary clinical evidence 
of effectiveness of the drug or of a plausible pharmacologic effect of 
the drug to make expanded access use a reasonable therapeutic option in 
the anticipated patient population. Section 312.315(c) contains 
additional submission requirements that apply to use of an 
investigational drug for intermediate-size patient populations. The 
expanded access submission must state whether the drug is being 
developed or is not being developed and describe the patient population 
to be treated. If the drug is not being actively developed, the sponsor 
must explain why the drug cannot currently be developed for the 
expanded access use and under what circumstances the drug could be 
developed. If the drug is being studied in a clinical trial, the 
sponsor must explain why the patients to be treated cannot be enrolled 
in the clinical trial and under what circumstances the sponsor will 
conduct a clinical trial in these patients.
4. Treatment IND or Protocol
    Section 312.320 describes the treatment IND or treatment protocol 
currently codified in Sec. Sec.  312.34 and 312.35. Section 312.320(b) 
states that the expanded access submission must include information 
adequate to satisfy FDA that the criteria for all expanded access uses 
and those specific to the treatment IND or protocol have been met. The 
criteria specific to a treatment IND or treatment protocol are: (1) The 
drug is being investigated in a controlled clinical trial designed to 
support a marketing application for the expanded access use or all 
clinical trials of the drug have been completed, (2) the sponsor is 
pursuing marketing approval of the drug for the expanded access use 
with due diligence, and (3) there is sufficient clinical evidence of 
safety and effectiveness to support the treatment use. Such evidence 
will ordinarily consist of data from phase 3 trials, but could consist 
of compelling data from completed phase 2 trials. When the expanded 
access use is for an immediately life-threatening disease or condition, 
the available scientific evidence, taken as a whole, could provide a 
reasonable basis to conclude that the investigational drug may be 
effective for the expanded access use and will not expose patients to 
an unreasonable and significant risk of illness or injury. This 
evidence will ordinarily consist of clinical data from phase 3 or phase 
2 trials, but could be based on more preliminary clinical evidence.

B. Estimates of Reporting Burden

    Our estimate of the amount of time required to complete an expanded 
access submission is based on the assumption that either the submission 
will be made by the drug developer or the submitter will have obtained 
a right of reference from the drug developer. We expect an increase in 
the number of submissions for expanded access for individual patients 
and for intermediate-size patient populations as a result of this final 
rule.
1. Individual Patient Expanded Access
    From 1997 to 2005, we received on average approximately 659 
submissions for the treatment use of investigational drugs by 
individual patients per year. This estimate is based on our records of 
the number of individual patient IND submissions (primarily from 
physicians) and a survey of our review divisions on the prevalence of 
individual patient protocol exception submissions received from 
commercial drug sponsors. As indicated in the table below, we expect an 
increase in the number of individual patient expanded access 
submissions because the final rule will increase awareness of the 
option for individual patients to gain access to investigational drugs 
and decrease the perceived difficulty of obtaining such access. We 
anticipate that the increase in individual patient expanded access INDs 
or protocols will be greatest in the years immediately following 
implementation of the final rule and will at some point level off or 
possibly even decline. This leveling off or decline will occur when a 
significant volume of individual patient expanded access INDs or 
protocols have accumulated for a variety of drugs, and the individual 
patient expanded access INDs or protocols for those drugs are then 
replaced with intermediate-size patient population expanded access INDs 
or protocols that enroll multiple subjects.
    We estimate that preparation and submission of an individual 
patient expanded access IND or protocol submission will require a total 
of approximately 8 hours.
2. Intermediate-Size Patient Population Expanded Access
    Although intermediate-size patient population expanded access INDs 
or protocols have not previously been described in regulation, 
investigational drugs have been made available informally for treatment 
use to such populations. Based on an internal survey of our review 
divisions, we estimate that, for the period 2000 through 2002, we 
received approximately 55 submissions per year that we consider 
expanded access for an intermediate-size patient population under the 
final rule. As indicated in table 9, we anticipate that this number 
will increase under the final rule because there will be greater 
awareness of this option. In addition, the anticipated increase in 
volume of submissions for expanded access for individual patients 
discussed previously is expected to increase the number of submissions 
for expanded access for intermediate-size patient populations because 
the final rule encourages the consolidation of multiple individual 
patient INDs or protocols for a given expanded access use.
    Information provided by our review divisions indicates that 
preparation and

[[Page 40942]]

submission of an intermediate-size patient population IND will require 
a total of approximately 120 hours.
3. Treatment IND or Treatment Protocol
    We do not expect the final rule to have an impact on the overall 
number of treatment INDs or treatment protocols because this type of 
expanded access is already established in FDA regulations at Sec. Sec.  
312.34 and 312.35. Therefore, we do not expect the provisions of this 
final rule regarding treatment INDs or treatment protocols to impose 
any increased paperwork burden. The burden for these submissions, as 
currently required under Sec.  312.35, is already approved by OMB under 
OMB control number 0910-0014.
    Description of Respondents: Licensed physicians and manufacturers, 
including small business manufacturers.
    Table 9 of this document presents the annualized reporting burden 
for the total number of expanded access submissions by type of expanded 
access use. The estimates in the table are based on data from section 
VI of this document and are calculated by averaging the projected 
number of submissions for the first 3 years after implementation of 
this final rule.

                                 Table 9.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                      No. of         No. of Responses                           Hours per
21 CFR Section     Respondents        per Respondent      Total  Responses       Response         Total Hours
----------------------------------------------------------------------------------------------------------------
Sec.  Sec.                    988                     1                988                  8              7,904
 312.305 and
 312.310(b)
----------------------------------------------------------------------------------------------------------------
Sec.  Sec.                     68                     1                 68                120              8,160
 312.305(b)
 and
 312.315(c)
----------------------------------------------------------------------------------------------------------------
Total                                                                                                     16,064
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection.

    The information collection provisions in this final rule have been 
submitted to OMB for review. Prior to the effective date of this final 
rule, FDA will publish a notice in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection provisions in this final rule. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

VIII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has tentatively determined that 
the rule does not contain policies that have substantial direct effects 
on the States, on the relationship between the National Government and 
the States, or on the distribution of power and responsibilities among 
the various levels of government. Accordingly, the agency has 
tentatively concluded that the rule does not contain policies that have 
federalism implications as defined in the order and, consequently, a 
federalism summary impact statement is not required.

List of Subjects

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 316

    Administrative practice and procedure, Drugs, Investigations, 
Medical research, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
312 and 316 are amended as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

0
1. The authority citation for 21 CFR part 312 is revised to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371; 
42 U.S.C. 262.

0
2. Section 312.30 is amended by revising paragraph (c) to read as 
follows:

Sec.  312.30  Protocol amendments.

* * * * *
     (c) New investigator. A sponsor shall submit a protocol amendment 
when a new investigator is added to carry out a previously submitted 
protocol, except that a protocol amendment is not required when a 
licensed practitioner is added in the case of a treatment protocol 
under Sec.  312.315 or Sec.  312.320. Once the investigator is added to 
the study, the investigational drug may be shipped to the investigator 
and the investigator may begin participating in the study. The sponsor 
shall notify FDA of the new investigator within 30 days of the 
investigator being added.
* * * * *

Sec.  312.34   [Removed]

0
3. Section 312.34 is removed.

Sec.  312.35   [Removed]

0
4. Section 312.35 is removed.

Sec.  312.36   [Removed]

0
5. Section 312.36 is removed.

0
6. Section 312.42 is amended by revising paragraph (b)(3) to read as 
follows:

Sec.  312.42   Clinical holds and requests for modification.

* * * * *
    (b) * * *
    (3) Clinical hold of an expanded access IND or expanded access 
protocol. FDA may place an expanded access IND or expanded access 
protocol on clinical hold under the following conditions:
    (i) Final use. FDA may place a proposed expanded access IND or 
treatment use protocol on clinical hold if it is determined that:
    (A) The pertinent criteria in subpart I of this part for permitting 
the expanded access use to begin are not satisfied; or
    (B) The expanded access IND or expanded access protocol does not 
comply with the requirements for expanded access submissions in subpart 
I of this part.
    (ii) Ongoing use. FDA may place an ongoing expanded access IND or 
expanded access protocol on clinical hold if it is determined that the 
pertinent criteria in subpart I of this part for permitting the 
expanded access are no longer satisfied.
* * * * *

0
7. Part 312 is amended by adding and reserving subpart H, and by adding 
subpart I, consisting of Sec. Sec.  312.300 through 312.320, to read as 
follows:
Subpart H--[Reserved]
Subpart I--Expanded Access to Investigational Drugs for Treatment Use
Sec.
312.300 General.

[[Page 40943]]

312.305 Requirements for all expanded access uses.
312.310 Individual patients, including for emergency use.
312.315 Intermediate-size patient populations.
312.320 Treatment IND or treatment protocol.

Subpart I--Expanded Access to Investigational Drugs for Treatment 
Use

Sec.  312.300  General.

    (a) Scope. This subpart contains the requirements for the use of 
investigational new drugs and approved drugs where availability is 
limited by a risk evaluation and mitigation strategy (REMS) when the 
primary purpose is to diagnose, monitor, or treat a patient's disease 
or condition. The aim of this subpart is to facilitate the availability 
of such drugs to patients with serious diseases or conditions when 
there is no comparable or satisfactory alternative therapy to diagnose, 
monitor, or treat the patient's disease or condition.
    (b) Definitions. The following definitions of terms apply to this 
subpart:
    Immediately life-threatening disease or condition means a stage of 
disease in which there is reasonable likelihood that death will occur 
within a matter of months or in which premature death is likely without 
early treatment.
    Serious disease or condition means a disease or condition 
associated with morbidity that has substantial impact on day-to-day 
functioning. Short-lived and self-limiting morbidity will usually not 
be sufficient, but the morbidity need not be irreversible, provided it 
is persistent or recurrent. Whether a disease or condition is serious 
is a matter of clinical judgment, based on its impact on such factors 
as survival, day-to-day functioning, or the likelihood that the 
disease, if left untreated, will progress from a less severe condition 
to a more serious one.

Sec.  312.305   Requirements for all expanded access uses.

    The criteria, submission requirements, safeguards, and beginning 
treatment information set out in this section apply to all expanded 
access uses described in this subpart. Additional criteria, submission 
requirements, and safeguards that apply to specific types of expanded 
access are described in Sec. Sec.  312.310 through 312.320.
    (a) Criteria. FDA must determine that:
    (1) The patient or patients to be treated have a serious or 
immediately life-threatening disease or condition, and there is no 
comparable or satisfactory alternative therapy to diagnose, monitor, or 
treat the disease or condition;
    (2) 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 to be treated; and
    (3) Providing the investigational drug for the requested use will 
not interfere with the initiation, conduct, or completion of clinical 
investigations that could support marketing approval of the expanded 
access use or otherwise compromise the potential development of the 
expanded access use.
    (b) Submission. (1) An expanded access submission is required for 
each type of expanded access described in this subpart. The submission 
may be a new IND or a protocol amendment to an existing IND. 
Information required for a submission may be supplied by referring to 
pertinent information contained in an existing IND if the sponsor of 
the existing IND grants a right of reference to the IND.
    (2) The expanded access submission must include:
    (i) A cover sheet (Form FDA 1571) meeting the requirements of Sec.  
312.23(a);
    (ii) The rationale for the intended use of the drug, including a 
list of available therapeutic options that would ordinarily be tried 
before resorting to the investigational drug or an explanation of why 
the use of the investigational drug is preferable to the use of 
available therapeutic options;
    (iii) The criteria for patient selection or, for an individual 
patient, a description of the patient's disease or condition, including 
recent medical history and previous treatments of the disease or 
condition;
    (iv) The method of administration of the drug, dose, and duration 
of therapy;
    (v) A description of the facility where the drug will be 
manufactured;
    (vi) Chemistry, manufacturing, and controls information adequate to 
ensure the proper identification, quality, purity, and strength of the 
investigational drug;
    (vii) Pharmacology and toxicology information adequate to conclude 
that the drug is reasonably safe at the dose and duration proposed for 
expanded access use (ordinarily, information that would be adequate to 
permit clinical testing of the drug in a population of the size 
expected to be treated); and
    (viii) A description of clinical procedures, laboratory tests, or 
other monitoring necessary to evaluate the effects of the drug and 
minimize its risks.
    (3) The expanded access submission and its mailing cover must be 
plainly marked ``EXPANDED ACCESS SUBMISSION.'' If the expanded access 
submission is for a treatment IND or treatment protocol, the applicable 
box on Form FDA 1571 must be checked.
    (c) Safeguards. The responsibilities of sponsors and investigators 
set forth in subpart D of this part are applicable to expanded access 
use under this subpart as described in this paragraph.
    (1) A licensed physician under whose immediate direction an 
investigational drug is administered or dispensed for an expanded 
access use under this subpart is considered an investigator, for 
purposes of this part, and must comply with the responsibilities for 
investigators set forth in subpart D of this part to the extent they 
are applicable to the expanded access use.
    (2) An individual or entity that submits an expanded access IND or 
protocol under this subpart is considered a sponsor, for purposes of 
this part, and must comply with the responsibilities for sponsors set 
forth in subpart D of this part to the extent they are applicable to 
the expanded access use.
    (3) A licensed physician under whose immediate direction an 
investigational drug is administered or dispensed, and who submits an 
IND for expanded access use under this subpart is considered a sponsor-
investigator, for purposes of this part, and must comply with the 
responsibilities for sponsors and investigators set forth in subpart D 
of this part to the extent they are applicable to the expanded access 
use.
    (4) Investigators. In all cases of expanded access, investigators 
are responsible for reporting adverse drug events to the sponsor, 
ensuring that the informed consent requirements of part 50 of this 
chapter are met, ensuring that IRB review of the expanded access use is 
obtained in a manner consistent with the requirements of part 56 of 
this chapter, and maintaining accurate case histories and drug 
disposition records and retaining records in a manner consistent with 
the requirements of Sec.  312.62. Depending on the type of expanded 
access, other investigator responsibilities under subpart D may also 
apply.
    (5) Sponsors. In all cases of expanded access, 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 the expanded 
access use, providing licensed

[[Page 40944]]

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), 
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. Depending on 
the type of expanded access, other sponsor responsibilities under 
subpart D may also apply.
    (d) Beginning treatment--(1) INDs. An expanded access IND goes into 
effect 30 days after FDA receives the IND or on earlier notification by 
FDA that the expanded access use may begin.
    (2) Protocols. With the following exceptions, expanded access use 
under a protocol submitted under an existing IND may begin as described 
in Sec.  312.30(a).
    (i) Expanded access use under the emergency procedures described in 
Sec.  312.310(d) may begin when the use is authorized by the FDA 
reviewing official.
    (ii) Expanded access use under Sec.  312.320 may begin 30 days 
after FDA receives the protocol or upon earlier notification by FDA 
that use may begin.
    (3) Clinical holds. FDA may place any expanded access IND or 
protocol on clinical hold as described in Sec.  312.42.

Sec.  312.310   Individual patients, including for emergency use.

    Under this section, FDA may permit an investigational drug to be 
used for the treatment of an individual patient by a licensed 
physician.
    (a) Criteria. The criteria in Sec.  312.305(a) must be met; and the 
following determinations must be made:
    (1) The physician 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; and
    (2) FDA must determine that the patient cannot obtain the drug 
under another IND or protocol.
    (b) Submission. The expanded access submission must include 
information adequate to demonstrate that the criteria in Sec.  
312.305(a) and paragraph (a) of this section have been met. The 
expanded access submission must meet the requirements of Sec.  
312.305(b).
    (1) If the drug is the subject of an existing IND, the expanded 
access submission may be made by the sponsor or by a licensed 
physician.
    (2) A sponsor may satisfy the submission requirements by amending 
its existing IND to include a protocol for individual patient expanded 
access.
    (3) A licensed physician may satisfy the submission requirements by 
obtaining from the sponsor permission for FDA to refer to any 
information in the IND that would be needed to support the expanded 
access request (right of reference) and by providing any other required 
information not contained in the IND (usually only the information 
specific to the individual patient).
    (c) Safeguards. (1) Treatment is generally limited to a single 
course of therapy for a specified duration unless FDA expressly 
authorizes multiple courses or chronic therapy.
    (2) 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.
    (3) FDA may require sponsors to monitor an individual patient 
expanded access use if the use is for an extended duration.
    (4) 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.
    (d) Emergency procedures. If there is an emergency that requires 
the patient to be treated before a written submission can be made, FDA 
may authorize the expanded access use to begin without a written 
submission. The FDA reviewing official may authorize the emergency use 
by telephone.
    (1) Emergency expanded access use may be requested by telephone, 
facsimile, or other means of electronic communications. For 
investigational biological drug products regulated by the Center for 
Biologics Evaluation and Research, the request should be directed to 
the Office of Communication, Outreach and Development, Center for 
Biologics Evaluation and Research, 301-827-1800 or 1-800-835-4709, e-
mail: [email protected]. For all other investigational drugs, the 
request for authorization should be directed to the Division of Drug 
Information, Center for Drug Evaluation and Research, 301-796-3400, e-
mail: [email protected]. After normal working hours, the request 
should be directed to the FDA Office of Emergency Operations, 301-443-
1240, e-mail: [email protected].
    (2) The licensed physician or sponsor must explain how the expanded 
access use will meet the requirements of Sec. Sec.  312.305 and 312.310 
and must agree to submit an expanded access submission within 15 
working days of FDA's authorization of the use.

Sec.  312.315   Intermediate-size patient populations.

    Under this section, FDA may permit an investigational drug to be 
used for the treatment of a patient population smaller than that 
typical of a treatment IND or treatment protocol. FDA may ask a sponsor 
to consolidate expanded access under this section when the agency has 
received a significant number of requests for individual patient 
expanded access to an investigational drug for the same use.
    (a) Need for expanded access. Expanded access under this section 
may be needed in the following situations:
    (1) Drug not being developed. The drug is not being developed, for 
example, because the disease or condition is so rare that the sponsor 
is unable to recruit patients for a clinical trial.
    (2) Drug being developed. The drug is being studied in a clinical 
trial, but patients requesting the drug for expanded access use are 
unable to participate in the trial. For example, patients may not be 
able to participate in the trial because they have a different disease 
or stage of disease than the one being studied or otherwise do not meet 
the enrollment criteria, because enrollment in the trial is closed, or 
because the trial site is not geographically accessible.
    (3) Approved or related drug. (i) The drug is an approved drug 
product that is no longer marketed for safety reasons or is unavailable 
through marketing due to failure to meet the conditions of the approved 
application, or
    (ii) The drug contains the same active moiety as an approved drug 
product that is unavailable through marketing due to failure to meet 
the conditions of the approved application or a drug shortage.
    (b) Criteria. The criteria in Sec.  312.305(a) must be met; and FDA 
must determine that:
    (1) There is enough evidence that the drug is safe at the dose and 
duration proposed for expanded access use to justify a clinical trial 
of the drug in the approximate number of patients expected to receive 
the drug under expanded access; and
    (2) There is at least preliminary clinical evidence of 
effectiveness of the drug, or of a plausible pharmacologic effect of 
the drug to make expanded access use a reasonable therapeutic option in 
the anticipated patient population.
    (c) Submission. The expanded access submission must include 
information adequate to satisfy FDA that the criteria in Sec.  
312.305(a) and paragraph (b) of this section have been met. The 
expanded

[[Page 40945]]

access submission must meet the requirements of Sec.  312.305(b). In 
addition:
    (1) The expanded access submission must state whether the drug is 
being developed or is not being developed and describe the patient 
population to be treated.
    (2) If the drug is not being actively developed, the sponsor must 
explain why the drug cannot currently be developed for the expanded 
access use and under what circumstances the drug could be developed.
    (3) If the drug is being studied in a clinical trial, the sponsor 
must explain why the patients to be treated cannot be enrolled in the 
clinical trial and under what circumstances the sponsor would conduct a 
clinical trial in these patients.
    (d) Safeguards. (1) Upon review of the IND annual report, FDA will 
determine whether it is appropriate for the expanded access to continue 
under this section.
    (i) If the drug is not being actively developed or if the expanded 
access use is not being developed (but another use is being developed), 
FDA will consider whether it is possible to conduct a clinical study of 
the expanded access use.
    (ii) If the drug is being actively developed, FDA will consider 
whether providing the investigational drug for expanded access use is 
interfering with the clinical development of the drug.
    (iii) As the number of patients enrolled increases, FDA may ask the 
sponsor to submit an IND or protocol for the use under Sec.  312.320.
    (2) The sponsor is responsible for monitoring the expanded access 
protocol to ensure that licensed physicians comply with the protocol 
and the regulations applicable to investigators.

Sec.  312.320  Treatment IND or treatment protocol.

    Under this section, FDA may permit an investigational drug to be 
used for widespread treatment use.
    (a) Criteria. The criteria in Sec.  312.305(a) must be met, and FDA 
must determine that:
    (1) Trial status. (i) The drug is being investigated in a 
controlled clinical trial under an IND designed to support a marketing 
application for the expanded access use, or
    (ii) All clinical trials of the drug have been completed; and
    (2) Marketing status. The sponsor is actively pursuing marketing 
approval of the drug for the expanded access use with due diligence; 
and
    (3) Evidence. (i) When the expanded access use is for a serious 
disease or condition, there is sufficient clinical evidence of safety 
and effectiveness to support the expanded access use. Such evidence 
would ordinarily consist of data from phase 3 trials, but could consist 
of compelling data from completed phase 2 trials; or
    (ii) When the expanded access use is for an immediately life-
threatening disease or condition, the available scientific evidence, 
taken as a whole, provides a reasonable basis to conclude that the 
investigational drug may be effective for the expanded access use and 
would not expose patients to an unreasonable and significant risk of 
illness or injury. This evidence would ordinarily consist of clinical 
data from phase 3 or phase 2 trials, but could be based on more 
preliminary clinical evidence.
    (b) Submission. The expanded access submission must include 
information adequate to satisfy FDA that the criteria in Sec.  
312.305(a) and paragraph (a) of this section have been met. The 
expanded access submission must meet the requirements of Sec.  
312.305(b).
    (c) Safeguard. The sponsor is responsible for monitoring the 
treatment protocol to ensure that licensed physicians comply with the 
protocol and the regulations applicable to investigators.

PART 316--ORPHAN DRUGS

0
8. The authority citation for 21 CFR part 316 continues to read as 
follows:

    Authority:  21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.

0
9. Section 316.40 is revised to read as follows:

Sec.  316.40   Treatment use of a designated orphan drug.

    Prospective investigators seeking to obtain treatment use of 
designated orphan drugs may do so as provided in subpart I of this 
chapter.

    Dated: July 20, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-19005 Filed 8-12-09; 8:45 am]
BILLING CODE 4160-01-S
```