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U.S. Department of Health and Human Services

CFR - Code of Federal Regulations Title 21

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The information on this page is current as of April 1 2018.

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[Code of Federal Regulations]
[Title 21, Volume 1]
[Revised as of April 1, 2018]
[CITE: 21CFR99]





TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER A--GENERAL
 
PART 99DISSEMINATION OF INFORMATION ON UNAPPROVED/NEW USES FOR MARKETED DRUGS, BIOLOGICS, AND DEVICES
 

Subpart A--General Information

Sec. 99.1 Scope.

(a) This part applies to the dissemination of information on human drugs, including biologics, and devices where the information to be disseminated:

(1) Concerns the safety, effectiveness, or benefit of a use that is not included in the approved labeling for a drug or device approved by the Food and Drug Administration for marketing or in the statement of intended use for a device cleared by the Food and Drug Administration for marketing; and

(2) Will be disseminated to a health care practitioner, pharmacy benefit manager, health insurance issuer, group health plan, or Federal or State Government agency.

(b) This part does not apply to a manufacturer's dissemination of information that responds to a health care practitioner's unsolicited request.

Sec. 99.3 Definitions.

(a) Agency or FDA means the Food and Drug Administration.

(b) For purposes of this part, a clinical investigation is an investigation in humans that tests a specific clinical hypothesis.

(c) Group health plan means an employee welfare benefit plan (as defined in section 3(1) of the Employee Retirement Income Security Act of 1974 (29 U.S.C. 1002(1))) to the extent that the plan provides medical care (as defined in paragraphs (c)(1) through (c)(3) of this section and including items and services paid for as medical care) to employees or their dependents (as defined under the terms of the plan) directly or through insurance, reimbursement, or otherwise. For purposes of this part, the term medical care means:

(1) Amounts paid for the diagnosis, cure, mitigation, treatment, or prevention of disease, or amounts paid for the purpose of affecting any structure or function of the body;

(2) Amounts paid for transportation primarily for and essential to medical care referred to in paragraph (c)(1) of this section; and

(3) Amounts paid for insurance covering medical care referred to in paragraphs (c)(1) and (c)(2) of this section.

(d) Health care practitioner means a physician or other individual who is a health care provider and licensed under State law to prescribe drugs or devices.

(e) Health insurance issuer means an insurance company, insurance service, or insurance organization (including a health maintenance organization, as defined in paragraph (e)(2) of this section) which is licensed to engage in the business of insurance in a State and which is subject to State law which regulates insurance (within the meaning of section 514(b)(2) of the Employee Retirement Income Security Act of 1974 (29 U.S.C. 1144(b)(2))).

(1) Such term does not include a group health plan.

(2) For purposes of this part, the term health maintenance organization means:

(i) A Federally qualified health maintenance organization (as defined in section 1301(a) of the Public Health Service Act (42 U.S.C. 300e(a)));

(ii) An organization recognized under State law as a health maintenance organization; or

(iii) A similar organization regulated under State law for solvency in the same manner and to the same extent as such a health maintenance organization.

(f) Manufacturer means a person who manufactures a drug or device or who is licensed by such person to distribute or market the drug or device. For purposes of this part, the term may also include the sponsor of the approved, licensed, or cleared drug or device.

(g) New use means a use that is not included in the approved labeling of an approved drug or device, or a use that is not included in the statement of intended use for a cleared device.

(h) Pharmacy benefit manager means a person or entity that has, as its principal focus, the implementation of one or more device and/or prescription drug benefit programs.

(i) A reference publication is a publication that:

(1) Has not been written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer;

(2) Has not been edited or significantly influenced by such a manufacturer;

(3) Is not solely distributed through such a manufacturer, but is generally available in bookstores or other distribution channels where medical textbooks are sold;

(4) Does not focus on any particular drug or device of a manufacturer that disseminates information under this part and does not have a primary focus on new uses of drugs or devices that are marketed or are under investigation by a manufacturer supporting the dissemination of information; and

(5) Does not present materials that are false or misleading.

(j) Scientific or medical journal means a scientific or medical publication:

(1) That is published by an organization that has an editorial board, that uses experts who have demonstrated expertise in the subject of an article under review by the organization and who are independent of the organization, to review and objectively select, reject, or provide comments about proposed articles, and that has a publicly stated policy, to which the organization adheres, of full disclosure of any conflict of interest or biases for all authors or contributors involved with the journal or organization;

(2) Whose articles are peer-reviewed and published in accordance with the regular peer-review procedures of the organization;

(3) That is generally recognized to be of national scope and reputation;

(4) That is indexed in the Index Medicus of the National Library of Medicine of the National Institutes of Health; and

(5) That is not in the form of a special supplement that has been funded in whole or in part by one or more manufacturers.

(k) Supplemental application means:

(1) For drugs, a supplement to support a new use to an approved new drug application;

(2) For biologics, a supplement to an approved license application;

(3) For devices that are the subject of a cleared 510(k) submission and devices that are exempt from the 510(k) process, a new 510(k) submission to support a new use or, for devices that are the subject of an approved premarket approval application, a supplement to support a new use to an approved premarket approval application.

Subpart B--Information To Be Disseminated

Sec. 99.101 Information that may be disseminated.

(a) A manufacturer may disseminate written information concerning the safety, effectiveness, or benefit of a use not described in the approved labeling for an approved drug or device or in the statement of intended use for a cleared device, provided that the manufacturer complies with all other relevant requirements under this part. Such information shall:

(1) Be about a drug or device that has been approved, licensed, or cleared for marketing by FDA;

(2) Be in the form of:

(i) An unabridged reprint or copy of an article, peer-reviewed by experts qualified by scientific training or experience to evaluate the safety or effectiveness of the drug or device involved, which was published in a scientific or medical journal. In addition, the article must be about a clinical investigation with respect to the drug or device and must be considered to be scientifically sound by the experts described in this paragraph; or

(ii) An unabridged reference publication that includes information about a clinical investigation with respect to the drug or device, which experts qualified by scientific training or experience to evaluate the safety or effectiveness of the drug or device that is the subject of the clinical investigation would consider to be scientifically sound;

(3) Not pose a significant risk to the public health;

(4) Not be false or misleading. FDA may consider information disseminated under this part to be false or misleading if, among other things, the information includes only favorable publications when unfavorable publications exist or excludes articles, reference publications, or other information required under 99.103(a)(4) or the information presents conclusions that clearly cannot be supported by the results of the study; and

(5) Not be derived from clinical research conducted by another manufacturer unless the manufacturer disseminating the information has the permission of such other manufacturer to make the dissemination.

(b) For purposes of this part:

(1) FDA will find that all journal articles and reference publications (as those terms are defined in 99.3) are scientifically sound except:

(i) Letters to the editor;

(ii) Abstracts of a publication;

(iii) Those regarding Phase 1 trials in healthy people;

(iv) Flagged reference publications that contain little or no substantive discussion of the relevant clinical investigation; and

(v) Those regarding observations in four or fewer people that do not reflect any systematic attempt to collect data, unless the manufacturer demonstrates to FDA that such reports could help guide a physician in his/her medical practice.

(2) A reprint or copy of an article or reference publication is "unabridged" only if it retains the same appearance, form, format, content, or configuration as the original article or publication. Such reprint, copy of an article, or reference publication shall not be disseminated with any information that is promotional in nature. A manufacturer may cite a particular discussion about a new use in a reference publication in the explanatory or other information attached to or otherwise accompanying the reference publication under 99.103.

Sec. 99.103 Mandatory statements and information.

(a) Any information disseminated under this part shall include:

(1) A prominently displayed statement disclosing:

(i) For a drug, "This information concerns a use that has not been approved by the Food and Drug Administration." For devices, the statement shall read, "This information concerns a use that has not been approved or cleared by the Food and Drug Administration." If the information to be disseminated includes both an approved and unapproved use or uses or a cleared and uncleared use or uses, the manufacturer shall modify the statement to identify the unapproved or uncleared new use or uses. The manufacturer shall permanently affix the statement to the front of each reprint or copy of an article from a scientific or medical journal and to the front of each reference publication disseminated under this part;

(ii) If applicable, the information is being disseminated at the expense of the manufacturer;

(iii) If applicable, the names of any authors of the information who were employees of, or consultants to, or received compensation from the manufacturer, or who had a significant financial interest in the manufacturer during the time that the study that is the subject of the dissemination was conducted up through 1 year after the time the article/reference publication was written and published;

(iv) If applicable, a statement that there are products or treatments that have been approved or cleared for the use that is the subject of the information being disseminated; and

(v) The identification of any person that has provided funding for the conduct of a study relating to the new use of a drug or device for which such information is being disseminated; and

(2) The official labeling for the drug or device;

(3) A bibliography of other articles (that concern reports of clinical investigations both supporting and not supporting the new use) from a scientific reference publication or scientific or medical journal that have been previously published about the new use of the drug or device covered by the information that is being disseminated, unless the disseminated information already includes such a bibliography; and

(4) Any additional information required by FDA under 99.301(a)(2). Such information shall be attached to the front of the disseminated information or, if attached to the back of the disseminated information, its presence shall be made known to the reader by a sticker or notation on the front of the disseminated information and may consist of:

(i) Objective and scientifically sound information pertaining to the safety or effectiveness of the new use of the drug or device and which FDA determines is necessary to provide objectivity and balance. This may include information that the manufacturer has submitted to FDA or, where appropriate, a summary of such information and any other information that can be made publicly available; and

(ii) An objective statement prepared by FDA, based on data or other scientifically sound information, bearing on the safety or effectiveness of the new use of the drug or device.

(b) Except as provided in paragraphs (a)(1)(i) and (a)(4) of this section, the statements, bibliography, and other information required by this section shall be attached to such disseminated information.

(c) For purposes of this section, factors to be considered in determining whether a statement is "prominently displayed" may include, but are not limited to, type size, font, layout, contrast, graphic design, headlines, spacing, and any other technique to achieve emphasis or notice. The required statements shall be outlined, boxed, highlighted, or otherwise graphically designed and presented in a manner that achieves emphasis or notice and is distinct from the other information being disseminated.

Sec. 99.105 Recipients of information.

A manufacturer disseminating information on a new use under this part may only disseminate that information to a health care practitioner, a pharmacy benefit manager, a health insurance issuer, a group health plan, or a Federal or State Government agency.

Subpart C--Manufacturer's Submissions, Requests, and Applications

Sec. 99.201 Manufacturer's submission to the agency.

(a) Sixty days before disseminating any written information concerning the safety, effectiveness, or benefit of a new use for a drug or device, a manufacturer shall submit to the agency:

(1) An identical copy of the information to be disseminated, including any information (e.g., the bibliography) and statements required under 99.103;

(2) Any other clinical trial information which the manufacturer has relating to the effectiveness of the new use, any other clinical trial information that the manufacturer has relating to the safety of the new use, any reports of clinical experience pertinent to the safety of the new use, and a summary of such information. For purposes of this part, clinical trial information includes, but is not limited to, published papers and abstracts, even if not intended for dissemination, and unpublished manuscripts, abstracts, and data analyses from completed or ongoing investigations. The reports of clinical experience required under this paragraph shall include case studies, retrospective reviews, epidemiological studies, adverse event reports, and any other material concerning adverse effects or risks reported for or associated with the new use. If the manufacturer has no knowledge of clinical trial information relating to the safety or effectiveness of the new use or reports of clinical experience pertaining to the safety of the new use, the manufacturer shall provide a statement to that effect;

(3) An explanation of the manufacturer's method of selecting the articles for the bibliography (e.g., the databases or sources and criteria (i.e., subject headings/keywords) used to generate the bibliography and the time period covered by the bibliography); and

(4) If the manufacturer has not submitted a supplemental application for the new use, one of the following:

(i) If the manufacturer has completed studies needed for the submission of a supplemental application for the new use:

(A) A copy of the protocol for each completed study or, if such protocol was submitted to an investigational new drug application or an investigational device exemption, the number(s) for the investigational new drug application or investigational device exemption covering the new use, the date of submission of the protocol(s), the protocol number(s), and the date of any amendments to the protocol(s); and

(B) A certification stating that, "On behalf of [insert manufacturer's name], I certify that [insert manufacturer's name] has completed the studies needed for the submission of a supplemental application for [insert new use] and will submit a supplemental application for such new use to the Food and Drug Administration no later than [insert date no later than 6 months from date that dissemination of information under this part can begin]"; or

(ii) If the manufacturer has planned studies that will be needed for the submission of a supplemental application for the new use:

(A) The proposed protocols and schedule for conducting the studies needed for the submission of a supplemental application for the new use. The protocols shall comply with all applicable requirements in parts 312 of this chapter (investigational new drug applications) and 812 of this chapter (investigational device exemptions). The schedule shall include the projected dates on which the manufacturer expects the principal study events to occur (e.g., initiation and completion of patient enrollment, completion of data collection, completion of data analysis, and submission of the supplemental application); and

(B) A certification stating that, "On behalf of [insert manufacturer's name], I certify that [insert manufacturer's name] will exercise due diligence to complete the clinical studies necessary to submit a supplemental application for [insert new use] and will submit a supplemental application for such new use to the Food and Drug Administration no later than [insert date no later than 36 months from date that dissemination of information under this part can begin or no later than such time period as FDA may specify pursuant to an extension granted under 99.303(a)];" or

(iii) An application for exemption from the requirement of a supplemental application; or

(5) If the manufacturer has submitted a supplemental application for the new use, a cross-reference to that supplemental application.

(b) The manufacturer's attorney, agent, or other authorized official shall sign the submission and certification statement or application for exemption. If the manufacturer does not have a place of business in the United States, the submission and certification statement or application for exemption shall contain the signature, name, and address of the manufacturer's attorney, agent, or other authorized official who resides or maintains a place of business in the United States.

(c) The manufacturer shall send three copies of the submission and certification statement or application for exemption to FDA. The outside of the shipping container shall be marked as "Submission for the Dissemination of Information on an Unapproved/New Use." The manufacturer shall send the submission and certification statement or application for exemption to the appropriate FDA component listed in paragraphs (c)(1) through (c)(3) of this section.

(1) For biological products and devices regulated by the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002;

(2) For human drug products, biological products, and devices regulated by the Center for Drug Evaluation and Research, the Division of Drug Marketing, Advertising, and Communications (HFD-42), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857; or

(3) For medical devices, the Promotion and Advertising Policy Staff (HFZ-302), Office of Compliance, Center for Devices and Radiological Health, Food and Drug Administration, 2098 Gaither Rd., Rockville, MD 20850.

(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.

[63 FR 64581, Nov. 20, 1998, as amended at 70 FR 14980, Mar. 24, 2005; 80 FR 18090, Apr. 3, 2015]

Sec. 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."

Sec. 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 or using an alternative dose if monotherapy studies could not be conducted).

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

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

(3) Require the manufacturer to 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.

Sec. 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 submission 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 a new 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.

Sec. 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 60-day 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 and may consider any other appropriate information, including, but not limited to, any pending or previously approved applications for exemption submitted by the manufacturer.

(c) FDA may grant an application for an exemption if FDA determines that:

(1) It would be economically prohibitive for the manufacturer to incur the costs necessary to submit a supplemental application for a new use, which at a minimum requires:

(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

Sec. 99.401 Corrective actions and cessation 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 within 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.

Sec. 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 notified by FDA that its exemption approval has been terminated, file a supplemental application for the new use that is the subject of the information being disseminated under the exemption, certify, under 99.201(a)(4)(i) or (a)(4)(ii) that it will file a supplemental application for the new use, or cease disseminating the information on the new use. FDA may require a manufacturer that ceases dissemination of information on the new use to undertake corrective action.

Sec. 99.405 Applicability of labeling, adulteration, and misbranding authority.

The dissemination of information relating to a new use for a drug or device may constitute labeling, evidence of a new intended use, adulteration, or misbranding of the drug or device if such dissemination fails to comply with section 551 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360aaa) and the requirements of this part. A manufacturer's failure to exercise due diligence in submitting the clinical studies that are necessary for the approval of a new use that is the subject of information disseminated under this part or in beginning or completing such clinical studies shall be deemed a failure to comply with section 551 of the act and the requirements of this part.

Subpart F--Recordkeeping and Reports

Sec. 99.501 Recordkeeping and reports.

(a) A manufacturer disseminating information under this part shall:

(1) Maintain records sufficient to allow the manufacturer to take corrective action as required by FDA. The manufacturer shall make such records available to FDA, upon request, for inspection and copying. Such records shall either:

(i) Identify, by name, those persons receiving the disseminated information; or

(ii) Identify, by category, the recipients of the disseminated information, unless FDA requires the manufacturer to retain records identifying individual recipients of the disseminated information. Manufacturers whose records identify recipients by category only shall:

(A) Identify subcategories of recipients where appropriate (e.g., oncologists, pediatricians, obstetricians, etc.); and

(B) Ensure that any corrective action to be taken will be sufficiently conspicuous to individuals within that category of recipients;

(2) Maintain an identical copy of the information disseminated under this part; and

(3) Upon the submission of a supplemental application to FDA, notify the appropriate office identified in 99.201(c) of this part.

(b) A manufacturer disseminating information on a new use for a drug or device shall, on a semiannual basis, submit to the FDA office identified in 99.201(c) of this part:

(1) A list containing the titles of articles and reference publications relating to the new use of drugs or devices that the manufacturer disseminated to a health care practitioner, pharmacy benefit manager, health insurance issuer, group health plan, or Federal or State Government agency. The list shall cover articles and reference publications disseminated in the 6-month period preceding the date on which the manufacturer provides the list to FDA;

(2) A list identifying the categories of health care practitioners, pharmacy benefit managers, health insurance issuers, group health plans, or Federal or State Government agencies that received the articles and reference publications in the 6-month period described in paragraph (b)(1) of this section. The list shall also identify which category of recipients received a particular article or reference publication;

(3) A notice and summary of any additional clinical research or other data relating to the safety or effectiveness of the new use, and, if the manufacturer possesses such clinical research or other data, a copy of the research or data. Such other data may include, but is not limited to, new articles published in scientific or medical journals, reference publications, and summaries of adverse effects that are or may be associated with the new use;

(4) If the manufacturer is conducting studies necessary for the submission of a supplemental application, the manufacturer shall submit periodic progress reports on these studies to FDA. Such reports shall describe the studies' current status (i.e., progress on patient enrollment, any significant problems that could affect the manufacturer's ability to complete the studies, and expected completion dates). If the manufacturer discontinues or terminates a study before completing it, the manufacturer shall, as part of the next periodic progress report, state the reasons for such discontinuation or termination; and

(5) If the manufacturer was granted an exemption from the requirements to submit a supplemental application for the new use, any new or additional information that relates to whether the manufacturer continues to meet the requirements for such exemption. This information may include, but is not limited to, new or additional information regarding revenues from the product that is the subject of the dissemination and new or additional information regarding the persuasiveness of the data on the new use, including information regarding whether the new use is broadly accepted as current standard medical treatment or therapy.

(c) A manufacturer shall maintain a copy of all information, lists, records, and reports required or disseminated under this part for 3 years after it has ceased dissemination of such information and make such documents available to FDA for inspection and copying.

Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360c, 360e, 360aa-360aaa-6, 371, and 374; 42 U.S.C. 262.
Source: 63 FR 64581, Nov. 20, 1998, unless otherwise noted.

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