Charging for Investigational Drugs; Proposed Rule

[Printable PDF]

[Federal Register: December 14, 2006 (Volume 71, Number 240)]
[Proposed Rules]
[Page 75168-75181]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14de06-17]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 312

[Docket No. 2006N-0061]
RIN 0910-AF13

Charging for Investigational Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its investigational new drug application (IND) regulation concerning
charging patients for investigational new drugs. FDA is proposing to
revise the current charging regulation to clarify the circumstances in
which charging for an investigational drug in a clinical trial is
appropriate, to set forth criteria for charging for an investigational
drug for the different types of expanded access for treatment use
described in the agency's proposed rule on expanded access for
treatment use of investigational drugs published elsewhere in this
issue of the Federal Register, and to clarify what costs can be
recovered for an investigational drug. The proposed rule is intended to
permit charging for a broader range of investigational and expanded
access uses than is explicitly permitted in current regulations.

DATES: Submit written or electronic comments by March 14, 2007. Submit
written comments on the information collection requirements by January
16, 2007.

ADDRESSES: You may submit comments, identified by Docket No. 2006N-0061
and/or RIN number 0910-AF13, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov.

Follow the instructions for submitting comments.
Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments.

Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN
number has been assigned) for this rulemaking. All comments received
may be posted without change to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
, including any personal information provided. For

additional information on submitting comments, see the ``Comments''
heading of the SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or

[[Page 75169]]

comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm

and insert the docket number(s), found in brackets in the heading of
this document, into the ``Search'' box and follow the prompts and/or go
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
The Office of Management and Budget (OMB) is still experiencing
significant delays in the regular mail, including first class and
express mail, and messenger deliveries are not being accepted. To
ensure that comments on the information collection are received, OMB
recommends that written comments be faxed to the Office of Information
and Regulatory Affairs, OMB, Attn: Desk Officer for FDA, FAX: 202-395-
6974.

FOR FURTHER INFORMATION CONTACT:
For the Center for Drug Evaluation and Research: Colleen L.
Locicero, Center for Drug Evaluation and Research (HFD-101), Food and
Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 4200,
Silver Spring, MD 20993-0002, 301-796-2270.
For the Center for Biologics Evaluation and Research: Steve 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. The Current Regulation
II. Why the Current Charging Rule Needs to be Revised
A. Overview
B. Criteria for Charging in a Clinical Trial
C. Charging for Expanded Access for Treatment Use
D. Recoverable Costs
III. Description of the Proposed Rule
A. General Requirements
B. Clinical Trials
C. Expanded Access for Treatment Use
D. Recoverable Costs
IV. Legal Authority
V. Environmental Impact
VI. Analysis of Economic Impacts
A. Objectives of the Proposed Action
B. The Need for the Proposed Rule
C. Why Allow Charging?
D. Baseline for the Analysis
E. Nature of the Impact
F. Benefits of the Proposed Rule
G. Costs of the Proposed Rule
H. Minimizing the Impact on Small Entities
VII. Paperwork Reduction Act of 1995
VIII. Federalism
IX. Request for Comments

I. The Current Regulation

FDA's current regulation on charging for an investigational drug is
Sec. 312.7(d) (21 CFR 312.7(d)). Section 312.7(d) was first proposed
in the Federal Register of June 9, 1983 (48 FR 26720), and reproposed
March 19, 1987 (52 FR 8850) (the 1987 proposal). The final rule
published in the Federal Register of May 22, 1987 (52 FR 19466) (the
1987 final rule). Under Sec. 312.7(d), FDA may authorize charging for
an investigational drug used in a clinical trial under an IND and for
an investigational drug used in a treatment protocol or treatment IND.
Section 312.7(d)(1) provides that a sponsor who wishes to charge
for an investigational drug in a clinical trial must provide a full
written explanation of why charging is necessary for the sponsor to
undertake or continue the clinical trial, e.g., why distribution of the
drug to test subjects should not be considered part of the normal cost
of doing business.
Section 312.7(d)(2) sets out the following four conditions that
must be met to charge for an investigational drug used under a
treatment protocol or treatment IND:
There must be adequate enrollment in the ongoing clinical
investigations under the authorized IND;
Charging must not constitute commercial marketing of a new
drug for which a marketing application has not been approved;
The drug must not be commercially promoted or advertised;
and
The sponsor of the drug must be actively pursuing
marketing approval with due diligence.
Section 312.7(d)(2) also provides that to charge for an
investigational drug used in a treatment IND or treatment protocol, the
sponsor must submit an information amendment under Sec. 312.31 (21 CFR
312.31) of the IND regulations. Authorization for charging goes into
effect automatically 30 days after FDA receives the information
amendment, unless the agency notifies the sponsor to the contrary.
Section 312.7(d)(3) provides that a sponsor may not commercialize
an investigational drug by charging a price larger than that necessary
to recover costs of manufacture, research, development, and handling of
the investigational drug.
Section 312.7(d)(4) provides that FDA will withdraw authorization
to charge if it determines that charging is interfering with the
development of a drug for marketing approval or that the criteria for
the authorization are no longer being met.

II. Why the Current Charging Rule Needs to be Revised

A. Overview

There are three principal reasons for revising the current charging
regulation.
First, the provisions of the current charging regulation concerning
charging for investigational drugs in a clinical trial need to be
revised to take into account circumstances that were not anticipated
when the original rule was adopted in 1987. FDA expected that requests
to charge in a clinical trial would be limited to requests to charge
for the sponsor's drug being tested in the trial. In fact, the agency
has received few such requests. Far more common are requests to charge
for approved drugs in trials when the drugs must be obtained from
another company. The approved drug may be used in a trial of the
sponsor's drug as an active control or in combination with the
sponsor's drug. Even more common are requests to charge for approved
drugs used in studies by a third party (not a manufacturer) that are
intended to study new uses of the approved drug or to compare two
drugs. FDA believes that requests to charge for investigational drugs
in these situations may be appropriate, but that the criteria for
evaluation of such requests are different from those that apply when
the request to charge is for the sponsor's drug being tested in a
clinical trial. Accordingly, the agency believes the current charging
regulation needs to be revised to provide criteria for charging for
approved drugs used in clinical trials.
Second, the provisions of the current charging regulation related
to treatment use provide for charging patients for investigational
drugs only when those drugs are provided under a treatment IND or
treatment protocol. Elsewhere in this issue of the Federal Register,
FDA is proposing to add to part 312 (21 CFR part 312) new subpart I
concerning ``Expanded Access to Investigational Drugs for Treatment
Use.'' That proposed rule would retain the treatment IND and treatment
protocol provisions in the current regulation with minor modifications,
and provide for two additional categories of expanded access for
treatment use--expanded access for individual patients and expanded
access for intermediate size patient populations. The current charging
rule needs to be revised to provide authority to charge for
investigational drugs for these two new categories of expanded access
for treatment use.
Third, FDA believes the current charging regulation needs to be
revised to specify the types of costs that can be

[[Page 75170]]

recovered. The language of the current charging rule is not very
specific and does not provide sufficient guidance to sponsors on the
costs that can be recovered. Moreover, because of the different
justifications for charging in a clinical trial and charging for
treatment use, the agency believes that the costs appropriate for
recovery also differ.
The reasons why FDA believes the current charging regulation needs
to be revised are described more fully in sections II.B, C, and D of
this document.

B. Criteria for Charging in a Clinical Trial

Generally, the costs of conducting a clinical trial are costs that
the sponsor should bear. Conducting a clinical trial is part of the
drug development process, and drug development is an ordinary business
expense for a commercial sponsor. If the investigational drug proves
successful in clinical trials, the sponsor will recoup its development
costs by marketing the drug for its approved indication. Because
research subjects who participate in a clinical trial are permitting
themselves to be exposed to a drug that has not been proven to be
effective and that may also pose safety risks, subjects generally
should not be expected to pay for the drug. In fact, in return for
their willingness to be exposed to an unapproved drug, subjects in
clinical trials are usually compensated, rather than charged for the
drug.
The current regulation on charging requires a sponsor who wishes to
charge for an investigational drug in a clinical trial to provide a
full written explanation of why charging is necessary for the sponsor
to undertake or continue the clinical trial (e.g., why distributing the
study drug to test subjects should not be considered part of the normal
cost of doing business). However, the regulation does not specify the
criteria that FDA would use to evaluate the sponsor's explanation for
why charging is necessary to undertake the trial or why the cost of a
drug should not be considered part of the normal cost of doing
business.
The preambles to the reproposed and final rules, however, were more
specific about the circumstances in which FDA believed charging for an
investigational drug in a clinical trial might be appropriate. In the
preamble to the 1987 reproposal, the agency stated that ``extremely
high costs could warrant the sale of drugs used in clinical trials''
(52 FR 8850 at 8854). The agency indicated that allowing charging for
very expensive drugs could be particularly advantageous by ``permitting
small and fledgling companies to test products that are extremely
expensive to produce * * *'' (52 FR 8850 at 8854). In the preamble to
the 1987 final rule, the agency also stated that ``cost recovery is
justified in clinical trials only when necessary to further the study
and development of promising drugs that might otherwise be lost to the
medical armamentarium'' (52 FR 19466 at 19474).
Thus, the philosophy behind the current charging regulation was
that authorizing charging in a clinical trial required an exceptional
circumstance, including evidence that the drug might provide an
advantage over available therapy and that the study for which charging
is requested is necessary to further the development of the drug and
could not be conducted without charging. FDA is now proposing to
describe in regulation specific criteria for charging that are
consistent with the policies articulated in the preambles to the
reproposed and final rules. These criteria are described in greater
detail in section III.B of this document.
As discussed in section II.A of this document, FDA now believes
that charging for an investigational drug in a clinical trial may also
be appropriate when the clinical trial includes approved drugs that
must be obtained from another company. The approved drug may be used in
a trial of the sponsor's drug as an active control or in combination
with the sponsor's drug. In another situation, an approved drug may
need to be obtained from the marketer of that drug for use in studies
by a third party (not the manufacturer) that are intended to study a
new use for the approved drug or to compare two drugs. Thus, FDA is now
proposing to revise the charging rule to include criteria that apply to
these two situations when an approved drug is used in a clinical trial.
These criteria are described in section III.B of this document.

C. Charging for Expanded Access for Treatment Use

Charging for the cost of an investigational drug for expanded
access for treatment use is a very different situation from charging
for a drug in a clinical trial. Treatment use is not a necessary part
of the drug development process and does not benefit the pharmaceutical
companies by leading to systematic accumulation of data intended to
support marketing authorization. Rather, treatment use is primarily
intended to benefit very sick patients by permitting them to receive
investigational drugs to treat their diseases and conditions, with
collection of information about the drug being incident to the intent
to treat. FDA wants to encourage sponsors to make investigational drugs
available to seriously ill patients who lack satisfactory alternative
treatment and might benefit from these drugs. However, making
investigational drugs available for expanded access for treatment use
is potentially costly, especially when many patients are involved.
Therefore, the agency believes that sponsors should be permitted to
charge patients for investigational drugs for expanded access for
treatment use, provided that charging will not impede the progress of
drug development.
The current charging regulation in Sec. 312.7(d)(2) contains FDA's
criteria for allowing a sponsor to charge for investigational drugs for
treatment use under a treatment IND or treatment protocol in accordance
with Sec. Sec. 312.34 and 312.35. Elsewhere in this issue of the
Federal Register, FDA is proposing to add to part 312 new subpart I
(Expanded Access to Investigational Drugs for Treatment Use), which
would retain the treatment IND and protocol provisions in the current
regulation with minor modifications, and provide for two additional
categories of expanded access for treatment use that have not
previously been described in regulation, (1) expanded access for
individual patients and (2) expanded access for intermediate size
patient populations. FDA is proposing to revise the current charging
regulation to incorporate criteria to permit charging for these newly
described categories of expanded access for treatment use. The criteria
that must be met to charge for these uses are described in more detail
in section III.C of this document.

D. Recoverable Costs

FDA is also proposing to revise the regulation on charging to
clearly describe the costs a sponsor can include in its cost recovery
calculation for an investigational drug. Under the current charging
regulation, a sponsor may not charge a price ``larger than that
necessary to recover costs of manufacture, research, development, and
handling of the investigational drug'' (Sec. 312.7(d)(3)). In FDA's
experience, this provision has been prone to varied interpretations,
sometimes resulting in unrealistic cost calculations. For example, some
sponsors have interpreted the provision as allowing cost recovery for
all possible costs associated with the research, development,
manufacture, and handling of the drug from the inception of drug
development. Some sponsors have also interpreted Sec. 312.7(d)(3) as
permitting cost recovery for the entire

[[Page 75171]]

cost of facilities designed to produce the drug in quantities that
would be adequate for the ultimate marketing of the drug. These
interpretations typically result in a cost that cannot reasonably be
recovered from the number of patients who will be receiving the
investigational drug.
FDA believes the current cost recovery provision was intended to
permit a sponsor to recover the costs associated with providing an
expensive drug product to study subjects in a clinical trial or making
a drug product available for treatment use. FDA does not believe the
intent was to allow a sponsor to recover the costs of research and
development of a drug before it is marketed. The proposed rule is
intended to clearly describe what costs may be recovered by a sponsor
by providing criteria that are less susceptible to varied
interpretations. These criteria are described in section III.D of this
document.

III. Description of the Proposed Rule

The proposed rule would remove paragraph (d) of current Sec. 312.7
that discusses charging for and commercialization of investigational
drugs. The proposed rule would create new Sec. 312.8 describing
general requirements for charging for investigational drugs, specific
requirements pertaining to charging for investigational drugs in a
clinical trial, charging for investigational drugs for treatment use
under proposed subpart I (described elsewhere in this issue of the
Federal Register), and requirements for determining what costs can be
recovered when charging for an investigational drug.

A. General Requirements

Proposed Sec. 312.8(a) describes the following general
requirements and conditions for charging for investigational new drugs.
A sponsor who wishes to charge for an investigational drug must do the
following:
Comply with the applicable requirements for the type of
use for which charging is requested (either in a clinical trial or for
treatment use) (proposed Sec. 312.8(a)(1)),
Provide justification that the amount to be charged
reflects only those costs that are permitted to be recovered (proposed
Sec. 312.8(a)(2)), and
Obtain prior written authorization from FDA (proposed
Sec. 312.8(a)(3)).
The requirement in the proposed rule to obtain prior written
authorization from FDA to charge for any investigational drug would be
a change from the provisions of the current charging regulation. At the
present time, sponsors must obtain prior written approval from FDA to
charge for an investigational drug in a clinical trial (Sec.
312.7(d)(1)). On the other hand, authorization to charge for an
investigational drug in a treatment protocol or treatment IND goes into
effect automatically 30 days after receipt by FDA of an information
amendment concerning charging, unless FDA notifies the sponsor to the
contrary (Sec. 312.7(d)(2)). The proposal to require sponsors to
obtain prior written authorization to charge for all types of expanded
access is consistent with the agency's current practice of reviewing
requests to charge for investigational drugs in treatment protocols or
treatment INDs. The agency wants to review requests to charge for any
type of expanded access to ensure that the criteria for charging have
been met and that the amount to be charged does not exceed the costs
permissible under the proposed rule.
Proposed Sec. 312.8(a)(4) provides that FDA will withdraw
authorization to charge if it determines that charging is interfering
with the development of a drug for marketing approval or that the
criteria for the authorization are no longer being met.

B. Clinical Trials

Proposed Sec. 312.8(b) describes specific requirements pertaining
to charging for an investigational drug in a clinical trial. This
provision addresses three situations in which FDA may authorize
charging for an investigational drug in a clinical trial, including
investigational use of an approved drug.
Proposed Sec. 312.8(b)(1) describes criteria for charging for the
sponsor's own drug in a clinical trial. The cost of an investigational
drug used in a clinical trial is an anticipated cost of drug
development and should ordinarily be borne by the sponsor. Therefore,
FDA believes that charging should be permitted only when three
circumstances are present. First, charging should be allowed only to
facilitate development of a promising new drug or indication that might
not otherwise be developed, or to obtain important safety information
that might not otherwise be obtained. Accordingly, the proposed rule
provides that a sponsor wishing to charge for its investigational drug
in a clinical trial must provide some evidence of potential clinical
benefit that, if demonstrated in clinical investigations, would provide
a significant advantage over available products in the diagnosis,
treatment, mitigation, or prevention of a disease or condition
(proposed Sec. 312.8(b)(1)(i)).
Second, charging should be permitted only for a trial that is
necessary for the development of the drug. Therefore, the sponsor must
demonstrate that the data to be obtained from the clinical trial would
be essential to establishing that the drug is effective or safe for the
purpose of obtaining initial marketing approval of the drug, or that it
would support a significant change in the labeling of the sponsor's
approved drug (proposed Sec. 312.8(b)(1)(ii)). For example, the trial
could be designed to provide data that would support approval of a new
indication or generate important comparative safety information. The
type of products that are likely to meet these two criteria are also
likely to be eligible for fast track development programs and priority
review (see FDA's guidance for industry on ``Fast Track Drug
Development Programs--Designation, Development, and Application
Review,'' including the priority review policies for the Centers for
Drug Evaluation and Research and Biologics Evaluation and Research in
appendix 3 (available on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm
)).

Third, charging must be necessary to the conduct of the clinical
trial. Under proposed Sec. 312.8(b)(1)(iii), a sponsor would be
required to demonstrate that clinical development of the drug could not
be continued without charging because the cost of the drug is
extraordinary. The cost of the drug may be extraordinary because of
manufacturing complexity, scarcity of a natural resource, the large
quantity of drug needed (e.g., due to the size or duration of the
trial), or some combination of these or other extraordinary
circumstances.
Proposed Sec. 312.8(b)(2) describes criteria for charging for an
approved drug that a sponsor must obtain from another entity for use as
an active control or in combination with another drug in a clinical
trial designed to evaluate the effectiveness or safety of the sponsor's
investigational drug. In these situations, the study subjects typically
must receive some therapy for their disease or condition because using
a placebo control would be unethical. In addition, the subjects often
would be treated with the approved drug in the course of medical
practice if they were not participating in the clinical trial.
Therefore, FDA believes the threshold for charging in this situation
should be lower than the threshold for charging by a sponsor for the
sponsor's own investigational drug. To charge for an approved drug in
this situation, a

[[Page 75172]]

sponsor must demonstrate that the trial is of adequate design to
evaluate the safety or effectiveness of the sponsor's drug and that the
drug is not being provided free of charge by its manufacturer (proposed
Sec. 312.8(b)(2)(i) and (b)(2)(ii)).
Proposed Sec. 312.8(b)(3) describes criteria for charging for an
approved drug that must be obtained from another entity in a clinical
trial designed to evaluate the approved drug (e.g., for another
indication). This provision is primarily intended to enable sponsors
who are not commercial entities in the business of drug development to
study new uses of approved drugs that might not be of commercial
interest to the drug's manufacturer or to conduct studies that provide
additional information about a drug that might not otherwise be
obtained. Typically, these sponsors are sponsor-investigators
conducting relatively small trials at a single site. Such sponsors lack
the resources of commercial sponsors and are not conducting the
research for commercial purposes, so they will not be able to recover
the cost of obtaining the approved drug by marketing the drug, for
example, for a new indication. The agency believes these kinds of
trials should be encouraged because they may yield important data about
less commercially viable uses of a drug. Therefore, FDA believes the
threshold for charging by a sponsor in this situation should be lower
than the threshold for charging for the sponsor's own investigational
drug. To charge for an approved drug in this situation, a sponsor must
demonstrate that the clinical trial of the approved drug is of adequate
design to evaluate the safety or effectiveness of a new indication, or
provide important safety information related to an approved indication,
and that the drug is not being provided free of charge by its
manufacturer (proposed Sec. 312.8(b)(3)(i) and (b)(3)(ii)).
Proposed Sec. 312.8(b)(4) provides that the authorization to
charge for a drug in a clinical trial would ordinarily continue for the
duration of the clinical trial because it is unlikely that the need for
charging would change during the course of the trial. However, proposed
Sec. 312.8(b)(4) gives FDA the discretion to specify a duration
shorter than the length of the trial. FDA may specify a shorter
duration if, for example, there is a particular concern that the
authorization to charge has the potential to delay the development of a
drug for marketing approval.

C. Expanded Access for Treatment Use

Proposed Sec. 312.8(c) sets forth the criteria for charging for
the three types of expanded access to investigational drugs for
treatment use described in proposed subpart I of part 312 described
elsewhere in this issue of the Federal Register. Proposed subpart I
describes two types of treatment use (expanded access for individual
patients and expanded access for intermediate size patient populations)
not previously described in FDA's regulations and, therefore, not
specifically contemplated by the existing charging regulation. The
agency's principal concern with charging patients in expanded access
settings for investigational drugs is that charging not interfere with
the development of drugs for commercial marketing. Accordingly,
proposed Sec. 312.8(c)(1) would require a sponsor wishing to charge
for an investigational drug for any of the three types of expanded
access under proposed subpart I to provide reasonable assurance that
charging will not interfere with developing the drug for marketing
approval.
For the types of expanded access to investigational drugs described
in proposed subpart I, FDA believes it is less likely that the limited
numbers of patients who might obtain individual patient expanded access
to an investigational drug (Sec. 312.305 of proposed subpart I) or
intermediate size patient population expanded access (Sec. 312.310 of
proposed subpart I) would impede development of a drug or indication.
The potential to interfere with drug development is greatest for
treatment use under a treatment IND or protocol (Sec. 312.320 of
proposed subpart I). Treatment INDs or protocols can attract large
numbers of patients and thus have the potential to significantly affect
enrollment in the clinical trials needed to establish safety and
effectiveness. Accordingly, proposed Sec. 312.8(c)(2) sets forth
specific information that would be required to reasonably assure FDA
that charging for an investigational drug under a treatment IND or
protocol will not interfere with drug development. Sponsors would be
required to provide evidence of sufficient enrollment in any ongoing
clinical trials needed for marketing approval to reasonably assure FDA
that the trials will be completed as planned (proposed Sec.
312.8(c)(2)(i)). Sponsors would also be required to provide evidence of
adequate progress in the development of the drug for marketing approval
(proposed Sec. 312.8(c)(2)(ii)). Such evidence could include
successful meetings with FDA before submission of a new drug
application (NDA), submission of an NDA, or completion of other
significant drug development milestones. Sponsors would also be
required to submit information under their general investigational
plans (Sec. 312.23(a)(3)(iv)) specifying the drug development
milestones they plan to meet in the coming year (proposed Sec.
312.8(c)(2)(iii)).
Proposed Sec. 312.8(c)(3) specifies that the authorization to
charge be limited to the number of patients authorized to receive the
drug for treatment use, if there is a limitation. For example, the
authorization to charge for an investigational drug under an individual
patient expanded access submission would be limited to a single
patient. Similarly, the authorization to charge under an intermediate
size patient population expanded access submission would be limited to
the number of patients permitted to receive the drug under that
particular intermediate patient population expanded access IND or
protocol.
Proposed Sec. 312.8(c)(4) provides that FDA will ordinarily
authorize charging for expanded access for treatment use under proposed
subpart I to continue for 1 year from the time of FDA authorization. It
also provides FDA the discretion to specify a shorter authorization.
FDA proposes to limit the authorization to charge to a period of 1 year
or less to permit the agency to periodically assess whether the
criteria for charging continue to be met. FDA anticipates that it would
exercise its discretion to specify a shorter duration when there is a
particular concern that charging could interfere with drug development.
Proposed Sec. 312.8(c)(4) provides that a sponsor may request that FDA
reauthorize charging for additional periods.

D. Recoverable Costs

Proposed Sec. 312.8(d) describes the kinds of costs that are
recoverable when charging for an investigational drug in a clinical
trial and for expanded access for treatment use under proposed subpart
I. The purpose of permitting charging for an investigational drug in a
clinical trial is to permit a sponsor to recover the costs of a drug
when the drug is extraordinarily expensive. Thus, proposed Sec.
312.8(d)(1) would limit cost recovery to the direct costs of making the
investigational drug available in these situations. Indirect costs
could not be recovered.
Proposed Sec. 312.8(d)(1)(i) describes direct costs as costs
incurred by a sponsor that can be specifically and exclusively
attributed to providing the drug for the investigational use for which
FDA has authorized cost recovery. Direct costs include costs per unit
to manufacture the drug (e.g., raw

[[Page 75173]]

materials, labor, and nonreusable supplies and equipment used to
manufacture the quantity of drug needed for the use for which charging
is authorized) or costs to acquire the drug from another manufacturing
source, and direct costs to ship and handle (e.g., store) the drug.
Indirect costs are costs that are not attributable solely to making
the drug available for the investigational use for which charging is
requested. For example, expenditures for physical plant and equipment
that are incurred primarily for the purpose of producing large
quantities of the drug for commercial sale after approval, or for
making the drug available for a variety of investigational uses, are
not appropriate for cost recovery for these investigational uses
because these are costs that would be incurred even if the clinical
trial or expanded access use for which charging is authorized did not
occur. Proposed Sec. 312.8(d)(1)(ii) states that indirect costs
include costs incurred primarily to produce the drug for commercial
sale (e.g., costs for facilities and equipment used to manufacture the
supply of investigational drug, but that are primarily intended to
produce large quantities of the drug for eventual commercial sale) and
research and development, administrative, labor, or other costs that
would be incurred even if the clinical trial or treatment use for which
charging is authorized did not occur.
Sponsors who provide investigational drugs for expanded access for
treatment use for intermediate size patient populations and for
treatment INDs and protocols incur costs in addition to the anticipated
and ordinary costs of drug development. The purpose of permitting cost
recovery for expanded access use is to encourage sponsors to make
investigational drugs available for treatment use. Thus, proposed Sec.
312.8(d)(2) would permit a sponsor to recover the costs of
administering treatment use programs for intermediate size patient
populations and for treatment INDs and protocols, as well as the direct
costs of the drug. The proposed rule would not authorize sponsors to
recover administrative costs associated with expanded access for
individual patients because these costs would be so minor.
Proposed Sec. 312.8(d)(2) provides that, in addition to the direct
costs of the drug described in proposed Sec. 312.8(d)(1), a sponsor
may recover the costs of monitoring the expanded access use, complying
with IND reporting requirements, and other administrative costs
directly associated with making a drug available for treatment use
under Sec. Sec. 312.315 and 312.320 of proposed subpart I.
Sponsors who provide investigational drugs for expanded access for
treatment use for intermediate size patient populations and for
treatment INDs and protocols incur costs in addition to the anticipated
and ordinary costs of drug development. The purpose of permitting cost
recovery for expanded access use is to encourage sponsors to make
investigational drugs available for treatment use. Thus, proposed Sec.
312.8(d)(2) would permit a sponsor to recover the costs of
administering treatment use programs for intermediate size patient
populations and for treatment INDs and protocols, as well as the direct
costs of the drug. The proposed rule would not authorize sponsors to
recover administrative costs associated with expanded access for
individual patients because these costs would be so minor.
Proposed Sec. 312.8(d)(3) provides that, to support its
calculation for cost recovery, a sponsor must provide supporting
documentation to show that the cost calculation is consistent with the
relevant requirements in proposed Sec. 312.8(d). If such documentation
relies on financial information or accounting methods beyond the
expertise of FDA reviewers, FDA may request that a sponsor provide
independent certification that its cost recovery calculation is
consistent with the requirements of this section.

IV. Legal Authority

FDA has the authority under the Federal Food, Drug, and Cosmetic
Act (the act) to permit charging for an investigational new drug under
the conditions set forth in this proposed rule. This proposed rule
would clarify and slightly expand the charging scheme that is already
in place. It is based on the agency's\1\ authority to issue regulations
pertaining to the investigational use of drugs, section 505(i) of the
act (21 U.S.C. 355(i)), its authority pertaining to expanded access to
unapproved drugs for treatment use, section 561 of the act (21 U.S.C.
360bbb), and its general grant of rulemaking authority for the
efficient enforcement of the act, section 701(a) of the act (21 U.S.C.
371(a)).
---------------------------------------------------------------------------

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

Section 505(i) of the act directs the agency 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. It is this authority that underlies FDA's IND
regulations in part 312. The proposed rule would add to and clarify the
existing IND regulations by revising the current charging regulation to
explain the circumstances under which charging for an investigational
drug is appropriate in a clinical trial and to clarify what costs can
be recovered.
Section 561 of the act, added by the Food and Drug Administration
Modernization Act of 1997 (Public Law 105-115), provides additional
authority for this proposed rule. One of that section's preconditions
to providing an investigational drug for treatment use is that the
sponsor submit a protocol consistent with regulations issued under
section 505(i) of the act. (See section 561(b)(1)(4) and (c) of the
act.) This rulemaking, proposed under section 505(i) of the act, sets
out the circumstances under which charging for an investigational drug
is appropriate for treatment use in an expanded access program as well
as in a clinical trial and clarifies what costs can be recovered.
Section 701(a) of the act gives FDA the authority to issue
regulations for the efficient enforcement of the act. Further
discussion of FDA's legal authority regarding charging can be found at
52 FR 19466 at 19472 (May 22, 1987).

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 proposed 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 proposed rule is not an economically significant regulatory action
as defined by the Executive order.

[[Page 75174]]

The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Currently, the agency does not believe that the
proposed rule will have a significant economic impact on a substantial
number of small entities. Nevertheless, we recognize our uncertainty
regarding the number and size distribution of affected entities as well
as the economic impact of the proposed rule on those entities.
Therefore, the analysis presented below, along with other relevant
sections of this document, constitutes the agency's initial regulatory
flexibility analysis. The agency specifically requests detailed public
comment regarding the number of affected small entities as well as the
potential economic impact of the proposed rule on those 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 approximately $122 million, using the most current
(2005) Implicit Price Deflator for the Gross Domestic Product. FDA does
not expect this proposed rule to result in any one-year expenditure
that would meet or exceed this amount.

A. Objectives of the Proposed Action

FDA is proposing this action to clarify and expand on an existing
regulation (in place since 1987) that permits sponsors to charge
patients for investigational drugs. Currently, FDA may authorize
charging for an investigational drug used in a clinical trial or under
a treatment IND or treatment protocol. This proposed rule would expand
the agency's authority to permit charging for investigational drugs in
a number of other situations. In clinical trial settings, the proposed
rule would add provisions that permit charging for another entity's
approved drug--either for use as an active control, as combination
therapy with its own drug, or to study new indications. The proposed
rule would also add provisions that permit charging for investigational
drugs for all of the various types of expanded access for treatment use
described under proposed subpart I of part 312. Finally, the proposed
rule describes more specifically the types of costs that could be
recovered when charging for an investigational drug.

B. The Need for the Proposed Rule

This proposed rule is needed for several reasons. The current
charging regulation only provides for charging for a sponsor's own drug
in a clinical trial. However, since the charging rule was adopted in
1987, FDA has received requests to charge in a clinical trial for
approved drugs that must be obtained from another company. In one
situation, an approved drug is being used in a clinical trial as an
active control or in combination with the sponsor's drug. In another
situation, a third party who is not a manufacturer requests permission
to charge for an approved drug that is being studied in the hope of
discovering new uses for that drug. The proposed rule would authorize
charging for approved drugs in these situations and provide criteria
governing such requests to charge.
The proposed rule is also needed to establish charging provisions
for types of expanded access for treatment use other than the treatment
IND or treatment protocol. Elsewhere in this issue of the Federal
Register, FDA is proposing to amend part 312 of its regulations by
adding subpart I concerning expanded access to investigational drugs
for treatment use. In addition to the treatment IND or treatment
protocol currently described in FDA regulations, the expanded access
proposed rule would specifically authorize expanded access for
individual patients, including in emergencies, and expanded access for
intermediate size patient populations. The expanded access proposed
rule is intended to improve access to investigational drugs for
patients with serious or life-threatening conditions who have exhausted
other therapeutic options and may benefit from such therapies. This
proposed rule is necessary to establish provisions that would permit
charging for investigational drugs for all of the types of expanded
access use described under proposed subpart I.
Finally, the proposed rule is needed to clarify and better explain
the types of costs sponsors are permitted to recover through charging.
The current regulatory language describing the costs a sponsor can
recover when charging for an investigational drug has proven difficult
to interpret and apply. Some sponsors have interpreted the language
broadly to permit recovery of costs much greater than those directly
attributable to providing the investigational drug for the approved
treatment use. In addition, ambiguities in the current regulatory
language may have caused inefficiencies leading some drug sponsors to
devote more resources than necessary to the preparation and submission
of charging requests.

C. Why Allow Charging?

The expense of conducting a clinical trial is considered a normal
cost of drug development that should be recovered through sales after
marketing approval. However, in some clinical trial settings, a sponsor
may incur extraordinary costs compared to typical drug development
expenses. An extraordinary cost burden may arise because of unusually
high manufacturing costs, the quantity of the drug required, the number
of patients involved, the expected duration of treatment, or some
combination of these factors. The agency believes that allowing cost
recovery through charging may be appropriate in these instances, but
only as a last resort source of funding to facilitate development of a
promising new therapy that could not otherwise be developed.
In some clinical trials, it may be necessary for a sponsor to
obtain an approved drug from another entity. The approved drug may be
used as an active control or in combination with the sponsor's drug in
a clinical trial designed to evaluate the effectiveness or safety of
the sponsor's investigational drug. In these situations, the study
subjects typically must receive some therapy for their disease or
condition because using a placebo control would be unethical. In
addition, the subjects often would be treated with the approved drug in
the course of medical practice if they were not participating in the
clinical trial. Therefore, FDA believes the threshold for charging in
this situation should be lower than the threshold for charging for the
sponsor's own investigational drug.
In other situations, an approved drug must be obtained by a third
party (not the manufacturer) to study the drug in a clinical trial for
a new indication or to obtain important safety information about an
approved indication. Researchers conducting such clinical trials are
primarily noncommercial entities who are not in the business of drug
development. Typically, these sponsor-investigators conduct relatively
small trials at a single site. Since such sponsors lack the resources
of commercial sponsors and do not conduct the research for commercial
purposes, they will not be able to recover the cost of obtaining the
approved drug by marketing the drug, for example, for a new indication.
The agency believes these kinds of trials should be encouraged because
they may

[[Page 75175]]

yield important data about less commercially viable uses of a drug or
additional drug safety information. Therefore, FDA believes the
threshold for charging by a sponsor in this situation should be lower
than the threshold for charging for the sponsor's own investigational
drug.
In contrast to clinical trials, granting expanded access to
investigational drugs for treatment use primarily benefits individual
patients and is not intended typically to generate data needed to
support marketing approval. Thus, the costs to sponsors associated with
making a drug available for expanded access are not considered typical
drug development expenditures. For this reason, the agency believes
that it is generally more appropriate to permit sponsors to charge for
expanded access to investigational drugs for treatment use. Allowing
charging in expanded access settings may also provide financial
incentives for sponsors to make investigational drugs more widely
available in these situations.

D. Baseline for the Analysis

During the period 1997 through 2005, FDA received an average of
2,046.6 INDs per year. During this same period, the agency received an
annual average of 22.6 requests to charge patients for investigational
drugs. Thus, only about 1.1 percent (0.011 = 22.6 / 2,046.6) of all
INDs received by the agency on an annual basis were associated with
charging requests. Similarly, FDA received an average of 1.1 treatment
IND or treatment protocol charging requests per year during this
period. Thus, requests to charge under treatment INDs or treatment
protocols were associated with about 0.06 percent (0.0006 = 1.1 /
2,046.6) of all INDs received by the agency each year. Finally, FDA
received an average of 15.6 other charging requests per year during
this period. These requests were to charge patients for expanded access
to investigational drugs in situations other than individual patient or
emergency INDs, and treatment INDs or treatment protocols. Such
situations would generally include requests to charge for expanded
access in intermediate-size patient populations and under clinical
trials. Because the intermediate-size patient population IND or
protocol is not currently established in regulation, a more precise
distribution of other charging requests cannot be determined.
Nevertheless, other charging requests were associated with about 0.76
percent (0.0076 = 15.6 / 2,046.6) of all INDs received by the agency
each year from 1997 through 2005. This information is summarized in
table 1 below.

Table 1. Baseline Data for Number of INDs and Charging Requests by Category
--------------------------------------------------------------------------------------------------------------------------------------------------------
Treatment IND/ or Protocol
Category Total INDs All Charging Requests Requests Other Charging Requests
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number 2,046.6 22.6 1.1 15.6
--------------------------------------------------------------------------------------------------------------------------------------------------------
Percent of all INDs 100.0% 1.1% 0.06% 0.76%
--------------------------------------------------------------------------------------------------------------------------------------------------------

FDA also received an average of 659 individual patient and
emergency INDs per year during the period 1997 through 2005. This
number represents approximately 32.2 percent (0.322 = 659 / 2,046.6) of
all INDs received by the agency each year. During this same period, FDA
received an average of 7.1 charging requests for individual patient or
emergency INDs or protocols per year. Thus, charging requests are
associated with about 1.1 percent (0.0108 = 7.1 / 659) of all
individual patient and emergency INDs or protocols received by the
agency each year. This information is summarized in table 2 below.

Table 2: Baseline Data for Number of Individual Patient/Emergency INDs
------------------------------------------------------------------------
Individual Patient or
Category Emergency INDs Charging Requests
------------------------------------------------------------------------
Number 659.0 7.1
------------------------------------------------------------------------
Percent 100.0% 1.1%
------------------------------------------------------------------------

E. Nature of the Impact

The proposed rule would affect patients who lack effective
therapeutic alternatives for serious and life-threatening conditions;
sponsors who develop drugs to treat serious and life-threatening
conditions; and FDA in determining whether to authorize charging for
investigational drugs. By clarifying requirements and establishing the
full range of situations in which it may be appropriate to charge for
an investigational drug, the proposed rule would improve patient access
by providing a financial incentive for sponsors to make promising
therapies more widely available. Thus, this proposed rule should help
to facilitate patient access to drugs that could not be provided
without charging and permit sponsors to study drugs that might
otherwise be too costly to develop.
By describing in regulation the full range of situations in which
charging for an investigational drug may be permitted, this proposed
rule would likely increase the volume of charging requests somewhat.
However, by clarifying the circumstances under which charging would be
permitted and specifying the types of costs that sponsors could
recover, this proposed rule should also make the process of obtaining
authorization to charge more transparent and more efficient. Given the
small percentage of all INDs that include charging requests, FDA
believes that the impact of the proposed rule will not be significant.
This proposed rule could also increase treatment expenses for some
patients who obtain investigational drugs for which charging is
permitted, or for third party payors if they choose to reimburse
patients for some or all of the costs of such drugs. The agency
believes that such costs would not be excessive and would be justified
by the primary benefit of this proposed rule, making investigational
drugs available for treatment use that could not otherwise be made
available without charging. The potential impact of specific provisions
of the proposed rule is discussed in greater detail in the following
paragraphs.
1. Charging in a Clinical Trial
a. Charging for a sponsor's drug in a clinical trial. The existing
charging regulation has permitted charging for investigational drugs in
clinical trials intended to support marketing approval since 1987. This
proposed rule is intended only to clarify the situations in which
charging for a sponsor's investigational drug in such a clinical trial
is appropriate. Therefore, FDA does not expect this proposed rule to
have a significant effect on the number of requests to charge for
sponsors'

[[Page 75176]]

investigational drugs in clinical trials to support initial marketing
approval.
b. Charging for an approved drug in a clinical trial. As discussed
in section II.A of this document, a major reason for revising the
current charging regulation is to describe criteria for charging for
approved drugs in clinical trials that are subject to part 312. These
criteria are needed because the bulk of the requests to charge in the
clinical trial setting have been requests to charge for approved drugs
and the existing criteria do not readily apply to this situation.
By explicitly acknowledging that charging for an approved drug in a
clinical trial subject to part 312 is possible under appropriate
circumstances, this proposed rule should increase awareness of this
option and thus stimulate requests to charge. The extent to which the
volume of such requests might increase is uncertain. FDA's experience
is that sponsors are most likely to request to charge when the drug is
quite expensive and that expense represents a substantial burden
relative to the sponsor's resources. Because prescription drugs are
becoming increasingly expensive, it is reasonable to expect that
approved products used in clinical trials will become increasingly
expensive as well. However, because charging may affect a sponsor's
ability to enroll subjects in clinical trials in a timely manner, FDA
believes that sponsors will continue to be reluctant to charge unless
the cost is truly burdensome. Therefore, FDA does not anticipate a
substantial increase in the number of these requests to charge.
2. Charging for Expanded Access for Treatment Uses Described Under
Proposed Subpart I
a. Expanded access for individual patients. FDA anticipates that
there would be some increase in the number of requests to charge for
investigational drugs for expanded access for individual patients. By
establishing in regulation that it may be permissible to charge for an
investigational drug for expanded access for individual patients, this
proposed rule should increase awareness of the option to charge and
thereby stimulate additional requests. In addition, as discussed in the
preamble to the expanded access proposed rule, that rule is anticipated
to initially increase the overall volume of expanded access for
individual patients, which may also lead to some increase in the volume
of requests to charge.
For the period 1997 through 2005, FDA received an average of 7.1
requests per year to charge for such use, or about 1.1 percent (0.011 =
7.1 charging requests/659 single patient INDs per year) of all
individual patient treatment use. The extent to which the volume of
requests to charge for expanded access for individual patients would
increase under the proposed rule is uncertain. Historically, sponsors
have been willing to provide an investigational drug to an individual
patient free of charge in most cases, presumably because the cost is
not great. However, this willingness may be tempered somewhat if there
is an increase in the volume of requests for expanded access for
individual patients received by a particular sponsor, especially if the
cost of the drug is relatively high. There may also be some increase in
the number of requests to charge for expanded access for individual
patients because the prevalence of costly drugs is increasing. At this
time, FDA has no reasoned basis to project a percentage increase in the
number of charging requests for expanded access to investigational
drugs for individual patients. However, because the cost of providing a
drug to a single patient is usually not a substantial burden for a
sponsor, FDA believes that the number of requests to charge for
individual patient expanded access would continue to represent a
relatively small percentage of such use.
b. Expanded access for intermediate size patient populations. By
establishing in regulation that it is possible to charge for expanded
access to an investigational drug for treatment use in an intermediate
size patient population, the proposed rule should increase awareness
that charging may be permitted for such uses, thereby stimulating
requests to charge. Because access to expanded access for intermediate
size patient populations has to date been authorized informally, FDA
does not have records to indicate the number of times charging has been
requested or permitted for this type of treatment use. If charging has
been permitted in these situations, the authorizations would have been
grouped with, and cannot be differentiated from, the authorizations to
charge under clinical trials.
FDA does not anticipate a significant number of charging requests
for expanded access for intermediate size patient populations.
Historically, sponsors have been willing to provide drugs free of
charge to a limited number of patients for treatment use. As in the
case of expanded access for individual patients, we expect this
behavior would continue.
c. Treatment INDs and treatment protocols. The agency's current
regulations allowing charging for investigational drugs under a
treatment IND or treatment protocol (in place since 1987) would be
clarified, but not significantly altered, by the proposed rule.
Therefore, the agency does not anticipate that the proposed rule would
lead to a change in the number of requests to charge under treatment
protocols or treatment INDs.
3. Costs Recoverable When Charging for an Investigational Drug
Finally, the proposed rule clarifies and better explains the types
of costs sponsors are permitted to recover through charging. In
particular, sponsors would be limited to recovery of the direct or
marginal costs associated with making an investigational drug available
for the approved treatment use. Direct costs that would be recoverable
under the proposed rule include per unit manufacturing costs and
shipping and handling costs. In addition, the proposed rule would
permit sponsors to recover the costs of monitoring an expanded access
protocol, complying with IND reporting requirements, and other
administrative costs directly associated with expanded access for an
intermediate size patient population and for a treatment IND or
protocol.
4. Summary
The agency does not expect the number of requests to charge for a
sponsor's drug in a clinical trial, or to charge for an investigational
drug under a treatment IND or treatment protocol, to be affected
because the proposed rule does not significantly change the existing
regulation. The agency does expect some incremental impact from the
proposed provisions that would allow charging for approved drugs in
clinical trial and for expanded access for single patients and
intermediate size patient populations. The agency believes the impact
of these provisions would be limited for the reasons described
previously in this document, but we are unable to estimate the
quantitative impact because of a lack of reliable data. Thus, the
following discussion describes, in general terms, the nature of the
associated benefits and costs.

F. Benefits of the Proposed Rule

Because FDA currently has no data that would allow us to predict
the quantitative impact of the proposed rule, it is not possible to
accurately quantify the magnitude of any expected incremental benefits
at this time. We would expect the number of requests to charge for
investigational drugs for expanded access use to increase somewhat.
However, the number of additional patients that would gain

[[Page 75177]]

access to investigational drugs as a result and the extent to which
these patients would benefit from such access are highly uncertain.
Establishing in regulation all of the situations in which charging
is permissible and clearly specifying the types of costs that are
eligible for recovery would ease the administrative burdens associated
with obtaining authorization to charge and could improve patient access
to investigational drugs for treatment use. Private benefits would
accrue to individual patients receiving the drugs, whereas social
benefits would accrue if society also values these individual patient
benefits. Because the overall impact of the proposed rule is not
expected to be significant, the potential for any new regulatory
benefits is somewhat limited.
In formulating the proposed rule, FDA considered the interests of
patients, drug sponsors, and the general public. Concerning charging
for investigational drugs in expanded access settings, the agency
concluded that seriously ill patients could often benefit from
increased access to investigational drugs that have not yet been
approved for marketing. On the other hand, greater patient access to
investigational drugs outside of the clinical trial setting could have
the potential to delay approvals of drugs to treat serious and life-
threatening conditions (e.g., by reducing incentives for potential
subjects to enroll in clinical trials). If allowing charging were to
adversely affect the drug approval process, the general population
would experience diminished social benefits due to the reduced or
delayed availability of new therapies approved for marketing by FDA.
The proposed rule would address this tension by allowing sponsors
to charge for investigational drugs in expanded access settings as long
as the sponsor provides reasonable assurance that charging will not
interfere with development of the drug for marketing approval. In this
way, the proposed rule would effectively address the interests of those
patient populations that would benefit from having greater access to
investigational drugs and the broader interests of society in having
safe and effective therapies approved for marketing and widely
available.
The proposed rule would limit sponsors to recovery of the direct or
marginal costs associated with making the drug available. Direct costs
that are recoverable under the proposed rule include per unit
manufacturing costs and shipping and handling costs. Indirect or fixed
costs incurred for joint or common objectives and physical plant and
equipment expenditures for producing marketable quantities of the drug
would be specifically excluded under the cost recovery provisions of
the proposed rule. The agency believes that these cost recovery
provisions would prevent sponsors from inappropriately shifting the
normal financial risks associated with new drug development onto
patients when they charge for drugs in clinical trial settings. For
expanded access use, the limitation to direct cost recovery would also
ensure that drug development costs that properly belong to sponsors are
not shifted to patients.

G. Costs of the Proposed Rule

Although the proposed rule largely clarifies current agency
practice, some additional paperwork costs would be incurred to the
extent that the rule increases the total number of sponsor requests to
charge patients for investigational drugs. The information requirements
associated with the proposed rule are not expected to impose a
significant burden. Drug sponsors who wish to charge for
investigational drugs would need to review the rule to become familiar
with its provisions and to gather the evidence and information
necessary to support charging requests. Because of the lack of data
described previously in this document, we are unable to generate
quantitative estimates of compliance costs at this time. The agency
expects that any incremental cost burdens would likely be small and
widely dispersed among affected entities for a number of reasons.
First, regulations covering charging for investigational drugs in
clinical trials and under treatment INDs or treatment protocols have
been in place since 1987. As a result, the primary incremental impact
of the proposed rule would be limited to the new charging provisions
for the following: (1) Clinical trials using approved drugs and (2) the
new mechanisms for expanded access for treatment use described under
proposed subpart I of part 312. Second, the agency does not expect that
these proposed charging provisions would lead to a large increase in
the total number of charging requests. Because it is not usually
extraordinarily expensive to make an investigational drug available to
a single patient or a limited number of patients, the agency does not
anticipate that the number of charging requests for expanded access to
investigational drugs for single patients or intermediate size patient
populations would increase substantially. Finally, requests to charge
are relatively infrequent and the expense necessary to prepare a
charging request would ordinarily be small compared to the overall cost
of preparing the expanded access submission.
The agency estimates that, on average, 48 hours would be needed to
prepare a request to charge under the proposed rule. This estimate is
based on FDA's experience in reviewing charging requests under the 1987
regulation and on a projection of the increased paperwork burden
associated with the proposed rule.
FDA believes that 80 percent, or about 38 hours, of this burden
would be associated with establishing that the amount proposed to be
charged is limited to the direct costs of making the drug available.
The agency believes that the cost justification portion of the charging
request would need to be performed by a cost accountant qualified to
assess the direct costs of charging. Information available on the
Internet indicates that median total compensation for a Cost Accountant
IV (senior level) was approximately $102,000 per year in 2004 or about
$49 per hour ($102,138/2,080 hours).\2\ Thus the cost associated with
certifying the amount to be charged is expected to be about $1,900 ($49
per hour x 38 hours) per charging request.
---------------------------------------------------------------------------

\2\See http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://swz.salary.com/salarywizard/layoutscripts/swzl_newsearch.asp
, last viewed 7/6/05. (FDA has verified the Web site

address, but we are not responsible for subsequent changes to the
Web site after this document publishes in the Federal Register.)
---------------------------------------------------------------------------

The remaining burden--20 percent or about 10 hours--for the
preparation of a charging request would consist of a brief
demonstration that the criteria for charging that are not related to
the amount to be charged have been met. When the request is to charge
for a drug used in a clinical trial, this information would ordinarily
be available as part of the normal drug development process. When the
request is to charge for a drug for expanded access, the primary
criterion is to show that charging will not interfere with development
of the drug for marketing. FDA believes that preparation of this
portion of the charging request would likely be performed by a mid-
level regulatory affairs person. Information available on the Internet
indicates that the total median compensation for a Regulatory Affairs
Specialist II (intermediate level) was approximately $80,000 or about
$39 per hour in 2004 ($80,288/2,080 hours).\3\ Thus, the cost to
demonstrate

[[Page 75178]]

that a charging request meets appropriate criteria is about $400 (10
hours x $39 per hour) per charging request.
---------------------------------------------------------------------------

\3\See http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://swz.salary.com/salarywizard/layoutscripts/swzl_newsearch.asp
, last viewed 7/6/05. (FDA has verified the Web site

Based on the figures presented previously in this document, FDA
estimates the cost to prepare and submit a charging request would thus
be about $2,300 ($1,900 + $400). We also believe that the total costs
associated with this proposed rule will be widely dispersed among
affected entities because charging requests are rare, and thus, a
particular sponsor would be expected to submit such a request very
infrequently.
A significant concern with the proposed rule relates to the
potential effect on access to investigational therapies for
economically disadvantaged individuals and the uninsured. Allowing
sponsors to charge could impose a significant financial burden on many
seriously ill individuals who lack therapeutic alternatives and could
preclude access by some needy patients. However, in the past, many
companies that have provided investigational drugs for treatment use
have often included assistance programs to cover the costs for those
who could not otherwise afford them. FDA expects this practice would
continue.

H. Minimizing the Impact on Small Entities

The agency does not believe that the proposed rule will have a
significant economic impact on a substantial number of small entities.
Nevertheless, we recognize our uncertainty regarding the number and
size distribution of affected entities as well as the economic impact
of the proposed rule on those entities. The agency specifically
requests detailed public comment regarding the number of affected small
entities as well as the potential economic impact of the proposed rule
on those entities.
According to agency records, the majority of treatment INDs and
treatment protocols (approximately 92 percent) are submitted by
commercial sponsors and government agencies that are not likely to meet
Small Business Administration (SBA) criteria defining a small entity in
the relevant industry sector. Thus, the agency believes that the vast
majority of requests to charge under expanded access submissions would
not be submitted by small entities. Most single patient INDs are for
treatment use and are submitted by individual physicians, and these
entities would be classified as small entities. However, for reasons
discussed previously, we do not anticipate that the volume of requests
to charge for individual patient expanded access would increase
substantially. Because expanded access for intermediate size patient
populations is not currently tracked by the agency, no data exist that
would allow the agency to identify either the number of sponsors in
this category or the number that would qualify as small entities. FDA
believes that requests to charge for investigational drugs in clinical
trials of a sponsor's drug, whether the drug charged for is the
sponsor's own drug or is an approved drug used for combination therapy
or as an active control, would generally be submitted by large
commercial drug sponsors. Requests to charge for an approved drug that
is being studied for a new use would likely come from researchers or
research organizations that meet the SBA standards for small business.
In sum, the agency believes that some entities submitting charging
requests would meet SBA small businesses criteria. However, because
this determination is uncertain, the agency specifically requests
detailed public comment regarding the number and size distribution of
entities that would be affected by the proposed rule, as well as the
economic impact of the rule on those entities. As discussed in section
V.E of this document, the agency expects that any incremental burden
associated with the proposed rule would be small and widely dispersed
among affected entities.
FDA considered several alternatives to the proposed rule. Each is
discussed in the following paragraphs:
Do not revise the current charging rule.
FDA considered and rejected this alternative because the current
charging rule does not address all of the types of requests to charge
for drugs in clinical trials received by the agency. Furthermore, the
current charging rule does not address all of the types of expanded
access to investigational drugs for treatment use specified under
proposed subpart I of part 312.
Do not permit charging for approved drugs in clinical
trials.
FDA considered this alternative. However, requests to charge for
investigational drugs in a clinical trial would then be limited to
requests to charge for the sponsor's drug that was being tested in the
trial. In fact, the agency has received few such requests. Far more
common are requests to charge for approved drugs in trials when the
drugs must be obtained from another company. The approved drug may be
used in a trial of the sponsor's drug as an active control or in
combination with the sponsor's drug. Even more common are requests to
charge for approved drugs used in studies by a third party (e.g., not
the manufacturer) that are intended to evaluate the approved drug, for
example, to discover a new use. FDA believes that requests to charge
for investigational drugs in these situations may be appropriate; thus
the agency believes the current charging rule should be revised to
specifically contemplate such requests and to provide criteria
applicable to such requests.
Do not permit charging for expanded access for individual
patients or for intermediate size patient populations.
FDA considered not revising the current regulation concerning
charging for treatment use and thus permitting charging only for
treatment INDs and treatment protocols. However, elsewhere in this
issue of the Federal Register, the agency is proposing to amend its
regulations concerning the treatment use of investigational drugs to
specifically authorize expanded access for individual patients and for
intermediate size patient populations. The purpose of that proposal is
to expand access to investigational drugs. In some situations,
permitting sponsors to charge for investigational drugs to be used by
individual patients or by intermediate size patient populations may be
the only way that such patients can receive access to these therapies
because sponsors may not be willing to provide the drugs free of
charge. Thus, consistent with the philosophy of the expanded access
rule, the agency decided to propose to permit charging for
investigational drugs in all expanded access settings to improve access
to investigational drugs for patients with serious or life-threatening
diseases or conditions who lack other therapeutic options and who may
benefit from such therapies.

VII. Paperwork Reduction Act of 1995

This proposed rule contains collections of information that are
subject to review by OMB under the Paperwork Reduction Act of 1995 (44
U.S.C. 3501-3520). ``Collection of information'' includes any request
or requirement that persons obtain, maintain, retain, or report
information to the agency, or disclose information to a third party or
to the public (44 U.S.C. 3502(3) and 5 CFR 1320.3(c)). The title,
description, and respondent description of the information collection
are shown in the following paragraphs, with an

[[Page 75179]]

estimate of the annual reporting burden. Included in the estimate is
the time for reviewing instructions, gathering and maintaining the data
needed, and completing and reviewing the collection of information.
FDA invites comments on the following topics: (1) Whether the
proposed collection of information is necessary for proper performance
of FDA's functions, including whether the information will have
practical utility; (2) the accuracy of FDA's estimate of the burden of
the proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
Title: Charging for Investigational Drugs
Description: The proposed rule describes the types of
investigational uses for which a sponsor may be able to charge,
including uses for which charging was not previously expressly
permitted, and the criteria for allowing charging for the identified
investigational uses. The proposed rule authorizes sponsors to request
to charge for investigational drugs used in clinical trials and for
investigational drugs for expanded access for treatment use. The
proposed rule also describes the types of costs that can be recovered
when charging for an investigational drug.
Section 312.8(a)(1) of the proposed rule provides that a sponsor
who wishes to charge for an investigational drug must meet the criteria
applicable to the specific sections of the proposal relating to
charging in a clinical trial or charging for expanded access.
Section 312.8(b) of the proposed rule describes the criteria for
charging in a clinical trial in three situations.
Proposed Sec. 312.8(b)(1) describes criteria for charging for the
sponsor's own drug in a clinical trial. To charge in this situation,
the sponsor must show the following three things. The sponsor must:
Provide evidence that the drug has a potential clinical
benefit that, if demonstrated in the clinical investigations, would
provide a significant advantage over available products in the
diagnosis, treatment, mitigation, or prevention of a disease or
condition;
Demonstrate that the data to be obtained from the clinical
trial would be essential to establishing that the drug is effective or
safe for the purpose of obtaining initial approval of a drug, or would
support a significant change in the labeling of an approved drug (e.g.,
new indication, inclusion of comparative safety information); and
Demonstrate that the clinical trial could not be conducted
without charging because the cost of the drug is extraordinary. The
cost may be extraordinary due to manufacturing complexity, scarcity of
a natural resource, the large quantity of drug needed (e.g., due to the
size or duration of the trial), or some combination of these or other
extraordinary circumstances.
Proposed Sec. 312.8(b)(2) describes criteria for charging for an
approved drug that a sponsor must obtain from another entity for use as
an active control or in combination with another drug in a clinical
trial designed to evaluate the effectiveness or safety of the sponsor's
investigational drug. To charge for an approved drug in this situation,
a sponsor must demonstrate that the trial is of adequate design to
evaluate the safety or effectiveness of the sponsor's drug and that the
drug is not being provided free of charge by its manufacturer.
Proposed Sec. 312.8(b)(3) describes criteria for charging for an
approved drug that must be obtained from another entity in a clinical
trial designed to evaluate the approved drug (e.g., for another
indication). To charge for an approved drug in this situation, a
sponsor must demonstrate that the clinical trial of the approved drug
is of adequate design to evaluate the safety or effectiveness of a new
indication or provide important safety information related to an
approved indication and that the drug is not being provided free of
charge by its manufacturer.
Proposed Sec. 312.8(c) describes criteria for charging for an
investigational drug for in an expanded access setting. The general
criterion to charge for expanded access for treatment use is that the
sponsor provide reasonable assurance that charging will not interfere
with developing the drug for marketing approval.
For treatment use under a treatment IND or treatment protocol, the
sponsor must also provide the following:
Evidence of sufficient enrollment in any ongoing clinical
trial(s) needed for marketing approval to reasonably assure FDA that
the trial(s) will be successfully completed as planned;
Evidence of adequate progress in the development of the
drug for marketing approval; and
Information submitted under its general investigational
plan (Sec. 312.23(a)(3)(iv)) specifying the drug development
milestones the sponsor plans to meet in the next year.
Section 312.8(a)(2) of the proposed rule provides that a sponsor
who wishes to charge for an investigational drug must justify the
amount to be charged.
Section 312.8(d) of the proposed rule describes more specifically
the costs that are potentially recoverable. Proposed Sec. 312.8(d)(1)
provides that a sponsor may recover only the direct costs of making the
investigational drug available. Proposed Sec. 312.8(d)(1)(i) defines
direct costs as costs incurred by a sponsor that can be specifically
and exclusively attributed to providing the drug for the
investigational use for which FDA has authorized cost recovery. Direct
costs include costs per unit to manufacture the drug (e.g., raw
materials, labor, and nonreusable supplies and equipment used to
manufacture the quantity of drug needed for the use for which charging
is authorized) or costs to acquire the drug from another manufacturing
source, and direct costs to ship and handle (e.g., store) the drug.
Proposed Sec. 312.8(d)(1)(ii) states that indirect costs include
costs that are incurred primarily to produce the drug for commercial
sale. Such costs include, e.g., costs for facilities and equipment that
are used to manufacture the supply of investigational drug, but that
are primarily intended to produce large quantities of drug for eventual
commercial sale and research and development, administrative, labor, or
other costs that would be incurred even if the clinical trial or
expanded access for which charging is authorized did not occur.
Proposed Sec. 312.8(d)(2) provides that when the sponsor is
charging for making the drug available for expanded access for an
intermediate size patient population or for a treatment IND or protocol
under subpart I, the sponsor may also recover the costs of monitoring
the protocol, complying with IND reporting requirements, and other
administrative costs directly associated with the expanded access in
addition to the sponsor's direct costs.
Description of Respondents: Licensed physicians and manufacturers,
including small business manufacturers.
Estimates of Reporting Burden
Table 1 of this document presents the estimated annualized
reporting burden for the total number of charging requests. The
estimates in the table have been derived in the following manner.
Between 1999 and 2003, FDA received approximately 25 requests to charge
for investigational drugs annually. FDA estimates that there will be a
25 to 50 percent increase in requests to charge if

[[Page 75180]]

the proposed rule is finalized. These requests are expected to be
requests to charge for expanded access for single patients and
intermediate size patient populations and for approved drugs in
clinical trials. Accordingly, table 1 of this document gives the total
annual responses as 38 (25 x 1.50 = 37.5). FDA's experience has been
that, in general, a single sponsor does not make multiple requests to
charge for investigational drugs in the same year. However, the agency
anticipates that multiple requests may increase somewhat if, as we
expect, the number of individual patient treatment uses increases.
Thus, we have assumed that the number of annual respondents will be 35.
FDA believes the largest portion of the paperwork burden associated
with the proposed rule would be to justify the request to charge by
showing that the amount proposed to be charged is limited to the direct
costs of making the drug available (proposed Sec. 312.8(d)(1)). When
the sponsor requests to charge for making the drug available for
expanded access by an intermediate size patient population or through a
treatment IND or treatment protocol, the sponsor may also recover the
costs of monitoring the treatment use protocol, complying with IND
reporting requirements, and other administrative costs directly
associated with the expanded access (proposed Sec. 312.8(d)(2)). The
sponsor would also need to support its suggested charge for these
expenses.
The remaining portion of the paperwork burden associated with the
proposed rule would be to show that the criteria applicable to the
specific type of charging request (i.e., the type of clinical trial
(proposed Sec. 312.8(b)) or type of expanded access (proposed Sec.
312.8(c))) have been met.
FDA estimates the average number of hours needed to prepare a
request to charge for an investigational drug under the proposed rule
as 48. This estimate is based on FDA's experience in reviewing charging
requests in the past and on a projection of the increased paperwork
burden associated with the proposed rule.

Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
No. of No. of Responses Total Annual Hours Per
21 CFR Section Respondents per Respondent Responses Response Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.8 35 1.08 38 48 1,824
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

VIII. Federalism

FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has 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 concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.

IX. Request for Comments

Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. Received comments may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.

List of Subjects in 21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 312 be amended as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

1. The authority citation for 21 CFR part 312 continues to read as
follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 371,
381, 382, 383, 393; 42 U.S.C. 262.

Sec. 312.7 [Amended]

2. Section 312.7 is amended by removing paragraph (d) and by
revising the section heading to read as follows:

Sec. 312.7 Promotion of investigational drugs.

* * * * *
3. Section 312.8 is added to subpart A to read as follows:

Sec. 312.8 Charging for investigational drugs.

(a) General criteria for charging. (1) A sponsor must meet the
applicable requirements in paragraph (b) of this section for charging
in a clinical trial or paragraph (c) of this section for charging for
expanded access to an investigational drug treatment use under subpart
I of this part.
(2) A sponsor must justify the amount to be charged in accordance
with paragraph (d) of this section.
(3) A sponsor must obtain prior written authorization from FDA to
charge for an investigational drug.
(4) FDA will withdraw authorization to charge if it determines that
charging is interfering with the development of a drug for marketing
approval or that the criteria for the authorization are no longer being
met.
(b) Charging in a clinical trial--(1) Charging for a sponsor's
drug. A sponsor who wishes to charge for its investigational drug,
including investigational use of its approved drug, must:
(i) Provide evidence that the drug has a potential clinical benefit
that, if demonstrated in the clinical investigations, would provide a
significant advantage over available products in the diagnosis,
treatment, mitigation, or prevention of a disease or condition;
(ii) Demonstrate that the data to be obtained from the clinical
trial would be essential to establishing that the drug is effective or
safe for the purpose of obtaining initial approval of a drug, or would
support a significant change in the labeling of an approved drug (e.g.,
new indication, inclusion of comparative safety information); and
(iii) Demonstrate that the clinical trial could not be conducted
without charging because the cost of the drug is extraordinary. The
cost may be extraordinary due to manufacturing complexity, scarcity of
a natural resource, the large quantity of drug needed (e.g., due to the
size or duration of the trial), or some combination of these or other
extraordinary circumstances.

[[Page 75181]]

(2) Charging for an approved drug obtained from another entity for
use as an active control or in combination with another drug. A sponsor
who wishes to charge for an approved drug that it must obtain from
another entity for use as an active control or in combination with its
investigational drug in a clinical trial of the sponsor's
investigational drug must:
(i) Demonstrate that the clinical trial is adequately designed to
evaluate the safety or effectiveness of the sponsor's drug; and
(ii) Demonstrate that the holder of the approved application is not
providing the drug to the sponsor free of charge.
(3) Charging for an approved drug obtained from another entity in a
clinical trial of that drug. A sponsor who wishes to charge for an
approved drug that it must obtain from another source for use in a
clinical trial intended to evaluate the acquired drug must:
(i) Demonstrate that the clinical trial is adequately designed to
evaluate the safety or effectiveness of a new indication or to provide
important safety information related to an approved indication; and
(ii) Demonstrate that the holder of the approved application is not
providing the drug to the sponsor free of charge.
(4) Duration of charging in a clinical trial. Unless FDA specifies
a shorter period, charging may continue for the length of the clinical
trial.
(c) Charging for expanded access to investigational drug for
treatment use. (1) A sponsor who wishes to charge for expanded access
to an investigational drug for treatment use under subpart I of this
part must provide reasonable assurance that charging will not interfere
with developing the drug for marketing approval.
(2) For expanded access under Sec. 312.320, such assurance must
include:
(i) Evidence of sufficient enrollment in any ongoing clinical
trial(s) needed for marketing approval to reasonably assure FDA that
the trial(s) will be successfully completed as planned;
(ii) Evidence of adequate progress in the development of the drug
for marketing approval; and
(iii) Information submitted under the general investigational plan
(Sec. 312.23(a)(3)(iv)) specifying the drug development milestones the
sponsor plans to meet in the next year.
(3) The authorization to charge is limited to the number of
patients authorized to receive the drug under the treatment use, if
there is a limitation.
(4) Unless FDA specifies a shorter period, charging for expanded
access to an investigational drug for treatment use under subpart I of
this part may continue for one year from the time of FDA authorization.
A sponsor may request that FDA reauthorize charging for additional
periods.
(d) Costs recoverable when charging for an investigational drug.
(1) A sponsor may recover only the direct costs of making the
investigational drug available.
(i) Direct costs are costs incurred by a sponsor that can be
specifically and exclusively attributed to providing the drug for the
investigational use for which FDA has authorized cost recovery. Direct
costs include costs per unit to manufacture the drug (e.g., raw
materials, labor, and nonreusable supplies and equipment used to
manufacture the quantity of drug needed for the use for which charging
is authorized) or costs to acquire the drug from another manufacturing
source, and direct costs to ship and handle (e.g., store) the drug.
(ii) Indirect costs include costs incurred primarily to produce the
drug for commercial sale (e.g., costs for facilities and equipment used
to manufacture the supply of investigational drug, but that are
primarily intended to produce large quantities of drug for eventual
commercial sale) and research and development, administrative, labor,
or other costs that would be incurred even if the clinical trial or
treatment use for which charging is authorized did not occur.
(2) For expanded access to an investigational drug for treatment
use under Sec. Sec. 312.315 and 312.320, in 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.
(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.

Dated: December 6, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-9685 Filed 12-11-06; 10:01 am]

BILLING CODE 4160-01-S