[Federal Register Volume 78, Number 113 (Wednesday, June 12, 2013)]
[Rules and Regulations]
[Pages 35117-35135]
From the Federal Register Online via the Government Printing 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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    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, though many comments raised objections 
to and questions about certain aspects of the proposed rule.

[[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.
---------------------------------------------------------------------------

    \4\ This exemption from application user fees was enacted as 
part of the Prescription Drug User Fee Act of 1992, since 
reauthorized.
---------------------------------------------------------------------------

    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