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Device
Advice - Premarket Approval (PMA)Please note: As of October 1, 2002, FDA charges a fee for review of Premarket Approvals
Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. Due to the level of risk associated with Class III devices, FDA has determined that general and special controls alone are insufficient to assure the safety and effectiveness of class III devices. Therefore, these devices require a premarket approval (PMA) application under section 515 of the FD&C Act in order to obtain marketing clearance. Please note that some Class III preamendment devices may require a Class III 510(k). See "Historical Background" below for additional information.
PMA is the most stringent type of device marketing application required by FDA. The applicant must receive FDA approval of its PMA application prior to marketing the device. PMA approval is based on a determination by FDA that the PMA contains sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). An approved PMA is, in effect, a private license granting the applicant (or owner) permission to market the device. The PMA owner, however, can authorize use of its data by another.
The PMA applicant is usually the person who owns the rights, or otherwise has authorized access, to the data and other information to be submitted in support of FDA approval. This person may be an individual, partnership, corporation, association, scientific or academic establishment, government agency or organizational unit, or other legal entity. The applicant is often the inventor/developer and ultimately the manufacturer.
FDA regulations provide 180 days to review the PMA and make a determination. In reality, the review time is normally longer. Before approving or denying a PMA, the appropriate FDA advisory committee may review the PMA at a public meeting and provide FDA with the committee's recommendation on whether FDA should approve the submission. After FDA notifies the applicant that the PMA has been approved or denied, a notice is published on the Internet (1) announcing the data on which the decision is based, and (2) providing interested persons an opportunity to petition FDA within 30 days for reconsideration of the decision.
The regulation governing premarket approval is located in Title 21 Code of Federal Regulations (CFR) Part 814, Premarket Approval. A class III device that fails to meet PMA requirements is considered to be adulterated under section 501(f) of the FD&C Act and cannot be marketed.
Definitions (21 CFR 814.3)
30-day PMA supplement - a supplemental application to an approved PMA in accordance with 21 CFR 814.39(e).
Act – Federal Food, Drug, and Cosmetic Act (sections 201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 321-392).
Agency – U.S. Food and Drug Administration
CFR - Code of Federal Regulations
Federal Register (FR) – Publication of the federal government to establish new regulations or to change existing regulations.
FDA – U.S. Food and Drug Administration
GMP – Good Manufacturing Practices, also referred to as Quality System under 21 CFR 820
Humanitarian Device Exemption (HDE) - a premarket approval application submitted under 21 CFR 814 Subpart H seeking a humanitarian device exemption from the effectiveness requirements of sections 514 and 515 of the FD&C Act as authorized by section 520(m)(2) of the Act.
Humanitarian Use Device (HUD) - a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.
IDE – an approved or considered approved Investigational Device Exemption under 21 CFR 812 and section 520(g) of the FD&C Act.
Master file - a reference source that a person submits to FDA. A master file may contain detailed information on a specific manufacturing facility, process, methodology, or component used in the manufacture, processing, or packaging of a medical device.
Medical Device Amendment – an amendment to the Food, Drug, and Cosmetic Act signed into law on May 28, 1976. The amendments gave FDA authority to regulate medical devices.
Office of Communication, Education and Radiation Programs (OCER) – The office of FDA/CDRH that reviews PMA labeling.
Office of Regulatory Affairs (ORA) – The Office of Regulatory Affairs is responsible for facility inspections of FDA regulated establishments. ORA employees are located in FDA headquarter offices and in more than 150 offices throughout the U.S.
Office of Surveillance and Biometrics (OSB) – The office of FDA/CDRH responsible for statistical review of marketing applications and postmarket surveillance.
Office of Device Evaluation (ODE) – The office of FDA/CDRH responsible for the review of marketing applications.
PMA - any premarket approval application for a class III medical device, including all information submitted with or incorporated by reference. "PMA" includes a new drug application for a device under section 520(l) of the FD&C Act.
PMA amendment - information an applicant submits to FDA to modify a pending PMA or a pending PMA supplement.
PMA supplement - a supplemental application to an approved PMA for approval of a change or modification in a class III medical device, including all information submitted with or incorporated by reference.
Person - any individual, partnership, corporation, association, scientific or academic establishment, government agency or organizational unit, or any other legal entity.
Postamendment device – a device that is commercially distributed on or after May 28, 1976, the date the Medical Device Amendments of 1976 were signed into law.
Preamendment device – a device that was commercially distributed before May 28, 1976, the date of the Medical Device Amendments of 1976 were signed into law.
QS – Quality System, 21 CFR 820
Reasonable probablity - that it is more likely than not that an event will occur.
Serious, adverse health consequences - any significant adverse experience, including those which may be either life-threatening or involve permanent or long term injuries, but excluding injuries that are nonlife-threatening and that are temporary and reasonably reversible.
Statement of material fact - a representation that tends to show that the safety or effectiveness of a device is more probable than it would be in the absence of such a representation. A false affirmation or silence or an omission that would lead a reasonable person to draw a particular conclusion as to the safety or effectiveness of a device also may be a false statement of material fact, even if the statement was not intended by the person making it to be misleading or to have any probative effect.
Transitional Devices - Transitional devices are devices that were regulated as drugs prior to the May 28, 1976, the date the Medical Device Amendments were signed into law. Any device that was approved by the New Drug Application process is now governed by the PMA regulations. The original NDA approval number is maintained.
When a PMA is Required
PMA requirements apply to Class III devices, the most stringent regulatory category for medical devices. Device product classifications can be found by searching the Product Classification Database, http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm. The database search provides the name of the device, classification, and a link to the Code of Federal Regulations (CFR), if any. The CFR provides the device type name, identification of the device, and classification information.
A regulation number for Class III devices marketed prior to the 1976 Medical Device Amendments is provided in the CFR. The CFR for these Class III devices that require a PMA states that the device is Class III and will provide an effective date of the requirement for PMA. If the regulation in the CFR states that “No effective date has been established of the requirement for premarket approval,” a Class III 510(k) should be submitted.
Please note that PMA devices often involve new concepts and many are not of a type marketed prior to the Medical Device Amendments. Therefore, they do not have a classification regulation in the CFR. In this case, the product classification database will only cite the device type name and product code.
If it is unclear whether the unclassified device requires a PMA, use the three letter product code to search the PMA database and the Premarket Notification 510(k) database. These databases can be found by clicking on the hypertext links at the top of the product classification database web page. Enter only the three letter product code in the product code box. If there are 510(k)’s cleared by FDA and the new device is substantially equivalent to any of these cleared devices, then the applicant should submit a 510(k).
Furthermore, a new type of device may not be found in the product classification database. If the device is a high risk device (supports or sustains human life, is of substantial importance in preventing impairment of human health, or presents a potential, unreasonable risk of illness or injury) and has been found to be not substantially equivalent (NSE) to a Class I, II, or III [Class III requiring 510(k)] device, then the device must have an approved PMA before marketing in the U.S. Some devices that are found to be not substantially equivalent to a cleared Class I, II, or III (not requiring PMA) device, may be eligible for the de novo process as a Class I or Class II device. For additional information on the de novo process, see “New section 513(f)(2) - Evaluation of Automatic Class III Designation: Guidance for Industry and CDRH Staff” http://www.fda.gov/cdrh/modact/classiii.html or http://www.fda.gov/cdrh/modact/clasiii.pdf .
PMA requirements apply to Class III preamendment devices, , transitional devices, and postamendment devices.
Preamendment Devices
A preamendments device is one that was in commercial distribution before May 28, 1976, the date the Medical Device Amendments were signed into law. After the Medical Device Amendments became law, the classification of devices was determined by FDA classification panels. Eventually all Class III devices will require a PMA. However, preamendment Class III devices require a PMA only after FDA publishes a regulation calling for PMA submissions. The preamendment devices must have a PMA filed for the device by the effective date published in the regulation in order to continue marketing the device. The CFR will state the date that a PMA is required. Prior to the PMA effective date, the devices must have a cleared Premarket Notification 510(k) prior to marketing. Class III Preamendment devices that require a 510(k) are identified in the CFR as Class III and include the statement "Date premarket approval application (PMA) or notice of completion of product development protocol (PDP) is required. No effective date has been established of the requirement for premarket approval." Examples include intra-aortic balloon and control system (21 CFR 870. 3535), ventricular bypass (assist) device (21 CFR 870.3545), cardiovascular permanent pacemaker electrode (21 CFR 870.3680), and topical oxygen chamber for extremities (21 CFR 878.5650).
Postamendment Devices
A postamendment device is one that was first distributed commercially on or after May 28, 1976. Postamendment devices equivalent to preamendment Class III devices are subject to the same requirements as the preamendment devices.
Transitional Devices
Transitional devices are devices that were regulated by FDA as new drugs before May 28, 1976. Any Class III device that was approved by a New Drug Application (NDA) is now governed by the PMA regulations. The approval numbers for these devices begin with the letter N. These devices are identified in the CFR as Class III devices and state that an approval under section 515 of the Act (PMA) is required as of May 28, 1976 before this device may be commercially distributed. An example of such device is intraocular lenses (21 CFR 886.3600). Please note that some of the transitional devices have been subsequently downclassified to Class II.
Devices Used in Blood Establishments
The Center for Biologic, Evaluation, Research (CBER) has expertise in blood, blood products, and cellular therapies as well as the integral association of certain medical devices with these biological products. To utilize this expertise marketing and investigational device submissions (Premarket Notification, Premarket Approval, and Investigational Device Exemption) for medical devices associated with the blood collection and processing procedures as well as those associated with cellular therapies are reviewed by CBER. Although these products are reviewed by CBER, the medical device laws and regulations still apply. The list of medical devices reviewed by CBER are available on the Internet http://www.fda.gov/cber/dap/devlst.htm
In addition to CDRH guidance on Premarket Approval, specific medical device guidance for devices reviewed by CBER is available at http://www.fda.gov/cber/devices.htm or by contacting:
Center for Biologics Evaluation and Research
Office of Communication, Training and Manufacturers Assistance (HFM-43)
1401 Rockville Pike, Room 200N
Rockville, MD 20852-1448 U.S.A.
Telephone Number: 301-827-2000 or 800-835-4709
Fax Number: 301-827-3843
Data Requirements
A Premarket Approval (PMA) application is a scientific, regulatory documentation to FDA to demonstrate the safety and effectiveness of the class III device. There are administrative elements of a PMA application, but good science and scientific writing is a key to the approval of PMA application. If a PMA application lacks elements listed in the administrative checklist, FDA will refuse to file a PMA application and will not proceed with the in-depth review of scientific and clinical data. If a PMA application lacks valid clinical information and scientific analysis on sound scientific reasoning, it will delay FDA’s review and approval. PMA applications that are incomplete, inaccurate, inconsist, omit critical information, and poorly organized have resulted in delays in approval or denial of PMA applications. Manufacturers should perform a quality control audit of a PMA application before sending it to FDA to assure that it is scientifically sound and presented in a well organized format.
Technical Sections: The technical sections containing data and information should allow FDA to determine whether to approve or disapprove the application. These sections are usually divided into non-clinical laboratory studies and clinical investigations.
Non-clinical Laboratory Studies’ Section: Non-clinical laboratory studies’ section includes information on microbiology, toxicology, immunology, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests. Non-clinical studies for safety evaluation must be conducted in compliance with 21CFR Part 58 (Good Laboratory Practice for Nonclinical Laboratory Studies).
Clinical Investigations’ Section: Clinical investigations’ section includes study protocols, safety and effectiveness data, adverse reactions and complications, device failures and replacements, patient information, patient complaints, tabulations of data from all individual subjects, results of statistical analyses, and any other information from the clinical investigations. Any investigation conducted under an Investigational Device Exemption (IDE) must be identified as such.
Like other scientific reports, FDA has observed problems with study designs, study conduct, data analyses, presentations, and conclusions. Investigators should always consult all applicable FDA guidance documents, industry standards, and recommended practices. Numerous device-specific FDA guidance documents that describe data requirements are available. The guidance document database on the Internet can be found at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfGGP/Search.cfm. Study protocols should include all applicable elements described in the device-specific guidance documents.
References
Section 515 of the Federal Food, Drug, and Cosmetic Act
See GPO Site
Class III Devices Subject to 515(b) Requirements, Compliance Policy Guide,
300.750 (CPG 7124.18)
http://www.fda.gov/ora/compliance_ref/cpg/cpgdev/cpg300-750.html
The Least Burdensome Provisions of the FDA Modernization Act of 1997:
Concept and Principles; Final Guidance for FDA and Industry
http://www.fda.gov/cdrh/ode/guidance/1332.html
http://www.fda.gov/cdrh/ode/guidance/1332.pdf
Overview
The review of a premarket approval application (PMA) is a four-step review process consisting of:
Filing a PMA (21 CFR. 814.42)
During the administrative and limited scientific review, FDA determines whether a PMA is suitable for filing by reviewing the PMA submission for information required by the FD&C Act, the PMA regulations (21 CFR 814), and Refuse to File policy. FDA has developed a Checklist for Filing Decision for PMAs.
The filing of an application means that FDA has made a threshold determination that the application is sufficiently complete to begin an in-depth review. Within 45 days after a PMA is received by FDA, the agency will notify the applicant whether the application has been filed. The letter will include the PMA reference number and the date FDA filed the PMA. Expedited review status, if appropriate, may be communicated at this time. The date of filing is the date that a PMA accepted for filing was received by the agency. The 180-day period for review of a PMA starts on the date of filing.
FDA will refuse to file the application for substantive review if a PMA application does not meet a minimum threshold of acceptability. If the information or data are presented unclearly or incompletely or are not capable of withstanding rigorous scientific review, FDA may consider the PMA incomplete and not file it. If FDA refuses to file a PMA, FDA will notify the applicant of the reasons for the refusal. This notice will identify the deficiencies in the application that prevent filing and will include the PMA reference number. FDA will advise the manufacturer of what information must be provided, or steps to be taken, to make the application fileable.
If FDA refuses to file the PMA, the applicant may:
Should the applicant decide to request a meeting concerning a refuse-to-file decision, the applicant must choose either: 1) an informal conference at which the decision not to file the application will be reviewed; or 2) a meeting with the ODE division to discuss the specific deficiencies and the measures necessary to correct these deficiencies. Please be advised that FDA will not typically grant requests for an informal conference and a meeting with the reviewing ODE division regarding this decision due to resource limitations. Applicants should either request an informal conference or schedule a meeting with the reviewing ODE division to discuss the preparation of an appropriate response.
FDA may refuse to file a PMA if FDA determines that any of the following applies:
In-depth review (21 CFR 814.44)
FDA will begin substantive review of the PMA after it is accepted
for filing (§814.42). During the review process, FDA will notify the PMA
applicant via major/minor deficiency letters of any information needed
by FDA to complete the review of the application. The applicant may request
to meet with FDA within 100 days of the filing of the PMA to discuss the
review status of the application. The procedure for "Day-100 Meetings"
can be found in the guidance document "Guidance on PMA Interactive
Procedures for Day-100 Meetings and Subsequent Deficiencies - for Use
by CDRH and Industry; Final"
http://www.fda.gov/cdrh/modact/day100mt.html
http://www.fda.gov/cdrh/modact/day100mt.pdf
If the applicant on their own initiative or at FDA`s request submits a PMA amendment (§814.37) which 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.
Panel Review (21 CFR 814.44)
FDA may refer the PMA to an outside panel of experts (advisory committee). In general, all PMAs for the first-of-a-kind device are taken before the appropriate advisory panel for review and recommendation. However, as soon as FDA believes that (1) the pertinent issues in determining the safety and effectiveness for the type of medical device are understood and (2) FDA has developed the ability to address those issues, future PMAs for devices of that type are not be taken before an advisory panel unless a particular application presents an issue that can best be addressed through panel review.
The PMA, or relevant portions, may be forwarded to each member of the appropriate FDA advisory committee for review. During the review process, FDA may communicate with the applicant [§814.37(b)] or with the advisory committee to respond to questions that may be raised by committee members or to provide additional information to the panel. FDA will maintain a record of all communications with the applicant and with the advisory committee.
If the PMA is referred to an advisory committee, the committee must hold a public meeting to review the PMA in accordance with 21 CFR 14. The advisory committee must submit a final report to FDA that includes the committee’s recommendation and the basis for such recommendation on the PMA. The advisory committee report and recommendation may be in the form of a meeting transcript signed by the chairperson of the committee.
The following documents provide guidance for panel review.
Panel Review of Premarket Approval Applications 5/3/91 (P91-2)
http://www.fda.gov/cdrh/p91-2.html
Criteria for Panel Review of PMA Supplements 1/30/86 (P86-3)
http://www.fda.gov/cdrh/p863.html
FDA takes into consideration the transcript of the meeting, the panel`s recommendation(s), and other information in reaching a final decision on the PMA. FDA informs the applicant whether FDA agrees with the panel`s recommendation or disagrees and what additional information is needed from the applicant (approvable/not approvable decision). If the application is approvable, the applicant must agree to the "Conditions of Approval."
Notification of Approval (§814.44)
Within 180 days of the date of filing of the PMA (§814.40), FDA will complete its review of the PMA and of the advisory committee`s report and recommendation and issue one of the following:
Approval Order
After FDA reviews the committee`s final report, the FDA will issue an order to the applicant that the PMA is approved if none of the reasons in §814.45 (Denial of approval for a PMA) for denying approval of the application applies. FDA will approve an application on the basis of draft final labeling. Approval will be based on the condition that the applicant submits to FDA a copy of the final printed labeling before marketing.
FDA will notify the public of the approval. The announcement of the decision and the availability of a summary of the safety and effectiveness data (SSED) on which the decision is based will be published on the Internet at http://www.fda.gov/cdrh/pmapage.html. The summary will include information about any adverse effects of the device on health. The announcement also provides the applicant and other interested persons an opportunity for administrative review of the FDA approval under section 515(d)(3) of the FD&C Act. On a quarterly basis, FDA will publish a list of approvals announced during that quarter in the Federal Register. When a notice of approval is published, data and information in the PMA file will be available for public disclosure in accordance with §814.9.
Approvable Letter
FDA will send the applicant an approvable letter if the application substantially meets the requirements of the FD&C Act, and FDA believes that 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 that FDA requires to be provided by the applicant or the conditions that the applicant is required to meet to obtain approval. FDA may require, for example, as a condition of approval:
The applicant may have to agree to a postapproval study, restrictions on prescription use, or restrictions on the training of individuals who may use the device before approval. The applicant may also be notified of required postmarket surveillance and/or tracking requirements.
In response to an approvable letter, the applicant may:
Not approvable letter
FDA will send the applicant a not approvable letter if FDA believes that the application may not be approved for one or more of the reasons given in §814.45(a) or if FDA is unable to reach an approvable decision due to a lack of significant information in the application. The not approvable letter will describe the deficiencies in the application, including each applicable ground for denial under section 515(d)(2)(A)-(E) of the FD&C Act. When practical, FDA will identify what is necessary to make the PMA approvable. In response to a not approvable letter, the applicant may:
FDA will consider a PMA to have been withdrawn voluntarily if:
Service of orders (21 CFR 814.17)
Any FDA orders, such as approval or denial, will generally be faxed and then sent to the PMA applicant or its designated agent by mail. A PMA applicant or its designated agent may arrange to pick up the FDA order at 9200 Corporate Blvd., Rockville, Maryland 20850 by contacting the PMA Staff at 301-594-2186.
Standard Conditions of Approval
The "Conditions of Approval" are the standard postapproval conditions imposed by FDA. These are applicable to all original PMAs and PMA supplements. As a condition of approval the sponsor agrees to abide by advertising and final printed labeling requirements and to submit adverse event reports, annual reports, and PMA supplements for certain changes. Additional specific conditions may be required for implanted devices. Applicants should carefully read the conditions of approval enclosed with the FDA approval letter. The "Conditions of Approval" is available on the Internet.http://www.fda.gov/cdrh/devadvice/pma/conditions.html
PMA Amendments 814.37
An applicant may amend a pending PMA or PMA supplement to revise existing information or to provide additional information.
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.
A PMA amendment submitted to FDA shall include the PMA or PMA supplement number assigned to the orignial submission and , if submitted on the applicants’s own initiative, the reason for submitting the amendment. FDA may extend the time required for its review of the PMA or PMA supplement:
If the applicant on its own itnitiatve 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 entended up to 180 days.
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.
Resubmitted PMAs 814.37
Applicants may voluntarily withdraw their 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, FDA will consider the pending PMA or PMA supplement to be withdrawn voluntarily by the applicant (abandoned).
An applicant may resubmit a PMA or PMA supplement that was withdrawn, that FDA has refused to accept for filing, or that FDA has denied approval. A resubmitted PMA or PMA supplement must comply with the requirements of §814.20 or §814.39 and must include the PMA number assigned to the original submission as well as the applicant`s reason for resubmission.
Steps in the PMA Application Process
, Approval Order, , SSED, Final Draft Labeling
Early Collaboration
Applicants are encouraged to contact FDA to obtain further guidance prior to the submission of a PMA application. This will be especially beneficial to new applicants who have not previously had contact with FDA and for applicants proposing to study new technologies or new uses for existing technologies. Early interaction with FDA should help to increase the applicant’s understanding of FDA requirements, regulations, and guidance documents, and will allow FDA personnel to familiarize themselves with the new technologies. Increased interaction between FDA and applicants should help to speed the regulatory process and minimize delays in the development of useful devices intended for human use.
The applicant may request a "PrePMA determination" meeting with FDA. This meeting held early in device development will provide the applicant with the agency`s determination of the type of valid scientific evidence that will be necessary to determine if the device is effective for its intended use. Additional information on early collaborations meetings can be found in "Early Collaboration Meetings under the FDA Modernization Act (FDAMA)" http://www.fda.gov/cdrh/ode/guidance/310.pdf
Once the applicant understands the review process through FDA regulations and guidance documents, the applicant is encouraged to contact the review divisions within the Office of Device Evaluation to discuss device-specific requirements. The PMA staff may be contacted for general questions relating to the PMA laws, regulations, policies, and administrative issues on (301) 594-2186.
FDA Action On a PMA
Denial of approval of a PMA (§814.45)
FDA may deny approval of a PMA if the applicant fails to follow the requirements of the PMA regulation or if FDA determines that any of the grounds for denying approval of a PMA specified in section 515(d)(2)(A)-(E) of the FD&C Act applies. In addition, FDA may deny approval of a PMA for any of the following reasons:
FDA will issue any order denying approval of a PMA in accordance with §814.17. The order will inform the applicant of the deficiencies in the PMA, including each applicable ground for denial under section 515(d)(2) of the FD&C Act and the regulations under Part 814, and, where practical, will identify measures required to place the PMA in approvable form. The order will include a notice of an opportunity to request review under section 515(d)(3) of the FD&C Act.
FDA will use the criteria specified in §860.7 (Determination of Safety and Effectiveness) in deciding whether to approve or deny approval of a PMA. FDA may use information other than that submitted by the applicant in making such determination.
FDA will publish a Federal Register notice of an order denying approval of the PMA. The notice will be placed on the Internet (http://www.fda.gov/cdrh) and will state that a detailed summary of information concerning the safety and effectiveness of the device, including information about any adverse effects on health, is available on the Internet and has been placed on public display. FDA will publish in the Federal Register after each quarter a list of the denials announced in that quarter. When a notice of denial of approval is made publicly available, data and information in the PMA file will be available for public disclosure in accordance with §814.9.
FDA will issue an order denying approval of a PMA after an approvable or not approvable letter has been sent and the applicant has:
Withdrawal of approval of a PMA (21 CFR 814.46)
FDA may issue an order withdrawing approval of a PMA if FDA determines from any information available that:
FDA may seek advice on scientific matters from any appropriate FDA advisory committee in deciding whether to withdraw approval of a PMA. FDA may also use information other than that submitted by the applicant in deciding whether to withdraw approval of a PMA.
Before issuing an order to withdraw approval of a PMA, FDA will issue the holder of the approved application a notice of opportunity for an informal hearing under 21 CFR 16. If the applicant does not request a hearing or, if after the 21 CFR 16 hearing is held, FDA decides to proceed with the withdrawal, FDA will issue an order withdrawing approval of the application. The order (§814.17) will state each ground for withdrawing approval and will include a notice of an opportunity for administrative review under section 515(e)(2) of the FD&C Act.
FDA will publish a Federal Register notice of an order withdrawing approval of a PMA. The notice will state that a detailed summary of information concerning the safety and effectiveness of the device, including information about any adverse effects on health, has been placed on public display and that copies are available upon request. When a notice of withdrawal of approval is published, data and information in the PMA file will be available for public disclosure under §814.9.
Temporary Suspension of Premarket Approval (§814.47)
If, after providing the sponsor with an opportunity for a regulatory informal hearing regarding the proposed withdrawal of PMA approval, and FDA determines there is a reasonable probability that continued distribution of a PMA-approved device would cause serious adverse health consequences or death, FDA shall by order temporarily suspend the PMA. In cases where there is sufficient grounds, FDA will proceed expeditiously to withdraw the PMA approval.
Section 515 of the Federal Food, Drug, and Cosmetic Act
http://www.fda.gov/opacom/laws/fdcact/fdcact5a.htm
PMA Refuse to File Procedures (P94-1)
http://www.fda.gov/cdrh/pma941.html
PMA Filing Decision (P90-2)
http://www.fda.gov/cdrh/pma90-2.html
Checklist for Filing Decision for PMA
http://www.fda.gov/cdrh/ode/checklist/pma.html
Clinical Utility and Premarket Approval (P91-1)
http://www.fda.gov/cdrh/p91-1.html
Panel Review of Premarket Approval Applications 5/3/91 (P91-2)
http://www.fda.gov/cdrh/p91-2.html
Criteria for Panel Review of PMA Supplements 1/30/86 (P86-3)
http://www.fda.gov/cdrh/p863.html
Panel Review of PMAs for "Me Too" Devices 7/25/86 (P86-6)
http://www.fda.gov/cdrh/p866.html
CDRH > Device Advice > Premarket Approval > PMA Review Fees
Overview
Fees
Exemptions and Waivers
When to Pay
How/Where to Send Payment
Qualification for Small Business Fees
Guidance Documents
On October 26, 2002 the Medical Device User Fee and Modernization Act of 2002 was signed into law. This law authorizes FDA to charge a fee for medical device product reviews. These fees apply to Premarket Approvals (PMAs), Product Development Protocols (PDPs), Biologics Licensing Applications (BLAs for certain medical devices reviewed by FDA's Center for Biologics Evaluation and Research), certain supplements, and Premarket Notifcation 510(k)s.
The fee must be paid for the above listed applications, unless the applicant is eligible for a waiver or exemption. Small businesses may qualify for a reduced fee. Payment must be received on or before the time the application is submitted. If the applicant has not paid all fees owed, FDA will consider the application incomplete and will not accept it for filing.
For fiscal year 2008 (October 1, 2007 through September 30, 2008), the fees for PMA applications are:
| FY 2008 Device Review User Fees (U.S. Dollars) | ||
| Type of Application |
Standard Fee | Small Business Fee (<$100 million sales) |
|---|---|---|
Premarket Application (PMA, PDP, BLA, PMR)* NOTE: The fee is waived for the first premarket application from firms with gross receipts or sales <$30 million. |
$185,000
|
$46,250
|
| Premarket Report (PMR) - premarket approval application for a reprocessed device | $185,000 | $46,250 |
| Efficacy Supplement (for BLA) | $185,000 | $46,250 |
| Panel-track Supplement | $138,750 | $34,688 |
| 180-day Supplement (There is no fee for manufacturing site change supplements.) |
$27,750 | $6,938 |
| Real-time Supplement | $12,950 | $3,237 |
| 30-Day Notice/135-Day PMA Supplement** | $2,960 | $1,480 |
| Annual Fee for Periodic Reporting on a Class III Device** | $6,475 | $1,619 |
| Special PMA Supplements |
No fee | No fee |
| Postapproval study protocol supplements or supplements that include labeling changes as a result of postapproval studies. | No fee | No fee |
* PMA=Premarket Approval; PDP=Product Development Protocol; BLA=Biologics License Application; PMR=Premarket Report (for a reprocessed device)
**New for FY08
The applicable fee corresponds with the date of receipt of the submission by FDA. Please note that FDA will consider the application incomplete and will not accept it for filing until the fee is paid in full. That is, the date of receipt is the date that the application has been received AND the fee is paid in full.
Guidance on assessing user fees can be found in "Assessing User Fees: PMA Supplement Definitions, Modular PMA Fees, BLA and Efficacy Supplement Definitions, Bundling Multiple Devices in a Single Application, and Fees for Combination Products" http://www.fda.gov/cdrh/mdufma/guidance/1201.pdf
FDA will adjust the fees each year to account for inflation, changes in workloads, and other factors. FDA will announce the new fees for the next fiscal year in a Federal Register notice by August 1 of each year.
The following types of applications require no fee.
The following exemptions or waivers apply.
Fee Exemptions and Waivers (No Fee for These) |
|
| Category |
Exemption or Waiver |
|---|---|
| First premarket application (PMA, PDP, BLA, or premarket report) from a small business with gross receipts or sales <$30 million . | One-time waiver of the fee that would otherwise apply. |
| Any application for a device intended solely for pediatric use. | Exempt from any fee. If an applicant obtains an exemption under this provision, and later submits a supplement for adult use, that supplement is subject to the fee then in effect for an original premarket application. |
| Any application from a State or Federal Government entity. | Exempt from any fee unless the device is to be distributed commercially. |
Payment must be received at or before the time the application is submitted. If the applicant has not paid all fees owed, FDA will consider the application incomplete and will not accept it for filing.
Submit the information and payment in the following order
Complete the Medical Device User Fee Cover Sheet
You should complete the Medical Device User Fee Cover Sheet (Form FDA-3601) online. The Medical Device User Fee Cover Sheet and instructions are available at http://www.fda.gov/oc/mdufma/coversheet.html
You will need to register to create a Medical Device User Fee Cover Sheet. Please note that the User Fee Cover Sheet website was enhanced on March 1, 2005. Even if you have registered in the User Fee Cover Sheet system previously to March 1, 2005, you will need to follow the instructions as a "New User."
You will need one of the following pieces of information to complete the registration process.
| Organization #: | 123456 |
| Dun and Bradstreet Number (DUNS) # | 123456789 |
| Employer Identification Number (EIN) # | 123456789 |
Additionally, you will need to identify a Principal Point of Contact (PPOC) in your organization who will be responsible for validating users for security purposes.
After you have registered and have created a user name and password, you will receive a confirmation email. You may then access the cover sheet creation page. A unique user fee Payment Identification Number will be generated on your cover sheet upon completion. You will need three copies of your completed User Fee Cover Sheet: one copy for your payment, one copy for your PMA application, and one copy for your records.
Frequently Asked Questions addresses common questions regarding the Medical Device User Fee Cover Sheet.
Submit Your Payment
Send a printed copy of your User Fee Cover Sheet with your payment. Be sure to include the Payment Identification Number (beginning with MD) and the FDA P.O. Box on your check, bank draft, or U.S. Postal Money Order. The review fee may be submitted by mail, courier, or wire transfer. Send your payment to:
By Mail:
Food and Drug Administration
P.O. Box 956733
St. Louis, MO 63195-6733By Courier:
If the check is sent by a courier, the courier may deliver the checks to:US Bank
Attn: Government Lockbox 956733
1005 Convention Plaza
St. Louis, MO 63101
(Note: This address is for courier delivery only. Contact the US Bank at (314) 418-4821 if you have any questions concerning courier delivery.)By Wire Transfer:
If using a wire transfer, you may send your payment using the following information. Please note that you are responsible for paying all wire transfer fees. FDA has found that wire transfer can delay proper crediting of your payment and may delay the start of your review.
Account Name: Food and Drug Administration
Account Number: 152302010631
Routing Number: 081000210
Swift Number: USBKUS44IMTAlso include your user fee Payment Identification Number from your Medical Device User Fee Cover sheet when you send payment by wire transfer.
Note: Contact US Bank at 314-418-4821 if you have a question about how to send payment by wire transfer. Your bank or financial institution may assess a fee for sending a wire transfer.
If needed for accounting purposes, FDA's tax identification number is 53-0196965.
Fees should arrive at the bank at least 1 day before the application arrives at FDA. FDA recommends that you send the payment to the bank 4-5 business days before the application arrives at FDA so there is no delay in starting the review of your application. FDA records as the application receipt date the latter of the following:
US Bank is required to notify FDA within 1-working day, using the Payment Identification Number.
Qualification for Small Business Fees
In FY 2008 (October 1, 2007 through September 30, 2008), firms with annual gross sales and revenues of $100 million or less, including gross sales and revenues of all affiliates, partners, and parent firms, may qualify for lower rates for PMAs, premarket reports, and supplements. The fee is waived for the first premarket application from firms with <$30 million gross receipts or sales .
An affliliate is defined by §737(8) of the FD&C Act: An affiliate means a business entity that has a relationship with a second business entity if, directly or indirectly,
To qualify, you must submit the MDUFMA Small Business Qualification Certification (Form FDA 3602). In addition, certified copies of you firm's Federal Income Tax Return for the most recent taxable year, including certified copies of the income tax returns of all affiliates, partners, and parent firms must be provided.
The following guidance and form should be used.
FY2008 MDUFMA Small Business Qualification Worksheet and Certification (Available Soon)
The Certification should be sent to:
MDUFMA Small Business Qualification (HFZ-222)
Division of Small Manufacturers, International and Consumer Assistance
1350 Piccard Dr.
Rockville, MD 20850
FDA will review the Certification within 60 days and send its decision that you are, or are not, a small business eligible for reduced or waived fees. If your firm qualifies as a small business, the decision letter will include a Small Busines Decision number. The Small Business Decision number is used on the Medical Device User Fee Cover Sheet (Form FDA 3601) to demonstrate that your firm is entitled to a reduced or waived fee. If you submit a reduced fee to FDA without a Small Business Decision number, the submission will not be accepted for filing.
The small business status expires at the end of each fiscal year (September 30th). A new MDUFMA Small Business Qualification Certification must be submitted each year to qualify as a small business.
Questions concerning Small Business Qualification should be directed to Division of Small Manufacturers, International and Consumer Assistance at 240-276-3150 (800-638-2041) or dsmica@cdrh.fda.gov
Bundling Multiple Devices or Multiple Indications in a Single Submission
Additional information and guidance on medical device user fees is available on the CDRH user fee website.
Traditional PMA
A PMA application involves many volumes of material to be submitted to FDA. The volumes include device description and intended use, nonclinical and clinical studies, case report forms, manufacturing methods, labeling, etc. In the traditional PMA method, the complete PMA application is submitted to FDA at once. This method is generally used if the device has already undergone clinical testing and has been approved in a country with established medical device regulations. FDA has established methods of early collaboration with the sponsor allowing devices to brought to market as early as possible. These methods include the Modular PMA, Streamlined PMA, and Product Development Protocol and are discussed below.
Modular PMA
In a Modular PMA the complete contents of a PMA are broken down into well-delineated components (or module) and each component is submitted to FDA as soon as the applicant has completed the module, compiling a complete PMA over time. The PMA is viewed as a compilation of sections or "modules," such as preclinical, clinical, manufacturing, that together become a complete application. This method is recommended for products that are in early stages of clinical study. This method is not appropriate when the applicant is very close to being ready to submit a PMA or when the device design is in a state of flux or likely to change.
The process begins with a PMA Shell which lays out the plan for submission of the modules. The shell is an outline of modules and identifies information necessary to support the filing and approval of a specific Class III product through a combined IDE-PMA process. The review team will work with applicants to develop a customized shell for each specific product that includes module contents and suggested timelines. It is developed individually with the manufacturer for a specific device.
FDA reviews each module separately as soon as it is received allowing manufacturers to receive timely feedback during the review process. This may allow more rapid closure when the last components are submitted because much of the review work will have already been done.
Additional information on the Modular PMA process can be found in the following documents:
Premarket Approval Application Modular Review
Streamlined PMA
The streamlined PMA is a pilot program in the Division of Clinical Laboratory Devices. A complete PMA is submitted as in a traditional PMA; however, the Streamlined PMA is for a device in which the technology and use are well known to FDA. A Streamlined PMA review may be appropriate for PMAs when there is either:
During the protocol and PMA review, the sponsor must be available for an interactive review process. Ideally, prior to beginning studies to determine the safety and effectiveness of the product to be included in this pilot program, the sponsor would submit its protocol for FDA review. Familiarity with the product and protocol as part of this up-front evaluation should streamline the review of the PMA once filed.
Additional information can be found in the following document:
In Vitro Diagnostic Model for a Pilot for Streamlined PMA Review
Product Development Protocol (§814.19)
In the product development protocol (PDP) method for gaining marketing approval, the clinical evaluation of a device and the development of necessary information for marketing approval are merged into one regulatory mechanism. Ideal candidates for the PDP process are those devices in which the technology is well established in industry. The PDP process provides the manufacturer with the advantage of predictability once the agreement has been reached with FDA.
The PDP allows a sponsor to come to early agreement with FDA as to what would be done to demonstrate the safety and effectiveness of a new device. Early interaction in the development cycle of a device allows a sponsor to address the concerns of the FDA before expensive and time consuming resources are expended.
The PDP is essentially a contract that describes the agreed upon details of design and development activities, the outputs of these activites, and acceptance criteria for these outputs. It establishes reporting milestones that convey important information to the FDA as it is generated, where they can be reviewed and responded to in a timely manner. The sponsor would be able to execute their PDP at their own pace, keeping FDA informed of its progress with these milestone reports. A PDP that has been declared completed by FDA is considered to have an approved PMA (§814.19).
Humanitarian Device Exemption (§814 Subpart H)
Overview
An Humanitarian Use Device (HUD) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year. A device manufacturer`s research and development costs could exceed its market returns for diseases or conditions affecting small patient populations. The HUD provision of the regulation provides an incentive for the development of devices for use in the treatment or diagnosis of diseases affecting these populations.
To obtain approval for an HUD, an humanitarian device exemption (HDE) application is submitted to FDA. An HDE is similar in both form and content to a premarket approval (PMA) application, but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The application, however, must contain sufficient information for FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, and that the probable benefit to health 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. Additionally, the applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that they could not otherwise bring the device to market.
An approved HDE authorizes marketing of the HUD. However, an HUD may only be used in facilities that have established a local institutional review board (IRB) to supervise clinical testing of devices and after an IRB has approved the use of the device to treat or diagnose the specific disease. The labeling for an HUD must state that the device is an humanitarian use device and that, although the device is authorized by Federal Law, the effectiveness of the device for the specific indication has not been demonstrated.
Form FDA-3674, ClinicalTrials.gov Data Bank
Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) included a provision that all HDE applications are required to be accompanied with certification that all applicable clinical trial information has been submitted to the ClinicalTrials.gov data bank.
Beginning December 26, 2007, HDE applications must include form FDA-3674. If your HDE includes data from a clinical trial, you must determine if your study is applicable for entry into the clinical trial registry data bank at ClinicalTrials.gov. Based on this determination, check box 9.B. or 9.C., and complete the applicable sections of the form. An applicable device clinical trial is a prospective clinical study of health outcomes comparing an intervention with a device against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes). See Title VIII - Clinical Trial Databases. Currently, FDA is reviewing the legislation and developing guidance on which clinical trials meet the definition of "applicable" trials and are required to report to ClinicalTrials.gov. Until FDA issues this guidance, the HDE sponsor is responsible for determining whether its studies meet the definition of an applicable trial and, therefore, are subject to reporting requirements.
Information on how to register your clinical trial(s) in the ClinicalTrials.gov data bank is available on the National Library of Medicine (NLM) Protocol Registration System (PRS) website.
Additional information on HUDs can be found in the following documents.
Humanitarian Use Program Information (includes a list of approved HDEs)
Humanitarian Devices Exemptions (HDE) Regulation Questions: and Answers
Humanitarian Devices Exemptions (HDE) Checklist for Filing Decision
*NEW*
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 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 investiations 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" .
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 CFR814.20(d). Refer to Item 31 in the preamble to the PMA regulation for further information.
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 availabe on the Internet at http://www.fda.gov/cdrh/comp/eprc.html
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 at http://www.fda.gov/cdrh/stdsprog.html.
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.
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 regulations, 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:
If the study was not conducted in compliance with these regulations, include a brief statement of the reason for the noncompliance.
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"
http://www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2
) 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" http://www.fda.gov/cdrh/dsma/pmaman/appdxe.html#P7_2 for further information.
Premarket Submissions Coversheet
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.
Premarket Submissions Coversheet
http://www.fda.gov/cdrh/manual/precovsh.html
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.
General Suggestions
Suggested Formats
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
[Date]
Document Mail Center (HFZ-401)
Center for Devices and Radiological Health
Food and Drug Administration
9200 Corporate Blvd.
Rockville, MD 20850
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].
Sincerely yours,
[signature]
[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:
The following information should be submitted in separate volumes:
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.
Send 6 copies of an original PMA, clearly identified as such, to:
Document Mail Center (HFZ-401)
Center for Devices and Radiological Health
Food and Drug Administration
9200 Corporate Blvd.
Rockville, MD 20850
Summary of Safety and Effectiveness Data (§814.44)
Overview
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.
Authority
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).
When required
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.
Purpose
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.
SSED preparation
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
PMA number*
Date of Panel recommendation*
Date of notice of approval to the applicant*
(*to be completed by FDA unless known to the applicant)
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)
Laboratory studies
Animal studies
Additional studies
Study design
Patient assessment
Demographic data
Data analysis and result
Device failures and replacements
Risk/benefit analysis
Safety
Effectiveness
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. Additional guidance on statistical evaluation of medical devices can be found in "Statistical Aspects of Submissions to FDA: A Medical Device Perspective." http://www.fda.gov/cdrh/osb/guidance/fod537.pdf (This guidance also includes "Observed Uses and Abuses of Statistical Procedures in Medical Device Submissions.")
PMA Review Statistical Checklist
http://www.fda.gov/cdrh/ode/84.pdf
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.
Premarket Approval Application Filing Review