1. Medical Device Premarket Submission Challenges and the Effect of MDUFA IV
Robin Fatzinger, RAC
VP, Regulatory Affairs
Aesculap

2. My background 27 years in medical device industry.
Responsible for Quality Control, Quality Assurance, Regulatory Affairs & Clinical Affairs.
Experience with in vitro diagnostics, cardiovascular devices, collagen based and other resorbable implants, spine, total joint, tissue closure devices (including glues, sutures, and RF seal & cut), neurosurgical devices, general surgical instruments and sterile container systems.
Recently took over Regulatory responsibility for autologous cartilage repair combination product under clinical investigation.
Active member of Advamed 510(k) working group.
Last 6 years team have submitted over (k)s

3. Aesculap 150 year old privately held company
Division of B. Braun family of companies
Based in Tuttlingen Germany
US Corporate HQ Center Valley, PA

4. In the beginning….
Food, Drug, & Cosmetic Act of 1938 included definition of medical device but FDA’s authority allowed only for “policing” through the 1960’s.
Early 70’s saw pacemaker failures and Dalken Shield IUD complications lead to the signing of the Medical Device Amendments of 1976.
CDC estimated that there were 7,900 IUD related hospitalizations in the first 6 mos. Of 1973

5. Medical Device Amendments
Implemented a risk based classification system for regulation of devices:
Class 1 - Low risk requiring general controls. Most exempt from premarket notification.
Class 2 - moderate risk requiring general controls and special controls. Most but not all require premarket notification [510(k)].
Class 3 - High risk requiring general controls and premarket approval (PMA).
General controls apply to all classes of medical devices and provide FDA with the means of regulating devices to assure their safety and effectiveness. General controls include but are not limited to provisions that relate to establishment registration and device listing; premarket notification, although most class I devices are exempt by regulation from this requirement; prohibitions against adulteration and misbranding; records and reports (eg. complaints/reportable events; and good manufacturing practices.

6. What are the main differences between submission types?
510(k)
PMA
Basis
Substantial Equivalence to predicate device
Safety and Effectiveness
Review Time
90 days
180 days
Content
Clinical data not normally required
Manufacturing and quality not normally required
Clinical data normally required
Manufacturing and quality data required
Inspection
No pre-approval inspection required
Pre-approval inspection required
Cost
$10,566
$310,764
Postmarket Requirements
No annual reports
Annual reports
Often postmarket clinical study

7. How do I know what class my device is?
Start with the FDA Product Code Database
Epidural Catheter. Searched for “catheter”. Both class 1 and 2 device product codes, need to narrow your search. Now let’s look at a more complicated device.

8. 510(k) is most common submission process
Basis is “substantial equivalence” to a predicate device.
Must have the same intended use and technological characteristics or the differences in the technological characteristics must not raise different questions regarding safety and effectiveness.
Intended Use = general purpose / function
Indications for Use = describes a specific disease, condition, and/or patient population

9. Where can I find a predicate device?
Key Points:
Select a predicate with identical indications for use (or very close).
Select a predicate with similar technology.
Select a predicate that has been cleared recently.
Important to work with Marketing to understand how the product will be marketed? Who is the competitor? What claims do they want to make?

10. What if I can’t find a predicate?
Submit a 513(g) request to FDA ($4,195 fee). FDA will respond with the required regulatory path either 510(k) or PMA.
Use the FDA Pre-Submission (Q-sub) Process.
File a de Novo ($93,229) after using one of the above processes for novel devices that are low to moderate risk. If a de Novo is rejected a PMA will be required.

11. So your device is class 2!

12. 510(k) Challenges - The RTA Process
Since 2013, FDA reviewers are required to use the RTA checklist (Refuse to Accept) in order to ensure that 510(k) applications are administratively complete prior to moving on to a more substantive review.
510(k) that are not complete are put on hold for up to 180 days.
Concern that deficiencies are not always administrative but are a result of more substantive review.
Always use the RTA checklist and include page numbers in the submission where information can be found. Provide scientific rationales for missing data.

13. 510(k) Challenges - Predicate Issues
FDA now encourages the use of a single predicate, but may allow “reference predicates”.
Since FDA has clarified that the regulations require a new device to have the same intended use AND the same technological characteristics, the use of “split predicates” (one predicate for intended use and another for technological characteristics) is no longer allowed by FDA.
Do not “play up” the differences in your device or what makes it special from a marketing perspective.

14. 510(k) Challenges - The Smart Template
FDA recently implemented Smart Template.
Intended to speed the review and ensure consistency across ODE.
Approximately 200 stock deficiencies written by subject matter experts (eg. sterilization, biocompatibility, etc).
Deficiencies can appear vague and require follow up clarification.
Concern that reviewers are “just checking the box”

15. 510(k) Challenges - Biocompatibility
In 2016 FDA finalized the guidance Use of International Standard ISO , "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process".
Required for all devices that come in direct or indirect contact with patient.
No longer acceptable to rely on “medical grade” or “long history of use” (eg, stainless steel instruments or implants).
Example is our epidural catheter. Clearly intended to be used in the epidural space and not come in contact with the dura. However, FDA considers the potential risk of accidental contact with dura and requires higher level of testing.

16. 510(k) Challenges - Colorants
Requests for colorant information has increased in recent years and applies to devices with direct and indirect patient contact, specifically if tissue contact is >30 days.
Chemical name and CAS number
Purity information, such as CFR color listing, raw material CoA, or testing for impurities.
Maximum amount of each color additive per device by weight.
This information can be difficult to obtain.
May avoid if predicate device is identical in colorant, material, & processing.
Biocompatibility alone may not suffice.

17. 510(k) Challenges - Sterilization
In 2016 FDA finalized the guidance Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile.
Manufacturers who use a “novel” sterilization method may have to undergo a FDA inspection prior to clearance.
Sterilization validation must be completed and summarized in 510(k).
Endotoxin testing requirements now extended to all implants.
FDA may request tighter endotoxin levels due to risk of improper use or accidental contact.

18. Substantial Equivalence Determination

19. After all the work ….
Substantial Equivalence (SE) decision = FDA clearance to market device.
Not Substantially Equivalent (NSE) decision = can not market product; resubmit 510(k), de Novo, or PMA may be required.
Possible reasons for NSE:
There is no predicate device.
Your device has a NEW intended use.
Your device has different technological characteristics compared to the predicate device and raises different questions regarding safety and effectiveness.
You did not demonstrate that your device is at least as safe and effective as the predicate.

20. MDUFA
Medical device user fees were first authorized in and then reauthorized in 2007, 2012, and most recently 2017, MDUFA IV.
Negotiations with industry add FDA performance goals.
Performance goals over the past few years have lead to significant review changes.

21. Notable MDUFA IV Changes
Significant rate increases for 510(k) and PMA submissions (47% and 25% respectively).
New user fee for de Novo submissions (set at 30% of PMA fee).
All submission deficiency letters must go through supervisory review.
All deficiency letters must include a statement explaining the basis for the deficiency and the reference to the applicable rule, guidance or standard.
Deficiencies will be categorized into major and minor.
Small business fees apply for firms earning $100m or less.

22. Notable MDUFA IV Changes
PMA total time to decision to drop from 320 days (FY ) to 290 days (FY )
510(k) total days from 124 for FY2018 to 108 days for FY2022.
De Novo reviews 150 “FDA days” for 50% of submissions in FY2018 improving to 70% by 2022.
Improved performance goal for pre-submissions (Q-sub).

23. New Q-sub process What is it?
Mechanism to obtain feedback on regulatory strategy, preclinical testing, and clinical testing
New Q-sub process
Day 1
Sponsor provides 3 or more proposed meeting dates
Day 15
　FDA completes RTA* and either accepts one of the sponsor’s dates or provides 2 alternatives prior to day 75
FDA and sponsor should agree on meeting date or FDA Manager contacts sponsor by day 40 to resolve scheduling
Day 30
Or 5 days ahead of scheduled meeting, FDA provides written feedback
Day 70
FDA to issue guidance by FY 2019

24. Notable MDUFA IV Changes
Provides authority for FDA to establish conformity assessment schemes for accrediting test labs.
Sponsors using the accredited labs would not have to submit test reports in their premarket submissions.
Legislation sets the groundwork for electronic submissions. FDA has until October 2020 to finalize guidance on an electronic template.
Small business fees apply for firms earning $100m or less.

26. Thank You & Questions