Expanded Access to Investigational Drugs for Treatment Use, 40900-40945 [E9-19005]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 74, Number 155 (Thursday, August 13, 2009)]
[Rules and Regulations]
[Pages 40900-40945]
From the Federal Register Online via the Government Printing 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 https://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 (https://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 https://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