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of the amendment request, the amendment would not result in exceeding the prevalence or cost recovery thresholds in 8316.21 (a)(1) or (a)(2) upon which the drug was originally designated.
(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)
$ 316.28 Publication of orphan-drug
designations. Each month FDA will update a publically available list of drugs designated as orphan drugs. A cumulative, updated list of all designated drugs will be provided annually. These will be placed on file at the FDA Dockets Management Branch, and will contain the following information:
(a) The name and address of the manufacturer and sponsor;
(b) The generic name and trade name, if any, of the drug and the date of the granting of orphan-drug designation;
(c) The rare disease or condition for which orphan-drug designation was granted; and
(d) The proposed indication for use of the drug.
8316.27 Change in ownership of or
phan-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 orphandrug 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 orphandrug 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:
8316.29 Revocation of orphan-drug
designation. (a) FDA may revoke orphan-drug designation for any drug if the agency finds that:
(1) The request for designation contained an untrue statement of material fact; or
(2) The request for designation omitted material information required by this part; or
(3) FDA subsequently finds that the drug in fact had not been eligible for orphan-drug designation at the time of submission of the request therefor.
(b) For an approved drug, revocation of orphan-drug designation also suspends or withdraws the sponsor's exclusive marketing rights for the drug but not the approval of the drug's marketing application.
(c) Where a drug has been designated as an orphan drug because the prevalence of a disease or condition (or, in the case of vaccines, diagnostic drugs, or preventive drugs, the target population) is under 200,000 in the United States at the time of designation, its designation will not be revoked on the ground that the prevalence of the disease or condition (or the target population) becomes more than 200,000 per
(2) Withdrawal for any reason of the marketing application for the drug in question; or
(3) Consent by the holder of exclusive approval to permit another marketing application to gain approval; or
(4) Failure of the holder of exclusive approval to assure a sufficient quantity of the drug under section 527 of the act and $316.36.
(b) 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 act until the expiration of the period of exclusive marketing of another drug product, FDA will so notify the sponsor in writing.
$316.30 Annual reports of holder of or
phan-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 $316.26.
$ 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 orphandrug product has been approved. 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 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.
8316.31 Scope of orphan-drug exclu
sive approval. (a) After approval of a sponsor's marketing application for a designated orphan-drug product for treatment of the rare disease or condition concerning which orphan-drug designation granted, FDA will not approve another sponsor's marketing application for the same drug 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 such time as, any of the following occurs:
(1) Withdrawal of exclusive approval or revocation of orphan-drug designation by FDA under any provision of this part; or
$316.36 Insufficient quantities of or
phan 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 obtain a copy of each guideline. A request for a copy of the list or for any guideline should be directed to the Office of Orphan Products Development (HF-35), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
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.
8316.52 Availability for public disclo
sure of data and information in re
quests and applications. (a) FDA will not publicly disclose the existence of a request for orphan-drug designation under section 526 of the act prior to final FDA action on the request unless the existence of the request has been previously publicly disclosed or acknowledged.
(b) Whether or not the existence of a pending request for designation has been publicly disclosed or acknowledged, no data or information in the request are available for public disclosure prior to final FDA action on the request.
(C) Upon final FDA action on a request for designation, FDA will determine the public availability of data and information in the request in accordance with part 20 and $314.430 of this chapter and other applicable statutes and regulations.
(d) In accordance with $316.28, FDA will make a cumulative list of all orphan drug designations available to the public and update such list monthly.
(e) FDA will not publicly disclose the existence of a pending marketing application for a designated orphan drug for the use for which the drug was designated unless the existence of the application has been previously publicly disclosed or acknowledged.
(f) FDA will determine the public availability of data and information contained in pending and approved marketing applications for designated orphan drug for the use for which the drug was designated in accordance with part 20 and $314.430 of this chapter and other applicable statutes and regulations.
Subpart E-Open Protocols for
§ 316.40 Treatment use of a designated
orphan drug. Prospective investigators seeking to obtain treatment use of designated orphan drugs may do so as provided in $312.34 of this chapter.
Subpart F-Availability of
PART 320-BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
8 316.50 Guidelines.
FDA's Office of Orphan Products Development will maintain and make publicly available a list of guidelines that apply to the regulations in this part. The list states how a person can
Subpart A-General Provisions
Sec. 320.1 Definitions.
Subpart B--Procedures for Determining the
Bioavailability of Bioequivalence of
320.21 Requirements for submission of in
vivo bioavailability and bioequivalence
data. 320.22 Criteria for waiver of evidence of in
vivo bioavailability or bioequivalence. 320.23 Basis for demonstrating in vivo bio
availability or bioequivalence. 320.24 Types of evidence to establish bio
availability or bioequivalence. 320.25 Guidelines for the conduct of an in
vivo bioavailability study. 320.26 Guidelines on the design of a single
dose in vivo bioavailability study. 320.27 Guidelines on the design of a mul
tiple-dose in vivo bioavailability study. 320.28 Correlation of bioavailability with an
acute pharmacological effect or clinical
evidence. 320.29 Analytical methods for an in vivo
bioavailability study. 320.30 Inquiries regarding bioavailability
and bioequivalence requirements and review of protocols by the Food and Drug
Administration. 320.31 Applicability of requirements regard
ing an “Investigational New Drug Appli
cation." 320.32 Procedures for establishing or amend
ing a bioequivalence requirement. 320.33 Criteria and evidence to assess actual
or potential bioequivalence problems. 320.34 Requirements for batch testing and
certification by the Food and Drug Ad
ministration. 320.35 Requirements for in vitro testing of
each batch, 320.36 Requirements for maintenance of
records of bioequivalence testing. 320.38 Retention of bioavailability samples. 320.63 Retention of bioequivalence samples.
AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 357, 371.
tion, that contains the active drug ingredient, generally, but not necessarily, in association with inactive ingredients.
(c) Pharmaceutical equivalents means drug products that contain identical amounts of the identical active drug ingredient, i.e., the same sat or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients, and that meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.
(d) Pharmaceutical alternatives means drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.
(e) Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain controlled release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.
(f) Bioequivalence requirement means a requirement imposed by the Food and
Subpart A-General Provisions
(a) Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
(b) Drug product means a finished dosage form, e.g., tablet, capsule, or solu
Drug Administration for in vitro and/or in vivo testing of specified drug products which must be satisfied as a condition of marketing.
(42 FR 1634, Jan. 7, 1977, as amended at 42 FR 1648, Jan. 7, 1977; 57 FR 17997, Apr. 28, 1992)
Subpart B-Procedures for Deter
mining the Bioavailability or Bioequivalence of Drug Products
SOURCE: 42 FR 1648, Jan. 7, 1977, unless otherwise noted.
quired to support the new indication for use.
(3) A change in the labeling to provide for a new dosage regimen or for an additional dosage regimen for a special patient population, e.g., infants, if clinical studies are required to support the new or additional dosage regimen.
(d) FDA may approve a full new drug application, or a supplemental application proposing any of the changes set forth in paragraph (c) of this section, that does not contain evidence of in vivo bioavailability or information to permit waiver of the requirement for in vivo bioavailability data, if all of the following conditions are met.
(1) The application was under review by FDA on July 7, 1977.
(2) The application is otherwise approvable.
(3) The application agrees to submit, within the time specified by FDA, either:
(i) Evidence demonstrating the in vivo bioavailability of the drug product that is the subject of the application;
$320.21 Requirements for submission
of in vivo bioavailability and bio
equivalence data. (a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall include in the application either:
(1) Evidence demonstrating the in vivo bioavailability of the drug product that is the subject of the application;
(2) Information to permit FDA to waive the submission of evidence demonstrating in vivo bioavailability.
(b) Any person submitting an abbreviated new drug application to FDA shall include in the application either:
(1) Evidence demonstrating that the drug product that is the subject of the abbreviated new drug application is bioequivalent to the reference listed drug (defined in $314.3(b)); or
(2) Information to show that the drug product is bioequivalent to the reference listed drug which would permit FDA to waive the submission of evidence demonstrating bioequivalence as provided in paragraph (f) of this section.
(c) Any person submitting a supplemental application to FDA shall include in the supplemental application the evidence or information set forth in paragraphs (a) and (b) of this section if the supplemental application proposes any of the following changes:
(1) A change in the manufacturing process, including a change in product formulation or dosage strength, beyond the variations provided for in the approved application.
(2) A change in the labeling to provide for a new indication for use of the drug product, if clinical studies are re
(ii) Information to permit FDA to waive demonstration of in vivo bioavailability.
(e) Evidence demonstrating the in vivo bioavailability and bioequivalence of a drug product shall be obtained using one of the approaches for determining bioavailability set forth in $320.24.
(f) Information to permit FDA to waive the submission of evidence demonstrating the in vivo bioavailability or bioequivalence shall meet the criteria set forth in 8320.24.
(8) Any person holding an approved full or abbreviated new drug application shall submit to FDA a supplemental application containing new evidence demonstrating the in vivo bioavailability or bioequivalence of the drug product that is the subject of the application if notified by FDA that:
(1) There are data demonstrating that the dosage regimen in the labeling is based on incorrect assumptions or facts regarding the pharmacokinetics of the drug product and that following this dosage regimen could potentially result in subtherapeutic or toxic levels;