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public health, the agency may, in accordance with $16.60(h) of this chapter, waive, suspend, or modify any part 16 procedure pursuant to $ 10.19 of this chapter.

(3) FDA shall deem the PMA holder's failure to request a hearing within the timeframe specified by FDA in the notice of opportunity for hearing to be a waiver.

(C) Temporary suspension order. If the PMA holder does not request a regulatory hearing or if, after the hearing, and after consideration of the administrative record of the hearing, FDA determines that there is a reasonable probability that the continued distribution of a device under an approved PMA would cause serious, adverse health consequences or death, the agency shall, under the authority of section 515(e)(3) of the act, issue an order to the PMA holder temporarily suspending approval of the PMA.

(d) Permanent withdrawal of approval of the PMA. If FDA issues an order temporarily suspending approval of a PMA, the agency shall proceed expeditiously, but within 60 days, to hold a hearing on whether to permanently withdraw approval of the PMA in accordance with section 515(e)(1) of the act and the procedures set out in $814.46.

(1) Restriction of the sale, distribution, or use of the device as provided by section 515(d)(1)(B)(ii) or 520(e) of the act.

(2) Continuing evaluation and periodic reporting on the safety, effectiveness, and reliability of the device for its intended use. FDA will state in the PMA approval order the reason or purpose for such requirement and the number of patients to be evaluated and the reports required to be submitted.

(3) Prominent display in the labeling of a device and in the advertising of any restricted device of warnings, hazards, or precautions important for the device's safe and effective use, including patient information, e.g., information provided to the patient on alternative modes of therapy and on risks and benefits associated with the use of the device.

(4) Inclusion of identification codes on the device or its labeling, or in the case of an implant, on cards given to patients if necessary to protect the public health.

(5) Maintenance of records that will enable the applicant to submit to FDA information needed to trace patients if such information is necessary to protect the public health. Under section 519(a)(4) of the act, FDA will require that the identity of any patient be disclosed in records maintained under this paragraph only to the extent required for the medical welfare of the individual, to determine the safety or effectiveness of the device, or to verify a record, report, or information submitted to the agency.

(6) Maintenance of records for specified periods of time and organization and indexing of records into identifiable files to enable FDA to determine whether there is reasonable assurance of the continued safety and effectiveness of the device.

(7) Submission to FDA at intervals specified in the approval order of periodic reports containing the information required by $814.84(b).

(8) Batch testing of the device.

(9) Such other requirements as FDA determines are necessary to provide reasonable assurance, or continued reasonable assurance, of the safety and effectiveness of the device.

[61 FR 15190, Apr. 5, 1996]

Subpart D-Administrative Review

[Reserved)

Subpart E-Postapproval

Requirements

$ 814.80 General.

A device may not be manufactured, packaged, stored, labeled, distributed, or advertised in a manner that is inconsistent with any conditions to approval specified in the PMA approval order for the device.

$814.82 Postapproval requirements.

(a) FDA may impose postapproval requirements in a PMA approval order or by regulation at the time of approval of the PMA or by regulation subsequent to approval. Postapproval requirements may include as a condition to approval of the device:

Subpart H-Humanitarian Use

Devices

SOURCE: 61 FR 33244, June 26, 1996, unless otherwise noted.

(b) An applicant shall grant to FDA access to any records and reports required under the provisions of this part, and shall permit authorized FDA employees to copy and verify such records and reports and to inspect at a reasonable time and in a reasonable manner all manufacturing facilities to verify that the device is being manufactured, stored, labeled, and shipped under approved conditions.

(c) Failure to comply with any postapproval requirement constitutes ground for withdrawal of approval of a PMA. (Approved by the Office of Management and Budget under control number 0910-0231) [51 FR 26364, July 22, 1986, as amended at 51 FR 43344, Dec. 2, 1986)

a

$814.84 Reports.

(a) The holder of an approved PMA shall comply with the requirements of part 803 and with any other requirements applicable to the device by other regulations in this subchapter or by order approving the device.

(b) Unless FDA specifies otherwise, any periodic report shall:

(1) Identify changes described in 8814.39(a) and changes required to be reported to FDA under $814.39(b).

(2) Contain a summary and bibliography of the following information not previously submitted as part of the PMA:

(i) Unpublished reports of data from any clinical investigations or nonclinical laboratory studies involving the device or related devices and known to or that reasonably should be known to the applicant.

(ii) Reports in the scientific literature concerning the device and known to or that reasonably should be known to the applicant. If, after reviewing the summary and bibliography, FDA concludes that the agency needs a copy of the unpublished or published reports, FDA will notify the applicant that copies of such reports shall be submitted. (Approved by the Office of Management and Budget under control number 0910-0231) (51 FR 26364, July 22, 1986, as amended at 51 FR 43344, Dec. 2, 1986)

8814.100 Purpose and scope.

(a) This subpart H implements section 520(m) of the act. The purpose of section 520(m) is, to the extent consistent with the protection of the public health and safety and with ethical standards, to encourage the discovery and use of devices intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the United States per year. This subpart provides procedures for obtaining:

(1) HUD designation of a medical device; and

(2) Marketing approval for the HUD notwithstanding the absence of reasonable assurance of effectiveness that would otherwise be required under sections 514 and 515 of the act.

(b) Although a HUD may also have uses that differ from the humanitarian use, applicants seeking approval of any non-HUD use shall submit a PMA as required under $814.20, or a premarket notification as required under part 807 of this chapter.

(c) Obtaining marketing approval for a HUD involves two steps:

(1) Obtaining designation of the device as a HUD from FDA's Office of Orphan Products Development, and

(2) Submitting an HDE to the Office of Device Evaluation (ODE), Center for Devices and Radiological Health (CDRH).

(d) A person granted an exemption under section 520(m) of the act shall submit periodic reports as described in $ 814.126(b).

(e) FDA may suspend or withdraw approval of an HDE after providing notice and an opportunity for an informal hearing. (61 FR 33244, June 26, 1996, as amended at 63 FR 59220, Nov. 3, 1998]

$814.102 Designation of HUD status.

(a) Request for designation. Prior to submitting an HDE application, the applicant shall submit a request for HUD

Subparts F-G [Reserved]

(2) Return the request to the applicant pending further review upon submission of additional information. This action will ensue if the request is incomplete because it does not on its face contain all of the information required under $814.102(a). Upon receipt of this additional information, the review period may be extended up to 45 days; or

(3) Disapprove the request for HUD designation based on a substantive review of the information submitted. FDA may disapprove a request for HUD designation if:

(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

designation to FDA's Office of Orphan Products Development. The request shall contain the following:

(1) A statement that the applicant requests HUD designation for a rare disease or condition or a valid subset of a disease or condition which shall be identified with specificity;

(2) The name and address of the applicant, the name of the applicant's primary contact person and/or resident agent, including title, address, and telephone number;

(3) A description of the rare disease or condition for which the device is to be used, the proposed indication or indications for use of the device, and the reasons why such therapy is needed. If the device is proposed for an indication that represents a subset of a common disease or condition, a demonstration that the subset is medically plausible should be included;

(4) A description of the device and a discussion of the scientific rationale for the use of the device for the rare disease or condition; and

(5) Documentation, with appended authoritative references,

demonstrate that the device is designed to treat or diagnose a disease or condition that affects or is manifested in fewer than 4,000 people in the United States per year. If the device is for diagnostic purposes,

the documentation must demonstrate that fewer than 4,000 patients per year would be subjected to diagnosis by the device in the United States. Authoritative references include literature citations in specialized medical journals, textbooks, specialized medical society proceedings, or governmental statistics publications. When no such studies or literature citations exist, the applicant may be able to demonstrate the prevalence of the disease or condition in the United States by providing credible conclusions from appropriate research or surveys.

(b) FDA action. Within 45 days of receipt of a request for HUD designation, FDA will take one of the following actions:

(1) Approve the request and notify the applicant that the device has been designated as a HUD based on the information submitted;

to

(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 designation 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.

8814.104 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 jus- (5) The amount to be charged for the tifies an omission in accordance with device and, if the amount is more than paragraph (d) of this section, an HDE $250, a report by an independent cershall include:

tified public accountant, made in ac(1) A copy of or reference to the de- cordance with the Statement on Standtermination made by FDA's Office of ards for Attestation established by the Orphan Products Development (in ac

American Institute of Certified Public cordance with $814.102) that the device

Accountants, or in lieu of such a requalifies as a HUD;

port, an attestation by a responsible (2) An explanation of why the device

individual of the organization, would not be available unless an HDE

verifying that the amount charged does were granted and a statement that no

not exceed the costs of the device's recomparable device (other than another

search, development, fabrication, and HUD approved under this subpart or a

distribution. If the amount charged is device under an approved IDE) is avail

$250 or less, the requirement for a reable to treat or diagnose the disease or

port by an independent certified public

accountant or an attestation by a recondition. The application also shall contain a discussion of the risks and

sponsible individual of the organiza

tion is waived. benefits of currently available devices

(c) Omission of information. If the apor alternative forms of treatment in

plicant believes that certain informathe United States;

tion required under paragraph (b) of (3) An explanation of why the prob- this section is not applicable to the deable benefit to health from the use of

vice that is the subject of the HDE, and the device outweighs the risk of injury

omits any such information from its or illness from its use, taking into ac

HDE, the applicant shall submit a count the probable risks and benefits of

statement that identifies and justifies currently available devices or alter

the omission. The statement shall be native forms of treatment. Such expla

submitted as a separate section in the nation shall include a description, ex- HDE and identified in the table of conplanation, or theory of the underlying tents. If the justification for the omisdisease process or condition, and

sion is not accepted by the agency, known or postulated mechanism(s) of FDA will so notify the applicant. action of the device in relation to the

(d) Address for submissions and cordisease process or condition;

respondence. Copies of all original (4) All of the information required to HDE's, amendments and supplements, be submitted under $814.20(b), except as well as any correspondence relating that:

to an HDE, shall be sent or delivered to (i) In lieu of the summaries, conclu- the Document Mail Center (HFZ-401), sions, and results from clinical inves- Office of Device Evaluation, Center for tigations required

under Devices and Radiological Health, Food 88 814.20(b)(3)(v)(B), (b)(3)(vi), and and Drug Administration, 9200 Cor(b)(6)(ii), the applicant shall include porate Blvd., Rockville, MD 20850. the summaries, conclusions, and re

(61 FR 33244, June 26, 1996, as amended at 63 sults of all clinical experience or inves- FR 59220, Nov. 3, 1998] tigations (whether adverse supportive) reasonably obtainable by the 8814.106 HDE amendments and resubapplicant that are relevant to an as

mitted HDE's. sessment of the risks and probable ben- An HDE or HDE supplement may be efits of the device; and

amended or resubmitted upon an appli(ii) In addition to the proposed label- cant's own initiative, or at the request ing

requirement set forth in of FDA, for the same reasons and in 8814.20(b)(10), the labeling shall bear the same manner as prescribed for the following statement: Humanitarian PMA's in $ 814.37, except that the timeDevice. Authorized by Federal law for frames set forth in $814.37(c)(1) and (d) use in the treatment or diagnosis) of do not apply. If FDA requests an HDE (specify disease or condition). The ef- applicant to submit an HDE amendfectiveness of this device for this use ment, and a written response to FDA's has not been demonstrated; and

request is not received within 75 days

or

[blocks in formation]

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

$814.108 Supplemental applications.

After FDA approval of an original HDE, an applicant shall submit supplements in accordance with the requirements 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 $814.110. The timeframes for review of, and FDA action on, an HDE supplement are the same as those provided in $814.114 for an HDE.

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

[63 FR 59220, 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]

$ 814.110 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.

$814.112 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

8814.116 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 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

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