510(k) Premarket Notification

 

Santhosh S, Dr. R. Kamaraj

Department of Pharmaceutical Regulatory Affairs, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur - 6030203, Kanchipuram, Tamilnadu, India.

 

ABSTRACT:

Premarket approval application is not essential but 510(k) must submit to FDA to market medical device in the U.S for human use. To conclude or to determine the device is substantially equivalent to the device which is already marketed. After getting a 510(k) clearance immediately device can be marketed by submitter. In such case where already marketed device is changed in its safety or effectiveness it might affect the manufacturer and there is essential to file a 510(k) submission by manufacturer. Manufacturer should submit 510(k) to FDA in case of modifications or changes in use, chemical composition, design, energy source etc,.510(k) submission depends upon the comparison between the already marketed device and new device in the U.S, to ascertain whether the device is safety and effectiveness.²

 

 

 

INTRODUCTION:

To sell a medium-risk medical device or IVD  510(k) is the technical dossier which is need to FDA. It is known as Pre-Market Notification. Detailed technical, safety, and performance information available in the 510(k) about a medical device. Before you can legally sell or distribute it in the United States FDA must review the 510(k) and "clear" your device.

 

To market or to sell a medium-risk medical device or IVD 510(k) technical dossier is essential by the FDA which is known as pre-market notification. In detail about the safety and performance information of the medical device is available in 510(k). your device should get clearance from the FDA and get reviewed by the FDA before to sell or distribute in the U.S.

 

510(k) is essential and required for all the medical devices and IVDs. 513(g) can be submitted if the product classification is not determined.

 

 

Preparation of FDA 510(k) for medical devices:

Preparing a 510(k) is a challenging task to FDA and it is fairly strict about how to organize the submission. 20 individual sections are required to address each 510(k) requirements. All required protocols, relevant test reports and other documents should be submitted as attachments.  Mostly eCopy (electronic document) 510(k)s review submission requirements to be taken for over 100 pages.¹

 

Who Can Submit a 510(k)?

Following members can submit 510(k) to Food and Drug Administration (FDA):

Manufacturers introducing a device in to the U.S. market;

 

If the device which is manufactured according to their own specifications, then for marketing the device in the U.S control manufacturer not required to submit 510(k) but finished manufacturer should submit 510(k).

1.      510 (k) must submitted by the specification developers to introduce into the U.S.

        For finished device Specifications are developed by the specifications for a finished device. Specification developer should submit the document it is not required to submit by the contract manufacturer.

2.      Relabelers and repackers who make modifications or changes in the labelling whose functions crucially  affect the device.

3.      510(k) should submit by the repackers or relabelers if any modifications or changes are made in the labelling.

4.      Foreign manufacturers/exporters (US representatives) should submit the 510(k).

 

When a 510(k) is Required:

There is a requirement of 510(k) is in following conditions such as:

1.      To vend a device in the U.S after May 28, 1976 510(k) is required to submit by the manufacture at least before 90 days even though it may have been clinical investigation or under development before that date.

2.      If any changes are made in already marketed device if the changes significantly effects safety or effectiveness then the manufacturer should submit 510(k) accordingly with 21 CFR 820.

 

When a 510(k) is Not Required:

510(k) is not required in certain cases such as:

1.      510(k) requirement is not essential if the device is not being distributed or marketed.

2.      If there is no changes in the labelling with same indications for warnings, contraindications and use then no need to submit the 510(k) by the holder.

3.      If no labelling changes are made in the use, warnings and contraindications then no need to submit the 510(k) by the holder.

4.      Before May 28, 1976 If device is legally in commercial distribution and if there is no changes or modifications in design, components, use and manufacturing method.

5.      If the foreign manufacturer got a 510(k) clearance for the device, then 510(k) is not essential.

6.      There are some of the Class I and class II device for the 510(k) is not essential for marketing device for the first time. These types of devices can be found on Medical Device Exemption (MDE) GMP Requirements and 510(k) but if the device be over the limitation i.e., in use, or operates using a fundamental technology than a legally marketed device then 510(k) is required to submit by the holder or manufacturer.²

 

Classification of medical device:

Classification of medical device is done based upon the risk which are classified into three different types:³

When Premarket Notification is reviewed by it, medical device is classified by FDA.

 

Class I (Low Risk):

These are determined as low risk device if they are misused they don’t cause any harm and they will not treat potentially fatal conditions. Class I devices does not require FDA approval, but they are controlled by other regulations and rules, likely adulteration, misbranding, information required by the customer must be given.

 

They are also available over the counter. Examples of Class I devices include latex gloves, Dental floss, and adhesive bandages.

 

Class II devices (medium risk):

These are called as “medium risk”. Harm can be occurred if they are misused and they are not used to treat fatal conditions.

 

Class II devices are Medical device which is marketed before May 28, 1976 if it is “substantially similar”. Manufacturer allows to sell without completing rest of the FDA approval process if FDA found Premarket Notification determines a “substantially similar” device.

 

Class III Devices (high risk):

Class III devices are high risk devices. If it is misused there is a chance of high risk of injury or death. Class III devices are devices for saving lives, or devices implanted in the body or both.

 

Manufacturer should follow Premarket Approval (PMA) process. Class III devices are not applicable for 510(k) clearances.⁴

 

Process of 510K Submission:

510(k) submissions for medical devices are reviewed by

·      The FDA’s Centre for Devices and Radiological Health (CDRH)

·      Especially by the Office of Device Evaluation (ODE) and

·      The Office of in Vitro Diagnostics Radiological Health (OIR).

 

OIR and ODE staff reviews the 510(k) submissions include chemists, physicians, biomedical engineers, microbiologists and other medical professionals.

 

Procedure for Log In:

Submitter should submit two copies of 510(k) to CBER’s or CDRH’s Document Control Centre (DCC). For medical device submission web page current mail address for CBER’S DCC’S and a link to CDRH’s DCC mailing address are provided.

 

1 copy must be an electronic copy (an eCopy).

Unique control number was given when DCC receives 510(k) submission. This is known as “K number” or “510(k) number”. 510(k) number begins with the letter “K” and followed by six digits. The first two digits represents the calendar year the submission was taken; submission number for the year was specified by the last four digits, starts with the 0001 and get increases with each new submission.

 

e.g. For calendar year 2014the first 510(k) submission would be K140001.

DCC conducts 2 verifications to assure that:

1.    Whether to confirm that the payment of fee had received properly for the submission user.

2.    Valid eCopy  of 510(k) submission was given.

 

If valid eCopy and fee should be paid by the submitter within 7 days of the receipt, then submitter receives the Hold Letter through email by the DCC. Within 180 calendar days from the date of submission submitter should resolve all the issues with the eCopy or use fee and if not, then submitter should submit the new copy.

 

If a valid eCopy and a proper user fee has been paid Acknowledgment Letter get receives from DCC through email.

 

If the proper fee and a valid eCopy submitted by the holder, then holder receives acknowledgement letter from the DCC through an email. Following are identified by the Acknowledgement Letter:

·      Receipt’s date (the date that FDA received the 510(k) submission, an eCopy and the proper user fee payment);

·      The receipt’s date (this is the day that 510(k) submission was received by FDA, valid eCopy, and proper user fee payment); and

·      510(k) number.⁵

 

Acceptance Review:

After OIR or ODE Division receives the Acknowledgement Letter DCC routes the 510(k) depends on the medical speciality and device which is listed in the submission of 510(k).

 

Within 15 days of submission electronic notification get receives by submitter, Acceptance Review which will,

·      Lead reviewer name assigned to the 510(k) and contact information; and

·      Determines the status of 510(k).

 

The result of the Acceptance Review as follows:

·      510(k) - accepted for substantive review; or

·      510(k) - not accepted for review; or

·      510(k) is under substantive review

 

Within 180 calendar days submitter should resolve all the issues and deficiencies occurred if not 510(k) gets deleted form and withdrawn form from the review system then submitter should submit a new copy.

Once it gets accepted, 510(k) undergoes the Substantive Review.

 

Substantive Review (both Interactive Review and Substantive Interaction):

Through a Substantive Interaction lead reviewer conducts a comprehensive review of the 510(k) submission during Substantive Review, which should take place within 60 calendar days of receipt of the 510(k) submission.

 

Substantive Interaction:

it is as follows:

·      Holder gets an email through an interactive review stating the FDA will clear any deficiencies; or

·      Additional information - request which keeps the submission on hold.

 

Interactive Review:

During the review of interaction submitter get communicates with the Lead Reviewer through:

·      Communication through telephone

·      Email

 

During interactive review lead reviewer may request (AI) additional information from the submitter can get the information directly to DCC or to the lead reviewer.

Note: A valid eCopy must include during the interactive review.

 

AI (Additional Information) Request

If the Lead Reviewer sends an AI Request, Submission is placed on hold. From the date of the AI Request the submitter has 180 calendar days to submit a complete response to the AI Request.

 

Submission is placed on hold, if AI request receives from the Lead Reviewer. From the date of AI Request to submit a complete response to the AI Request submitter contains 180 calendar days.

 

Note:

Within 180 calendar days response should get received by the holder from the day when the AI request has been requested by the holder and it should be received in the DCC. There will be no extensions are granted beyond 180 days.

 

If it doesn’t get complete within given 180 calendar days the submitter should submit a new copy for 510(k) clearance.

 

With a valid eCopy submitter must submit the response to the DCC. The response should:

·        List 510(k) number;

·        Include the submitter’s name;

·        For additional information list the date of FDA's request

·        In an organized manner provide the requested information.

 

Decision Letter:

For 510(k) FDA goal is 90 FDA days for MDUFA decision.

 

FDA will issue a decision letter to the submitter through email which is provided in the 510(k)-cover letter, when a decision is made.

 

Through an email submitter gets decision letter by the FDA when decision is made which is given in the 510(k)-cover letter.

 

When SE decision is received by 510(k) it is determined as cleared. To the SE letter will be sent as attachment to IFU.

 

Communication timeline with 510(k) Applicants:

During the review of 510(k) submissions MDUFA III performance goals are followed by the FDA.  From the below flowchart interaction mile stones and simplified event of summary are provided.⁵

 

during 510(k) Review communication timeline

 

Day 1: FDA receives 510(k) submission

By Day 7

FDA sends Acknowledgement letter Or FDA sends Hold Letter if unresolved issues with User Free and/or eCopy

By Day 15

FDA sends Acceptance Review   FDA informs submitter if 510(k) is accepted for substantive review or placed on RTA Hold

By Day 60

FDA Conducts substantive Review   FDA communicates via a substantive interaction to inform the submitter that the FDA will either proceed with interactive Review or that the 5410(k) will be placed on hold and Additional Information is required

By Day 90

FDA sends final MDUFA Decision on 510(k)

By Day 90

If MDUFA Decision is not reached by Day 100, FDA provides Missed MDUFA Decision Communication that identifies outstanding review issues

 

 

FDA review times for 510(K) submissions:

For 510(k) review90 calendar days for the FDA timeframe. If the FDA issues a Refuse-to-Accept (RTA) or Additional Information (AI) letter, which indicate the FDA needs more information or documentation to complete their review the 90-day review clock stops. Within 180 day calendar days responses to RTA and AI requests must be submitted.

 

510(K) Submission Methods:

Applicant may choose from the following three types 510(k) submissions from market clearance:

·      Abbreviated 510(K)

·      Traditional 510(K)

·      Special 510(K)

 

A s provided in 21 CFR 807 Traditional methods is the original complete submission as provided in 21 CFR 807. To streamline the evaluation of Premarket Notifications in 1998, FDA developed "The New 510(k) Paradigm". For obtaining 510(k) marketing clearance under certain instances The New 510(k) Paradigm provides two optional approaches to the Traditional 510(k) method: Abbreviated 510(k) and Special 510(k). The Special 510(k): Certain aspects of the Quality System Regulation is utilized by device modification and the Abbreviated 510(k) relies on the use of special controls, guidance documents, and recognized standards to facilitate 510(k) review.

 

To gain any details permit by the regulationsor statue FDA's ability does not get affect by the use of either alternative.⁶

 

 

 

 

 

 

 

Approval Process of 510(k):

The process of approval of 510(k) starts with filing of 510(k) form which is also known as Premarket Notification (PMN) as like the approval process of medical device. Before marketing the device manufacturer should wait for 90 days after filing the PMN. FDA examine the PMN and determines whether the device classified as class II or it is “substantially equivalent” to already marketed device.

 

If the risks and benefits are same as already marketed device i.e., if it substantially equivalent to already marketed device then it may get 510(k) clearance.

 

Without testing it allow the manufacturer to start vending the device if FDA has determined that the new device is similar to already marketed device. This is known as 510(k) clearance.

 

Evolution of the 510(k) Program:

On June 30, 1986 this guidance gives an updated information to the existing guidance document which was entitled “Guidance on the CDRH Premarket Notification Review Program, 510(k) Memorandum K86-3” (K86-3 Guidance). This latest updated guidance on febrauary 27, 1997 written and issued as final guidance and it is not updated since its initial publication date.⁷

 

CONCLUSION:

Section 510(k) of the FDA requires atleast  90 days before device manufacturer must register ,atleast 90 days before to market a medical device so that FDA can notify. This is known as PMN- also called 510(k) or premarket notification, from this FDA can determine whether the Medical device is substantially equivalent to already marketed device. If there is a change in material, design, chemical composition, manufacturing process, energy source, intended use manufacture of medical device should submit premarket notification.⁸

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

ACKNOWLEDGMENT:

Authors want to acknowledge the management of SRM College of Pharmacy, SRM Institute of Science and Technology for their valuable support.

 

 

REFERENCES:

1.     https://www.energobyul.com/resources/fda-510k-quick-answers

2.     https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/default.htm#top

3.     https://oig.hhs.gov/oei/reports/oei-04-10-00480.pdf

4.     http://www.rotlaw.com/legal-library/what-is-the-fdas-510k-approval-process/

5.     https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/ucm070201.htm

6.     https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/ucm134034.htm

7.     https://www.fda.gov/downloads/MedicalDevices/.../UCM284443.pdf

8.     https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/510kClearannces/

 

 

 

 

 

Accepted on 30.08.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(12): 5675-5780.