(d) The 60-day period shall begin when FDA receives a manufacturer's submission, including, where applicable, a certification statement or an application for an exemption.

§ 99.203 Request to extend the time for completing planned studies.

(a) A manufacturer may request, prior to or at the time of making a submission to FDA under $99.201, that FDA extend the 36-month time period for completing the studies and submitting a supplemental application for the new use that is the subject of the information to be disseminated. Such request must set forth the reasons that such studies cannot be completed and submitted in a supplemental application within 36 months.

(b) A manufacturer who has certified that it will complete the studies necessary to submit a supplemental application for a new use within a specified period of time from the date that dissemination of information under this part can begin under §99.201(a)(4)(ii), but later finds that it will be unable to complete such studies and submit a supplemental application within that time period may request an extension of time from FDA. The manufacturer, in its request for extension, shall identify the product, the new use, and shall:

(1) Describe the study or studies that cannot be completed on time and explain why the study or studies cannot be completed on time;

(2) Describe the current status of the incomplete study or studies and summarize the work conducted, including the dates on which principal events concerning the study or studies occurred; and

(3) Estimate the additional time needed to complete the studies and submit a supplemental application. The requested extension shall not exceed an additional 24 months.

(c) The manufacturer shall send three copies of the request for extension to the same FDA office that received the manufacturer's initial submission and certification statement. The outside of the envelope shall be marked as "Request for Time Extension-Dissemination of Information on an Unapproved Use.'

§ 99.205 Application for exemption from the requirement to file a supplemental application.

(a) In certain circumstances, described in paragraph (b) of this section, a manufacturer may submit an application for an exemption from the requirement to submit a supplemental application for a new use for purposes of disseminating information on that use.

(b) The manufacturer's application for an exemption shall identify the basis for the proposed exemption and shall include materials demonstrating that it would be economically prohibitive or that it would be unethical to conduct the studies necessary to submit a supplemental application for the

new use.

(1) If the basis for the manufacturer's application for exemption is that it would be economically prohibitive to incur the costs necessary to submit a supplemental application for a new use, the manufacturer shall, at a minimum, provide:

(i) Evidence explaining why existing data characterizing the safety and effectiveness of the drug or device, including data from the study described in the information to be disseminated, are not adequate to support the submission of a supplemental application for the new use. Such evidence shall include an analysis of all data relevant to the safety and effectiveness of the use, a summary of those data, and any documentation resulting from prior discussions with the agency concerning the adequacy of the existing data; and

(ii) Evidence demonstrating that the cost of the study or studies for the new use reasonably exceeds the expected revenue from the new use minus the costs of goods sold and marketing and administrative expenses attributable to the new use of the product. Such evidence shall include:

(A) A description of the additional studies that the manufacturer believes are necessary to support the submission of a supplemental application for the new use, including documentation from prior discussions, if any, with the agency concerning the studies that would be needed, and an estimate of the projected costs for such studies;

(B) The expected patient population for the new use;

(C) The expected revenue for the new use, including an explanation of the price at which the drug or device will be sold;

(D) Any exclusivity for the drug or device for the new use; and

(E) Any other information that the manufacturer has showing that conducting the studies on the new use would be economically prohibitive; and

(iii) An attestation by a responsible individual of the manufacturer or an individual acting on the manufacturer's behalf verifying that the estimates included with the submission are accurate and were prepared in accordance with generally accepted accounting procedures. The data underlying and supporting the estimates shall be made available to FDA upon request. Alternatively, a manufacturer may submit a report of an independent certified public accountant in accordance with the Statement of Standards for Attestation established by the American Institute of Certified Public Accountants and agreed upon procedures performed with respect to the estimates submitted under this section.

(2) If the basis for the manufacturer's application for exemption is that it would be unethical to conduct the studies necessary for the supplemental application for a new use, the manufacturer shall provide evidence:

(i) Explaining why existing data characterizing the safety and effectiveness of the drug or device, including data from the study described in the information to be disseminated, are not adequate to support the submission of a supplemental application for the new use. Such evidence shall include an analysis of all data relevant to the safety and effectiveness of the new use, a summary of those data, and any documentation resulting from prior discussions with the agency concerning the adequacy of the existing data; and

(ii) Explaining why it would be unethical to conduct the further studies that would be necessary for the approval of the new use. Such evidence shall establish that, notwithstanding the insufficiency of available data to support the submission of a supplemental application for the new use, the data are persuasive to the extent that withholding the drug or device in a

controlled study (e.g., by providing no therapy, a placebo, an alternative therapy, or an alternative dose) would pose an unreasonable risk of harm to human subjects. In assessing the appropriateness of conducting studies to support the new use, the manufacturer may provide evidence showing that the new use is broadly accepted as current standard medical treatment or therapy. The manufacturer shall also address the possibility of conducting studies in different populations or of modified design (e.g., adding the new therapy to existing treatments using an alternative dose if monotherapy studies could not be conducted).

or

Subpart D-FDA Action on Submissions, Requests, and Applications

§ 99.301 Agency action on a submission.

(a) Submissions. Within 60 days after receiving a submission under this part, FDA may:

(1) Determine that the manufacturer does not comply with the requirements under this part and that, as a result, the manufacturer shall not disseminate any information under this part;

(2) After providing the manufacturer notice and an opportunity for a meeting, determine that the information submitted regarding a new use fails to provide data, analyses, or other written matter that is objective and balanced and:

(i) Require the manufacturer to disseminate additional information, including information that the manufacturer has submitted to FDA or, where appropriate, a summary of such information or any other information that can be made publicly available, which, in the agency's opinion:

(A) Is objective and scientifically sound;

(B) Pertains to the safety or effectiveness of the new use; and

(C) Is necessary to provide objectivity and balance; and

(ii) Require the manufacturer to disseminate an objective statement prepared by FDA that is based on data or other scientifically sound information available to the agency and bears on

197-062 D-16

the safety or effectiveness of the drug or device for the new use; and

to

(3) Require the manufacturer maintain records that will identify individual recipients of the information that is to be disseminated when such individual records are warranted due to special safety considerations associated with the new use.

(b) Protocols/Studies. Within 60 days after receiving a submission under this part, FDA shall:

(1) If the manufacturer has planned studies that will be needed for the submission of a supplemental application for the new use, review the manufacturer's proposed protocols and schedule for completing such studies and determine whether the proposed protocols are adequate and whether the proposed schedule for completing the studies is reasonable. FDA shall notify the manufacturer of its determination; or

(2) If the manufacturer has completed studies that the manufacturer believes would be an adequate basis for the submission of a supplemental application for the new use, conduct a review of the protocols submitted for such studies to determine whether they are adequate. FDA shall notify the manufacturer of its determination.

§ 99.303 Extension of time for completing planned studies.

(a) Upon review of a drug or device manufacturer's proposed protocols and schedules for conducting studies needed for the submission of a supplemental application for a new use, FDA may, with or without a request for an extension from the manufacturer, determine that such studies cannot be completed and submitted within 36 months. The agency may exercise its discretion in extending the time period for completing the studies and submitting a supplemental application. Extensions under this paragraph are not subject to any time limit, but shall be made before the manufacturer begins the studies needed for the submission of a supplemental application for the new use.

(b) The manufacturer may, after beginning the studies needed for the submission of a supplemental application for a new use, request in writing that FDA extend the time period for conducting studies needed for the submis

sion of a supplemental application for a new use and submitting a supplemental application to FDA. FDA may grant or deny the request or, after consulting the manufacturer, grant an extension different from that requested by the manufacturer. FDA may grant a manufacturer's request for an extension if FDA determines that the manufacturer has acted with due diligence to conduct the studies needed for the submission of a supplemental application for a new use and to submit such a supplemental application to FDA in a timely manner and that, despite such actions, the manufacturer needs additional time to complete the studies and submit the supplemental application. Extensions under this paragraph shall not exceed 24 months.

(c) If FDA extends the time period for completing the studies and submitting a supplemental application under paragraph (a) of this section after the manufacturer has submitted a certification under $99.201(a)(4)(ii)(B), or if FDA grants a manufacturer's request for an extension under paragraph (b) of this section, the manufacturer shall submit certification under § 99.201(a)(4)(ii)(B) that sets forth the timeframe within which clinical studies will be completed and a supplemental application will be submitted to FDA.

a

new

§ 99.305 Exemption from the_requirement to file a supplemental application.

(a) Within 60 days after receipt of an application for an exemption from the requirement of a supplemental application, FDA shall approve or deny the application.

(1) If FDA does not act on the application for an exemption within the 60day period, the application for an exemption shall be deemed to be approved.

(2) If an application for an exemption is deemed to be approved, FDA may, at any time, terminate such approval if it determines that the requirements for granting an exemption have not been met. FDA shall notify the manufacturer if the approval is terminated.

(b) In reviewing an application for an exemption, FDA shall consider the materials submitted by the manufacturer

(i) That existing data characterizing the safety and effectiveness of the drug or device, including data from the study described in the information to be disseminated are not adequate to support the submission of a supplemental application for the new use; and (ii) That the cost of the study or studies for the new use reasonably exceeds the expected revenue from the new use minus the cost of goods sold and marketing and administrative expenses attributable to the new use of the product, and there are not less expensive ways to obtain the needed information; or

(2) It would be unethical to conduct clinical studies needed to support the submission of a supplemental application for the new use because:

(i) Existing data characterizing the safety and effectiveness of the drug or device, including data from the study described in the information to be disseminated are not adequate to support the submission of a supplemental application for the new use; and

(ii) Although available evidence would not support the submission of a supplemental application for the new use, the data are persuasive to the extent that withholding the drug or device in a controlled study would pose an unreasonable risk of harm to human subjects and no studies in different populations or of modified design can be utilized. In determining whether it would be unethical to conduct clinical studies, the agency shall consider, in addition to the persuasiveness of available evidence of effectiveness, whether the new use of the drug or device is broadly accepted as current standard medical treatment or therapy.

Subpart E-Corrective Actions and Cessation of Dissemination

ces

§ 99.401 Corrective actions and sation of dissemination of information.

(a) FDA actions based on post dissemination data. If FDA receives data after a manufacturer has begun disseminating information on a new use and, based on that data, determines that the new use that is the subject of information disseminated under this part may not be effective or may present a significant risk to public health, FDA shall consult the manufacturer and, after such consultation, take appropriate action to protect the public health. Such action may include ordering the manufacturer to cease disseminating information on the new use and to take appropriate corrective action.

(b) FDA actions based on information disseminated by a manufacturer. If FDA determines that a manufacturer is disseminating information that does not comply with the requirements under this part, FDA may:

(1) Provide to the manufacturer an opportunity to bring itself into compliance with the requirements under this part if the manufacturer's noncompliance constitutes a minor violation of these requirements; or

(2) Order the manufacturer to cease dissemination of information and to take corrective action. FDA shall issue such an order only after it has:

(i) Provided notice to the manufacturer regarding FDA's intent to issue an order to cease dissemination; and

(ii) Provided to the manufacturer an opportunity for a meeting. FDA need not provide an opportunity for a meeting if the manufacturer certified that it will submit a supplemental application for the new use within 6 months of the date that dissemination can begin and the noncompliance involves a failure to submit such supplemental application.

(c) FDA actions based on a manufacturer's supplemental application. FDA may order a manufacturer to cease disseminating information under this part and to take corrective action if:

(1) In the case of a manufacturer that has submitted a supplemental application for the new use, FDA determines

that the supplemental application does not contain adequate information for approval of the new use;

(2) In the case of a manufacturer that has certified that it will submit a supplemental application for the new use within 6 months, the manufacturer has not, within the 6-month period, submitted a supplemental application for the new use;

(3) In the case of a manufacturer that has certified that it will submit a supplemental application for the new use Iwithin 36 months or within such time as FDA has determined to be appropriate under § 99.303(a) or (b), such manufacturer has not submitted the supplemental application within the certified time, or FDA, after an informal hearing, has determined that the manufacturer is not acting with due diligence to initiate or complete the studies necessary to support a supplemental application for the new use; or

(4) In the case of a manufacturer that has certified that it will submit a supplemental application for the new use within 36 months or within such time as FDA has determined to be appropriate under § 99.303(a) or (b), the manufacturer has discontinued or terminated the clinical studies that would be necessary to support a supplemental application for a new use.

(d) Effective date of orders to cease dissemination. An order to cease dissemination of information shall be effective upon date of receipt by the manufacturer, unless otherwise stated in such order.

(e) Cessation of dissemination by a noncomplying manufacturer. A manufacturer that begins to disseminate information in compliance with this part, but subsequently fails to comply with this part, shall immediately cease disseminating information under this part. A manufacturer that discontinues, terminates, or fails to conduct with due diligence clinical studies that it certified it would complete under § 99.201(a)(4)(ii) shall be deemed not in compliance with this part. A manufacturer shall notify FDA immediately if it ceases dissemination under this paragraph.

§ 99.403 Termination of approvals of applications for exemption.

(a) FDA may, at any time, terminate the approval of an application for an exemption from the requirement to file a supplemental application if:

(1) The application for an exemption had been deemed to be approved because the agency had not acted on the application within 60 days after its receipt by FDA;

(2) The manufacturer is disseminating written information on the new use; and

(3) FDA determines that it would be economically and ethically possible for the manufacturer to conduct the clinical studies needed to submit a supplemental application for the new use.

(b) If FDA terminates a deemed approval of an application for an exemption under paragraph (a) of this section, FDA also may:

(1) Order the manufacturer to cease disseminating information; and

(2) Order the manufacturer to take action to correct the information that has been disseminated if FDA determines that the new use described in the disseminated information would pose a significant risk to public health.

(c) FDA shall notify the manufacturer if it terminates the deemed approval of an application for an exemption under paragraph (a) of this section. If FDA also issues an order to cease dissemination of information, the manufacturer shall comply with the order no later than 60 days after its receipt.

(d) FDA may, at any time, terminate the approval of an application for an exemption from the requirement to file a supplemental application for a new use if, after consulting with the manufacturer that was granted such exemption, FDA determines that the manufacturer no longer meets the requirements for an exemption on the basis that it is economically prohibitive or unethical to conduct the studies needed to submit a supplemental application for the new use.

(e) If FDA terminates an approval of an application for an exemption under paragraph (d) of this section, the manufacturer must, within 60 days of being