drug for which approval is sought or a method of using such drug and to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product.

(vi) Any patent certification or statement required under section 505(b)(2) of the act with respect to any relevant patents that claim the listed drug or that claim any other drugs on which investigations relied on by the applicant for approval of the application were conducted, or that claim a use for the listed or other drug.

(vii) If the applicant believes the change for which it is seeking approval is entitled to a period of exclusivity, the information required under § 314.50(j).

(2) The applicant shall submit a review copy that contains the technical sections described in §314.50(d)(1), except that §314.50(d)(1)(ii)(c) shall contain the proposed or actual master production record, including a description of the equipment, to be used for the manufacture of a commercial lot of the drug product, and paragraph (d)(3), and the technical sections described in paragraphs (d)(2), (d)(4), (d)(5), (d)(6), and (f) when needed to support the modification. Each of the technical sections in the review copy is required to be separately bound with a copy of the information required under §314.50 (a), (b), and (c) and a copy of the proposed labeling.

(3) The information required by §314.50 (d)(2), (d)(4) (if an anti-infective drug), (d)(5), (d)(6), and (f) for the listed drug on which the applicant relies shall be satisfied by reference to the listed drug under paragraph (a)(1)(iii) of this section.

(4) The applicant shall submit a field copy of the application that contains the technical section described in § 314.50(d)(1), a copy of the information required under §314.50(a) and (c), and certification that the field copy is a true copy of the technical section described in § 314.50(d)(1) contained in the archival and review copies of the application.

(b) An application may not be submitted under this section for a drug

product whose only difference from the reference listed drug is that:

(1) The extent to which its active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the reference listed drug; or

(2) The rate at which its active ingredient(s) is absorbed or otherwise made available to the site of action is unintentionally less than that of the reference listed drug.

[57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec. 28, 1992, as amended at 58 FR 47351, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994]

$314.55 Pediatric use information.

(a) Required assessment. Except as provided in paragraphs (b), (c), and (d) of this section, each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective. Where the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies. Studies may not be needed in each pediatric age group, if data from one age group can be extrapolated to another. Assessments of safety and effectiveness required under this section for a drug product that represents a meaningful therapeutic benefit over existing treatments for pediatric patients must be carried out using appropriate formulations for each age group(s) for which the assessment is required.

(b) Deferred submission. (1) FDA may, on its own initiative or at the request of an applicant, defer submission of some or all assessments of safety and effectiveness described in paragraph (a) of this section until after approval of the drug product for use in adults. Deferral may be granted if, among other

reasons, the drug is ready for approval in adults before studies in pediatric patients are complete, or pediatric studies should be delayed until additional safety or effectiveness data have been collected. If an applicant requests deferred submission, the request must provide a certification from the applicant of the grounds for delaying pediatric studies, a description of the planned or ongoing studies, and evidence that the studies are being or will be conducted with due diligence and at the earliest possible time.

(2) If FDA determines that there is an adequate justification for temporarily delaying the submission of assessments of pediatric safety and effectiveness, the drug product may be approved for use in adults subject to the requirement that the applicant submit the required assessments within a specified time.

(c) Waivers (1) General. FDA may grant a full or partial waiver of the requirements of paragraph (a) of this section on its own initiative or at the request of an applicant. A request for a waiver must provide an adequate justification.

(2) Full waiver. An applicant may request a waiver of the requirements of paragraph (a) of this section if the applicant certifies that:

(i) The drug product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients and is not likely to be used in a substantial number of pediatric patients;

(ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed; or

(iii) There is evidence strongly suggesting that the drug product would be ineffective or unsafe in all pediatric age groups.

(3) Partial waiver. An applicant may request a waiver of the requirements of paragraph (a) of this section with respect to a specified pediatric age group, if the applicant certifies that:

(i) The drug product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients in that age group, and is not likely to be used in a substantial number of patients in that age group;

(ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group is so small or geographically dispersed;

(iii) There is evidence strongly suggesting that the drug product would be ineffective or unsafe in that age group;

or

(iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.

(4) FDA action on waiver. FDA shall grant a full or partial waiver, as appropriate, if the agency finds that there is a reasonable basis on which to conclude that one or more of the grounds for waiver specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the ground that it is not possible to develop a pediatric formulation, the waiver will cover only those pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that the product would be ineffective or unsafe in pediatric populations, this information will be included in the product's labeling.

(5) Definition of "meaningful therapeutic benefit". For purposes of this section and §201.23 of this chapter, a drug will be considered to offer a meaningful therapeutic benefit over existing therapies if FDA estimates that:

(i) If approved, the drug would represent a significant improvement in the treatment, diagnosis, or prevention of a disease, compared to marketed products adequately labeled for that use in the relevant pediatric population. Examples of how improvement might be demonstrated include, for example, evidence of increased effectiveness in treatment, prevention, or diagnosis of disease, elimination or substantial reduction of a treatment-limiting drug reaction, documented enhancement of compliance, or evidence of safety and effectiveness in a new subpopulation; or

(ii) The drug is in a class of drugs or for an indication for which there is a need for additional therapeutic options.

(d) Exemption for orphan drugs. This section does not apply to any drug for an indication or indications for which orphan designation has been granted

(a) Except as provided in paragraph (b) of this section, the applicant may submit an amendment to an application that is filed under §314.100, but not yet approved. The submission of a major amendment (for example, an amendment that contains significant new data from a previously unreported study or detailed newnalyses of previously submitted data), whether on the applicant's own initiative or at the invitation of the agency, constitutes an agreement by the applicant under section 505(c) of the act to extend the date by which the agency is required to reach a decision on the application. Ordinarily, the agency will extend the review period for a major amendment but only for the time necessary to review the new information. However, the agency may not extend the review period more than 180 days. If the agency extends the review period for the application, the director of the division responsible for reviewing the application will notify the applicant of the length of the extension. The submission of an amendment that is not a major amendment will not extend the review period. An amendment that contains new clinical data from a previously unreported study shall contain a financial certification or disclosure statement or both as required by part 54 of this chapter, or FDA may refuse to accept any such amendment.

(b)(1) An unapproved application may not be amended if all of the following conditions apply:

(i) The unapproved application is for a drug for which a previous application has been approved and granted a period of exclusivity in accordance with section 505(c)(3)(D)(ii) of the act that has not expired;

(ii) The applicant seeks to amend the unapproved application to include a published report of an investigation that was conducted or sponsored by the applicant entitled to exclusivity for the drug;

(iii) The applicant has not obtained a right of reference to the investigation

described in paragraph (b)(1)(ii) of this section; and

(iv) The report of the investigation described in paragraph (b)(1)(ii) of this section would be essential to the approval of the unapproved application.

(2) The submission of an amendment described in paragraph (b)(1) of this section will cause the unapproved application to be deemed to be withdrawn by the applicant under §314.65 on the date of receipt by FDA of the amendment. The amendment will be considered a resubmission of the application, which may not be accepted except as provided in accordance with section 505(c)(3)(D)(ii) of the act.

(c) The applicant shall submit a field copy of each amendment to §314.50(d)(1). The applicant, other than a foreign applicant, shall include in its submission of each such amendment to FDA a statement certifying that a field copy of the amendment has been sent to the applicant's home FDA district office.

[50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8, 1993; 63 FR 5252, Feb. 2, 1998]

§314.65 Withdrawal by the applicant of an unapproved application.

An applicant may at any time withdraw an application that is not yet approved by notifying the Food and Drug Administration in writing. The agency will consider an applicant's failure to respond within 10 days to an approvable letter under §314.110 or a not approvable letter under §314.120 to be a request by the applicant to withdraw the application. A decision to withdraw the application is without prejudice to refiling. The agency will retain the application and will provide a copy to the applicant on request under the fee schedule in §20.42 of FDA's public information regulations.

for in the application. The notice is required to describe the change fully. Depending on the type of change, the applicant shall notify FDA about it in a supplemental application under paragraph (b) or (c) of this section or by inclusion of the information in the annual report to the application under paragraph (d) of this section. Notwithstanding the requirements of paragraphs (b) and (c) of this section, an applicant shall make a change provided for in those paragraphs (for example, the deletion of an ingredient common to many drug products) in accordance with a notice, or regulation published in the FEDERAL REGISTER that provides for a less burdensome notification of the change (for example, by notification at the time a supplement is submitted or in the next annual report). Except for a supplemental application providing for a change in the labeling, the applicant, other than a foreign applicant, shall include in each supplemental application providing for change under paragraph (b) or (c) of this section a statement certifying that a field copy of the supplement has been provided to the applicant's home FDA district office.

a

(b) Supplements requiring FDA approval before the change is made. An applicant shall submit a supplement, and obtain FDA approval of it, before making the changes listed below in the conditions in an approved application, unless the change is made to comply with an official compendium. An applicant may ask FDA to expedite its review of a supplement if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover should be plainly marked: "Supplement-Expedited Review Re

quested."

(1) Drug substance. A change affecting the drug substance to accomplish any of the following:

(i) To relax the limits for a specification;

(ii) To establish a new regulatory analytical method;

(iii) To delete a specification or regulatory analytical method;

(iv) To change the synthesis of the drug substance, including a change in

solvents and a change in the route of synthesis.

(v) To use a different facility or establishment to manufacture the drug substance, where: (a) the manufacturing process in the new facility or establishment differs materially from that in the former facility or establishment, or (b) the new facility or establishment has not received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process.

(2) Drug product. A change affecting the drug product to accomplish any of the following:

(i) To add or delete an ingredient, or otherwise to change the composition of the drug product, other than deletion of an ingredient intended only to affect the color of the drug product;

(ii) To relax the limits for a specification;

(iii) To establish a new regulatory analytical method;

(iv) To delete a specification or regulatory analytical method;

(v) To change the method of manufacture of the drug product, including changing or relaxing an in-process control;

(vi) To use a different facility or establishment, including a different contract laboratory or labeler, to manufacture, process, or pack the drug product;

(vii) To change the container and closure system for the drug product (for example, glass to high density polyethylene (HDPE), or HDPE to polyvinyl chloride) or change a specification or regulatory analytical method for the container and closure system;

(viii) To change the size of the container, except for solid dosage forms, without a change in the container and closure system.

(ix) To extend the expiration date of the drug product based on data obtained under a new or revised stability testing protocol that has not been approved in the application.

(x) To establish a new procedure for reprocessing a batch of the drug product that fails to meet specifications.

(xi) To add a code imprint by printing with ink on a solid oral dosage form drug product.

(xii) To add a code imprint by embossing, debossing, or engraving on a modified release solid oral dosage form drug product.

(3) Labeling. (i) Any change in labeling, except one described in paragraphs (c)(2) or (d) of this section.

(ii) If applicable, any change to a Medication Guide required under part 208 of this chapter, except for changes in the information specified § 208.20(b)(8)(iii) and (b)(8)(iv).

in

(c) Supplements for changes that may be made before FDA approval. An applicant shall submit a supplement at the time the applicant makes any kind of change listed below in the conditions in an approved application, unless the change is made to comply with an official compendium. A supplement under this paragraph is required to give a full explanation of the basis for the change, identify the date on which the change is made, and, if the change concerns labeling, include 12 copies of final printed labeling. The applicant shall promptly revise all promotional labeling and drug advertising to make it consistent with any change in the labeling. The supplement and its mailing cover should be plainly marked: "Special Supplement-Changes Being Effected."

(1) Adds a new specification or test method or changes in the methods, facilities (except a change to a new facility), or controls to provide increased assurance that the drug will have the characteristics of identity, strength, quality, and purity which it purports or is represented to possess;

(2) Changes labeling to accomplish any of the following:

(i) To add or strengthen a contraindication, warning, precaution, or adverse reaction;

(ii) To add or strengthen a statement about drug abuse, dependence, or overdosage; or

(iii) To add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the product.

(iv) To delete false, misleading, or unsupported indications for use or claims for effectiveness.

(3) To use a different facility or establishment to manufacture the drug substance, where: (i) The manufac

turing process in the new facility or establishment does not differ materially from that in the former facility or establishment, and (ii) the new facility or establishment has received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process.

(d) Changes described in the annual report. An applicant shall not submit a supplement to make any change in the conditions in an approved application, unless otherwise required under paragraph (b) or (c) of this section, but shall describe the change in the next annual report required under §314.81. Some examples of changes that can be described in the annual report are the following:

(1) Any change made to comply with an official compendium.

(2) A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form.

(3) An editorial or similar minor change in labeling.

(4) The deletion of an ingredient intended only to affect the color of the drug product.

(5) An extension of the expiration date based upon full shelf-life data obtained from a protocol approved in the application.

(6) A change within the container and closure system for the drug product (for example, a change from one high density polyethylene (HDPE) to another HDPE), except a change in container size for nonsolid dosage forms, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium.

(7) The addition or deletion of an alternate analytical method.

(8) A change in the size of a container for a solid dosage form, without a change from one container and closure system to another.

(9) The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint.