- Required Elements
- Premarket Submissions Coversheet
- Cover Letters
- Suggested Format and Address
- Summary of Safety and Effectiveness Data (§814.44)
- Statistical Checklist
- PMA Review Checklist
Certification of Compliance with ClinicalTrials.gov Data Bank, FDA-3674*
*Beginning December 26, 2007, all PMA applications must include a completed copy of form FDA-3674. See Form FDA-3674, ClinicalTrials.gov Data Bank for additional information.
Required Elements (§814.20)
There is no preprinted form for a PMA Application. Unless an omission is justified by the applicant [§814.20(d)], a PMA must include all of the following:
- The name and address of the applicant.
- A table of contents that specifies the volume and page number for each item referred to in the table.
- The PMA must include separate sections on nonclinical laboratory studies and on clinical investigations involving human subjects.
- Six copies of the PMA are required, each bound in one or more numbered volumes of reasonable size. To facilitate review by the advisory committee(s), additional copies may be requested by FDA.
- Trade secret or confidential commercial or financial information must be included in all copies of the PMA. The applicant must identify in at least one copy any information that they believe to be trade secret or confidential commercial or financial information.
- A summary section in sufficient detail to provide a general understanding of the data and information in the application. Tip: The summary section should contain brief statements of major points found elsewhere in the PMA and should be approximately 10 to 15 pages in length.
The summary section must contain the following information:
Indications for use. Give a general description of the disease or condition that the device will diagnose, treat, prevent, cure, or mitigate and include a description of the patient population for which the device is intended.
Device description. Explain 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.
Alternative practices and procedures. Describe any alternative practices or procedures for diagnosing, treating, preventing, curing, or mitigating the disease or condition for which the device is intended.
Tip: Include a statement such as "other commercially available devices" if similar class III products are available. Do not include any treatment practices or procedures that are considered investigational.
Marketing history. Give a brief description of the foreign and U.S. marketing history, if any, of the device known to the applicant. At a minimum, include 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.
Tip: It would be appropriate to include dates of introduction into each country, information about the quantity of product distributed in each country, a brief description of any experience reporting mechanism, a summary of any adverse experiences reported, and information about any withdrawals for any reason related to the safety or effectiveness. Withdrawals because of poor sales or physician disfavor should not be included. A U.S. marketing history may occur if the device is marketed under 510(k) for a different intended use. The description must 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.
Summary of studies. This section must contain a summary of the results of technical data (nonclinical and clinical studies) under §814.20(b)(6) and an abstract of any other data, information, or report described in the PMA under §814.20(b)(8)(ii). The summary must include a description of the objective of each study, a description of the experimental design of the study (or hypothesis tested), a brief discussion of how the data were collected and analyzed, and a brief description of the findings and conclusions, whether positive, negative or inconclusive.
The summary must include a summary of nonclinical laboratory studies submitted in the application and a summary of the clinical investigations involving human subjects. The summary of the clinical investigations should include a discussion of subject selection and exclusion criteria, study population demographics, study period, safety and effectiveness data, adverse reactions and complications, patient discontinuation, device failures and replacements, tabulations of data from all individual subject reporting 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, contraindications and precautions for use of the device, and other information from the clinical investigations, as appropriate. Any investigation conducted under an IDE must be identified.
Conclusions drawn from the studies. Discuss how the data and information in the application constitute valid scientific evidence within the meaning of 21 CFR 860.7, Determination of Safety and Effectiveness, and provide reasonable assurance that the device is safe and effective for its intended use. A concluding discussion must 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 that the applicant intends to conduct following approval of the PMA.
Tip: The applicant's summary section should objectively link the medical claim(s) for the device to the hypotheses tested and conclusions drawn from the findings of all studies and investigations. Biased presentation of the study data and inclusion of promotional claims are to be avoided. When preparing the summary section, the applicant should be able to detect and correct any accountability discrepancies, incomplete reporting and study design deficiencies which an in-depth scientific review would discover. A properly developed summary section by the applicant can serve as the basis for FDA's Summary of Safety and Effectiveness Data and will facilitate the FDA and panel review process. A full and explicit account of the clinical investigations and supporting data is needed to meet the legal requirements imposed by the FD&C Act. For a more detailed discussion of how to design, document, and present a clinical investigation to demonstrate safety and effectiveness, see "Statistical Guidance for Clinical Trials for Non-diagnostic Medical Devices".
- A complete description of:
- the device, including pictorial representations;
- each of the functional components or ingredients of the device if the device consists of more than one physical component or ingredient;
- the properties of the device relevant to the diagnosis, treatment, prevention, cure, or mitigation of a disease or condition;
- the principles of operation of the device; and
- the methods, facilities, and controls used in 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 practices can make a knowledgeable judgment about the quality control used in the manufacture of the device. Additional guidance on manufacturing information to include in the PMA application can be found in "Quality System Information for Certain Premarket Application Reviews".
Tip: If complete manufacturing information is not available at the time the PMA is submitted, its temporary omission may be justified as provided in 21 CFR 814.20(d). Refer to Item 31 in the preamble to the PMA regulation for further information.
Reference to any performance standard or voluntary standard.
Performance standard refers to those promulgated under Part 514 of the FD&C Act or the Radiation Control for Health and Safety Act of 1968 (RCHSA) in effect or proposed at the time of the PMA submission. At this time the performance standard for electrode lead wires and patient cables under 21 CFR 898 is the only performance standard established for medical devices. Performance standards established under RCHSA can be found in 21 CFR Parts 1000 through 1050. Access to RCHSA performance standards is available on the Internet.
A voluntary standard refers to one that is specifically applicable to any aspect of the safety or effectiveness of the device and developed in accordance with the FDA policy statement on standards development published in the Federal Register of October 23, 1985 (50 FR 43081). FDA recognized many voluntary standards. Guidance on the recognition and use of consensus standards as well as a database of FDA recognized consensus standards can be found on the Internet.
The applicant must provide adequate information to demonstrate how the device meets, or justify any deviation from, any of the mandatory performance standards noted above and explain any deviation from a voluntary standard.
Technical sections containing data and information in sufficient detail to permit FDA to determine whether to approve or deny the application.
These sections and their contents are as follows:
Results of nonclinical laboratory studies – This section should contain the results of the nonclinical laboratory studies with the device including the 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 study was conducted in compliance with 21 CFR 58, Good Laboratory Practice for Nonclinical Laboratory Studies. If the study was not conducted in compliance with this regulation, provide a brief statement of the reason for the noncompliance.
Results of clinical investigations involving human subjects – This section should include clinical protocols, number of investigators and subjects per investigator, a discussion of subject selection and exclusion criteria, study population demographics, 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 reporting 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, contraindications and precautions for use of the device, and other information from the clinical investigations, as appropriate. The analysis and discussion should address the impact, if any, on the safety and effectiveness measures. Additional information such as an analysis and discussion of any potential biases related to gender, race/ethnicity, etc. should be included. Any differences in safety and/or effectiveness should be described in the labeling.
Information on clinical studies involving human subjects shall include the following statements with respect to each study:
- that it either was conducted in compliance with the Institutional Review Board regulations under 21 CFR 56 or was not subject to the regulations under 21 CFR 56.104 or 21 CFR 56.105,
- that it was conducted in compliance with the Informed Consent regulation under 21 CFR 50, and
- that it was conducted in compliance with Investigational Device Exemptions regulations under 21 CFR 812 concerning sponsors of clinical investigations and clinical investigators.
If the study was not conducted in compliance with these regulations, include a brief statement of the reason for the noncompliance.
- For a PMA supported solely by data from one investigator, a justification showing why data and other information from a single investigator is sufficient to demonstrate the safety and effectiveness of the device and to ensure reproducibility of test results.
- A bibliography of all published reports not already submitted under §814.20(b)(6), whether adverse or supportive, that are known to or should reasonably be known to the applicant and that concern the safety or effectiveness of the device. Applicants should consider providing a copy of all of the key articles, a brief summarization of the salient features of the article, and a brief discussion of how the article relates to the safety and effectiveness evaluation for their device.
An identification, discussion, and analysis of any other data, information, or report relevant to an evaluation of the safety and effectiveness of the device that are known to or should reasonably be known to the applicant from any source, foreign or domestic. This includes information from investigations other than those proposed in the application and from commercial marketing experience.
- 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 should name the location at which FDA may examine and test one or more devices.
- Copies of all proposed labeling for the device. Such labeling may include, for example, instructions for installation and any information, literature, or advertising that constitutes labeling under Part 201(m) of the FD&C Act. Note: Any advertising devised by applicant that does not constitute labeling would not be required to be submitted and reviewed prior to approval of the PMA.
- 21 CFR 814.20(b)(11) states that an environmental assessment in accordance with 21 CFR 25 must be included in the PMA application. Please note that PMAs do not ordinarily require an environmental assessment (EA) or environmental impact statements (EIS) if the device is of the same type and for the same use as a previously approved device [§25.34(d)]. Please refer to the PMA Special Consideration section for additional information.
- A financial certification or disclosure statement or both as required by 21 CFR 54.
- Such other information as FDA may request. If necessary, FDA will obtain the concurrence of the appropriate FDA advisory committee before requesting additional information.
Other information. Pertinent information already in FDA files and specifically referred to by an applicant may be incorporated into a PMA by reference. Information in a master file (see "Master Files") 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 writing by the person who submitted the information or the master file.
Omissions. If an applicant believes that certain required information under §814.20(b) is not applicable to the device and omits any such information from their PMA, the applicant must submit a statement that identifies the omitted information and justifies the omission. The statement must be submitted as a separate section in the PMA and identified in the table of contents. If FDA does not accept the justification for the omission, FDA will notify the applicant.
Tip: An applicant may request a waiver for the manufacturing information to be submitted later in the application process. Any delayed submission of the manufacturing information may cause a delay in the Quality System inspection process.
Updates. An applicant must periodically update its pending application with any new safety and effectiveness information learned about the device from ongoing or completed studies that may affect an evaluation of the safety and effectiveness of the device or that may affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling. The updated report must be consistent with the data-reporting provisions of the protocol. The applicant must submit three copies of any updated report and must include in the report the PMA number assigned by FDA. These updates are considered to be amendments to the pending PMA. The timeframe for review of a PMA will not be extended due to the submission of an update report unless the update is a major amendment [§814.37(c)(1)]. An applicant must submit these reports three months after the filing date, following receipt of an approvable letter, and at any other time as requested by FDA. Note: This periodic updating is limited to studies sponsored by the applicant or to which the applicant has reasonable access.
Color additive. A color additive used in or on the device is subject to Part 721 of the FD&C Act and must be listed for such use by FDA. If the color additive has not previously been listed by FDA for such use, an applicant may request FDA to list the color additive by submitting a color additive petition under 21 CFR 71 to the Center for Food Safety and Applied Nutrition (CFSAN). Alternatively, the request may be submitted to CDRH as part of as the PMA. If the request is submitted in the PMA, three copies of the color additive petition information must be included, each bound in one or more numbered volumes of reasonable size. A PMA for a device that contains a color additive that is subject to Part 721 of the FD&C Act will not be approved until a color additive is listed by FDA for use in or on the device. See "Color Additives for Medical Devices" for further information.
The completion of this Premarket Submission Coversheet is voluntary and will not affect any Food and Drug Administration (FDA) decision concerning your submission, but will help FDA's Center for Devices and Radiological Health process your submission more efficiently by placing administrative data elements in a consistent format for data entry purposes. The coversheet was developed to reduce the number of administrative deficiencies common in many submissions.
The information provided should apply only to a single accompanying submission; please do not send cover sheets for any previous submissions. When submitting an amendment or supplement, identify the document number and type of submission, and then complete only the information which has changed since your most recent cover sheet relating to the same submission. The coversheet should be used only for submissions that are referenced in the coversheet.
An applicant's cover letter should accurately identify the type of PMA submission, i.e., an original PMA, PMA supplement, PMA amendment to a pending PMA or PMA supplement, periodic report, etc. and include information needed for FDA tracking purposes. To expedite its processing, the following suggestions and formats have been prepared.
- Use the applicant's letterhead or that of the applicant's authorized representative. Provide a valid email address since all letters from FDA will be sent via email to the applicant.
- Address the cover letter as indicated under "Original PMA Cover Letter" below. To minimize misrouting, do not include an FDA staff member's name in the address.
- If submitted by someone other than the applicant (e.g., lawyer or consultant), the identity of the applicant must be included.
- For an original PMA, specify the indication for use for which FDA approval is requested.
- If applicable, include the reference numbers for any premarket notification, investigational device exemption, reclassification petition, or color additive petition submitted by the applicant.
- Indicate whether the submission includes an environmental assessment.
- Date and sign the cover letter and include a copy in the first volume of each copy of the PMA submission.
The full format of the cover letter for an original PMA appears below. For other types of PMA submissions, only the subject section and opening sentence(s) are provided. In several instances, alternative opening statements are included to address specific situations.
Original PMA Cover Letter
PMA Document Mail Center - WO66-G609
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
SUBJECT: Original PMA for [device trade name and model number if applicable]
To Whom It May Concern:
[Applicant's name] is submitting this original premarket approval application for the [device trade name], [device generic name] intended for use in [indication for use].
Clinical studies of the above device were initiated on [date] and [were/were not] conducted under an approved investigational device exemption [give IDE number if a significant risk device]. [If applicable, include the FDA reference number for any premarket notification, reclassification petition, or color additive petition submitted for this device].
[Include a paragraph providing the name and address of each facility involved in the manufacture of the device and indicate whether the facility is prepared for an FDA inspection. If not prepared, provide an expected date when the facility will be ready for inspection. If a waiver of the QS information is requested, provide an anticipated date that the information will be provided.]
If another document is incorporated by reference, e.g., a master file, please include the original letter of authorization as an attachment to this cover letter.
The existence of this PMA and the data and other information that it contains are confidential, and the protection afforded to such confidential information by 18 USC 1905, 21 USC 331(j), 5 USC 552, and other applicable laws is hereby claimed. [Tip: confidentiality claims cannot be made unless the applicant has complied with the applicable requirements.
If there are questions regarding this submission, [name] may be contacted at [give telephone number including area code].
[Name and title of applicant's representative]
Amendment to Original PMA
SUBJECT: Amendment to [original PMA or PMA supplement reference number] for [device trade name]
Unsolicited submission of additional information
[Applicant's name] is submitting this amendment to its [premarket approval application] [original PMA reference number] for the [device trade name] to provide [identify the additional information being provided].
In order to facilitate FDA's handling of PMA applications, the following recommendations are offered:
- Use paper with nominal dimensions of 8 ½" by 11".
- Use at least a 1 ½ " wide left margin to allow for binding into jackets.
- Use 3-hole punched paper to allow for binding into jackets.
- If the submission exceeds 2" in thickness, separate into volumes and identify volume number.
- Clearly and prominently identify submission as original PMA application or, for additional submissions to a PMA application, clearly identify the FDA assigned document number (e.g., P960000) and the type of submission (e.g., amendment, supplement or report) or response (e.g., response to an FDA letter dated _______).
- All copies of each submission must be identical.
- Sequentially number the pages, providing a detailed table of contents, and use tabs to identify each section. This will help to facilitate the review of your submission.
- All copies of the first volume of each submission must include a signed and dated cover letter.
- Do not combine PMAs, IDEs, and 510(k)s together. They must be separate submissions.
- Only the PMA applicant on record with FDA may amend, supplement, or submit reports to their PMA, unless the PMA includes the original and not a copy of an appropriate letter of authorization from the applicant permitting another person to submit information on the applicant’s behalf. If the information on the applicant’s company name or designated submitter information changes, please notify FDA in the form of an amendment to the PMA or PMA Supplement.
The following information should be submitted in separate volumes:
- Manufacturing Information.
- Environmental Assessment, if applicable.
- Color Additives, if applicable.
- Individual Subject Report Forms.
A PMA or PMA supplement, if applicable, is required by §814.20(b)(6)(ii) to include copies of individual subject report forms for each subject who died during a clinical investigation or who did not complete the investigation. Before submitting the PMA, the applicant should consult with the ODE reviewing division to determine the information to be included in these report forms, how many copies are required, and whether these report forms will be required for other subjects enrolled in the study (e.g., subjects experiencing specified adverse effects or complications).
A PMA must be signed by the applicant or an authorized U.S. representative. If the applicant does not reside or have a place of business within the U.S., the PMA must be countersigned by an authorized representative who does. The applicant must also provide the representative's name and address.
Please refer to the eCopy guidance for current information on the number of copies and the format (paper versus eCopy) you must send to the Document Control Center (DCC) address. The eCopy guidance also provides the current DCC address.
The FD&C Act requires that FDA prepare a detailed summary of the safety and effectiveness data on which the approval or denial decision is based.
The Summary of Safety and Effectiveness Data (SSED) is a document mandated by 520(h)(1)(A) of the FD&C Act (the act). It is to be publicly available upon issuance of an order approving or denying approval of a premarket approval application (PMA).
Approval/denial decisions for original PMA applications must include an SSED. An SSED is also prepared for submissions designated by CDRH as panel-track supplements. An abbreviated SSED is required for approval of a PMA based on a licensing agreement. The abbreviated SSED is acceptable because the scientific data on which the PMA relies were previously described in the SSED for the application which is being licensed.
The SSED is an FDA document (originally submitted by the applicant and modified by FDA) which is intended to present a reasoned, objective, and balanced critique of the scientific evidence which served as the basis of the decision to approve or deny the PMA . The SSED documents that there was reasonable assurance of safety and effectiveness for the device as labeled based on the nonclinical and clinical studies described in the PMA. The SSED is a summation of both the positive and negative aspects of the PMA. the scientific evidence. For a PMA to be approved, potential risks versus possible benefits assessment must favor this action. The SSED summarizes these judgments.
Initially FDA intended drafting the publicly releasable SSED, which is based on the SSED the applicant is required to submit under 21 CFR 814.20. If FDA must substantially rewrite the applicant's SSED, FDA will often go back to the applicant and request that they make another attempt at writing the publicly releasable SSED. Unfortunately, the applicant SSED too often differs from FDA's objective, i.e., it contains only the positive aspects of the device, it contains marketing language, etc. Consequently, an edit-rewrite exercise often results. Since minor variations in SSED formats are possible, it is best to consult previously released SSEDs (preferably recent ones for similar devices) for guidance. Since the SSED deals with scientific/technical data and will be read by many non-professionals, it is best to keep the format clear by grouping study objective(s), study methods, results, interpretation(s), and conclusion(s) for each study or substudy. An overall statement/conclusion integrating the individual study outcomes in the light of safety and effectiveness and risk versus benefits and your conclusions can then be written.
Level of comprehension
The SSED should be written for the comprehension of a college graduate, but not necessarily a science graduate or professional in the device specific area. Medical and scientific terms should be used whenever needed, but it is preferred that simpler, generally recognized terminology be used (provided it can be used without suffering loss of meaning).
Format for Summary of Safety and Effectiveness Data
The following is the format of the summary of safety and effectiveness data prepared by FDA. PMA applicants can facilitate this step of the PMA process by following this format in preparing the summary of safety and effectiveness data required under §814.20(b)(3).
Device generic name
Device trade name
Applicant’s name and address
Date of Panel recommendation*
Date of notice of approval to the applicant*
(*to be completed by FDA unless known to the applicant)
- Indications for Use
- Device Description
- Contraindications, Warnings, and Precautions
- Alternative Practices and Procedures
- Marketing History
- Potential Adverse Effects of the Device on Health
Tip: Include any information concerning actual or potential adverse effects that the device may have on health (e.g. if an implanted device, discuss the fate of the device in the body)
Summary of Preclinical Studies
Summary of Clinical Studies
Data analysis and result
Device failures and replacements
Conclusions Drawn from the Studies
- Panel Recommendations (To be completed by FDA)
- CDRH Decision (To be completed by FDA)
- Approval Specifications (To be completed by FDA)
The PMA Review Statistical Checklist lists the required elements of the statistical aspects of the PMA submission. This list is used to screen all PMA applications before in-depth review by the Division of Biostatistics. The absence of any of these elements may be sufficient to reject an in-depth statistical review. It is essential, therefore, that the applicant check to determine that the statistical reports in the submission are complete.
The checklist referenced below is used by PMA reviewers to determine the completeness of a PMA and is a part of the Blue Book Memo, PMA Refuse to File Procedures 5/2/94 (P94-1). PMA applicants may also wish to use the checklist to assure the completeness of the application.
References for PMA Application Contents
21 CFR 814.20 21 CFR 820 Guidance for Industry and Food and Drug Administration Staff - Acceptance and Filing Reviews for Premarket Approval Applications (PMAs)(PDF - 370KB) Quality System Information for Certain Premarket Application Reviews; Guidance for Industry and FDA Staff Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices Guidance for Industry, FDA Reviewers and Compliance on Off-The-Shelf Software Use in Medical Devices PMA Review Statistical Checklist (PDF Only)(PDF - 69KB)