CFR Subpart B

CFR Subpart B
in effect

21 C.F.R. § 814.20 Application.

(a) The applicant or an authorized representative shall sign the PMA. If the applicant does not reside or have a place of business within the United States, the PMA 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) Unless the applicant justifies an omission in accordance with paragraph (d) of this section, a PMA shall include in electronic format: (1) The name and address of the applicant. (2) A table of contents that specifies the volume and page number for each item referred to in the table. A PMA shall include separate sections on nonclinical laboratory studies and on clinical investigations involving human subjects. A PMA shall be submitted as a single version. The applicant shall include information that it believes to be trade secret or confidential commercial or financial information in the PMA and identify the information that it believes to be trade secret or confidential commercial or financial information. (3) A summary in sufficient detail that the reader may gain a general understanding of the data and information in the application. The summary shall contain the following information: (i) Indications for use. A general description of the disease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the patient population for which the device is intended. (ii) Device description. An explanation of how the device functions, the basic scientific concepts that form the basis for the device, and the significant physical and performance characteristics of the device. A brief description of the manufacturing process should be included if it will significantly enhance the reader's understanding of the device. The generic name of the device as well as any proprietary name or trade name should be included. (iii) Alternative practices and procedures. A description of existing alternative practices or procedures for diagnosing, treating, preventing, curing, or mitigating the disease or condition for which the device is intended. (iv) Marketing history. A brief description of the foreign and U.S. marketing history, if any, of the device, including a list of all countries in which the device has been marketed and a list of all countries in which the device has been withdrawn from marketing for any reason related to the safety or effectiveness of the device. The description shall include the history of the marketing of the device by the applicant and, if known, the history of the marketing of the device by any other person. (v) Summary of studies. An abstract of any information or report described in the PMA under paragraph (b)(8)(ii) of this section and a summary of the results of technical data submitted under paragraph (b)(6) of this section. Such summary shall include a description of the objective of the study, a description of the experimental design of the study, a brief description of how the data were collected and analyzed, and a brief description of the results, whether positive, negative, or inconclusive. This section shall include the following: (A) A summary of the nonclinical laboratory studies submitted in the application; (B) A summary of the clinical investigations involving human subjects submitted in the application including a discussion of subject selection and exclusion criteria, study population, study period, safety and effectiveness data, adverse reactions and complications, patient discontinuation, patient complaints, device failures and replacements, results of statistical analyses of the clinical investigations, contraindications and precautions for use of the device, and other information from the clinical investigations as appropriate (any investigation conducted under an IDE shall be identified as such). (vi) Conclusions drawn from the studies. A discussion demonstrating that the data and information in the application constitute valid scientific evidence within the meaning of § 860.7 and provide reasonable assurance that the device is safe and effective for its intended use. A concluding discussion shall present benefit and risk considerations related to the device including a discussion of any adverse effects of the device on health and any proposed additional studies or surveillance the applicant intends to conduct following approval of the PMA. (4) A complete description of: (i) The device, including pictorial representations; (ii) Each of the functional components or ingredients of the device if the device consists of more than one physical component or ingredient; (iii) The properties of the device relevant to the diagnosis, treatment, prevention, cure, or mitigation of a disease or condition; (iv) The principles of operation of the device; and (v) The methods used in, and the facilities and controls used for, the manufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with current good manufacturing practice can make a knowledgeable judgment about the quality control used in the manufacture of the device. (5) Reference to any performance standard under section 514 of the Federal Food, Drug, and Cosmetic Act or under section 534 of Subchapter C—Electronic Product Radiation Control of the Federal Food, Drug, and Cosmetic Act (formerly the Radiation Control for Health and Safety Act of 1968) in effect or proposed at the time of the submission and to any voluntary standard that is relevant to any aspect of the safety or effectiveness of the device and that is known to or that should reasonably be known to the applicant. The applicant shall— (i) Provide adequate information to demonstrate how the device meets, or justify any deviation from, any performance standard established under section 514 of the Federal Food, Drug, and Cosmetic Act or under section 534 of Subchapter C—Electronic Product Radiation Control of the Federal Food, Drug, and Cosmetic Act (formerly the Radiation Control for Health and Safety Act of 1968); and (ii) Explain any deviation from a voluntary standard. (6) The following technical sections which shall contain data and information in sufficient detail to permit FDA to determine whether to approve or deny approval of the application: (i) A section containing results of the nonclinical laboratory studies with the device including microbiological, toxicological, immunological, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests as appropriate. Information on nonclinical laboratory studies shall include a statement that each such study was conducted in compliance with part 58, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance. (ii) A section containing results of the clinical investigations involving human subjects with the device including clinical protocols, number of investigators and subjects per investigator, subject selection and exclusion criteria, study population, study period, safety and effectiveness data, adverse reactions and complications, patient discontinuation, patient complaints, device failures and replacements, tabulations of data from all individual subject report forms and copies of such forms for each subject who died during a clinical investigation or who did not complete the investigation, results of statistical analyses of the clinical investigations, device failures and replacements, contraindications and precautions for use of the device, and any other appropriate information from the clinical investigations. Any investigation conducted under an IDE shall be identified as such. Information on clinical investigations involving human subjects shall include the following: (A) For clinical investigations conducted in the United States, a statement with respect to each investigation that it either was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the informed consent regulations in part 50 of this chapter; or if the investigation was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with these requirements does not justify failure to provide information on a relevant clinical investigation. (B) For clinical investigations conducted in the United States, a statement that each investigation was conducted in compliance with part 812 of this chapter concerning sponsors of clinical investigations and clinical investigators, or if the investigation was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with these requirements does not justify failure to provide information on a relevant clinical investigation. (C) For clinical investigations conducted outside the United States that are intended to support the PMA, the requirements under § 812.28 of this chapter apply. If any such investigation was not conducted in accordance with good clinical practice (GCP) as described in § 812.28(a), include either a waiver request in accordance with § 812.28(c) or a brief statement of the reason for not conducting the investigation in accordance with GCP and a description of steps taken to ensure that the data and results are credible and accurate and that the rights, safety, and well-being of subjects have been adequately protected. Failure or inability to comply with these requirements does not justify failure to provide information on a relevant clinical investigation. (7) For a PMA supported solely by data from one investigation, a justification showing that data and other information from a single investigator are sufficient to demonstrate the safety and effectiveness of the device and to ensure reproducibility of test results. (8)(i) A bibliography of all published reports not submitted under paragraph (b)(6) of this section, whether adverse or supportive, known to or that should reasonably be known to the applicant and that concern the safety or effectiveness of the device. (ii) An identification, discussion, and analysis of any other data, information, or report relevant to an evaluation of the safety and effectiveness of the device known to or that should reasonably be known to the applicant from any source, foreign or domestic, including information derived from investigations other than those proposed in the application and from commercial marketing experience. (iii) Copies of such published reports or unpublished information in the possession of or reasonably obtainable by the applicant if an FDA advisory committee or FDA requests. (9) One or more samples of the device and its components, if requested by FDA. If it is impractical to submit a requested sample of the device, the applicant shall name the location at which FDA may examine and test one or more devices. (10) Copies of all proposed labeling for the device. Such labeling may include, e.g., instructions for installation and any information, literature, or advertising that constitutes labeling under section 201(m) of the Federal Food, Drug, and Cosmetic Act. (11) An environmental assessment under § 25.20(n) prepared in the applicable format in § 25.40, unless the action qualifies for exclusion under § 25.30 or § 25.34. If the applicant believes that the action qualifies for exclusion, the PMA shall under § 25.15(a) and (d) provide information that establishes to FDA's satisfaction that the action requested is included within the excluded category and meets the criteria for the applicable exclusion. (12) A financial certification or disclosure statement or both as required by part 54 of this chapter. (13) Information concerning uses in pediatric patients. The application must include the following information, if readily available: (i) A description of any pediatric subpopulations (neonates, infants, children, adolescents) that suffer from the disease or condition that the device is intended to treat, diagnose, or cure; and (ii) The number of affected pediatric patients. (14) Such other information as FDA may request. If necessary, FDA will obtain the concurrence of the appropriate FDA advisory committee before requesting additional information. (c) Pertinent information in FDA files specifically referred to by an applicant may be incorporated into a PMA by reference. Information in a master file or other information submitted to FDA by a person other than the applicant will not be considered part of a PMA unless such reference is authorized in a record submitted to FDA by the person who submitted the information or the master file. If a master file is not referenced within 5 years after the date that it is submitted to FDA, FDA will return the master file to the person who submitted it. (d) If the applicant believes that certain information required under paragraph (b) of this section to be in a PMA is not applicable to the device that is the subject of the PMA, and omits any such information from its PMA, the applicant shall submit a statement that identifies the omitted information and justifies the omission. The statement shall be submitted as a separate section in the PMA 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. (e) The applicant shall periodically update its pending application with new safety and effectiveness information learned about the device from ongoing or completed studies that may reasonably affect an evaluation of the safety or effectiveness of the device or that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling. The update report shall be consistent with the data reporting provisions of the protocol. The applicant shall submit any update report in electronic format and shall include in the report the number assigned by FDA to the PMA. These updates are considered to be amendments to the PMA. The time frame for review of a PMA will not be extended due to the submission of an update report unless the update is a major amendment under § 814.37(c)(1). The applicant shall submit these reports— (1) 3 months after the filing date; (2) Following receipt of an approvable letter; and (3) At any other time as requested by FDA. (f) If a color additive subject to section 721 of the Federal Food, Drug, and Cosmetic Act is used in or on the device and has not previously been listed for such use, then, in lieu of submitting a color additive petition under part 71 of this chapter, at the option of the applicant, the information required to be submitted under part 71 may be submitted as part of the PMA. When submitted as part of the PMA, the information shall be submitted in electronic format. A PMA for a device that contains a color additive that is subject to section 721 of the Federal Food, Drug, and Cosmetic Act will not be approved until the color additive is listed for use in or on the device. (g) Additional information on FDA policies and procedures, as well as links to PMA guidance documents, is available on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/default.htm. (h) If you are sending a PMA, PMA amendment, PMA supplement, or correspondence with respect to a PMA, you must send the submission to the appropriate address as follows: (1) For devices regulated by the Center for Devices and Radiological Health, send it to the current address displayed on the website https://www.fda.gov/cdrhsubmissionaddress. (2) For devices regulated by the Center for Biologics Evaluation and Research, send it to the current address displayed on the website https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm385240.htm. (3) For devices regulated by the Center for Drug Evaluation and Research, send it to: Central Document Control Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.

21 C.F.R. § 814.37 PMA amendments and resubmitted PMAs.

(a) An applicant may amend a pending PMA or PMA supplement to revise existing information or provide additional information. (b)(1) FDA may request the applicant to amend a PMA or PMA supplement with any information regarding the device that is necessary for FDA or the appropriate advisory committee to complete the review of the PMA or PMA supplement. (2) FDA may request the applicant to amend a PMA or PMA supplement with information concerning pediatric uses as required under §§ 814.20(b)(13) and 814.39(c)(2). (c) A PMA amendment submitted to FDA shall include the PMA or PMA supplement number assigned to the original submission and, if submitted on the applicant's own initiative, the reason for submitting the amendment. FDA may extend the time required for its review of the PMA, or PMA supplement, as follows: (1) If the applicant on its own initiative or at FDA's request submits a major PMA amendment (e.g., an amendment that contains significant new data from a previously unreported study, significant updated data from a previously reported study, detailed new analyses of previously submitted data, or significant required information previously omitted), the review period may be extended up to 180 days. (2) If an applicant declines to submit a major amendment requested by FDA, the review period may be extended for the number of days that elapse between the date of such request and the date that FDA receives the written response declining to submit the requested amendment. (d) An applicant may on its own initiative withdraw a PMA or PMA supplement. If FDA requests an applicant to submit a PMA amendment and a written response to FDA's request is not received within 180 days of the date of the request, FDA will consider the pending PMA or PMA supplement to be withdrawn voluntarily by the applicant. (e) An applicant may resubmit a PMA or PMA supplement after withdrawing it or after it is considered withdrawn under paragraph (d) of this section, or after FDA has refused to accept it for filing, or has denied approval of the PMA or PMA supplement. A resubmitted PMA or PMA supplement shall comply with the requirements of § 814.20 or § 814.39, respectively, and shall include the PMA number assigned to the original submission and the applicant's reasons for resubmission of the PMA or PMA supplement.

21 C.F.R. § 814.39 PMA supplements.

(a) After FDA's approval of a PMA, an applicant shall submit a PMA supplement for review and approval by FDA before making a change affecting the safety or effectiveness of the device for which the applicant has an approved PMA, unless the change is of a type for which FDA, under paragraph (e) of this section, has advised that an alternate submission is permitted or is of a type which, under section 515(d)(6)(A) of the act and paragraph (f) of this section, does not require a PMA supplement under this paragraph. While the burden for determining whether a supplement is required is primarily on the PMA holder, changes for which an applicant shall submit a PMA supplement include, but are not limited to, the following types of changes if they affect the safety or effectiveness of the device: (1) New indications for use of the device. (2) Labeling changes. (3) The use of a different facility or establishment to manufacture, process, or package the device. (4) Changes in sterilization procedures. (5) Changes in packaging. (6) Changes in the performance or design specifications, circuits, components, ingredients, principle of operation, or physical layout of the device. (7) Extension of the expiration date of the device based on data obtained under a new or revised stability or sterility testing protocol that has not been approved by FDA. If the protocol has been approved, the change shall be reported to FDA under paragraph (b) of this section. (b) An applicant may make a change in a device after FDA's approval of a PMA for the device without submitting a PMA supplement if the change does not affect the device's safety or effectiveness and the change is reported to FDA in post approval periodic reports required as a condition to approval of the device, e.g., an editorial change in labeling which does not affect the safety or effectiveness of the device, or if the change is consistent with a predetermined change control plan (PCCP) approved under section 515C of the act. (c)(1) All procedures and actions that apply to an application under § 814.20 also apply to PMA supplements except that the information required in a supplement is limited to that needed to support the change. A summary under § 814.20(b)(3) is required for only a supplement submitted for new indications for use of the device, significant changes in the performance or design specifications, circuits, components, ingredients, principles of operation, or physical layout of the device, or when otherwise required by FDA. The applicant shall submit a PMA supplement in electronic format and shall include information relevant to the proposed changes in the device. A PMA supplement shall include a separate section that identifies each change for which approval is being requested and explains the reason for each such change. The applicant shall submit additional information, if requested by FDA, in electronic format. The time frames for review of, and FDA action on, a PMA supplement are the same as those provided in § 814.40 for a PMA. (2) The supplement must include the following information: (i) Information concerning pediatric uses as required under § 814.20(b)(13). (ii) If information concerning the device that is the subject of the supplement was previously submitted under § 814.20(b)(13) or under this section in a previous supplement, that information may be included by referencing a previous application or submission that contains the information. However, if additional information required under § 814.20(b)(13) has become readily available to the applicant since the previous submission, the applicant must submit that information as part of the supplement. (d)(1) After FDA approves a PMA, any change described in paragraph (d)(2) of this section to reflect newly acquired information that enhances the safety of the device or the safety in the use of the device may be placed into effect by the applicant prior to the receipt under § 814.17 of a written FDA order approving the PMA supplement provided that: (i) The PMA supplement and its mailing cover are plainly marked “Special PMA Supplement—Changes Being Effected”; (ii) The PMA supplement provides a full explanation of the basis for the changes; (iii) The applicant has received acknowledgement from FDA of receipt of the supplement; and (iv) The PMA supplement specifically identifies the date that such changes are being effected. (2) The following changes are permitted by paragraph (d)(1) of this section: (i) Labeling changes that add or strengthen a contraindication, warning, precaution, or information about an adverse reaction for which there is reasonable evidence of a causal association. (ii) Labeling changes that add or strengthen an instruction that is intended to enhance the safe use of the device. (iii) Labeling changes that delete misleading, false, or unsupported indications. (iv) Changes in quality controls or manufacturing process that add a new specification or test method, or otherwise provide additional assurance of purity, identity, strength, or reliability of the device. (e)(1) FDA will identify a change to a device for which an applicant has an approved PMA and for which a PMA supplement under paragraph (a) is not required. FDA will identify such a change in an advisory opinion under § 10.85, if the change applies to a generic type of device, or in correspondence to the applicant, if the change applies only to the applicant's device. FDA will require that a change for which a PMA supplement under paragraph (a) is not required be reported to FDA in: (i) A periodic report under § 814.84 or (ii) A 30-day PMA supplement under this paragraph. (2) FDA will identify, in the advisory opinion or correspondence, the type of information that is to be included in the report or 30-day PMA supplement. If the change is required to be reported to FDA in a periodic report, the change may be made before it is reported to FDA. If the change is required to be reported in a 30-day PMA supplement, the change may be made 30 days after FDA files the 30-day PMA supplement unless FDA requires the PMA holder to provide additional information, informs the PMA holder that the supplement is not approvable, or disapproves the supplement. The 30-day PMA supplement shall follow the instructions in the correspondence or advisory opinion. Any 30-day PMA supplement that does not meet the requirements of the correspondence or advisory opinion will not be filed and, therefore, will not be deemed approved 30 days after receipt. (f) Under section 515(d) of the act, modifications to manufacturing procedures or methods of manufacture that affect the safety and effectiveness of a device subject to an approved PMA do not require submission of a PMA supplement under paragraph (a) of this section and are eligible to be the subject of a 30-day notice. A 30-day notice shall describe in detail the change, summarize the data or information supporting the change, and state that the change has been made in accordance with the requirements of part 820 of this chapter. The manufacturer may distribute the device 30 days after the date on which FDA receives the 30-day notice, unless FDA notifies the applicant within 30 days from receipt of the notice that the notice is not adequate. If the notice is not adequate, FDA shall inform the applicant in writing that a 135-day PMA supplement is needed and shall describe what further information or action is required for acceptance of such change. The number of days under review as a 30-day notice shall be deducted from the 135-day PMA supplement review period if the notice meets appropriate content requirements for a PMA supplement. (g) The submission and grant of a written request for an exception or alternative under § 801.128 or § 809.11 of this chapter satisfies the requirement in paragraph (a) of this section.

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