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(i) There is insufficient evidence to support the estimate that the disease or condition for which the device is designed to treat or diagnose affects or is manifested in fewer than 4,000 people in the United States per year;

(ii) FDA determines that, for a diagnostic device, 4,000 or more patients in the United States would be subjected to diagnosis using the device per year;

or

(iii) FDA determines that the patient population defined in the request is not a medically plausible subset of a larger population.

(c) Revocation of designation. FDA may revoke a HUD gn if the agency finds that:

(1) The request for designation contained an untrue statement of material fact or omitted material information;

or

(2) Based on the evidence available, the device is not eligible for HUD designation.

(d) Submission. The applicant shall submit two copies of a completed, dated, and signed request for HUD designation to: Office of Orphan Products Development (HF-35), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

able to treat or diagnose the disease or condition. The application also shall contain a discussion of the risks and benefits of currently available devices or alternative forms of treatment in the United States;

(3) An explanation of why the probable benefit to health from the use of the device outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Such explanation shall include a description, explanation, or theory of the underlying disease process or condition, and known or postulated mechanism(s) of action of the device in relation to the disease process or condition;

(4) All of the information required to be submitted under $814.20(b), except that:

(i) In lieu of the summaries, conclusions, and results from clinical investigations required

under 88 814.20(b)(3)(v)(B), (b)(3)(vi), and (b)(6)(ii), the applicant shall include the summaries, conclusions, and results of all clinical experience or investigations (whether adverse or supportive) reasonably obtainable by the applicant that are relevant to an assessment of the risks and probable benefits of the device; and

(ii) In addition to the proposed labeling requirement set forth in $814.20(b)(10), the labeling shall bear the following statement: Humanitarian Device. Authorized by Federal law for use in the [treatment or diagnosis) of [specify disease or condition). The effectiveness of this device for this use has not been demonstrated; and

(5) The amount to be charged for the device and, if the amount is more than $250, a report by an independent certified public accountant, made in accordance with the Statement on Standards for Attestation established by the American Institute of Certified Public Accountants, or in lieu of such a report, an attestation by a responsible individual of the organization, verifying that the amount charged does not exceed the costs of the device's research, development, fabrication, and distribution. If the amount charged is $250 or less, the requirement for a report by an independent certified public

$814.104 Original applications.

(a) United States applicant or representative. The applicant or an authorized representative shall sign the HDE. If the applicant does not reside or have a place of business within the United States, the HDE shall be countersigned by an authorized representative residing or maintaining a place of business in the United States and shall identify the representative's name and address.

(b) Contents. Unless the applicant justifies an omission in accordance with paragraph (d) of this section, an HDE shall include:

(1) A copy of or reference to the determination made by FDA's Office of Orphan Products Development (in accordance with $814.102) that the device qualifies as a HUD;

(2) An explanation of why the device would not be available unless an HDE were granted and a statement that no comparable device (other than another HUD approved under this subpart or a device under an approved IDE) is avail

ments for PMA's under $814.39, except that a request for a new indication for use of a HUD shall comply with requirements set forth in 8814.110. The timeframes for review of, and FDA action on, an HDE supplement are the same as those provided in $814.114 for an HDE.

[63 FR 59220, Nov. 3, 1998]

accountant or an attestation by a responsible individual of the organization is waived.

(c) Omission of information. If the applicant believes that certain information required under paragraph (b) of this section is not applicable to the device that is the subject of the HDE, and omits any such information from its HDE, the applicant shall submit a statement that identifies and justifies the omission. The statement shall be submitted as a separate section in the HDE and identified in the table of contents. If the justification for the omission is not accepted by the agency, FDA will so notify the applicant.

(d) Address for submissions and correspondence. Copies of all original HDE's, amendments and supplements, as well as any correspondence relating to an HDE, shall be sent or delivered to the Document Mail Center (HFZ-401), Office of Device Evaluation, Center for Devices and Radiological Health, Food and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850. [61 FR 33244, June 26, 1996, as amended at 63 FR 59220, Nov. 3, 1998]

$814.110 New indications for use.

(a) An applicant seeking a new indication for use of a HUD approved under this subpart H shall obtain a new designation of HUD status in accordance with $814.102 and shall submit an original HDE in accordance with $814.104.

(b) An application for a new indication for use made under $814.104 may incorporate by reference any information or data previously submitted to the agency under an HDE.

$ 814.106 HDE amendments and resub

mitted HDE's. An HDE or HDE supplement may be amended or resubmitted upon an applicant's own initiative, or at the request of FDA, for the same reasons and in the same manner as prescribed for PMA's in $814.37, except that the timeframes set forth in $814.37(c)(1) and (d) do not apply. If FDA requests an HDE applicant to submit an HDE amendment, and a written response to FDA's request is not received within 75 days of the date of the request, FDA will consider the pending HDE or HDE supplement to be withdrawn voluntarily by the applicant. Furthermore, if the HDE applicant, on its own initiative or at FDA's request, submits a major amendment

described in $814.37(c)(1), the review period may be extended up to 75 days. [63 FR 59220, Nov. 3, 1998]

8814.112 Filing an HDE.

(a) The filing of an HDE means that FDA has made a threshold determination that the application is sufficiently complete to permit substantive review. Within 30 days from the date an HDE is received by FDA, the agency will notify the applicant whether the application has been filed. FDA may refuse to file an HDE if any of the following applies:

(1) The application is incomplete because it does not on its face contain all the information required under $ 814.104(b);

(2) FDA determines that there is a comparable device available (other than another HUD approved under this subpart or a device under an approved IDE) to treat or diagnose the disease or condition for which approval of the HUD is being sought; or

(3) The application contains an untrue statement of material fact or omits material information.

(4) The HDE is not accompanied by a statement of either certification or disclosure, or both, as required by part 54 of this chapter.

(b) The provisions contained in $814.42(b), (c), and (d) regarding notification of filing decisions, filing dates, the start of the 75-day review period, and applicant's options in response to

as

8814.108 Supplemental applications.

After FDA approval of an original HDE, an applicant shall submit supplements in accordance with the require

FDA refuse to file decisions shall apply to HDE's.

[61 FR 33244, June 26, 1996, as amended at 63 FR 5254, Feb. 2, 1998; 63 FR 59221, Nov. 3, 1998]

$814.114 Timeframes for reviewing an

HDE. Within 75 days after receipt of an HDE that is accepted for filing and to which the applicant does not submit a major amendment, FDA shall send the applicant an approval order, an approvable letter, a not approvable letter (under $814.116), or an order denying approval (under $814.118).

(63 FR 59221, Nov. 3, 1998]

$814.116 Procedures for review of an

HDE. (a) Substantive review. FDA will begin substantive review of an HDE after the HDE is accepted for filing under $814.112. FDA may refer an original HDE application to a panel on its own initiative, and shall do so upon the request of an applicant, unless FDA determines that the application substantially duplicates information previously reviewed by a panel. If the HDE is referred to a panel, the agency shall follow the procedures set forth under $814.44, with the exception that FDA will complete its review of the HDE and the advisory committee report and recommendations within 75 days from receipt of an HDE that is accepted for filing under $814.112 or the date of filing as determined under $814.106, whichever is later. Within the later of these two timeframes, FDA will issue an approval order under paragraph (b) of this section, an approvable letter under paragraph (c) of this section, a not approvable letter under paragraph (d) of this section, or an order denying approval of the application under $814.118(a).

(b) Approval order. FDA will issue to the applicant an order approving an HDE if none of the reasons in $814.118 for denying approval of the application applies. FDA will approve an application on the basis of draft final labeling if the only deficiencies in the application concern editorial or similar minor deficiencies in the draft final labeling. Such approval will be conditioned upon the applicant incorporating the speci

fied labeling changes exactly as directed and upon the applicant submitting to FDA a copy of the final printed labeling before marketing. The notice of approval of an HDE will be published in the FEDERAL REGISTER in accordance with the rules and policies applicable to PMA'S submitted under $814.20. Following the issuance of an approval order, data and information in the HDE file will be available for public disclosure in accordance with 8 814.9(b) through (h), as applicable.

(c) Approvable letter. FDA will send the applicant an approvable letter if the application substantially meets the requirements of this subpart and the agency believes it can approve the application if specific additional information is submitted or specific conditions are agreed to by the applicant. The approvable letter will describe the information FDA requires to be provided by the applicant or the conditions the applicant is required to meet to obtain approval. For example, FDA may require as a condition to approval:

(1) The submission of certain information identified in the approvable letter, e.g., final labeling;

(2) Restrictions imposed on the device under section 520(e) of the act;

(3) Postapproval requirements as described in subpart E of this part; and

(4) An FDA inspection that finds the manufacturing facilities, methods, and controls in compliance with part 820 of this chapter and, if applicable, that verifies records pertinent to the HDE.

(d) Not approvable letter. FDA will send the applicant a not approvable letter if the agency believes that the application may not be approved for one or more of the reasons given in $ 814.118. The not approvable letter will describe the deficiencies in the application and, where practical, will identify measures required to place the HDE in approvable form. The applicant may respond to the not approvable letter in the same manner as permitted for not approvable letters for PMA's under $814.44(f), with the exception that if a major HDE amendment is submitted, the review period may be extended up to 75 days.

(e) FDA will consider an HDE to have been withdrawn voluntarily if:

(1) The applicant fails to respond in writing to a written request for an amendment within 75 days after the date FDA issues such request;

(2) The applicant fails to respond in writing to an approvable or not approvable letter within 75 days after the date FDA issues such letter; or

(3) The applicant submits a written notice to FDA that the HDE has been withdrawn. [61 FR 33244, June 26, 1996, as amended at 63 FR 59221, Nov. 3, 1998]

scribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations in part 58 of this chapter and no reason for the noncompliance is provided or, if it is. the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study:

(7) Any clinical investigation involving human subjects described in the HDE, subject to the institutional review board regulations in part 56 of this chapter or the informed consent regulations in part 50 of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected;

(8) The applicant does not permit an authorized FDA employee an opportunity to inspect at a reasonable time and in a reasonable manner the facilities and controls, and to have access to and to copy and verify all records pertinent to the application; or

(9) The device's HUD designation should be revoked in accordance with $814.102(c).

(b) If FDA issues an order denying approval of an application, the agency will comply with the same notice an) disclosure provisions required

for PMA's under $814.45(b) and (d), as applicable.

(c) FDA will issue an order denying approval of an HDE after an approvable or not approvable letter has been sen: and the applicant:

(1) Submits a requested amendment but any ground for denying approval of the application under $814.118(a) sti. applies;

(2) Notifies FDA in writing that the requested amendment will not be submitted; or

(3) Petitions for review under sectio 515(d)(3) of the act by filing a petitior in the form of a petition for reconsider ation under $10.33 of this chapter.

(d) Before issuing an order with drawing approval of an HDE, FDA wil provide the applicant with notice and an opportunity for a hearing as na quired for PMA's under $814.46(c) and

$814.118 Denial of approval or with

drawal of approval of an HDE. (a) FDA may deny approval or withdraw approval of an application if the applicant fails to meet the requirements of section 520(m) of the act or of this part, or of any condition of approval imposed by an IRB or by FDA, or any postapproval requirements imposed under $814.126. In addition, FDA may deny approval or withdraw approval of an application if, upon the basis of the information submitted in the HDE or any other information before the agency, FDA determines that:

(1) There is a lack of a showing of reasonable assurance that the device is safe under the conditions of use prescribed, recommended, or suggested in the labeling thereof;

(2) The device is ineffective under the conditions of

prescribed, recommended, or suggested in the labeling thereof;

(3) The applicant has not demonstrated that there is a reasonable basis from which to conclude that the probable benefit to health from the use of the device outweighs the risk of injury or illness, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment;

(4) The application or a report submitted by or on behalf of the applicant contains an untrue statement of material fact, or omits material information;

(5) The device's labeling does not comply with the requirements in part 801 or part 809 of this chapter;

(6) A nonclinical laboratory study that is described in the HDE and that is essential to show that the device is safe for use under the conditions pre

use

(d), and will provide the public with no- proval by the IRB located at the faciltice in accordance with $814.46(e), as ity or by a similarly constituted IRB applicable.

that has agreed to oversee such use. In (61 FR 33244, June 26, 1996, as amended at 63

such an emergency situation, the phyFR 59221, Nov. 3, 1998]

sician shall, within 5 days after the use

of the device, provide written notifica$814.120 Temporary suspension of ap

tion to the chairman of the IRB of such proval of an HDÉ.

use. Such written notification shall inAn HDE or HDE supplement may be

clude the identification of the patient temporarily suspended for the same

involved, the date on which the device reasons and in the same manner as pre

was used, and the reason for the use. scribed for PMA's in $814.47.

(b) Withdrawal of IRB approval. A

holder of an approved HDE shall notify [63 FR 59221, Nov. 3, 1998]

FDA of any withdrawal of approval for

the use of a HUD by a reviewing IRB $814.122 Confidentiality of data and information.

within 5 working days after being noti

fied of the withdrawal of approval. (a) Requirement for disclosure. The "HDE file" includes all data and infor

(61 FR 33244, June 26, 1996, as amended at 63

FR 59221, Nov. 3, 1998] mation submitted with or referenced in the HDE, any IDE incorporated into

8814.126 Postapproval requirements the HDE, any HDE amendment or sup- and reports. plement, any report submitted under $814.126, any master file, or any other

(a) An HDE approved under this subrelated submission. Any record in the

part H shall be subject to the postHDE file will be available for public approval requirements and reports set disclosure in accordance with the pro

forth under subpart E of this part, as visions of this section and part 20 of

applicable, with the exception of this chapter.

$814.82(a)(7). In addition, medical de(b) Ertent of disclosure. Disclosure by

vice reports submitted to FDA in comFDA of the existence and contents of

pliance with the requirements of part an HDE file shall be subject to the

803 of this chapter shall also be subsame rules that pertain to PMA's

mitted to the IRB of record. under $814.9(b) through (h), as applica

(b) In addition to the reports identible.

fied in paragraph (a) of this section,

the holder of an approved HDE shall $814.124 Institutional Review Board prepare and submit the following comrequirements.

plete, accurate, and timely reports: (a) IRB approval. The HDE holder is (1) Periodic reports. An HDE applicant responsible for ensuring that a HUD is required to submit reports in accordapproved under this subpart is adminis

ance with the approval order. Unless tered only in facilities having an Insti- FDA specifies otherwise, any periodic tutional Review Board (IRB)

report shall include: stituted and acting pursuant to part 56 (i) An update of the information reof this chapter, including continuing quired under $814.102(a) in a separately review of use of the device. In addition, bound volume; a HUD may be administered only if (ii) An update of the information resuch use has been approved by the IRB quired under $814.104(b)(2), (b)(3), and located at the facility or by a similarly (b)(5); constituted IRB that has agreed to (iii) The number of devices that have oversee such use and to which the local been shipped or sold since initial marIRB has deferred in a letter to the HDE keting approval under this subpart H holder, signed by the IRB chair or an and, if the number shipped or sold exauthorized designee. If, however, a phy- ceeds 4,000, an explanation and estisician in an emergency situation deter- mate of the number of devices used per mines that approval from an IRB can- patient. If a single device is used on not be obtained in time to prevent seri- multiple patients, the applicant shall ous harm or death to a patient, a HUD submit an estimate of the number of may be administered without prior ap- patients treated or diagnosed using the

con

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