40900 Federal Register / Vol. 74, No. 155 / Thursday, August 13, 2009 / Rules and Regulations 

addition to the direct costs described in 

paragraph (d)(1)(i) of this section, a 

sponsor may recover the costs of 

monitoring the expanded access IND or 

protocol, complying with IND reporting 

requirements, and other administrative 

costs directly associated with the 

expanded access IND. 

(3) To support its calculation for cost 

recovery, a sponsor must provide 

supporting documentation to show that 

the calculation is consistent with the 

requirements of paragraphs (d)(1) and, if 

applicable, (d)(2) of this section. The 

documentation must be accompanied by 

a statement that an independent 

certified public accountant has 

reviewed and approved the calculations. 

Dated: July 20, 2009. 

Jeffrey Shuren, 

Associate Commissioner for Policy and 

Planning. 

[FR Doc. E9–19004 Filed 8–12–09; 8:45 am] 

BILLING CODE 4160–01–S 

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. 

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; intermediatesize 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 (§ 312.36). 

However, § 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 


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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 (§§ 312.34, 312.35, 

and 312.36), revising § 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 intermediatesize patient populations (smaller than 

those typical of a treatment IND or 

treatment protocol); and 

• Expanded access treatment IND or 

treatment protocol (described in 

previous §§ 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 § 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 § 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 § 312.300(b) to 

include a definition of ‘‘serious disease 

or condition.’’ 

• Revises proposed § 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 § 312.310(a)(2) to 

omit the words ‘‘type of.’’ 

• Revises proposed § 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 § 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 § 316.40. However, because 

§ 316.40 references the requirements of 

§ 312.34, which is being withdrawn, 

FDA has revised § 316.40 to remove the 

reference to § 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 


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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 lifethreatening 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 


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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 AfricanAmerican 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/ 

SpeedingAccesstoImportant

NewTherapies/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 § 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 § 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 


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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, § 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 sponsorinvestigator. 

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 AfricanAmericans 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 


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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 (§ 312.33) and/or IND 

safety reports (§ 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 


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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 

§ 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 


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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-ofpocket). 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 


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subpart E uses the term ‘‘lifethreatening.’’ 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 (§ 312.300 and 312.300(a)) 

Proposed § 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 

§ 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 § 312.300(a) states that the intent is 

to make investigational drugs available 

to ‘‘seriously ill patients,’’ while the 

general criteria in § 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 

§ 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 (§ 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 lifethreatening 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 


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for authorizing a treatment IND under 

proposed § 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 lifethreatening 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 § 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 

§ 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 


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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 (§ 312.305) 

Proposed § 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 (§ 312.305(a)), the general 

submission requirements for the 

expanded access INDs described in 

subpart I (§ 312.305(b)), and safeguards 

applicable to those expanded access 

uses (§ 312.305(c)). 

Proposed § 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 § 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 

§ 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 § 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 

§ 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, § 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 lifethreatening 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 riskbenefit 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 

(§ 312.305(a)(2)). The comment argued 

that, in interposing itself into the riskbenefit 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 


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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., shortterm 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 


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requirements for all expanded access 

protocols. 

i. Individual Patient Evidentiary 

Standard 

Proposed § 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 lifethreatening 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 lifethreatening 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 lifethreatening 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 lifethreatening 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 


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from specific phases of drug 

development. FDA also believes a twotiered 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 § 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 

§ 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 intermediatesize expanded access for serious 

diseases or conditions and intermediatesize expanded access for immediately 

life-threatening diseases or conditions. 

For INDs for immediately lifethreatening 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 intermediatesize 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 § 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 immediatelylife 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 lifethreatening 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 lowfrequency, serious toxicity as early as 

possible, and before very large numbers 

of patients have been exposed. This 


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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 § 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 § 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 § 312.34(a) of FDA’s current 

regulation instead of the new proposed 

language in § 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 § 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 § 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-lifethreatening, 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 § 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 § 312.320(a)(3) of this final 

rule. 

c. Non-interference with drug 

development. 

Proposed § 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 § 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 


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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 § 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 

(§ 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 § 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 

§ 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 § 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. 


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(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 

(§ 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 

(§ 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 § 312.305(b)(2) requires 

that an expanded access submission 

include: 

• A cover sheet (Form FDA 1571) 

meeting the requirements of § 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 


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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 sponsorinvestigators. 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 § 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 WellCharacterized, 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 § 312.315(c) 

describes requirements specifically 

applicable to submissions for 

intermediate-size population expanded 

access INDs. Proposed § 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 

§ 312.315(c)(2) requires that the sponsor 


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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 § 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 intermediatesize 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 § 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 

§ 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 

§ 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 § 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 § 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 

§ 312.62. 

a. ‘‘Person’’ v. ‘‘individual or entity.’’ 

(Comment 47) One comment 

recommended that proposed 

§ 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 § 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 § 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 

§§ 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 § 312.57. 

Proposed § 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 

§ 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 § 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 


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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 § 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 §§ 312.32 and 

312.33. FDA’s primary interest is the 

expedited reporting of serious and 

unexpected events as required by 

§ 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 

§ 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 lifethreatening conditions are extremely 

vulnerable and may not fully 

comprehend the information they are 

provided about a drug by health care 


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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 § 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 


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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 (§ 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 socalled ‘‘Common Rule’’). Current FDA 

regulations (§§ 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 


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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 § 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 § 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 § 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 

§ 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 physicianinvestigator 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 § 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 § 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) 

* * *’’ 


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i. Monitoring of expanded access 

INDs. 

The proposed rule makes the sponsor 

responsible for monitoring of expanded 

access INDs or protocols. Proposed 

§ 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 (§ 312.56). Proposed 

§ 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 § 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 § 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 

§ 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 


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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 § 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 

§ 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 § 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 § 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 § 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 § 312.315 or 

§ 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 

§ 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 multipatient 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 

§ 312.315 or § 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 intermediatesize 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 § 312.315 or § 312.320, FDA will 

have probably already concluded that 


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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 § 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 § 312.315 or 

§ 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 § 312.310(c)(4). If FDA asks 

the sponsor to submit an IND or 

protocol for use under § 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 § 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 § 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 §§ 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 §§ 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 § 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 


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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 § 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 


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comments stated that, although the 

proposed rule contemplated that 

§ 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 intermediatesize 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 § 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) 

(§ 312.315(a)(1)) 

• To make a drug that is being 

developed available to patients who 

cannot participate in clinical trials of 

the drug (§ 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 

(§ 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 

(§ 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 § 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 


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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 intermediatesize 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 intermediatesize 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 


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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 crossreference 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 intermediatesize 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 (§ 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 § 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 FDAregulated (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 § 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 § 312.42(b)(3) specifies the 

conditions under which FDA may place 

an expanded access IND or protocol on 

clinical hold. Proposed § 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 


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requirements in subpart I. Proposed 

§ 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. privatesector 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 


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Federal Register / Vol. 74, No. 155 / Thursday, August 13, 2009 / Rules and Regulations 40931 

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.’’ 

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 

agency1 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. 

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 


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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 lifethreatening 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 


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Federal Register / Vol. 74, No. 155 / Thursday, August 13, 2009 / Rules and Regulations 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

Category Total INDs Individual Patient or 

Emergency IND 

Treatment IND 

or 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 

Category Average No. 

of Submissions 

No. of 

Patients 

Minimum No. 

of Individuals 

Maximum No. 

of Individuals 

Individual Patient or Emergency IND 659 1 659 659 

Small Patient Population/Other 55 10 to 100 550 5,500 

Treatment IND or Protocol 4.6 100 to 10,000 460 46,000 

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 


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40934 Federal Register / Vol. 74, No. 155 / Thursday, August 13, 2009 / Rules and Regulations 

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 Implementation of Final Rule Expected Percent Increase in Individual Patient Submissions 

Expected No. of Individual Patient Submissions1

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 

1Based 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 


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volume of individual patient expanded 

access submissions discussed 

previously in this document is expected 

to increase the number of intermediatesize 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

Year After Implementation of Final Rule Expected Percent Increase in IntermediateSize Patient Population Submissions 

Expected No. of Intermediate-Size Patient 

Population Submissions1

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 

1Based 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 openlabel 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 openlabel 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 


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40936 Federal Register / Vol. 74, No. 155 / Thursday, August 13, 2009 / Rules and Regulations 

2See 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.) 

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). 

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 


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3See 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). 

4See 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.) 

5See footnote 4 of this document. 

6See footnote 4 of this document. 

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. 

TABLE 5.—NO. OF ADDITIONAL INDIVIDUAL PATIENT EXPANDED ACCESS SUBMISSIONS AND ESTIMATED ANNUAL COSTS

Year After Implementation of Final Rule Expected Increase in the No. of Individual 

Patient Submissions1

Expected Cost of Additional Individual Patient Submissions2

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 

1Based on increases in the number of individual patient expanded access submissions implied by the estimates presented in table 2 of this 

document. 2Based 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). 

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). 

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). 

Based on the information presented, 

the agency estimates that the total cost 

to prepare and submit an intermediatesize 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 intermediatesize 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

Year After Implementation After Final Rule 

Expected Increase in the No. of Intermediate-Size Patient Population Submissions1

Expected Cost of Additional IntermediateSize Patient Population Submissions2

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 


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TABLE 6.—NO. OF ADDITIONAL INTERMEDIATE-SIZE PATIENT POPULATION EXPANDED ACCESS SUBMISSIONS AND

ESTIMATED ANNUAL COSTS—Continued 

Year After Implementation After Final Rule 

Expected Increase in the No. of Intermediate-Size Patient Population Submissions1

Expected Cost of Additional IntermediateSize Patient Population Submissions2

4 14 to 27 $186,900 to $360,450 

5 14 to 27 $186,900 to $360,450 

1Based on increases in the number of intermediate-size patient population expanded access submissions implied by the estimates presented 

in table 3 of this document 2Based 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 Final Rule One-Time Fixed 

Cost Variable Cost Annual Cost1

1 $0 $109,350 to $218,700 $109,350 to $218,700 

2 $0 $170,700 to $319,575 $170,700 to $319,575 

3 $0 $285,450 to $501,075 $285,450 to $501,075 

4 $0 $325,500 to $567,825 $325,500 to $567,825 

5 $0 $325,500 to $567,825 $325,500 to $567,825 

1Since 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, 


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Federal Register / Vol. 74, No. 155 / Thursday, August 13, 2009 / Rules and Regulations 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 intermediatesize 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

Category Expected No. of 

Additional Submissions 

No. of 

Patients 

Minimum No. of 

Additional Individuals 

Maximum No. of 

Additional Individuals 

Individual Patient or Emergency IND 132 to 395 1 132 395 

Small Patient Population/Other 3 to 27 10 to 100 30 2,700 

Treatment IND or Protocol 0 100 to 10,000 0 0 

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. 


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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 § 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 


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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 §§ 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 


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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 §§ 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 § 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 BURDEN1

21 CFR Section No. of 

Respondents 

No. of Responses 

per Respondent 

Total 

Responses 

Hours per 

Response Total Hours 

§§ 312.305 and 312.310(b) 988 1 988 8 7,904 

§§ 312.305(b) and 312.315(c) 68 1 68 120 8,160 

Total 16,064 

1There 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. 

■ 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 

■ 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. 

■ 2. Section 312.30 is amended by 

revising paragraph (c) to read as follows: 

§ 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 § 312.315 or § 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. 

* * * * * 

§ 312.34 [Removed] 

■ 3. Section 312.34 is removed. 

§ 312.35 [Removed] 

■ 4. Section 312.35 is removed. 

§ 312.36 [Removed] 

■ 5. Section 312.36 is removed. 

■ 6. Section 312.42 is amended by 

revising paragraph (b)(3) to read as 

follows: 

§ 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. 

* * * * * 

■ 7. Part 312 is amended by adding and 

reserving subpart H, and by adding 

subpart I, consisting of §§ 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. 


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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 

§ 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. 

§ 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 §§ 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 § 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 

§ 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 §§ 312.32 and 

312.33, ensuring that licensed 

physicians are qualified to administer 

the investigational drug for the 

expanded access use, providing licensed 


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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 § 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 

§ 312.30(a). 

(i) Expanded access use under the 

emergency procedures described in 

§ 312.310(d) may begin when the use is 

authorized by the FDA reviewing 

official. 

(ii) Expanded access use under 

§ 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 § 312.42. 

§ 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 

§ 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 § 312.305(a) and paragraph (a) of this 

section have been met. The expanded 

access submission must meet the 

requirements of § 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 

§ 312.315 or § 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: 

ocod@fda.hhs.gov. 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: 

druginfo@fda.hhs.gov. After normal 

working hours, the request should be 

directed to the FDA Office of Emergency 

Operations, 301–443–1240, e-mail: 

emergency.operations@fda.hhs.gov. 

(2) The licensed physician or sponsor 

must explain how the expanded access 

use will meet the requirements of 

§§ 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. 

§ 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 

§ 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 § 312.305(a) and paragraph (b) of this 

section have been met. The expanded 


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access submission must meet the 

requirements of § 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 § 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. 

§ 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 

§ 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 § 312.305(a) and paragraph (a) of this 

section have been met. The expanded 

access submission must meet the 

requirements of § 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 

■ 8. The authority citation for 21 CFR 

part 316 continues to read as follows: 

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

360dd, 371. 

■ 9. Section 316.40 is revised to read as 

follows: 

§ 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 


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