Federal Register, Volume 78 Issue 113 (Wednesday, June 12, 2013)

[Federal Register Volume 78, Number 113 (Wednesday, June 12, 2013)]
[Rules and Regulations]
[Pages 35117-35135]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-13930]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 316

[Docket No. FDA-2011-N-0583]
RIN 0910-AG72

Orphan Drug Regulations

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing final
regulations amending the 1992 Orphan Drug Regulations issued to
implement the Orphan Drug Act. These amendments are intended to clarify
regulatory provisions and make minor improvements to address issues
that have arisen since those regulations were issued.

DATES: This rule is effective August 12, 2013.

FOR FURTHER INFORMATION CONTACT: Erica K. McNeilly, Office of Orphan
Products Development, Food and Drug Administration, Bldg. 32, rm. 5271,
10903 New Hampshire Ave., Silver Spring, MD 20993, 301-796-8660.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Overview of the Final Rule
III. Summary of and Response to Comments
A. Demonstration of an ``Orphan Subset'' of a Non-Rare Disease
or Condition
B. Eligibility for Orphan-Drug Designation of a Drug That Was
Previously Approved for the Same Use or Indication
C. Eligibility for Multiple Orphan-Drug Exclusive Approvals
D. Demonstration of Clinical Superiority--Major Contribution to
Patient Care
E. Name of the Drug
F. Required Drug Description and Scientific Rationale in a
Request for Orphan-Drug Designation
G. Responding to a Deficiency Letter From FDA on an Orphan-Drug
Designation Request
H. Publication of Orphan-Drug Designations
I. FDA Recognition of Orphan-Drug Exclusive Approval
J. Miscellaneous Comment
K. Initial Paperwork Burden Estimates
IV. Environmental Impact
V. Legal Authority
VI. Implementation Plan
VII. Executive Order 13132: Federalism
VIII. Paperwork Reduction Act of 1995
IX. Analysis of Impacts
A. Background
B. Benefits and Costs of the Proposed Rule
C. Small Business Analysis

I. Background

In the Federal Register of October 19, 2011 (76 FR 64868), FDA
issued a proposed rule to amend the Orphan Drug Regulations (part 316
(21 CFR part 316)), to clarify certain regulatory language and propose
areas of minor improvement regarding orphan-drug designation and
orphan-drug exclusivity. The proposed rule addressed the following
aspects of the Orphan Drug Regulations: (1) Demonstration of an
appropriate ``orphan subset'' of persons with a particular disease or
condition that otherwise affects 200,000 or more persons in the United
States (``non-rare disease or condition''), for the purpose of
designating a drug for use in that subset; (2) eligibility for
designation of a drug that is otherwise the same drug for the same use
as a previously approved drug; (3) eligibility for multiple orphan-drug
exclusive approvals when a drug is designated for use in a rare disease
or condition,\1\ but is then separately approved for different
indication(s) or use(s) within that particular rare disease or
condition; (4) requirement for demonstrating clinical superiority for
the purpose of orphan-drug exclusive approval when the drug is
otherwise the same as a previously approved drug for the same use or
indication; (5) requirement for submitting the name of the drug in a
designation request; (6) required drug description and scientific
rationale in a designation request; (7) required information in a
designation request relating to the sponsor's interest in the drug; (8)
timing of a request for orphan-drug designation; (9) responding to a
deficiency letter from FDA on an orphan-drug designation request; (10)
FDA publication of information regarding orphan-drug designations; (11)
FDA recognition of orphan-drug exclusive approval; (12) miscellaneous
terminology changes; and (13) an address change.
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\1\ Section 526(a) of the Federal Food, Drug and Cosmetic Act
(FD&C Act) defines a ``rare disease or condition'' to include any
disease or condition that affects fewer than 200,000 persons in the
United States.
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[[Page 35118]]

II. Overview of the Final Rule

This rule largely finalizes the revisions as proposed, with several
changes for clarity and accuracy and one substantive change involving
publication when a drug no longer has orphan-drug designation. The main
changes from the proposed rule are as follows:
Adding a definition of ``orphan subset'' to Sec.
316.3(b)(13), using a definition that is consistent with the
explanation of orphan subset in the proposed rule.
Clarifying the existing regulation in accordance with
FDA's long-standing practice that a designated drug is eligible for
orphan exclusive approval only if the same drug has not already been
approved for the same use or indication,\2\ by adding clarifying
language to Sec. Sec. 316.3(b)(12), 316.31(a), and 316.34(a).
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\2\ Elsewhere in this preamble, we use the phrase ``same use''
as short-hand for ``same use or indication.''
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Removing the language in the proposed rule that, to
demonstrate clinical superiority in terms of ``major contribution to
patient care'' (Sec. 316.3(b)(3)(iii)), the drug must provide safety
and effectiveness ``comparable to the approved drug.'' This language
incorrectly implied that FDA would require direct proof of
comparability to the already approved drug to demonstrate that a drug
provides a major contribution to patient care (e.g., through non-
inferiority trials).
Adding an email address to the list of contact information
required in requests for designation (Sec. 316.20(b)(2)), and making a
related edit to the provision addressing the contact information
required for permanent-resident agents (Sec. 316.22).
Clarifying that a designation request need include only
``relevant'' in vitro laboratory data, as well as data from ``clinical
experience'' with the drug in the rare disease or condition (Sec.
316.20(b)(4)). The proposal had omitted the qualifier ``relevant''
before in vitro laboratory data and had limited the clinical data to
data from ``clinical investigations.'' FDA may in some cases consider
other clinical data, such as well-documented case histories or
significant human experience with the drug, as appropriate.
Clarifying that, whenever FDA considers a designation
request voluntarily withdrawn, FDA will notify the sponsor in writing
(Sec. 316.24(a)). The proposal had erroneously implied that FDA would
so notify the sponsor in writing only if the request was considered
voluntarily withdrawn because FDA had denied a sponsor's request for an
extension of time to respond to a deficiency letter, and not also if
the sponsor had simply failed to respond, or request an extension of
time to respond, within 1 year of issuance of the deficiency letter.
Clarifying that, in addition to the reasons already
expressly specified in Sec. 316.25, FDA can refuse to grant a
designation request if the request is otherwise ineligible for
designation under part 316 (Sec. 316.25(b)). This revision merely
codifies FDA's longstanding interpretation.
Stating that FDA's publicly available posting of
designated drugs will include whether a drug is no longer designated if
the drug loses designation after the effective date of this final rule
(Sec. 316.28). This information used to be deducible from FDA's
publication of hard copy quarterly lists of designated drugs: Drugs no
longer designated would appear on earlier hard copy lists but not on
later ones. Once FDA switched to Internet publication, this information
was no longer deducible owing to database limitations at the time. FDA
is also making a technical correction to Sec. 316.28 to reflect that
FDA no longer places an annual list of designated drugs on file at
FDA's Division of Dockets Management.
Making explicit an option that has always existed for
sponsors--that sponsors may voluntarily withdraw a designation request,
or an actual designation, at any time by submitting a written request
to FDA (Sec. 316.24(d)).
Clarifying that the scope of orphan exclusive approval is
limited to the indication(s) or use(s) for which the designated drug is
approved (Sec. 316.31(a) and 316.31(b)). The proposal had used the
term ``subset'' instead of ``indication(s) or use(s)'' (i.e., where a
drug is approved for only a subset of patients with the rare disease or
condition for which the drug is designated), which readers may have
confused with the regulatory concept of ``orphan subset'' at Sec.
316.20(b)(6). A reference to ``orphan subset'' was not intended at
Sec. 316.31. Orphan subset is a regulatory concept relevant to
eligibility for orphan-drug designation, whereas this regulation at
Sec. 316.31 concerns the scope of orphan exclusive approval.
Clarifying that a designated drug that is otherwise the
same as a previously approved drug receives 7-years market exclusivity
(``orphan-drug exclusivity'') upon approval only if the sponsor of the
second-in-time drug demonstrates upon approval that its drug is
clinically superior to the previously approved drug (Sec. 316.34(c)).
This language corrects two possible misinterpretations of the proposed
rule, by clarifying that: (1) Sponsors may have to demonstrate clinical
superiority to obtain orphan-drug exclusivity even if they did not have
to submit a plausible hypothesis of clinical superiority to obtain
designation (e.g., if the same drug is approved for the same use after
the designation but before the approval of the sponsor's drug); and (2)
FDA will recognize orphan-drug exclusivity as long as clinical
superiority to the previously approved drug is demonstrated, regardless
of whether the sponsor substantiates the particular hypothesis of
clinical superiority upon which designation was based (e.g., the drug
may in fact be safer for a different reason than that hypothesized at
the designation stage, or it may be demonstrated to be more effective
instead of safer).
Updating the FDA address listed at Sec. Sec. 316.22 and
316.50 (in addition to doing so at Sec. 316.4, as proposed) and adding
an online address for the Orange Book at Sec. 316.34(b).
This rule is intended to assist sponsors who are seeking and who
have obtained orphan-drug designation of their drugs, as well as FDA in
administering the orphan drug program. As described in the proposed
rule (76 FR 64868), FDA believes these revisions will clarify,
streamline, and improve the orphan-drug designation process. These
amendments are fully consistent with the Orphan Drug Act (Pub. L. 97-
414) and continue to provide incentives for the development of
potentially promising orphan drugs that may not otherwise be developed
and approved, including drugs that are potentially safer or more
effective than already approved drugs.

III. Summary of and Response to Comments

FDA received comments on the proposed rule from 14 entities, mainly
from companies and trade associations of companies that are marketing
or hope to market orphan drugs. On the whole, the comments were
strongly supportive of the orphan drug program and recognized the need
for clarity in FDA requirements. Many comments also raised objections
to and questions about certain aspects of the proposed rule,
particularly the deletion of the phrase ``medically plausible'' from
Sec. 316.20 and clarification of the requirement for demonstrating
clinical superiority to obtain orphan-drug exclusive approval.
Below, FDA responds to the comments in the order in which the
sections were presented in the proposed rule. To make it easier to
identify comments and our responses, the word

[[Page 35119]]

``Comment,'' in parentheses, appears before the comment's description
and the word ``Response,'' in parentheses, appears before our response.
We have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same number.
The number assigned to each comment is purely for organizational
purposes and does not signify the comment's value, importance, or the
order in which it was received.

A. Demonstration of an ``Orphan Subset'' of a Non-Rare Disease or
Condition \3\
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\3\ As in the proposed rule, in this final rule FDA is not
changing the regulatory provisions allowing sponsors to obtain
orphan-drug designation for a drug intended for a disease or
condition affecting 200,000 or more people, or for a vaccine,
diagnostic drug, or preventive drug to be administered to 200,000 or
more people per year, if there is no reasonable expectation that
research and drug development costs can be recovered by sales of the
drug in the United States. (Sec. Sec. 316.20(b)(8)(ii) and
316.21(c)).
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(Comment 1) Four comments objected to the proposal to delete
``medically plausible'' from the regulatory provision describing an
orphan subset at Sec. 316.20(b)(6), on the ground that this proposal
would appear to narrow eligibility for orphan-drug designation. These
comments asked FDA to retain ``medically plausible'' in the regulation.
(Response) FDA carefully considered whether to retain ``medically
plausible'' in the regulatory provision describing an orphan subset at
Sec. 316.20(b)(6). Because of the confusion created by the term
``medically plausible,'' FDA decided to finalize the description of
orphan subset as proposed. This confusion was manifest in the very
comments objecting to the proposal and asking that the term ``medically
plausible'' be retained.
As explained in the proposed rule (76 FR 64868 at 64869 to 64870),
the term ``medically plausible'' has been misinterpreted by sponsors to
mean any medically recognizable or clinically distinguishable subset of
persons with a particular disease or condition--a misunderstanding
reflected in some of the comments described previously. This
misinterpretation of ``medically plausible,'' if accepted by FDA, could
result in artificially narrow subsets for the purpose of orphan-drug
designation. It could permit a non-rare disease or condition to be
artificially subdivided into smaller groups for establishing subsets
that are under the prevalence limit for designation. FDA does not
believe that such an approach would serve the intent of the Orphan Drug
Act, as explained in the proposed rule (76 FR 64868 at 64869 to 64870).
Use of such artificial orphan populations to obtain orphan-drug
designation and its related benefits would divert resources away from
research and development of drugs for true orphan diseases and
conditions. Further, it would encourage sponsors to study and seek
approval for use of a drug in the narrowest possible artificial patient
groupings within a disease or condition in order to avail themselves of
the orphan-drug incentives, including tax benefits and orphan-drug
exclusive approval, when other patients with the disease or condition
would also benefit from use of the drug. Under this scenario, sponsors
could even potentially ``game'' approvals by seeking successive narrow
approvals of a drug to avail themselves of orphan-drug benefits when
the overall approved use is not an orphan use. These outcomes would be
inconsistent with the Orphan Drug Act.
By removing ``medically plausible'' from Sec. 316.120(b)(6) and
instead inserting a description of what orphan subset means, FDA aims
to dispel the confusion created by the term ``medically plausible.''
This description is consistent with how FDA has long interpreted
``medically plausible'' in the context of orphan subsets. It is
intended to make clear to sponsors that an orphan subset is a
regulatory concept specific to the Orphan Drug regulations, and that it
does not simply mean any medically recognizable or clinically
distinguishable subset of persons with a particular disease or
condition (as the term ``medically plausible'' in this context may have
been erroneously interpreted to imply). Under FDA's longstanding
approach, eligibility for orphan subsets rests on whether use of the
drug in a subset of persons with a non-rare disease or condition may be
appropriate but use of the drug outside of that subset (in the
remaining persons with the non-rare disease or condition) would be
inappropriate owing to some property(ies) of the drug, for example,
drug toxicity, mechanism of action, or previous clinical experience
with the drug. This is the same requirement as the requirement that FDA
long employed for identifying ``medically plausible'' subsets for the
purpose of orphan-drug designation. To be clear, FDA has never
interpreted ``medically plausible'' to mean what these comments appear
to claim it means. Thus, contrary to what these comments suggest,
replacing ``medically plausible'' with a description of orphan subset
will not result in a narrowing of eligibility for orphan-drug
designation.
Partly in response to the confusion expressed by these comments,
FDA is making a slight edit to Sec. 316.20(b)(6) to expressly
incorporate the term ``orphan subset.'' In place of the opening clause,
``Where a drug is under development for only a subset of persons with a
particular disease or condition that otherwise affects 200,000 or more
people,'' FDA is inserting the following language: ``Where a sponsor
requests orphan-drug designation for a drug for only a subset of
persons with a particular disease or condition that otherwise affects
200,000 or more people (`orphan subset'), . . . '' This edit has two
advantages: it incorporates an overt reference to ``orphan subset''
into the regulatory language, and it clarifies that sponsors can seek
designation of a drug for an orphan subset before they begin developing
that drug. FDA is also adding ``orphan subset'' to the definition
section at Sec. 316.3(b)(13), as follows: ``Orphan subset of a non-
rare disease or condition (`orphan subset') means that use of the drug
in a subset of persons with a non-rare disease or condition may be
appropriate but use of the drug outside of that subset (in the
remaining persons with the non-rare disease or condition) would be
inappropriate owing to some property(ies) of the drug, for example,
drug toxicity, mechanism of action, or previous clinical experience
with the drug.''
Finally, we note that we are retaining the term ``medically
plausible'' elsewhere in part 316 when describing whether the
scientific rationale for use of the drug for the rare disease or
condition is adequate (Sec. 316.25(a)(2)) and whether the hypothesis
of clinical superiority, if required, is plausible (Sec.
316.25(a)(3)). Unlike in the orphan subset context, the term
``medically plausible'' has not caused confusion among sponsors in
these contexts. FDA is therefore retaining the original ``medically
plausible'' terminology at Sec. 316.25(a).
(Comment 2) Many comments asked FDA to clarify what subsets may be
appropriate for the purpose of orphan-drug designation.
(Response) FDA advises sponsors that an orphan subset cannot be
considered without reference to the drug, specifically to the property
or properties of the drug that preclude its use in the remaining
persons with the non-rare disease or condition, outside of the orphan
subset. FDA explained in the proposed rule (76 FR 64868 at 64869 to
64870) what factors may inform whether an appropriate orphan subset
exists for the purpose of orphan-drug designation. In response to these
comments, FDA is providing further explanation here.
Factors that may inform whether an appropriate orphan subset exists

[[Page 35120]]

include pharmacologic or biopharmaceutical properties of the drug and
previous clinical experience with the drug. For example:
Toxicity of the Drug: The toxicity profile of the drug may
render it appropriate for use in only a subset of persons with a non-
rare disease or condition. For example, patients with the disease or
condition who can be treated with other, less toxic therapies may not
be appropriate candidates for the drug; however, a subset of patients
with the disease or condition who are refractory to, or intolerant of,
other less toxic drugs may exist and may be the only appropriate
candidates for treatment with the more toxic drug.
Mechanism of Action of the Drug (e.g., antibody-specific
or biomarker-based drug): The mechanism of action of a drug may limit
use of a drug to only a subset of patients with a non-rare disease or
condition. For example, use of a certain targeted therapy (e.g.,
antibody-specific or biomarker-based drug) may be appropriate in only a
subset of patients with a non-rare disease or condition owing to its
targeting mechanism (e.g., only in patients with the subtypes of tumors
that possess the specific antigen targeted or only those patients with
the specific biomarker targeted).
Previous Clinical Experience With the Drug: Information on
the drug's activity available from completed clinical trials or
published in clinical literature may be used to establish an orphan
subset. For example, if relevant data show that the drug has no
significant activity in the remaining subset of patients with high
grade tumors or with a certain biomarker, respectively, then patients
with low grade tumors or without that biomarker may constitute an
orphan subset within a given disease or condition.
Factors that may not inform whether an orphan subset exists were
also addressed in the proposed rule (76 FR 64868 at 64869 to 64870).
These factors may include, by way of example:
Clinical Trial Eligibility: An orphan subset is not
appropriate where the subset of interest is defined only by eligibility
to enroll in a given clinical trial to support a specific indication
for use of a drug, where other persons with the disease or condition
may also be appropriate candidates for the drug. That is, patients with
a given disease or condition who simply meet inclusion or exclusion
criteria for a trial do not automatically qualify as an orphan subset
absent some property(ies) of the drug that would render its use
inappropriate in the remaining persons with the disease or condition.
Sponsor's Plan to Study the Drug for a Select Indication:
An orphan subset does not exist simply because the sponsor plans to
study the drug for a select indication within a disease or condition
absent some property(ies) of the drug that would render its use
inappropriate in the remaining persons with the disease or condition.
Particular Disease Grade or Stage: An orphan subset does
not exist for a drug for use in a subset of persons with a particular
pathohistologic grade or clinical stage of a specific malignancy absent
some property(ies) of the drug that would render its use inappropriate
in the remaining persons with the disease or condition.
Price: An orphan subset does not exist simply because the
high price of a drug may render it unlikely to be used in a broader
population with the disease or condition. The sponsor must show that
use of the drug in the remaining persons with the disease or condition
would be scientifically or medically inappropriate, not simply unlikely
because of price or other factors.
(Comment 3) Many of the comments expressed concern that, in order
to establish an orphan subset, sponsors would have to prove a negative:
That the drug would not potentially benefit other subsets of persons
with the non-rare disease or condition. As one comment noted, ``There
may be reason to encourage study of a treatment for a clinically
distinct subgroup, even if that treatment could also be used to treat a
different clinically distinct subgroup or even a larger group with the
same disease.''
(Response) FDA understands the concern about ``proof of a
negative,'' but advises sponsors that an orphan subset cannot be
artificially narrow. As noted in response to comments 1 and 2, an
orphan subset must be based on some property(ies) of the drug, such as
toxicity or mechanism of action, that would render its use
inappropriate in the remaining persons with the disease or condition.
This showing is not necessarily ``proof of a negative,'' as these
comments may suggest; it need not necessarily rise to the level of
``scientific proof'' as that term in commonly understood.
Some of the concerns expressed by these comments are best addressed
through discussion of what constitutes a distinct ``disease or
condition'' for the purpose of orphan-drug designation. A drug that
shows promise in multiple, different rare diseases or conditions may be
eligible for multiple designations, one for each disease or condition,
because FDA considers the prevalence within each disease or condition.
For example, the same drug may be eligible for three separate
designations: One for the treatment of ovarian cancer, one for the
treatment of multiple myeloma, and one for the treatment of Kaposi's
sarcoma, even if the cumulative prevalence of all three diseases or
conditions would exceed 200,000. As long as the prevalence of each
disease or condition is under 200,000, no orphan subset need be shown.
If, however, the drug is for a disease or condition that exceeds the
prevalence limit of 200,000, then the sponsor would need to establish
an orphan subset based on some property(ies) of the drug, as described
previously in the responses to comments 1 and 2.
Whether a given medical condition constitutes a distinct ``disease
or condition'' for the purpose of orphan-drug designation depends on a
number of factors, assessed cumulatively, including: Pathogenesis of
the disease or condition; course of the disease or condition; prognosis
of the disease or condition; and resistance to treatment. These factors
are analyzed in the context of the specific drug for which designation
is requested. For example, based on a cumulative assessment of the
previous factors, FDA currently considers pneumonia in cystic fibrosis
patients to be a different ``disease or condition'' than community-
acquired pneumonia when evaluating orphan-drug designation requests for
products that treat respiratory infection. Thus, assuming the
prevalence of pneumonia in cystic fibrosis patients in the United
States is under 200,000, but the pool of all pneumonia cases exceeds
200,000, sponsors seeking orphan-drug designation for a drug for
pneumonia in cystic fibrosis patients need not establish an orphan
subset from the larger pool of all pneumonia patients. They need not,
in other words, provide a rationale for why only cystic fibrosis
patients with pneumonia (and not patients with community-acquired
pneumonia) would be appropriate candidates for the drug. By contrast,
FDA currently considers stage 1 breast cancer to be the same ``disease
or condition'' as stage 4 breast cancer when evaluating orphan-drug
designation requests for products that treat breast cancer. Because the
prevalence of breast cancer currently exceeds 200,000, sponsors seeking
orphan-drug designation for a breast cancer drug would need to
demonstrate why only a subset of patients with breast cancer (e.g.,
patients with stage 4 breast cancer) would be appropriate candidates
for the drug. FDA acknowledges that what is considered a

[[Page 35121]]

distinct ``disease or condition'' may change over time as scientific
understanding evolves, which would affect prevalence determinations.
If FDA considers the disease or condition in question to be a
distinct ``disease or condition'' for the purpose of orphan-drug
designation, then drugs for that disease or condition may be eligible
for orphan-drug designation even if they may potentially benefit other
patient groups (e.g., drugs for pneumonia in cystic fibrosis patients
may be eligible for designation even if they may potentially benefit
patients with community-acquired pneumonia). Assuming prevalence of the
relevant disease or condition is under 200,000, no orphan subset need
be shown; sponsors would not need to justify limiting use of the drug
to only that rare disease or condition. A drug could thus be eligible
for multiple designations if it meets the applicable criteria for
orphan-designation for multiple diseases or conditions, one disease or
condition per designation.
(Comment 4) One comment noted that the European Medicines Agency
(EMA) uses the term ``medically plausible'' in its orphan drug program,
and advised FDA to consult with EMA before removing the term from FDA
regulations.
(Response) FDA reminds sponsors that, although FDA is replacing the
term ``medically plausible'' with a description of what constitutes an
orphan subset, FDA is not changing its longstanding approach to
identifying when appropriate subsets exist for the purpose of orphan-
drug designation. FDA is aware that EMA uses the term ``medically
plausible'' in evaluating whether medicinal products are eligible for
orphan-drug designation in the European Union. FDA appreciates that
harmonization with EMA, where feasible, benefits many stakeholders, and
to that end has created with EMA a ``Common Application'' for orphan-
drug designation. There are, however, differences in the statutory and
regulatory criteria for, and regulatory benefits associated with,
orphan-drug designation in the United States compared to the European
Union. Absent a myriad of legislative changes, FDA and EMA cannot
completely harmonize in their approaches to designation. FDA believes
that any benefit to be gained by retaining the term ``medically
plausible'' in its regulations purely because the EMA employs the term
is outweighed by the confusion this term has engendered among sponsors
seeking designation from FDA.
(Comment 5) Two comments agreed with the proposal to replace
``medically plausible'' with a description of orphan subset. One of
these comments requested the following two clarifications from FDA:
One, that orphan subsets can exist regardless of whether the drug may
be used or investigated in other subsets of persons with the non-rare
disease or condition, as long as there is a reasonable scientific or
medical basis for use of the drug in the subset of interest; and two,
that orphan subsets can be based on biomarkers and other facets of
``personalized medicine'' (e.g., antibody-specific treatments).
(Response) The responses to comments 1 to 3 also address these
comments. Consistent with FDA's longstanding approach, eligibility for
orphan subsets rests on whether some property(ies) of the drug render
its use inappropriate in the remaining persons with the disease or
condition, outside of the subset of interest. FDA disagrees that an
orphan subset can exist whenever there is a basis for using the drug in
the subset of interest, regardless of whether the drug can also be used
in the remaining persons with the disease or condition. FDA does,
however, recognize that orphan subsets may be predicated on biomarker-
based and other targeted treatments as a principle for limiting the use
of a drug to only a subset of patients with a non-rare disease or
condition (e.g., the subset with the specific biomarker targeted).

B. Eligibility for Orphan-Drug Designation of a Drug That Was
Previously Approved for the Same Use or Indication

(Comment 6) Four comments were opposed to the proposal to delete
the word ``orphan'' from the phrase ``approved orphan drug'' in
Sec. Sec. 316.3(b)(3), 316.20(a) and (b)(5), and the proposal to
revise Sec. 316.25(a)(3) to read ``already approved drug for the same
disease or condition'' (in place of ``[a drug] that already has orphan-
drug exclusive approval for the same disease or condition''), on the
ground that FDA should grant designation more liberally by never
requiring a plausible hypothesis of clinical superiority at the
designation stage, even if the drug is otherwise the same as a
previously approved drug (whether or not such previously approved drug
has orphan exclusive approval). These comments interpret section 526 of
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C.
360bb) to mandate orphan-drug designation of any drug for a rare
disease or condition, even those that are the same drug as a previously
approved drug, regardless of clinical superiority, as long as the
designation request for the drug is submitted before submission of the
marketing application. At the same time, these comments acknowledge
that, in order for the drug to receive and/or break orphan exclusivity
under section 527 of the FD&C Act (21 U.S.C. 360cc), clinical
superiority would need to be demonstrated upon approval if the drug is
otherwise the same as a previously approved drug for the same use or
indication.
According to these comments, more liberal granting of orphan-drug
designation without changing orphan-drug exclusivity requirements would
further the intent of the Orphan Drug Act, by fostering development of
rare disease treatments without undercutting the exclusivity incentive/
protection. Specifically, more liberal orphan-drug designation--even if
orphan-drug exclusivity is not even theoretically available--would
expand the universe of rare disease treatments eligible for the
benefits (other than exclusivity) associated with designation under the
Orphan Drug Act: particularly, Federal tax credits for the cost of
conducting human clinical testing and exemption from application user
fees.\4\ These comments noted that the benefits associated with
designation have expanded since passage of the Patient Protection and
Affordable Care Act (ACA) in 2010 (Pub. L. 111-148), to include
exemption from the annual pharmaceutical fee (excise tax) levied by ACA
and exclusion from the 340B Drug Discount Program. According to these
comments, Congress used orphan-drug designation as a ``proxy'' for
protection of rare disease treatments in the ACA but without
necessarily realizing that not all rare disease treatments are eligible
for orphan-drug designation.
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\4\ This exemption from application user fees was enacted as
part of the Prescription Drug User Fee Act of 1992, since
reauthorized.
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Two of these comments identify plasma protein therapies, in
particular, as deprived of the benefits related to orphan-drug
designation. Macromolecules are considered to be the ``same drug''
under the Orphan Drug regulations if they have the same principal
molecular structure, despite some differences in structural features.
If the ``same drug'' has already been approved for the same use,
designation requires a plausible hypothesis of clinical superiority. As
one of these comments explained, ``This [framework] affects the plasma
protein therapeutics industry significantly because various drugs
within each therapeutic class of

[[Page 35122]]

products are considered to have the same principal molecular structures
and would not be considered different under the regulations without a
showing of clinical superiority, despite the fact that each therapy is
a unique, non-interchangeable biological product. This has important
ramifications for the plasma industry because it has developed an
exceptionally diverse selection of branded products within each
therapeutic class, thus the industry's portfolio is predominantly
composed of second-to-market products indicated to treat rare diseases,
but not orphan designated.'' Because many plasma protein therapies lack
orphan-drug designation, they are apparently ineligible for the
legislative incentives for rare disease treatments enacted in other
statutes, despite being indicated solely for rare diseases. According
to comments, this outcome ``contradicts the overall purpose of the
[Orphan Drug Act]'' by ``threatening the industry's capacity to
continue to explore rare disease therapies.''
(Response) FDA appreciates this perspective from industry about the
impact that obtaining--or not obtaining--orphan-drug designation under
the Orphan Drug Act may have under other statutes unrelated to the
Orphan Drug Act. Nevertheless, FDA continues to believe that the
current framework is the best means for giving effect to the intent of
the Orphan Drug Act, to provide incentives for sponsors to develop
promising drugs for rare diseases and conditions that would not
otherwise be developed and approved, including drugs that are
potentially safer or more effective than already approved drugs. (See
H.R. Rep. 97-840, Pt. 1, at 6 (1982); Orphan Drug Act, Pub. L. 97-414,
Sec. 1; see also Genentech, Inc. v. Bowen, 676 F. Supp. 301, 312
(D.D.C. 1987) (``The legislative history is replete with references to
the fundamental need to provide treatment for presently untreated
patients.'') (emphasis added).
FDA is, however, considering the feasibility of issuing a draft
guidance document on what may constitute a plausible hypothesis of
clinical superiority for certain categories of products, for example
plasma-derived products, which may help address some of the concerns
articulated previously.
(Comment 7) One comment opposed this proposal as an apparent
``expansion'' of the circumstances in which FDA would require a
plausible hypothesis of clinical superiority, rather than a
clarification of existing practice. This comment maintained that any
clinical superiority requirement undermines the incentive structure of
the Orphan Drug Act because clinical superiority can be difficult to
prove.
(Response) As explained in the proposed rule (76 FR 64868 at
64870), FDA is not expanding the circumstances in which it will require
a plausible hypothesis of clinical superiority for orphan-drug
designation. It is merely clarifying its longstanding practice. In the
absence of a clinical superiority hypothesis, the Agency does not
interpret the Orphan Drug regulations to permit designation of a drug
that is otherwise the same as a drug that is already approved for the
same use, regardless of whether the previously approved drug obtained
orphan-drug designation or was eligible for orphan-drug exclusivity.
For a more detailed description of how FDA interprets its current
regulations, see the response to comment 8. FDA believes this
interpretation best reflects the intent of Orphan Drug Act, as
explained in response to comment 6, by encouraging the development of
potentially safer and more effective orphan drugs--rather than
encouraging minor modifications to already approved drugs that confer
no meaningful benefit to patients.
In response to the comment that clinical superiority can be
difficult to prove, FDA advises sponsors that the clinical superiority
requirements for orphan-drug designation and orphan-drug exclusivity
are different: designation requires a plausible hypothesis of clinical
superiority, exclusivity requires a demonstration of clinical
superiority. As FDA has elsewhere explained (56 FR 3338 at 3341,
January 29, 1991), this difference is intended to encourage the
development of improved versions of existing drugs while protecting any
applicable orphan-drug exclusivity. The former is achieved through
liberally granting designation based on a plausible hypothesis of
clinical superiority, allowing drugs to benefit from development
incentives that flow from designation. The latter is achieved through
reserving orphan-drug exclusivity for a subsequent drug--allowing the
subsequent drug to be approved during the pendency of the already
approved drug's exclusivity period (if any) and with its own period of
orphan-drug exclusivity--provided that clinical superiority is
demonstrated upon approval. This framework fulfills the main purpose of
the Orphan Drug Act, to foster the development and innovation of orphan
drug therapies, while taking care not to ``render [orphan-drug
exclusivity] meaningless'' (57 FR 62077, December 29, 1992) e.g., by
allowing any minor change to render a subsequent drug different from a
previously approved drug and therefore not blocked by orphan-drug
exclusivity. At the same time, if the sponsor of a subsequent drug that
it is otherwise the same as a previously approved drug demonstrates
clinical superiority to the previously approved drug, that subsequent
drug may gain marketing approval and its own orphan-drug exclusivity,
despite any existing exclusivity for the previously approved drug; it
would also be eligible for exclusivity upon a clinical superiority
showing where the previously approved drug's exclusivity period has run
or never existed. FDA has implemented the Orphan Drug Act in this way
to fulfill Congress' aim of incentivizing the development and
innovation of orphan drugs and to ensure that orphan exclusivity has
value to sponsors, while limiting its scope so that it does not
``preclude significant improvements in treating rare diseases'' (56 FR
3338).
(Comment 8) One comment objected to FDA's characterizing this
proposal as ``clarifying current practice'' on the ground that FDA
appears to be contradicting its current regulations. According to this
comment, current Sec. 316.25 lists the only reasons that FDA can ever
decline to grant a designation request--and Sec. 316.25 does not
expressly list, as a reason, failure to include a plausible hypothesis
of clinical superiority where the drug is the same as a previously
approved drug that does not have orphan-drug exclusivity.
(Response) FDA disagrees that it is changing its current practice.
As FDA explained in the proposed rule (76 FR 64868 at 64870), FDA has
consistently interpreted the Orphan Drug regulations (in particular,
Sec. 316.20(a) and (b)(5)) to require that designation requests
include a plausible hypothesis of clinical superiority if the drug is
the same as an already approved drug, regardless of whether the already
approved drug has orphan-drug exclusivity. If the same drug has already
been approved for the same use, with or without orphan-drug
exclusivity, designation without such a hypothesis would be
inappropriate because it would be inconsistent with the primary purpose
of the Orphan Drug Act, which is to provide incentives to develop
promising orphan drugs that would not otherwise be developed and
approved--not to encourage minor modifications to already approved
drugs that confer no meaningful benefit to patients. See H.R. Rep. 97-
840, Pt. 1, at 6 (1982); Orphan Drug Act, Public Law 97-414, Sec. 1;
see also Genentech, Inc. v. Bowen, 676 F. Supp. at 312 (``The
legislative history is replete with references to the

[[Page 35123]]

fundamental need to provide treatment for presently untreated
patients.'') (emphasis added).
FDA has never interpreted Sec. 316.25, in particular, as an
exhaustive list of the reasons that FDA can decline to grant
designation. Although Sec. 316.25 lists some reasons for refusing
designation, it does not reiterate all of the eligibility criteria for
designation that are embodied elsewhere in the statute and in part 316.
These eligibility criteria include that the designation request be
submitted before submission of the marketing application, as is
required by section 526(a) and Sec. 316.23(a), and that the product be
a drug, as is required by section 526(a) and Sec. 316.20. Under FDA's
longstanding interpretation, a request that failed to meet any of these
eligibility criteria would be denied on this ground alone without
resort to Sec. 316.25. An additional reason for not granting
designation that is not currently listed at Sec. 316.25, but is
reflected elsewhere in part 316 (Sec. 316.20(a) and (b)(5)), is if a
request for a drug is the same as a previously approved drug fails to
include a plausible hypothesis of clinical superiority where the
previously approved drug does not have orphan-drug exclusivity.
Consistent with the proposed rule, FDA is revising Sec. 316.25 in this
final rule to expressly include this reason in the enumerated list.
Similarly, FDA has never interpreted Sec. 316.24 to require
automatic designation if a product fails to meet eligibility criteria
captured elsewhere in part 316 but not reiterated in Sec. 316.25. If a
request is not eligible for designation because, for example, it fails
to include a plausible hypothesis of clinical superiority when the drug
is the same as a previously approved drug, or because the designation
request was submitted after the marketing application had been
submitted, then the request would not even fall into the ambit of Sec.
316.24 (``Granting orphan-drug designation'').
In response to this comment's assertion that Sec. 316.25 on its
face appears to be an exhaustive list of the reasons that FDA can
refuse to grant designation (especially when read alongside Sec.
316.24), FDA has decided to further amend Sec. 316.25(b) to make clear
that FDA will deny designation if the request is otherwise ineligible
for designation under part 316.
(Comment 9) One comment questioned why the preamble to the proposed
rule identified change in dosage form as an example of ``inappropriate
`evergreening' of exclusive approval periods'' (76 FR 64868 at 64870),
when some new dosage forms may provide significant patient benefit.
(Response) FDA agrees with this comment. Some new dosage forms may
be ``clinically superior'' to previously approved dosage forms of the
same drug under Sec. 316.3(b)(3) and thus eligible for their own 7-
year period of orphan exclusive approval. For example, a change in
delivery system from intravenous (IV) to oral may, in some cases and
for some drugs, constitute a ``major contribution to patient care''
under Sec. 316.3(b)(3)(iii). As stated in the preamble to the 1992
final rule, Orphan Drug Regulations (57 FR 62077 at 62079), whether a
change in delivery systems constitutes a major contribution to patient
care ``can only be decided on a case-by-case basis, considering the
nature of the disease or condition, the nature of the drug, the nature
of the mode of administration, and other factors.'' For more on major
contribution to patient care, see the responses to comments 14 and 15.
(Comment 10) One comment asked FDA to clarify that a sponsor that
improves its own drug by demonstrating patient benefit is eligible for
orphan-drug exclusivity for the improved drug, regardless of whether
the sponsor's first drug received orphan-drug exclusivity.
(Response) FDA advises that if, upon approval, an orphan-designated
drug is shown to be ``clinically superior'' under Sec. 316.3(b)(3) to
a previously approved drug, then it is eligible for orphan-drug
exclusive approval regardless of the identity of the sponsor (e.g.,
even if the sponsor of both drugs is the same).

C. Eligibility for Multiple Orphan-Drug Exclusive Approvals

(Comment 11) One comment expressed confusion about the language in
the preamble to the proposed rule (76 FR 64868 at 64870), ``If the
sponsor who originally obtained orphan exclusive approval of the drug
for only a subset of the orphan disease or condition for which the drug
was designated subsequently obtains approval of the drug for one or
more additional subsets of that orphan disease or condition, FDA will
recognize orphan-drug exclusive approval, as appropriate, for those
additional subsets from the date of such additional marketing
approval(s). Before obtaining such additional marketing approval(s),
the sponsor in this instance would not need to have obtained additional
orphan designation for the additional subset(s) of the orphan disease
or condition.'' The comment asked FDA to ensure that it would give
orphan exclusive approval only to drugs that have been formally
designated as orphan drugs, rather than giving orphan exclusive
approval to drugs for indications for which they do not have orphan-
drug designation.
(Response) FDA clarifies that the language excerpted previously
from the preamble to the proposed rule was intended to convey the
following circumstance: (1) A drug obtains orphan-drug designation for
a rare disease or condition, (2) a drug obtains marketing approval (and
orphan-drug exclusivity) for only select indications or uses within the
rare disease or condition for which the drug was designated, (3) the
sponsor subsequently obtains approval for additional (not previously
approved) indications or uses of the drug within the same rare disease
or condition for which the drug was designated, then (4) the drug may
be eligible for a new period of orphan-drug exclusivity for those new
approved indications or uses without the need to re-seek designation--
because these new (not previously approved) indications or uses would
fall within the scope of the original designation (i.e., because in
this example the drug was designated for the rare disease or condition,
not select indications or uses within that rare disease or condition).
This example was not intended to suggest that FDA would grant orphan
exclusive approval to a drug for a disease or condition for which the
drug was not designated.
FDA reminds sponsors that, when FDA designates an orphan drug, it
generally designates the drug for use by all persons with the rare
disease or condition (or the orphan subset within a non-rare disease or
condition) and expects that a sponsor will seek marketing approval of
the drug for all persons with the rare disease or condition (or the
orphan subset). FDA may, however, approve the drug for only select
indications or uses within the rare disease or condition (or the orphan
subset) because FDA can only approve a drug for the indications or uses
for which there is adequate data and information in the marketing
application to support approval. The scope of orphan-drug exclusivity
is limited to the indication(s) or use(s) for which the drug is
approved for marketing, even if the orphan-drug designation for the
drug is broader. For example, a drug may be designated for use in
ovarian cancer but approved for use in only stage 4 ovarian cancer,
based on the data and information in the marketing application. As new
data emerge, FDA may approve the drug for additional indications or
uses within the rare disease or condition for which the drug is
designated (e.g., stages 1, 2, and/or 3 of ovarian cancer). The
advantage to the sponsor in this

[[Page 35124]]

hypothetical scenario is that, if the drug is later approved for
additional indication(s) or use(s) within the rare disease or condition
for which it is designated, the sponsor would not have to submit
additional designation requests for the drug to cover these additional
indication(s) or use(s)--because they would fall within the original
designation. Additional orphan-drug exclusivity may attach upon
approval of these new (not previously approved) indications or uses
that are within the scope of the original designation.
In such a hypothetical scenario, a ``broad'' designation would not
prevent other sponsors from obtaining designation and/or marketing
approval for the same drug for the same rare disease or condition. If a
drug is approved for only certain indications or uses within a rare
disease or condition, a subsequent sponsor may obtain designation of
the same drug for the remaining (not previously approved) indications
or uses within the same rare disease or condition without having to
provide a plausible hypothesis of clinical superiority over the already
approved drug, provided that the prevalence of the entire disease or
condition remains under 200,000. Assume, for example, that a drug is
designated for use in ovarian cancer (all stages) but is approved for
use in only stages 1 and 2 of ovarian cancer (``first drug''). A
subsequent sponsor may seek designation of the same drug (``second
drug'') for the remaining unapproved uses within ovarian cancer (i.e.,
stages 3 and/or 4) without having to provide a plausible hypothesis of
clinical superiority over the first drug, although the prevalence
determination would be based on ovarian cancer regardless of stage
(unless an orphan subset were shown). Designation of the second drug
for the uses already approved for the first drug (i.e., stages 1 and 2
of ovarian cancer) would require a plausible hypothesis of clinical
superiority over the first already approved drug.
Prompted by the confusion expressed by comment 11, FDA has revised
proposed Sec. 316.31 for clarity. FDA has amended the final rule by
replacing ``subset [of uses]'' (i.e., a drug is approved for only a
subset of patients with the rare disease or condition for which the
drug is designated) with ``select indication(s) or use(s),'' at Sec.
316.31(a) and (b). The rule now uses the phrase ``indication(s) or
use(s)'' in place of ``subset [of uses]'' because readers may have
confused the latter with the regulatory concept of orphan subset at
Sec. 316.20(b)(6)--when a reference to ``orphan subset'' was not
intended at Sec. 316.31. Orphan subset is a regulatory concept
relevant to eligibility for orphan-drug designation (see the responses
to comments 1 to 3), whereas this regulation at Sec. 316.31 concerns
the scope of orphan-drug exclusive approval.
(Comment 12) One comment objected to FDA's practice, described
previously in response to comment 11, of generally designating a drug
for use by all persons with the rare disease or condition, even though
the drug may eventually be approved for only certain indication(s) or
use(s) within that rare disease or condition. Once the drug has already
been approved for certain indication(s) or use(s) within the rare
disease or condition (``first drug''), another sponsor seeking
designation of the same drug (``second drug'') for use in the same rare
disease or condition would need to provide a plausible hypothesis of
clinical superiority over the first drug for the indication(s) or
use(s) for which the first drug is approved. Alternatively, without
providing such a hypothesis, the sponsor may seek designation of the
second drug for only the unapproved indication(s) or use(s) within the
rare disease or condition. The comment maintained that this designation
practice could result in labeling confusion, Medicare reimbursement
confusion, increased likelihood of medication errors, and product
liability concerns, because end-users may have difficulty
differentiating between the trade names and labeling of orphan-
designated drugs that are approved for different uses within the same
rare disease or condition.
(Response) FDA advises that the concerns expressed by this comment
mainly concern the wording and scope of FDA-approved labeling, not
orphan-drug designation. Requests for orphan-drug designation are
submitted before the submission of a marketing application for a drug;
whatever the scope of a drug's designation, its FDA-approved labeling
will be determined by the data and information included in the
marketing application. The scope of designation, in other words, does
not determine the scope of FDA-approved labeling. As for the comment's
concern that several drugs that are the same may be approved for
different indications or uses within the same rare disease or
condition, as the 4th Circuit Court of Appeals has held, orphan-drug
exclusivity protects only the uses for which the drug is approved, not
any and all uses of the drug. See Sigma-Tau Pharms. v. Schwetz, 288
F.3d 141, 145 (2002).
(Comment 13) Another comment asked FDA to clarify that, in the
event a drug is designated for a given disease or condition, is
approved (and granted orphan-drug exclusivity) for only certain
indications or uses within that same disease or condition, and is
subsequently approved for additional indications or uses within that
same disease or condition, the drug is eligible for orphan-drug
exclusivity without the need to show clinical superiority.
(Response) FDA agrees that, in the example provided previously,
orphan-drug exclusivity may be obtained for the new indications or uses
of the drug within the same disease or condition for which the drug was
designated without the need to show clinical superiority, provided that
the same drug has not already been approved for these new indications
or uses. For more explanation, see the response to comment 11.

D. Demonstration of Clinical Superiority--Major Contribution to Patient
Care

(Comment 14) Five comments asked FDA to clarify what ``comparable
safety and effectiveness'' would mean in the context of major
contribution to patient care under Sec. 316.3(b)(3)(iii), and in
particular what level of proof would be required (e.g., non-inferiority
trials).
(Response) In response to these comments, FDA is deleting the
``safety and effectiveness comparable to the approved drug'' language
from the final rule because of the confusion this language engendered.
FDA did not intend to propose a new standard for major contribution to
patient care with this language; in particular, FDA did not mean to
suggest that direct proof of comparability to the already approved drug
would be required (e.g., through non-inferiority trials). Instead, FDA
intended to convey that major contribution to patient care
determinations can be complex and encompass consideration of a number
of factors that potentially implicate safety and effectiveness, which
are evaluated on a case-by-case basis for each drug product. For more
discussion of major contribution to patient care, see the responses to
comments 9 and 15.
(Comment 15) Several comments asked for clarification of the
meaning of ``major contribution to patient care.'' In particular, these
comments asked FDA to reiterate and expand the list of factors that FDA
had included in the preamble to the 1992 final rule, Orphan Drug
Regulations (57 FR 62077 at 62079). The comments proposed the following
additional factors: increased quality of life, reduced treatment
burden, and improved patient compliance.

[[Page 35125]]

(Response) The following factors, when applicable to severe or
life-threatening diseases, may in appropriate cases be taken into
consideration when determining whether a drug makes a major
contribution to patient care: convenient treatment location; duration
of treatment; patient comfort; reduced treatment burden; advances in
ease and comfort of drug administration; longer periods between doses;
and potential for self-administration. FDA declines to add ``increased
quality of life'' to this list because many factors already on the list
may be viewed as increasing quality of life, such as increased patient
comfort and longer periods between doses. FDA also declines to add
``improved patient compliance'' to the list of factors potentially
informing whether a drug provides a major contribution to patient care,
because FDA would expect improved patient compliance to be reflected in
other factors already on this list (e.g., increased patient comfort,
reduced treatment burden, etc.), if not otherwise reflected in greater
safety or greater effectiveness showings for the drug. For more on
major contribution to patient care, see the responses to comments 9 and
14.
(Comment 16) One comment asked FDA to delete the opening clause,
``in unusual cases,'' because major contribution to care findings
should be more customary in light of recent protein engineering and
extended release technologies, which allow for significant improvements
in patient care.
(Response) In FDA's experience, showings of major contribution to
patient care remain unusual. Although new technologies may increase the
number of drugs found to make such major contributions, FDA still
expects these showings to be less frequent than greater safety and
greater effectiveness showings. FDA is therefore retaining the clause,
``in unusual cases.''

E. Name of the Drug

(Comment 17) One comment objected to the requirement to include a
chemical name in the designation request at Sec. 316.20(b)(4), if
neither a generic nor trade name is available. Disclosing the chemical
name (especially pre-patent) may put sensitive commercial information
at risk, which could ``negatively impact the potential to secure
intellectual property rights and thus reduce the incentives for further
development.''
(Response) FDA advises that sponsors need not include a chemical
name in the designation request as long as they include a meaningful
descriptive name of the drug. The final rule, like the proposed rule,
is phrased in the disjunctive: ``the chemical name or a meaningful
descriptive name of the drug'' (emphasis added), if neither a generic
nor trade name is available. By meaningful descriptive name, we mean a
name that would be meaningful to the public. It could include
information about the product class or type, the mechanism of action,
how or where the product was derived, and other information as
appropriate. An example of a meaningful descriptive name could be
murine anti-CD30 monoclonal antibody, which describes the
deoxyribonucleic acid (DNA) source, the cell being targeted by the
product, and the product type. As described in the proposed rule (76 FR
64868 at 64872 to 64873), we do not consider internal business codes or
other similar identifiers to be meaningful descriptive names.

F. Required Drug Description and Scientific Rationale in a Request for
Orphan-Drug Designation

(Comment 18) One comment asked that FDA add the qualifier
``relevant'' to modify ``data'' in the phrase ``all data from in vitro
laboratory studies'' at Sec. 316.20(b)(4).
(Response) FDA agrees and has amended the final rule accordingly.
(Comment 19) One comment asked why FDA would limit the clinical
data to ``clinical investigations of the drug in the rare disease or
condition'' when there may be pharmacokinetic (PK) or pharmacodynamic
(PD) data in other conditions that are relevant to the proposed orphan
use.
(Response) FDA advises that such PK and PD data are not generally
relevant or necessary to an orphan drug designation request, and so FDA
is not amending the proposed rule to require such data as suggested.
Sponsors may, however, choose to provide such data if they believe such
data are relevant or necessary to their request, for example, to
provide a plausible hypothesis of clinical superiority over a
previously approved drug.
On its own initiative, FDA has revised the regulatory language,
``clinical investigations of the drug in the rare disease or
condition,'' for clarity. In this final rule, FDA has replaced
``clinical investigations'' with ``clinical experience'' to reflect
that FDA may in some cases consider clinical data from sources other
than clinical investigations, for example, from well-documented case
histories or significant human experience with the drug, as
appropriate. FDA will assess the relevance and significance of such
data on a case-by-case basis.

G. Responding to a Deficiency Letter From FDA on an Orphan-Drug
Designation Request

(Comment 20) One comment asked FDA to clarify that having a
designation request withdrawn or denied does not preclude re-submitting
a request.
(Response) FDA agrees, although notes that eligibility for orphan-
drug designation in terms of prevalence is evaluated at the time of the
submission of the request (see Sec. 316.21(b)). In the event a request
is newly submitted after being withdrawn or denied, FDA will determine
eligibility in terms of prevalence as of the date of the new
submission. In response to this comment, FDA is considering whether to
include language in its form letters to notify sponsors that they may
submit a new request if their request is considered withdrawn or
denied, but that eligibility in terms of prevalence will be evaluated
at the time of any new submission.
Prompted by this comment, FDA has re-evaluated proposed Sec.
316.24(a) for clarity and has made a ministerial edit. This edit makes
clear that FDA will notify the sponsor whenever a request is considered
voluntarily withdrawn, whether it is considered withdrawn because the
sponsor failed to respond to a deficiency letter or request an
extension of time to respond within 1 year, or because FDA denied the
request for an extension of time. The language as proposed erroneously
suggested that FDA would notify the sponsor in writing only in the
latter instance.

H. Publication of Orphan-Drug Designations

(Comment 21) Five comments objected to possible disclosure by FDA
of whether sponsors of designated drugs have submitted annual reports
as required under Sec. 316.30. In the preamble to the proposed rule
(76 FR 64868 at 64873), FDA inquired whether such disclosure would help
inform the public of the development status of orphan drugs. Many
comments maintained that such information would likely create confusion
and miscommunication, because failure to submit an annual report does
not necessarily signal that the sponsor has ceased drug development.
Many of these comments did, however, support broader disclosure of the
development status of orphan drugs through means they considered more
informative, such as: expanding the ClinicalTrials.gov database;
devising and publishing an ``inactive'' status for orphan drug
designations similar to the ``inactive'' status for Investigational New
Drug

[[Page 35126]]

(IND) applications (see 21 CFR 312.42(g)); and publishing when drugs no
longer have orphan-drug designation (e.g., because designation was
voluntarily withdrawn by the sponsor). Some of these comments cautioned
that any broader disclosure of orphan drug development status should be
carefully tailored so as not to reveal highly sensitive commercial
information that may violate legal protections and benefit only the
sponsor's competitors, not patients with rare diseases.
(Response) FDA agrees that publishing whether or not sponsors have
submitted annual reports as required under Sec. 316.30 may not
accurately inform the public as to the development status of orphan
drugs. FDA has carefully considered the alternative disclosures
suggested by the comments and has decided to adopt in this final rule
one suggested approach: namely, to publish when drugs no longer have
orphan-drug designation (either because the sponsor voluntarily
withdrew designation or because FDA revoked designation under Sec.
316.29).
FDA has amended Sec. 316.28 to state that the publicly available
cumulative posting of all drugs designated as orphan drugs, available
on its Web site at http://www.fda.gov/orphan/, will include whether a
drug no longer has designation and, if so, as of what date. The public
was formerly able to deduce that a drug had lost designation from FDA's
publication of hard copy quarterly lists of designated drugs: drugs no
longer designated would appear on earlier hard copy lists but not on
later ones. Once FDA switched to Internet publication, this information
was no longer deducible owing to database limitations at the time. Once
this rule takes effect, FDA will publish on the Internet a posting of
drugs that, after the effective date of this rule, lose designation,
but without specifying the reason (i.e., whether because the sponsor
voluntarily withdrew designation or because FDA revoked designation
under Sec. 316.29). Publishing only the fact that a drug is no longer
designated, and not also the underlying reason(s), mitigates any
competitive concerns. Stakeholders may then choose to contact the
sponsor for more information on the status of the drug's development.
FDA advises sponsors that it will not publish when a designation
request has been withdrawn; unlike designations, designation requests
are generally not made public unless disclosed by the sponsor.
FDA has made conforming amendments to Sec. 316.29 to reference
this change to Sec. 316.28. Relatedly, FDA has added a Sec. 316.24(d)
to this final rule to make express an option that has always existed
for sponsors--that they can voluntarily withdraw a designation request,
or a designation proper, at any time by requesting such a withdrawal in
writing from FDA. FDA will acknowledge such withdrawal in a letter to
the sponsor. Any current or pending benefits attendant to designation,
such as orphan-exclusive approval, will cease once designation is
voluntarily withdrawn from the date of FDA's acknowledgement letter.
The same holds true when FDA has revoked designation under Sec.
316.29. See Sec. 316.29(b). Any benefits that have already vested,
such as tax credits or user fee exemptions, would not be affected.
FDA has determined that a reproposal to reflect these edits is
neither necessary for reasoned decisionmaking nor desirable as a matter
of policy. As noted previously, the proposed rule (76 FR 64868 at
64873) stated that FDA was ``considering ways to make available to the
public information about the status of development for designated
orphan drugs'' and invited comments on whether to provide this
information to the public through disclosure of the submission status
of annual reports. All comments that addressed this topic supported
broader disclosure of some sort on the development status of orphan
drugs, just not disclosure of the submission status of annual reports.
Many of these comments specifically recommended publishing when a drug
loses designation. This information used to be deducible from FDA's
hard copy publication of quarterly lists of designated drugs; once FDA
switched to Internet publication, this information was no longer
deducible owing to database limitations at the time.
Finally, FDA has on its own initiative updated Sec. 316.28 to
reflect that, as of at least a decade ago, FDA no longer places an
annual list of designated drugs on file at the FDA Division of Dockets
Management. This is a technical amendment reflecting established
practice.
(Comment 22) One comment advised FDA that the best way to achieve
compliance with the annual reporting requirement is through one-on-one
interaction with sponsors who do not submit annual reports as required
under Sec. 316.30.
(Response) FDA agrees with this comment.
(Comment 23) One comment asked FDA to make public its finding on
the acceptability of specific prevalence data to reduce uncertainty
about designation requirements. ``This will allow sponsors to use
prevalence data already assessed by FDA and thereby streamline the
process for obtaining these data to complete applications.''
(Response) FDA does not accept this suggestion. As explained in the
preamble to the 1991 proposed rule, Orphan Drug Regulations, FDA
believes that such an approach would unfairly allow subsequent sponsors
to get a ``free ride'' in designation requests: ``FDA believes it
unfair to allow a subsequent sponsor to use a pioneer sponsor's
research data for the purpose of obtaining orphan-drug designation when
such research data would by law not otherwise be available to the
subsequent sponsor'' (56 FR 3338 at 3340). Further, prevalence data are
often specific to each designation request in terms of both the timing
of the request and the properties of the drug for which the request is
submitted. Under Sec. 316.21(b), eligibility in terms of prevalence is
determined at the time of the submission of the request. Under Sec.
316.20(b)(6), the prevalence estimate may be narrowed owing to one or
more properties of the drug that allow for the existence of an orphan
subset (i.e., only a subset of persons with the disease or condition
would be appropriate candidates for use of the drug). These two factors
make prevalence determinations specific to each request and further
counsel against FDA publicly disclosing prevalence data and the
acceptability thereof.
(Comment 24) Two comments asked FDA to revise its publicly
available posting of orphan designated drugs to include additional
information. One of these comments asked that the posting include all
designated biological products approved via a Biologics License
Application (BLA) and granted orphan-drug exclusivity, along with the
dates of grant and expiry; the other comment asked FDA to highlight
when a designated drug is approved for the orphan use but does not
receive orphan-drug exclusivity.
(Response) FDA advises that its current publicly available posting
of orphan designated drugs, available on its Web site at http://www.fda.gov/orphan/, includes biological drug products licensed via
BLA, in addition to drug products approved via a New Drug Application
(NDA). FDA is in the process of adding to this database reference to
any applicable orphan-drug exclusivity periods. Once this revision to
the database is complete, the absence of such information may possibly
indicate that the product did not receive orphan-drug exclusivity upon
approval (or alternatively that the information has not yet been
entered into the database).

[[Page 35127]]

Stakeholders may also contact sponsors directly for the information
and, for drugs approved via NDA, review the FDA's Approved Drug
Products With Therapeutic Equivalence Evaluations (the Orange Book),
available electronically at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.
FDA is making a ministerial edit to Sec. 316.34(b) in response to
this comment, to clarify that the Orange Book includes only information
about products approved under section 505 of the FD&C Act (21 U.S.C.
355). FDA is also adding an online address for the Orange Book.

I. FDA Recognition of Orphan-Drug Exclusive Approval

(Comment 25) Two comments objected to FDA approving an orphan-
designated drug but withholding orphan-drug exclusivity, for example,
if the drug is the same as a previously approved drug and clinical
superiority is not demonstrated upon marketing approval. These comments
contended that, under section 527 of the FD&C Act, orphan-drug
exclusivity should automatically attach once a designated drug is
approved for the rare disease or condition for which it was designated,
whether or not it is the first drug to be approved for this use. One of
these comments characterized FDA regulations at Sec. Sec. 316.31(a)
and 316.34(a) as apparently confirming this ``automatic award'' of
exclusivity upon approval of any designated drug.
(Response) FDA disagrees. FDA has long interpreted the Orphan Drug
Act to accord orphan exclusive approval only to the first drug approved
for the disease or condition (see 56 FR 3338 at 3341). The statute
cannot be logically read to confer exclusivity to every designated drug
that gets approved, as these comments suggest.
Section 527 generally confers exclusivity by prohibiting FDA from
approving later drugs after a previous drug has been designated and
approved. ``[I]f the Secretary [] approves an application . . . for a
drug designated under section 526 . . . the Secretary may not approve
another application . . . for such drug . . . until the expiration of
seven years from the date of the approval of the approved
application.'' Section 527(a) (emphasis added). Courts construing this
statute have held ``such drug'' to be ambiguous; they have further
upheld FDA's regulatory scheme to require a showing of clinical
superiority over a previously approved drug in order for the clinically
superior drug to not be blocked by another sponsor's exclusivity and to
be eligible for its own period of exclusivity. See, e.g., Baker Norton
Pharms. v. FDA, 132 F. Supp. 2d 30, 37 (D.D.C. 2001).
Section 527 is also ambiguous on the question of whether a drug may
be eligible for exclusivity when another drug that is the same has
already been approved for the same use. See section 527(a) (referring
to an approved drug and unapproved applications for such drug, but not
to any drugs approved previously to the approved drug). Under FDA's
longstanding interpretation, any such previously approved drug
precludes exclusivity absent a showing of clinical superiority because
sponsors could otherwise: (1) Obtain infinite, successive 7-year
periods of exclusivity for the same drug for the same use when the
previously approved drug had such exclusivity, known as
``evergreening,'' or (2) obtain an exclusivity period for a drug
without providing any meaningful benefit to patients over previously
approved therapies, when the previously approved drug did not have
orphan exclusivity. Both results would be at odds with the Orphan Drug
Act.
``Evergreening'' would allow orphan exclusivity to be extended
indefinitely for the same drug for the same use without any meaningful
benefit to patients, a result at odds with the 7-year exclusivity
period provided by the statute. See Baker, 132 F. Supp. at 37 (noting
with approval that, under FDA's interpretation, ``market exclusivity
rights are limited in time to seven years, and granted only for a
particular drug for a particular use''). Congress would not have
prescribed a definite period of exclusivity and at the same time
provided for means to indefinitely extend that period. Indeed, the
legislative history reflects this by stating that even if multiple
sponsors get designation for the same drug, ``only the first sponsor to
be approved is awarded the seven year market exclusivity for that drug
for the approved use.'' H.R. Rep. 100-473, at 6 (1987). Further, where
the first approved drug does not have orphan designation or
exclusivity, awarding orphan exclusivity to a second-in-time drug that
has not been shown to be clinically superior to the first approved
drug--as these comments suggest doing--would be incompatible with the
core objective of the Orphan Drug Act, to encourage development of
drugs that would not otherwise be developed and approved (not to
encourage minor modifications to already approved drugs that confer no
meaningful benefit to patients). See H.R. Rep. 97-840, Pt. 1, at 6
(1982); 56 FR 3338; Genentech, 676 F. Supp. at 305-06, 312.
FDA's longstanding interpretation of section 527--to accord orphan
exclusive approval only to the first approved drug for the disease or
condition (assuming it has been designated)--implements the exclusivity
period as written, is consistent with FDA's regulatory framework, and
best effectuates Congress' aim in enacting the Orphan Drug Act. FDA's
interpretation is also consistent with the decisions of courts that
have had occasion to address orphan exclusivity. See Genentech, 676 F.
Supp. at 304 (orphan exclusivity ``is reserved for the first
manufacturer to receive full FDA approval of its drug as safe and
effective for commercial sale,'' even if multiple drugs have orphan
designation); cf. Baker, 132 F. Supp. 2d at 31 (if two drugs are the
same under FDA regulations, ``the second drug may not be approved for
market exclusivity'').
Accordingly, FDA is retaining Sec. 316.34(c) in this final rule to
make clear that a designated drug will receive orphan-drug exclusivity
upon approval only if the same drug has not been previously approved
for the same orphan use: that is, if the drug is otherwise the same as
a previously approved drug, it will receive exclusivity only upon a
demonstration of clinical superiority. FDA is, however, amending the
final rule slightly so that it reads: ``If a drug is otherwise the same
drug as a previously approved drug for the same use or indication, FDA
will not recognize orphan-drug exclusive approval if the sponsor fails
to demonstrate upon approval that the drug is clinically superior to
the previously approved drug.'' \5\ This revision clarifies for
sponsors that, even if they obtained orphan-drug designation for a drug
without having to provide a plausible hypothesis of clinical
superiority (because the same drug was not yet approved for the same
orphan use), they will have to demonstrate clinical superiority in
order to obtain orphan-drug exclusivity if--in the interim between
their obtaining orphan-drug designation and marketing approval for
their drug--the same drug is approved for the same use.\6\ This
longstanding interpretation gives best effect to the intent of the
Orphan Drug Act, described previously.
---------------------------------------------------------------------------

\5\ The term ``upon approval'' in this context does not preclude
the possibility that clinical superiority may be demonstrated in a
supplemental submission for the drug after approval.
\6\ FDA's form letters granting orphan-drug designation alert
sponsors to this possibility.
---------------------------------------------------------------------------

This revision to Sec. 316.34(c) also corrects a possible
misunderstanding of the proposed rule. The proposed rule may have been
read to suggest that, if a designation is based on a plausible
hypothesis of clinical superiority, the

[[Page 35128]]

sponsor can obtain orphan-drug exclusivity only by substantiating the
precise hypothesis upon which the designation was based (e.g., this
drug is safer than the same previously approved drug because of the
elimination of a certain ingredient). Rather, under FDA's
interpretation, orphan-drug exclusivity would attach to a designated
drug that is otherwise the same as a previously approved drug as long
as it is shown to be clinically superior upon approval, whether or not
the showing of clinical superiority at the approval stage aligns with
the plausible hypothesis of clinical superiority provided at the
designation stage (e.g., if the drug is shown to be safer for a
different reason or is instead shown to be more effective). FDA
understands that a hypothesis of clinical superiority (required for
orphan-drug designation) is often devised early in the drug development
process, and that subsequent research may result in enhanced
understanding of the drug and possibly even changes to the drug itself.
To not recognize orphan-drug exclusivity for a designated drug that is
demonstrated to be clinically superior to a previously approved drug
that is otherwise the same, solely because the sponsor inaccurately
hypothesized the basis for clinical superiority, would contravene the
intent of the Orphan Drug Act. Recognizing exclusivity in this instance
encourages the development of safer and more effective orphan drugs.
Finally, in response to the assertion in this comment that
Sec. Sec. 316.31(a) and 316.34(a) apparently ``confirm'' that all
designated drugs receive orphan-drug exclusivity upon approval (whether
or not they are the first such drug approved), FDA has slightly revised
Sec. Sec. 316.3(b)(12), 316.31(a) and 316.34(a) to clarify that FDA
recognizes orphan-drug exclusivity for the designated drug only if the
same drug has not already been approved for the same use or indication.
This revision clarifies FDA's longstanding interpretation of these
provisions, as noted previously. Because this interpretation was
explained in the preamble to the proposed rule (76 FR 64868 at 64870 to
64873), and reflected in the proposed rule at Sec. 316.34(c), FDA has
determined that a reproposal to amend Sec. Sec. 316.3(b)(12),
316.31(a), and 316.34(a) in this manner is not required.
(Comment 26) One comment asked FDA to confirm that head-to-head
safety trials may not always be necessary to establish clinical
superiority based on greater safety, under Sec. 316.3(b)(3)(ii).
(Response) FDA agrees. The regulation at Sec. 316.3(b)(3)(ii)
expressly states that direct comparative clinical trials to demonstrate
greater safety may be necessary in only ``some cases.'' (By contrast,
the regulation at Sec. 316.3(b)(3)(i) states that direct comparative
clinical trials to demonstrate greater effectiveness is necessary in
``most cases.'') Instead of prescribing the precise type and amount of
evidence necessary for demonstrating ``greater safety in a substantial
portion of the target populations,'' the regulation at Sec.
316.3(b)(3)(ii) allows FDA to determine on a case-by-case basis what
type and amount of evidence suffice for a given drug.

J. Miscellaneous Comment

(Comment 27) One comment asked FDA to clarify when a sponsor may
lose orphan-drug designation once the drug is in widespread use for the
orphan indication.
(Response) A drug may be approved for multiples uses, some of which
have orphan-drug designation and some of which do not. Simply because a
drug is ``in widespread use'' does not mean that a sponsor will lose
orphan-drug designation. A sponsor may lose designation if, for
example, the drug was not in fact eligible for designation at the time
the request was submitted or if the request contained an untrue
statement of material fact. See Sec. 316.29(a).

K. Initial Paperwork Burden Estimates

(Comment 27) One comment stated that FDA had underestimated the
time it would take to prepare and submit each extension request under
Sec. 316.24(a), including time to develop and articulate a rationale
for the requested extension and to obtain internal approval of the
request before submission to FDA.
(Response) FDA has increased this estimate from 2 to 6 hours, as
described in section VIII.

IV. Environmental Impact

FDA has determined under 21 CFR 25.30(h) and 25.31(a) 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.

V. Legal Authority

FDA is issuing this final rule under the authority granted it by
the Orphan Drug Act (Pub. L. 97-414). In enacting the Orphan Drug Act,
Congress required FDA to issue regulations for the implementation of
sections 525 and 526 of the FD&C Act, relating to written FDA
recommendations on studies required for approval of marketing
applications of orphan drugs and for the designation of eligible drugs
as orphan drugs. In the Federal Register of December 29, 1992 (57 FR
62076) (1992 final rule), FDA issued a final rule for the
implementation of these sections as well as for the implementation of
section 527 of the FD&C Act and section 528 of the FD&C Act (21 U.S.C.
360dd), relating to exclusive marketing for orphan drugs and the
encouragement of sponsors to make orphan drugs available for treatment
on an ``open protocol'' basis before the drug has been approved for
general marketing. This final rule clarifies regulatory provisions in
the 1992 final rule and makes minor improvements to address issues that
have arisen since that rule took effect.
This final rule furthers the main purpose of the Orphan Drug Act,
to provide incentives to develop promising drugs for rare diseases or
conditions that would otherwise not be developed and approved,
including potentially safer or more effective orphan drugs. It does so
in several ways by:
Enhancing clarity for sponsors in seeking orphan-drug
designations and orphan-drug exclusive marketing approval;
Making clear that the possibility of orphan-drug
exclusivity remains for sponsors who develop a potentially promising
drug for use by the remaining persons affected by a rare disease or
condition after the same drug has been approved for only a portion of
that population;
Clarifying that orphan-drug exclusivity is given to a
designated drug upon approval only if it is the first drug approved for
the orphan use, thus encouraging innovation in rare disease treatments;
and
Helping ensure that the orphan-drug designation request,
at the time it is granted, is consistent with the purpose of the Orphan
Drug Act despite a lapse of time between the date of submission of the
initial request and a sponsor's response to a deficiency letter from
FDA.
An additional source of authority for this rule is section 701 of
the FD&C Act (21 U.S.C. 371). Under this section, FDA is authorized to
issue regulations for the efficient enforcement of the FD&C Act. This
final rule helps the efficient enforcement of the Orphan Drug Act
provisions by enhancing clarity and certainty in FDA's administration
of the orphan drug program.

VI. Implementation Plan

These regulatory changes take effect 60 days after the date of
publication of the final rule. The final rule applies only to original
orphan-designation

[[Page 35129]]

requests submitted on or after the effective date of the final rule. It
does not apply to: (1) Amendments submitted on or after the effective
date regarding previously submitted designation requests, or (2)
responses to deficiency letters submitted on or after the effective
date regarding previously submitted requests. The final rule has no
effect on the scope of or eligibility for orphan-drug exclusive
approval because it merely clarifies existing and longstanding FDA
practice. Under this final rule, FDA will publicize if a drug no longer
has designation only if the loss of designation occurs after the
effective date of the rule (either because of voluntary withdrawal by
the sponsor or because of revocation by FDA).

VII. Executive Order 13132: Federalism

FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the final
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.

VIII. Paperwork Reduction Act of 1995

This final rule contains information collection requirements that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). A description of these requirements is provided in the
paragraphs that follow with an estimate of the annual reporting burden.
Included in the estimate is the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.
Title: Orphan Drug Regulations
Description: The rule finalizes revisions to the Orphan Drug
regulations that clarify FDA policy and make minor improvements. The
revisions are intended to assist sponsors who are seeking and who have
obtained orphan-drug designations, as well as FDA in its administration
of the orphan drug program. For the initial PRA analysis, FDA estimated
the annual reporting burdens for the two collections of information
included in the proposed rule that were not already included in part
316 and already approved by OMB in accordance with the PRA (44 U.S.C.
3501-3520), under OMB control number 0910-0167. For this PRA analysis,
FDA likewise estimates the annual reporting burdens for these two
collections of information, which are being finalized as originally
proposed.
One requirement is that sponsors include in requests a chemical or
meaningful descriptive name of the drug, if neither a trade name nor a
generic name is available. By providing such information in the request
for designation, sponsors will help ensure that the name that FDA
ultimately publishes under Sec. 316.28 upon designation of the product
is accurate and meaningful to the public. Because sponsors are already
required to include a description of the drug in requests for
designation, the new requirement to include a chemical or meaningful
descriptive name is not expected to require much additional time or
effort from sponsors.
Based on historical data concerning the number of designation
requests for which neither a trade name nor a generic name for the drug
is available, FDA expects that about 20 requests per year would be
affected by this requirement. FDA estimates that it will take
approximately 0.2 hours, or 12 minutes, for sponsors to submit this
information. This estimate reflects both the length of time likely
required to submit the chemical name of the drug (less than 0.2 hours)
and the length of time likely required to submit a meaningful
descriptive name if a chemical name is not readily available (more than
0.2 hours).
Another requirement is that sponsors respond to deficiency letters
from FDA on designation requests within 1 year of issuance of the
deficiency letter, unless within that timeframe the sponsor requests in
writing an extension of time to respond. FDA will grant all reasonable
requests for an extension. In the event the sponsor fails to respond to
the deficiency or request an extension of time to respond within the 1-
year timeframe, FDA may consider the designation request voluntarily
withdrawn.
FDA believes this revision is necessary to ensure that deficient
designation requests do not become ``stale'' by the time they are
granted, such that the basis for the initial request may no longer hold
(i.e., the prevalence of the disease or condition may now exceed
200,000). Granting such designations despite a lapse of years and
change in factual circumstances concerning the disease or condition in
question may not serve the primary purpose of the Orphan Drug Act to
provide incentives for the development of drug products for ``rare
diseases or conditions'' as defined in section 526 of the FD&C Act.
This situation--where a request for designation languishes for a year
or more before being granted--is distinct from situations where a
designation request is granted but development of the drug languishes,
whether for scientific, business, or other reasons.
Based on historical data concerning the number of deficiency
letters that FDA has sent and the number of sponsors who have taken
longer than a year to respond, FDA estimates that it will receive
approximately 10 written requests each year for an extension of time to
respond. This number is likely an overestimate, because it is based on
historical data in the absence of any regulatory deadline for sponsors
to respond; FDA believes that at least some of the sponsors who have
taken longer than a year to respond have been capable of responding
earlier, but did not do so because they did not need to. In the initial
PRA analysis, FDA estimated that it would take approximately 2 hours to
prepare and submit each extension request, including time to develop
and articulate a rationale for the requested extension and to obtain
internal approval of the request before submission to FDA. In response
to one comment that 2 hours was an underestimate of the time required,
FDA has increased this estimate to 6 hours to better account for the
time needed to obtain internal approval of a request before submission
to FDA.
Description of Respondents: Persons and businesses, including small
businesses and manufacturers.

[[Page 35130]]

Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
21 CFR Section Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
316.20(b)(2).................................................. 20 1 20 * 0.2 4
316.24(a)..................................................... 10 ................ 1 6 60
-----------------------------------------------------------------------------------------
Total Burden Hours........................................ ................ ................ ................ ................ 64
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information. Except with respect to the revisions
addressed immediately previously, the revisions in this final rule merely clarify existing regulatory language and do not constitute a substantive or
material modification to the approved collections of information in current part 316. Cf. 5 CFR 1320.5(g). The collections of information in current
part 316 have been approved by OMB in accordance with the PRA (44 U.S.C. 3501-3520), under OMB control number 0910-0167.
* 12 minutes.

In compliance with the PRA (44 U.S.C. 3407(d)), the Agency has
submitted the information collection provisions of this final rule to
OMB for review. Prior to the effective date of this final rule, FDA
will publish a notice in the Federal Register announcing OMB's decision
to approve, modify, or disapprove the information collection provisions
in this final rule. An Agency may not conduct or sponsor, and a person
is not required to respond to, a collection of information unless it
displays a currently valid OMB control number.

IX. Analysis of Impacts

FDA has examined the impacts of the rule under Executive Order
12866, Executive Order 13563, the Regulatory Flexibility Act (5 U.S.C.
601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4).
Executive Orders 12866 and 13563 direct Agencies to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity).
The Agency believes that this final rule is not a significant
regulatory action as defined by Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because this rule primarily clarifies current
practice and any costs would be very small, the agency certifies that
the final rule will not have a significant economic impact on a
substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the 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 $139 million, using the most current (2011) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
rule to result in any 1-year expenditure that would meet or exceed this
amount.

A. Background

Our experience with orphan-drug designation requests over many
years has led us to conclude that sponsors are confused by some
portions of the current regulatory language. The Agency receives dozens
of requests for orphan-drug designation each year that are deficient in
some way that would prevent designation. We observe the same types of
deficiencies suggesting some problematic areas in our regulations.
Of the 324 requests for orphan-drug designation we received in
2010, 124 were denied or placed in abeyance so that the sponsor could
submit additional material to respond to the deficiencies. Of these, 79
were deficient because they did not identify an appropriate ``medically
plausible subset'' of a population with a non-rare disease or
condition. That nearly a quarter of the designation requests were
deficient in their subset analysis, and that problems with population
subsets constituted over all half of the deficiencies, highlights the
need to clarify existing regulatory language regarding subsets.
The confusion about regulatory language was not limited to issues
regarding population subsets. Many designation requests were deficient
because the submitted drug description was not adequate to establish
whether the drug was the same as one that has already been approved.
There were continuing problems with requests for drugs that are in fact
the same as drugs already approved but lack necessary information
regarding clinical superiority. Other requests lacked the data to
support the scientific rationale for the use of the drug in a rare
disease or condition. Addressing these deficiencies and resolving
sponsor inquiries consumes sponsor and FDA resources and extends the
orphan-drug designation process. The process would be less costly to
sponsors and FDA if sponsors had an authoritative source of information
about basic program requirements.
Basic program requirements are part of Federal regulation;
clarifying regulatory language to reduce costly confusion would have to
be done through rulemaking at the Federal level. This final rule
clarifies regulatory language to reduce sponsor and FDA costs and
streamline the orphan-drug designation process.

B. Benefits and Costs of the Proposed Rule

This final rule reduces costs to sponsors who might otherwise
submit deficient orphan-drug designation requests or face additional
costs to determine program requirements. It benefits sponsors and
promotes public health by clarifying requirements for sponsors who
might otherwise be discouraged from submitting designation requests
when their drug is in fact eligible for orphan-drug designation. The
rule also reduces costs to FDA from responding to sponsor inquiries and
deficient designation requests. There are small costs associated with
the requirement that sponsors either respond to deficiency letters
within a year or obtain an extension of time to respond.
We clarify what population or disease subsets may be eligible for
orphan-drug designation (Sec. 316.3(b)(13) and Sec. 316.20(b)(6)).
This action merely clarifies longstanding policy and should reduce
uncertainty about the requirements for orphan-drug designation, thus
resulting in fewer requests that do not result in orphan-

[[Page 35131]]

drug designation. In addition, some sponsors may realize that their
drug is not eligible for orphan-drug designation. Such sponsors would
save the cost they would have otherwise incurred in submitting a
request. FDA has recently (76 FR 3911) estimated a burden of 150 hours
to complete a designation request. At a benefit-adjusted hourly wage of
about $46 for a regulatory affairs official, sponsors not submitting a
request that cannot be granted would avoid $6,900 in labor costs.\7\
Under this rule, other sponsors would avoid the cost they would have
otherwise incurred addressing the subset deficiency. We do not have a
precise estimate of the time required to respond to a deficiency
letter; using 40 hours as a rough estimate implies $1,840 in avoided
labor costs. We do not possess a reliable estimate for the number of
avoided deficiency letters, but assuming FDA receives 79 subset-
deficient requests each year and one-half would not occur with the
clarified regulatory language, sponsors would avoid $72,680 in
additional labor costs. FDA would also avoid costs from responding to
these requests.
---------------------------------------------------------------------------

\7\ 2010 National Industry-Specific Occupational Employment and
Wage Estimates, U.S. Department of Labor Statistics, last modified
May 17, 2011 (www.bls.gov/oes/current/naics4_325400.htm); mean
compliance officer wage rate of $35.28 for pharmaceutical and
medicine manufacturing (North American Industry Classification
System (NAICS) 325400) plus a 30-percent increase for benefits.
---------------------------------------------------------------------------

FDA's longstanding interpretation of the Orphan Drug Act and Orphan
Drug regulations is that a designation request for a drug that is
otherwise the same as a drug previously approved for the same use must
include a plausible hypothesis of clinical superiority, regardless of
whether the already approved drug received orphan-drug designation and
exclusivity. FDA continues to receive requests that do not result in
orphan-drug designation because this interpretation is not explicit in
current regulation. This rule would make the regulatory language
explicitly state FDA's interpretation, reducing costs to sponsors and
FDA by reducing the number of deficient orphan-drug designation
requests.
FDA's longstanding practice has been that if a drug is approved for
only select indications or uses within a rare disease or condition for
which the drug is designated, FDA may grant orphan-drug designation and
orphan-drug exclusive approval for use of the same drug in one or more
of the remaining (not previously approved) indications or uses within
the rare disease or condition without requiring any showing of clinical
superiority. Current Sec. 316.31 does not explicitly mention this
prospect, which could deter confused sponsors from pursuing designation
for use of the drug in remaining indications or uses for which the drug
has not yet been approved. Clarifying this provision would not change
Agency policy but would benefit sponsors and public health by reducing
the risk of a sponsor failing to pursue designation when it would
otherwise do so.
We modify and clarify our requirements for the drug name. Current
regulations require the sponsor to submit the generic and trade name of
the drug, but do not specify how to name a drug for which there is no
generic name or trade name. In the past, sponsors have provided FDA
with their internal business codes, which are meaningless to the
general public. We require that a drug that has neither a generic nor a
trade name be identified according to its chemical name or a meaningful
descriptive name (i.e., one that would be meaningful to the public if
published). Chemical and descriptive names are readily accessible to
the sponsor and could be included in a designation request as easily as
an internal business code and any costs would be too small to
meaningfully quantify.
We clarify our requirements for the drug description and for the
data to support a drug's scientific rationale in an orphan-drug
designation request. Some requests for orphan-drug designation cannot
be acted upon because the drug descriptions are not adequate to
determine whether the drug in the submission is the same as a
previously approved drug. This rule clarifies the required drug
description in Sec. 316.20(b)(4), reducing the frequency of deficient
requests. Some requests lack the data to support a scientific rationale
while others include substantial additional data not needed to obtain
designation. In both situations, sponsors incur costs that could be
avoided with clearer requirements. We do not know the frequency of
these data problems nor do we know the costs associated with them, but
this rule reduces sponsor and FDA costs.
We eliminate Sec. 316.20(b)(9), which requires that the sponsor
submitting the request state whether it is the real party in interest
of the development and the intended or actual production and sales of
the product. This provision merely obtains information from the
sponsor; it does not provide a basis to disqualify any entity from
pursuing orphan-drug designation. There is no known use for the
information and it is our understanding that this provision may be
discouraging sponsors from using agents to submit requests on their
behalf, potentially increasing the cost to obtain orphan-drug
designation. We do not possess a reliable estimate for this cost.
Eliminating this provision clarifies our longstanding policy to accept
submissions from agents, which may reduce sponsor costs. Halting the
collection of information for which there is no known purpose would not
negatively impact public health.
We clarify the requirement regarding the timing of orphan-drug
designation requests (Sec. 316.23(a)). A sponsor may not submit an
orphan-drug designation request after it has submitted a marketing
application for the drug for that use. It is not clear in the current
regulatory language that one sponsor's marketing application would not
prevent a different sponsor from submitting a request for orphan-drug
designation for the same drug for the same orphan use and that this
subsequent sponsor would not have to submit a plausible hypothesis of
clinical superiority. Clarifying current policy benefits sponsors and
public health by reducing the likelihood of a confused sponsor failing
to seek orphan-drug designation for an eligible product.
We impose a 1-year time limit for sponsors to respond to deficiency
letters or request a time extension (Sec. 316.24(a)). Current
regulations do not impose time limits on sponsors replying to FDA
deficiency letters and we have no mechanism to encourage sponsors to
continue to actively pursue designation. Based on our experience with
the time required to address particular submission deficiencies and the
observed variation in time for sponsors to respond, some submission
requests do not appear to be part of an active effort to obtain orphan-
drug designation. We know of no public health benefit from open
inactive designation requests. We do not know if they exist because
sponsors gain nothing from the cost of formally withdrawing a request
or because there may be a strategic advantage to an inactive request
for designation. Sponsors who would otherwise respond to a deficiency
letter within 1 year would be unaffected by this proposal. Sponsors
actively pursuing designation but needing more than 1 year to respond
to a deficiency letter would be expected to submit a time extension
request to FDA. We assume approval for all extension requests from
sponsors actively pursuing orphan-drug designation and estimate a
request would require 6 hours of time from a regulatory affairs
specialist. At a benefit-adjusted hourly wage of $46, the cost to
submit an extension request is $276. Based on our

[[Page 35132]]

experience with deficiency letters and the frequency of responses
requiring more than 1 year, we estimate 10 requests for additional time
each year. The estimated annual cost of this provision is $2,760. We
assume sponsors not actively pursuing designation would not obtain
extensions and their requests would be considered to be withdrawn 1
year after the deficiency letter. We do not possess a reliable estimate
of the number of designation requests that would be withdrawn under
this proposal. Withdrawing inactive designation requests would improve
information about potential future orphan drugs, which would be
beneficial to potential sponsors and to the general public. There is at
least a potential for a cost to some sponsors, as we cannot rule out
the possibility of some small advantage to holding an inactive
designation request. Nevertheless, we estimate the cost of a withdrawal
in this case to be very small and to be extremely small relative to the
benefits of improved public information and the streamlined orphan-drug
designation process.
We clarify that sponsors can voluntarily withdraw a designation
request, or designation proper, at any time by submitting a written
request to FDA (Sec. 316.24(d)). This is consistent with current
practice and imposes no new costs on sponsors. Some sponsors are
unaware of this option so this will save sponsors and FDA costs
associated with unnecessary inquiries.
We clarify that FDA may refuse to grant a designation request if
the request is otherwise ineligible for designation under part 316
(Sec. 316.25(b)). Because this change merely codifies existing
practice, it is not expected to impose any new costs.
This rule provides that FDA will publish the fact a drug is no
longer designated (Sec. 316.28(e)). Sponsors who may otherwise have
been deterred from developing a drug because of another sponsor's
designation of the drug may now seek their own designation for that
drug and develop it upon learning that the first sponsor no longer has
designation. The cost to FDA to publish this information is too small
to reliably estimate.
According to longstanding policy, FDA does not recognize orphan-
drug exclusive approval when the sponsor of a drug that is otherwise
the same as a drug already approved for the same use fails to
demonstrate clinical superiority upon approval. We make this policy
explicit by adding proposed Sec. 316.34(c). This clarification is
applicable to only a very small portion of designated drugs and
benefits would be too small to reliably estimate.
We do not possess a single bottom line estimate for the total
monetized benefit of this rule. Avoiding half of the designation
requests that are deficient because of problems establishing population
subsets would save sponsors an estimated $73,000 annually. Subset
problems account for more than half of all deficiencies, so we estimate
the other clarifications to reduce deficient requests would reduce
sponsor costs by an additional amount less than $73,000. The total
estimated cost of this rule is an annual $2,760, attributable to the
submission of requests for additional time to respond to deficiency
letters.

C. Small Business Analysis

This rule applies to the sponsors of orphan-drug designation
requests. According to the Table of Small Business Size Standards, the
U.S. Small Business Administration considers pharmaceutical preparation
manufacturing entities (NAICS 325412) with 750 or fewer employees and
biological product (except diagnostic) manufacturing entities (NAICS
325414) with 500 or fewer employees to be small.\8\ According to the
2007 Economic Census, annual shipments for the 284 establishments in
NAICS 325412 with 0 to 4 employees are $240 million, which is $840,000
per establishment. Total annual shipments for the 250 establishments in
NAICS 325414 with 0 to 49 employees (the smallest group with value of
shipment data) are $720 million, which is $2.9 million per
establishment.
---------------------------------------------------------------------------

\8\ U. S. Small Business Administration, ``Table of Small
Business Size Standards Matched to North American Industry
Classification System Codes,'' November 5, 2010. http://www.sba.gov/sites/default/files/Size_Standards_Table.pdf
---------------------------------------------------------------------------

Most of the provisions of this rule clarify regulatory language
consistent with current practice, imposing no new costs. The 1-year
time limit to respond to FDA deficiency letters would result in
estimated costs of $276 per extension request. Costs from the
withdrawal of inactive submissions would be too small to reliably
quantify. A common threshold for determining a significant impact is 1
percent of annual shipments. Because the estimated cost of this rule is
approximately 1/33 of 1 percent of annual shipments for the smallest
affected establishments, we conclude this rule does not constitute a
significant impact on a substantial number of small entities.

List of Subjects in 21 CFR Part 316

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

Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
316 is amended as follows:

PART 316--ORPHAN DRUGS

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

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

0
2. Section 316.1 is amended by revising paragraphs (a)(1)(iii) and
(a)(2) to read as follows:

Sec. 316.1 Scope of this part.

(a) * * *
(1) * * *
(iii) Requests for gaining exclusive approval for a drug for a rare
disease or condition.
(2) Allowing a sponsor to provide an investigational drug under a
treatment protocol to patients who need the drug for treatment of a
rare disease or condition.
* * * * *

0
3. Section 316.3 is amended by revising paragraphs (b)(3) introductory
text, (b)(3)(i), and (b)(12), by redesignating paragraphs (b)(13) and
(b)(14) as paragraphs (b)(14) and (b)(15), respectively, and by adding
a new paragraph (b)(13) to read as follows:

Sec. 316.3 Definitions.

* * * * *
(b) * * *
(3) Clinically superior means that a drug is shown to provide a
significant therapeutic advantage over and above that provided by an
approved drug (that is otherwise the same drug) in one or more of the
following ways:
(i) Greater effectiveness than an approved drug (as assessed by
effect on a clinically meaningful endpoint in adequate and well
controlled clinical trials). Generally, this would represent the same
kind of evidence needed to support a comparative effectiveness claim
for two different drugs; in most cases, direct comparative clinical
trials would be necessary; or
* * * * *
(12) Orphan-drug exclusive approval or exclusive approval means
that, effective on the date of FDA approval as stated in the approval
letter of a marketing application for a sponsor of a designated orphan
drug, no approval will be given to a subsequent sponsor of the same
drug for the same use or indication for 7 years, except as

[[Page 35133]]

otherwise provided by law or in this part. A designated drug will
receive orphan-drug exclusive approval only if the same drug has not
already been approved for the same use or indication.
(13) Orphan subset of a non-rare disease or condition (``orphan
subset'') means that use of the drug in a subset of persons with a non-
rare disease or condition may be appropriate but use of the drug
outside of that subset (in the remaining persons with the non-rare
disease or condition) would be inappropriate owing to some
property(ies) of the drug, for example, drug toxicity, mechanism of
action, or previous clinical experience with the drug.
* * * * *

0
4. Section 316.4 is revised to read as follows:

Sec. 316.4 Address for submissions.

All correspondence and requests for FDA action under the provisions
of this rule should be addressed as follows: Office of Orphan Products
Development, Food and Drug Administration, Bldg. 32, Rm. 5271, 10903
New Hampshire Ave., Silver Spring, MD 20993.

0
5. Section 316.20 is amended by revising paragraphs (a), (b)(2),
(b)(3), (b)(4), (b)(5), and (b)(6), and by removing paragraph (b)(9) to
read as follows:

Sec. 316.20 Content and format of a request for orphan-drug
designation.

(a) A sponsor that submits a request for orphan-drug designation of
a drug for a specified rare disease or condition shall submit each
request in the form and containing the information required in
paragraph (b) of this section. A sponsor may request orphan-drug
designation of a previously unapproved drug, or of a new use for an
already marketed drug. In addition, a sponsor of a drug that is
otherwise the same drug as an already approved drug may seek and obtain
orphan-drug designation for the subsequent drug for the same rare
disease or condition if it can present a plausible hypothesis that its
drug may be clinically superior to the first drug. More than one
sponsor may receive orphan-drug designation of the same drug for the
same rare disease or condition, but each sponsor seeking orphan-drug
designation must file a complete request for designation as provided in
paragraph (b) of this section.
(b) * * *
(2) The name and address of the sponsor; the name of the sponsor's
primary contact person and/or resident agent including title, address,
telephone number, and email address; the generic and trade name, if
any, of the drug, or, if neither is available, the chemical name or a
meaningful descriptive name of the drug; and the name and address of
the source of the drug if it is not manufactured by the sponsor.
(3) A description of the rare disease or condition for which the
drug is being or will be investigated, the proposed use of the drug,
and the reasons why such therapy is needed.
(4) A description of the drug, to include the identity of the
active moiety if it is a drug composed of small molecules, or of the
principal molecular structural features if it is composed of
macromolecules; its physical and chemical properties, if these
characteristics can be determined; and a discussion of the scientific
rationale to establish a medically plausible basis for the use of the
drug for the rare disease or condition, including all relevant data
from in vitro laboratory studies, preclinical efficacy studies
conducted in an animal model for the human disease or condition, and
clinical experience with the drug in the rare disease or condition that
are available to the sponsor, whether positive, negative, or
inconclusive. Animal toxicology studies are generally not relevant to a
request for orphan-drug designation. Copies of pertinent unpublished
and published papers are also required.
(5) Where the sponsor of a drug that is otherwise the same drug as
an already approved drug seeks orphan-drug designation for the
subsequent drug for the same rare disease or condition, an explanation
of why the proposed variation may be clinically superior to the first
drug.
(6) Where a sponsor requests orphan-drug designation for a drug for
only a subset of persons with a particular disease or condition that
otherwise affects 200,000 or more people (``orphan subset''), a
demonstration that, due to one or more properties of the drug, the
remaining persons with such disease or condition would not be
appropriate candidates for use of the drug.
* * * * *

0
6. Section 316.21 is amended by revising paragraph (a)(1) and the
introductory text of paragraph (b) to read as follows:

Sec. 316.21 Verification of orphan-drug status.

(a) * * *
(1) Documentation as described in paragraph (b) of this section
that the number of people affected by the disease or condition for
which the drug is to be developed is fewer than 200,000 persons; or
* * * * *
(b) For the purpose of documenting that the number of people
affected by the disease or condition for which the drug is to be
developed is less than 200,000 persons, ``prevalence'' is defined as
the number of persons in the United States who have been diagnosed as
having the disease or condition at the time of the submission of the
request for orphan-drug designation. To document the number of persons
in the United States who have the disease or condition for which the
drug is to be developed, the sponsor shall submit to FDA evidence
showing:
* * * * *

0
7. Section 316.22 is revised to read as follows:

Sec. 316.22 Permanent-resident agent for foreign sponsor.

Every foreign sponsor that seeks orphan-drug designation shall name
a permanent resident of the United States as the sponsor's agent upon
whom service of all processes, notices, orders, decisions,
requirements, and other communications may be made on behalf of the
sponsor. Notifications of changes in such agents or changes of address
of agents should preferably be provided in advance, but not later than
60 days after the effective date of such changes. The permanent-
resident agent may be an individual, firm, or domestic corporation and
may represent any number of sponsors. The name of the permanent-
resident agent, address, telephone number, and email address shall be
provided to: Office of Orphan Products Development, Food and Drug
Administration, Bldg. 32, rm. 5271, 10903 New Hampshire Ave., Silver
Spring, MD 20993.

0
8. Section 316.23 is revised to read as follows:

Sec. 316.23 Timing of requests for orphan-drug designation;
designation of already approved drugs.

(a) A sponsor may request orphan-drug designation at any time in
its drug development process prior to the time that sponsor submits a
marketing application for the drug for the same rare disease or
condition.
(b) A sponsor may request orphan-drug designation of an already
approved drug for an unapproved use without regard to whether the prior
marketing approval was for a rare disease or condition.

0
9. Section 316.24 is amended by revising the section heading,
redesignating paragraphs (a) and (b) as

[[Page 35134]]

paragraphs (b) and (c), respectively, and by adding new paragraphs (a)
and (d) to read as follows:

Sec. 316.24 Deficiency letters and granting orphan-drug designation.

(a) FDA will send a deficiency letter to the sponsor if the request
for orphan-drug designation lacks information required under Sec. Sec.
316.20 and 316.21, or contains inaccurate or incomplete information.
FDA may consider a designation request voluntarily withdrawn if the
sponsor fails to respond to the deficiency letter within 1 year of
issuance of the deficiency letter, unless within that same timeframe
the sponsor requests in writing an extension of time to respond. This
request must include the reason(s) for the requested extension and the
length of time of the requested extension. FDA will grant all
reasonable requests for an extension. In the event FDA denies a request
for an extension of time, FDA may consider the designation request
voluntarily withdrawn. In the event FDA considers a designation request
voluntarily withdrawn, FDA will so notify the sponsor in writing.
* * * * *
(d) A sponsor may voluntarily withdraw an orphan-drug designation
request or an orphan-drug designation at any time after the request is
submitted or granted, respectively, by submitting a written request for
withdrawal to FDA. FDA will acknowledge such withdrawal in a letter to
the sponsor. Any benefits attendant to designation (such as orphan-
exclusive approval) will cease once designation is voluntarily
withdrawn, from the date of FDA's acknowledgement letter. If a sponsor
voluntarily withdraws designation, FDA will publicize such withdrawal
in accordance with Sec. 316.28.

0
10. Section 316.25 is amended by revising paragraphs (a)(1)(ii),
(a)(3), and (b) to read as follows:

Sec. 316.25 Refusal to grant orphan-drug designation.

(a) * * *
(1) * * *
(ii) Where the drug is intended for prevention, diagnosis, or
treatment of a disease or condition affecting 200,000 or more people in
the United States, the sponsor has failed to demonstrate that there is
no reasonable expectation that development and production costs will be
recovered from sales of the drug for such disease or condition in the
United States. A sponsor's failure to comply with Sec. 316.21 shall
constitute a failure to make the demonstration required in this
paragraph.
* * * * *
(3) The drug is otherwise the same drug as an already approved drug
for the same rare disease or condition and the sponsor has not
submitted a medically plausible hypothesis for the possible clinical
superiority of the subsequent drug.
(b) FDA may refuse to grant a request for orphan-drug designation
if the request for designation contains an untrue statement of material
fact or omits material information or if the request is otherwise
ineligible under this part.

0
11. Section 316.26 is revised to read as follows:

Sec. 316.26 Amendment to orphan-drug designation.

(a) At any time prior to approval of a marketing application for a
designated orphan drug, the sponsor holding designation may apply for
an amendment to the designated use if the proposed change is due to new
and unexpected findings in research on the drug, information arising
from FDA recommendations, or unforeseen developments in treatment or
diagnosis of the disease or condition.
(b) FDA will grant the amendment if it finds that the initial
designation request was made in good faith and that the amendment is
intended to conform the orphan-drug designation to the results of
unanticipated research findings, to unforeseen developments in the
treatment or diagnosis of the disease or condition, or to changes based
on FDA recommendations, and that, as of the date of the submission of
the amendment request, the amendment would not result in exceeding the
prevalence or cost recovery thresholds in Sec. 316.21(a)(1) or (a)(2)
upon which the drug was originally designated.

0
12. Section 316.28 is revised to read as follows:

Sec. 316.28 Publication of orphan-drug designations.

Each month FDA will update a publicly available cumulative posting
of all drugs designated as orphan drugs. These postings will contain
the following information:
(a) The name and address of the sponsor;
(b) The generic name and trade name, if any, or, if neither is
available, the chemical name or a meaningful descriptive name of the
drug;
(c) The date of the granting of orphan-drug designation;
(d) The designated use in the rare disease or condition; and
(e) If the drug loses designation after August 12, 2013, the date
of it no longer having designation.
0
13. Section 316.29 is amended by adding a new paragraph (d) to read as
follows:

Sec. 316.29 Revocation of orphan-drug designation.

* * * * *
(d) If FDA revokes orphan-drug designation, FDA will publicize that
the drug is no longer designated in accordance with Sec. 316.28(e).

0
14. Section 316.31 is amended by revising the introductory text of
paragraph (a), by redesignating paragraph (b) as paragraph (c), by
revising newly redesignated paragraph (c), and by adding new paragraph
(b) to read as follows:

Sec. 316.31 Scope of orphan-drug exclusive approval.

(a) FDA may approve a sponsor's marketing application for a
designated orphan drug for use in the rare disease or condition for
which the drug was designated, or for select indication(s) or use(s)
within the rare disease or condition for which the drug was designated.
Unless FDA previously approved the same drug for the same use or
indication, FDA will not approve another sponsor's marketing
application for the same drug for the same use or indication before the
expiration of 7 years from the date of such approval as stated in the
approval letter from FDA, except that such a marketing application can
be approved sooner if, and at such time as, any of the following
occurs:
* * * * *
(b) Orphan-drug exclusive approval protects only the approved
indication or use of a designated drug. If such approval is limited to
only particular indication(s) or uses(s) within the rare disease or
condition for which the drug was designated, FDA may later approve the
drug for additional indication(s) or uses(s) within the rare disease or
condition not protected by the exclusive approval. If the sponsor who
obtains approval for these new indication(s) or uses(s) has orphan-drug
designation for the drug for the rare disease or condition, FDA will
recognize a new orphan-drug exclusive approval for these new (not
previously approved) indication(s) or use(s) from the date of approval
of the drug for such new indication(s) or use(s).
(c) If a sponsor's marketing application for a drug product is
determined not to be approvable because approval is barred under
section 527 of the Federal Food, Drug, and Cosmetic Act until the
expiration of

[[Page 35135]]

the period of exclusive marketing of another drug, FDA will so notify
the sponsor in writing.

0
15. Section 316.34 is revised to read as follows:

Sec. 316.34 FDA recognition of exclusive approval.

(a) FDA will send the sponsor (or, the permanent-resident agent, if
applicable) timely written notice recognizing exclusive approval once
the marketing application for a designated orphan-drug product has been
approved, if the same drug has not already been approved for the same
use or indication. The written notice will inform the sponsor of the
requirements for maintaining orphan-drug exclusive approval for the
full 7-year term of exclusive approval.
(b) When a marketing application is approved under section 505 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) for a
designated orphan drug that qualifies for exclusive approval, FDA will
publish in its publication entitled ``Approved Drug Products With
Therapeutic Equivalence Evaluations'' information identifying the
sponsor, the drug, and the date of termination of the orphan-drug
exclusive approval. A subscription to this publication and its monthly
cumulative supplements is available from the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325, and
is also available online at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.
(c) If a drug is otherwise the same drug as a previously approved
drug for the same use or indication, FDA will not recognize orphan-drug
exclusive approval if the sponsor fails to demonstrate upon approval
that the drug is clinically superior to the previously approved drug.

0
16. Section 316.50 is revised to read as follows:

Sec. 316.50 Guidance documents.

FDA's Office of Orphan Products Development will maintain and make
publicly available a list of guidance documents that apply to the
regulations in this part. The list is maintained on the Internet and is
published annually in the Federal Register. A request for a copy of the
list should be directed to the Office of Orphan Products Development,
Food and Drug Administration, Bldg. 32, rm. 5271, 10903 New Hampshire
Ave., Silver Spring, MD 20993.

Dated: June 7, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-13930 Filed 6-11-13; 8:45 am]
BILLING CODE 4160-01-P