21 Cfr 316

21 CFR 316.20, 316, 21, 316.22, 316.26, 316.27, 316.30, 316.36

[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2006]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR316.20]

[Page 177-178]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)

PART 316_ORPHAN DRUGS--Table of Contents

Subpart C_Designation of an Orphan Drug

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 orphan indication for an already
marketed drug. In addition, a sponsor of a drug that is otherwise the
same drug as an already approved orphan 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) A sponsor shall submit two copies of a completed, dated, and
signed request for designation that contains the following:
(1) A statement that the sponsor requests orphan-drug designation
for a rare disease or condition, which shall be identified with
specificity.
(2) The name and address of the sponsor; the name of the sponsor's
primary contact person and/or resident agent including title, address,
and telephone number; the generic and trade name, if any, of the drug or
drug product; and the name and address of the source of the drug if it
is not manufactured by the sponsor.

[[Page 178]]

(3) A description of the rare disease or condition for which the
drug is being or will be investigated, the proposed indication or
indications for use of the drug, and the reasons why such therapy is
needed.
(4) A description of the drug and a discussion of the scientific
rationale for the use of the drug for the rare disease or condition,
including all data from nonclinical laboratory studies, clinical
investigations, and other relevant data that are available to the
sponsor, whether positive, negative, or inconclusive. 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 orphan 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 drug is under development for only a subset of persons
with a particular disease or condition, a demonstration that the subset
is medically plausible.
(7) A summary of the regulatory status and marketing history of the
drug in the United States and in foreign countries, e.g., IND and
marketing application status and dispositions, what uses are under
investigation and in what countries; for what indication is the drug
approved in foreign countries; what adverse regulatory actions have been
taken against the drug in any country.
(8) Documentation, with appended authoritative references, to
demonstrate that:
(i) The disease or condition for which the drug is intended affects
fewer than 200,000 people in the United States or, if the drug is a
vaccine, diagnostic drug, or preventive drug, the persons to whom the
drug will be administered in the United States are fewer than 200,000
per year as specified in Sec. 316.21(b), or
(ii) For a drug intended for diseases or conditions affecting
200,000 or more people, or for a vaccine, diagnostic drug, or preventive
drug to be administered to 200,000 or more persons per year in the
United States, there is no reasonable expectation that costs of research
and development of the drug for the indication can be recovered by sales
of the drug in the United States as specified in Sec. 316.21(c).
(9) A statement as to whether the sponsor submitting the request is
the real party in interest of the development and the intended or actual
production and sales of the product.
(c) Any of the information previously provided by the sponsor to FDA
under subpart B of this part may be referenced by specific page or
location if it duplicates information required elsewhere in this
section.

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[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2006]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR316.21]

[Page 178-180]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)

PART 316_ORPHAN DRUGS--Table of Contents

Subpart C_Designation of an Orphan Drug

Sec. 316.21 Verification of orphan-drug status.

(a) So that FDA can determine whether a drug qualifies for orphan-
drug designation under section 526(a) of the act, the sponsor shall
include in its request to FDA for orphan-drug designation under Sec.
316.20 either:
(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 product is indicated is fewer than 200,000 persons; or
(2) Documentation as described in paragraph (c) of this section that
demonstrates that there is no reasonable expectation that the sales of
the drug will be sufficient to offset the costs of developing the drug
for the U.S. market and the costs of making the drug available in the
United States.
(b) For the purpose of documenting that the number of people
affected by the disease or condition for which the drug product is
indicated 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 indicated, the sponsor shall submit to FDA evidence showing:
(1) The estimated prevalence of the disease or condition for which
the drug is being developed, together with a list of the sources
(including dates of information provided and literature citations) for
the estimate;

[[Page 179]]

(2) Upon request by FDA, the estimated prevalence of any other
disease or condition for which the drug has already been approved or for
which the drug is currently being developed, together with an
explanation of the bases of these estimates; and
(3) The estimated number of people to whom the drug will be
administered annually if the drug is a vaccine or is a drug intended for
diagnosis or prevention of a rare disease or condition, together with an
explanation of the bases of these estimates (including dates of
information provided and literature citations).
(c) When submitting documentation that there is no reasonable
expectation that costs of research and development of the drug for the
disease or condition can be recovered by sales of the drug in the United
States, the sponsor shall submit to FDA:
(1) Data on all costs that the sponsor has incurred in the course of
developing the drug for the U.S. market. These costs shall include, but
are not limited to, nonclinical laboratory studies, clinical studies,
dosage form development, record and report maintenance, meetings with
FDA, determination of patentability, preparation of designation request,
IND/marketing application preparation, distribution of the drug under a
``treatment'' protocol, licensing costs, liability insurance, and
overhead and depreciation. Furthermore, the sponsor shall demonstrate
the reasonableness of the cost data. For example, if the sponsor has
incurred costs for clinical investigations, the sponsor shall provide
information on the number of investigations, the years in which they
took place, and on the scope, duration, and number of patients that were
involved in each investigation.
(2) If the drug was developed wholly or in part outside the United
States, in addition to the documentation listed in paragraph (c)(1) of
this section:
(i) Data on and justification for all costs that the sponsor has
incurred outside of the United States in the course of developing the
drug for the U.S. market. The justification, in addition to
demonstrating the reasonableness of the cost data, must also explain the
method that was used to determine which portion of the foreign
development costs should be applied to the U.S. market, and what percent
these costs are of total worldwide development costs. Any data submitted
to foreign government authorities to support drug pricing determinations
must be included with this information.
(ii) Data that show which foreign development costs were recovered
through cost recovery procedures that are allowed during drug
development in some foreign countries. For example, if the sponsor
charged patients for the drug during clinical investigations, the
revenues collected by the sponsor must be reported to FDA.
(3) In cases where the drug has already been approved for marketing
for any indication or in cases where the drug is currently under
investigation for one or more other indications (in addition to the
indication for which orphan-drug designation is being sought), a clear
explanation of and justification for the method that is used to
apportion the development costs among the various indications.
(4) A statement of and justification for any development costs that
the sponsor expects to incur after the submission of the designation
request. In cases where the extent of these future development costs are
not clear, the sponsor should request FDA's advice and assistance in
estimating the scope of nonclinical laboratory studies and clinical
investigations and other data that are needed to support marketing
approval. Based on these recommendations, a cost estimate should be
prepared.
(5) A statement of and justification for production and marketing
costs that the sponsor has incurred in the past and expects to incur
during the first 7 years that the drug is marketed.
(6) An estimate of and justification for the expected revenues from
sales of the drug in the United States during its first 7 years of
marketing. The justification should assume that the total market for the
drug is equal to the prevalence of the disease or condition that the
drug will be used to treat. The justification should include:
(i) An estimate of the expected market share of the drug in each of
the

[[Page 180]]

first 7 years that it is marketed, together with an explanation of the
basis for that estimate;
(ii) A projection of and justification for the price at which the
drug will be sold; and
(iii) Comparisons with sales of similarly situated drugs, where
available.
(7) The name of each country where the drug has already been
approved for marketing for any indication, the dates of approval, the
indication for which the drug is approved, and the annual sales and
number of prescriptions in each country since the first approval date.
(8) A report of an independent certified public accountant in
accordance with Statement on Standards for Attestation established by
the American Institute of Certified Public Accountants on agreed upon
procedures performed with respect to the data estimates and
justifications submitted pursuant to this section. Cost data shall be
determined in accordance with generally accepted accounting principles.
(d) A sponsor that is requesting orphan-drug designation for a drug
designed to treat a disease or condition that affects 200,000 or more
persons shall, at FDA's request, allow FDA or FDA-designated personnel
to examine at reasonable times and in a reasonable manner all relevant
financial records and sales data of the sponsor and manufacturer.

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[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2006]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR316.22]

[Page 180]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)

PART 316_ORPHAN DRUGS--Table of Contents

Subpart C_Designation of an Orphan Drug

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 shall
be provided to: Office of Orphan Products Development (HF-35), Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

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[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2006]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR316.26]

[Page 181]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)

PART 316_ORPHAN DRUGS--Table of Contents

Subpart C_Designation of an Orphan Drug

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 indication stated in the orphan-drug designation if the
proposed change is due to new and unexpected findings in research on the
drugs, 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 indication 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.

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[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2006]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR316.27]

[Page 181]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)

PART 316_ORPHAN DRUGS--Table of Contents

Subpart C_Designation of an Orphan Drug

Sec. 316.27 Change in ownership of orphan-drug designation.

(a) A sponsor may transfer ownership of or any beneficial interest
in the orphan-drug designation of a drug to a new sponsor. At the time
of the transfer, the new and former owners are required to submit the
following information to FDA:
(1) The former owner or assignor of rights shall submit a letter or
other document that states that all or some rights to the orphan-drug
designation of the drug have been transferred to the new owner or
assignee and that a complete copy of the request for orphan-drug
designation, including any amendments to the request, supplements to the
granted request, and correspondence relevant to the orphan-drug
designation, has been provided to the new owner or assignee.
(2) The new owner or assignee of rights shall submit a statement
accepting orphan-drug designation and a letter or other document
containing the following:
(i) The date that the change in ownership or assignment of rights is
effective;
(ii) A statement that the new owner has a complete copy of the
request for orphan-drug designation including any amendments to the
request, supplements to the granted request, and correspondence relevant
to the orphan-drug designation; and
(iii) A specific description of the rights that have been assigned
and those that have been reserved. This may be satisfied by the
submission of either a list of rights assigned and reserved or copies of
all relevant agreements between assignors and assignees; and
(iv) The name and address of a new primary contact person or
resident agent.
(b) No sponsor may relieve itself of responsibilities under the
Orphan Drug Act or under this part by assigning rights to another person
without:
(1) Assuring that the sponsor or the assignee will carry out such
responsibilities; or
(2) Obtaining prior permission from FDA.

[57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993]

[[Page 182]]

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[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2006]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR316.30]

[Page 182]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)

PART 316_ORPHAN DRUGS--Table of Contents

Subpart C_Designation of an Orphan Drug

Sec. 316.30 Annual reports of holder of orphan-drug designation.

Within 14 months after the date on which a drug was designated as an
orphan drug and annually thereafter until marketing approval, the
sponsor of a designated drug shall submit a brief progress report to the
FDA Office of Orphan Products Development on the drug that includes:
(a) A short account of the progress of drug development including a
review of preclinical and clinical studies initiated, ongoing, and
completed and a short summary of the status or results of such studies.
(b) A description of the investigational plan for the coming year,
as well as any anticipated difficulties in development, testing, and
marketing; and
(c) A brief discussion of any changes that may affect the orphan-
drug status of the product. For example, for products nearing the end of
the approval process, sponsors should discuss any disparity between the
probable marketing indication and the designated indication as related
to the need for an amendment to the orphan-drug designation pursuant to
Sec. 316.26.

***********************************************************************

[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2006]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR316.36]

[Page 183]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)

PART 316_ORPHAN DRUGS--Table of Contents

Subpart D_Orphan-drug Exclusive Approval

Sec. 316.36 Insufficient quantities of orphan drugs.

(a) Under section 527 of the act, whenever the Director has reason
to believe that the holder of exclusive approval cannot assure the
availability of sufficient quantities of an orphan drug to meet the
needs of patients with the disease or condition for which the drug was
designated, the Director will so notify the holder of this possible
insufficiency and will offer the holder one of the following options,
which must be exercised by a time that the Director specifies:
(1) Provide the Director in writing, or orally, or both, at the
Director's discretion, views and data as to how the holder can assure
the availability of sufficient quantities of the orphan drug within a
reasonable time to meet the needs of patients with the disease or
condition for which the drug was designated; or
(2) Provide the Director in writing the holder's consent for the
approval of other marketing applications for the same drug before the
expiration of the 7-year period of exclusive approval.
(b) If, within the time that the Director specifies, the holder
fails to consent to the approval of other marketing applications and if
the Director finds that the holder has not shown that it can assure the
availability of sufficient quantities of the orphan drug to meet the
needs of patients with the disease or condition for which the drug was
designated, the Director will issue a written order withdrawing the drug
product's exclusive approval. This order will embody the Director's
findings and conclusions and will constitute final agency action. An
order withdrawing the sponsor's exclusive marketing rights may issue
whether or not there are other sponsors that can assure the availability
of alternative sources of supply. Once withdrawn under this section,
exclusive approval may not be reinstated for that drug.