FDA Regulatory Clearance using the 510(k) Pre-market Notification process can be a painful experience to unprepared companies. My focus at StarFish Medical is regulatory compliance. I believe it is important to consider Regulatory all the way through the development process, and not try to “bolt on” compliance at the end. Here are seven tips and advice developed over the years for painless (or less-pain) 510(k) submissions.

Clearance is required before legally marketing a medical device product for most medium risk Class II, high risk Class III, and unclassified devices. A Low Risk, Class I device, like an Elastic Bandage (product code FQM), does not require Regulatory Submission and does not need to follow FDA Good Manufacturing Practice Guidelines

The majority of Class II devices are cleared using the Pre-Market Notification process, commonly called 510(k) after the Federal Food, Drug and Cosmetic act reference number. Here, the submission compares their device with already legally marketed devices, and claims it is ‘Substantially Equivalent’ in terms of technology and indications for use. The device developer submits an application containing appropriate design information, testing standards and verification/validation evidence late in the device development program, and the FDA clears the device for sale based on the information provided. The cost is low (less than $5,000 to file with the FDA) and the timescales are short – the FDA promise a 90 day turnaround time, but this clock stops or resets if they need more information.

Class III, high risk devices (generally life sustaining or life critical) require Pre-Market Approval (PMA), where the FDA is involved at a very early stage in the development process, with an agreed Product Development Protocol that includes clinical validation data requirements. Class III devices also face the ongoing burden of maintaining the application, which must be re-reviewed by the FDA for even minor changes to the device.

Due to the cost of PMA submissions ($248,000, waived for first submission and reduced to $62,000 for Small Business exemption) and the high regulatory burden, most companies choose to develop Class II devices. For instance, changing a typo on the Instruction Manual (IFU) for a Class III device costs more than the entire Class II device 510(k) application fee.

Note there are some exceptions, such as certain Class I devices which still require 510(k) submission, like total Cholesterol blood test, and some Class II devices exempt from 510(k) requirement, such as pure tone audiometers. Finally, some Class III devices are being downgraded, but this is not a rapid process.

Here are seven tips on 510(k) submissions for companies developing Medical or In vitro Devices:

1. Have adequate resources for Strategic Planning, both as part of development and launch.
The companies which have most problems are those who just seek a ‘Rubber Stamp’ from the FDA. Companies who have a dedicated person, such as VP of Regulatory, are able to work with FDA to a much greater extent, understanding strategic pathways which help resolve predicate device suitability. The FDA’s paradigm is “Safety and Effectiveness”. They do not care if your business makes money or takes longer to get to market. This is important to remember. Saying “But that’s not fair, we are only a small company” does not affect the FDA’s decision making process. 

2. Plan your Regulatory Pathway.
The key here is the Indication for Use statement, which directly defines the required validation effort. There are several instances of companies who file a 510(k) with far too many claims – for example, diagnoses XXYYZZ, cures flat feet, bad breath, baldness etc. A more measured approach is to file a first 510(k) containing restricted indications for use, with the intent to demonstrate the device is safe at an adequate level of effectiveness for your desired, limited indication for use claim. Extra indications for use claims can be added later with a second 510(k) submission. When you have appropriate clinical data, your previously cleared 510(k) is now your predicate. An example is a new diagnostic device; the first 510(k) demonstrates safety and that the device is a tool or adjunct to be used in the clinical decision making process. The later 510(k) may say the device has diagnostic performance with Sensitivity, Specificity, Predictive values etc.

3. Follow FDA Guidance Documents.
The FDA issues “Guidance documents” for certain devices or processes. This is a euphemism: it actually means all deviations should have an extremely good, justifiable reason for not following their guidance. For example, the “Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices” gives consumer product software companies particular angst. A colleague discussed medical device software development in an earlier blog. Perhaps the most important FDA guidance is How to Prepare a Traditional 510(k), which refers the reader to other areas as appropriate.

4. Follow Recognized Standards.
The intent of standards is to irrefutably demonstrate performance, safety or both. With the emergence of “App” software, clients have been submitting ‘Devices’ based on a combined system of Tablet PCs running an App, and the FDA wants to see evidence the total system is safe. A better strategy would be to submit a software only submission. For complete electrical based systems, the following standards are extremely important, although there are many others, particularly device specific:

  • IEC60601-1 is required to demonstrate basic safety and essential performance of electrical medical equipment. If your Tablet PC is being used as a Medical Device, it must comply with all the associated Risk Management documentation required for third edition and have a test report demonstrating compliance to this standard. We have seen instances of 510(k) applications being denied by the FDA on this basis – arguing the Tablet PC is IEC60950 compliant only applies where there is no possibility of patient contact. I posted tips for IEC60601-1 compliance in an earlier blog.
  • IEC60601-1-2 is required to demonstrate Electro-Magnetic Compatibility (i.e. the device will not cause electrical interference, be interfered by or be affected by static discharge). Again, we have seen instances whereby the 510(k) application was denied without evidence of testing to this standard. A colleague posted tips for EMC compliance.
  • ISO10993 is required to demonstrate Biocompatibility, especially important for patient applied parts. The preferred route is to ensure all your materials are ISO10993 traceable with a readily available test report. Despite this, testing may still need to be repeated to confirm that material (injection mold houses) and/or sterilization processing does not introduce contamination which is non-biocompatible. However, using 10993 pre-certified materials does increase the likelihood these tests will pass. A colleague posted more on this in an earlier blog.

5. Watch out for the new, improved De-Novo process…
Which provides a regulatory clearance route for innovative medical devices that are low to moderate risk, without existing predicates. The core of the 510(k) process is to demonstrate your device is Substantially Equivalent to an already legally marketed device. This process can be in direct conflict with innovation and technology progress development.

For a while, 510(k)s were being submitted and cleared, but the actual predicate for Substantial Equivalence was a mix of desired functionality from several different predicates – the so called “Split Predicate”. This comparison with a non-existent, hypothetical device was identified as risky in the CDRH 510(k) Working Group preliminary report published in 2010. To address this, the working group proposed streamlining the De Novo process introduced in 1997. 

Presently, the De Novo process is effectively an appeal against the automatic Class III designation issued if your device ‘fails’ the 510(k) and is found not-substantially equivalent to a predicate device. A declined 510(k) due to lack of performance data can currently be resubmitted. So if you knew your exciting, novel device was low to medium risk but did not have a suitable predicate, you would still have to submit a 510(k) with the knowledge it would ‘fail’ and become Class III, then request De Novo reclassification to Class II. 

Even the best expectation management skills would make investors nervous with the business risk of this approach, which explains why there were only about 50 De Novo clearances from 1998 to 2009, an example being the Ingestible Telemetric Capsules. Draft guidance is available on the proposed streamlined De Novo process, published in October 2011, and an Amendment to Section 513(f) (which covers De Novo) of the Food, Drug and Cosmetic Act was made in July 2012. The FDA website states that the new De Novo Guidance is still being finalized, but it is likely that a Pre De Novo Submission (PDS) system will be put in place, which will hopefully avoid the scary “Fail a 510(k)” currently required. Stay tuned!

6. Meet with the FDA.
Another of the CDRH 510(k) Working Group’s recommendations was to facilitate high quality 510(k) submissions (especially for novel devices,) reducing the inefficiency of the FDA responding to poorly structured 510(k) submissions. The FDA is developing a Pre-Submission Program to allow easier engagement with the Agency.

I first met with the FDA CDRH in 2006 in Baltimore, where, after passing security, myself and my CEO were taken into a basement room for a scheduled IDE meeting. The next 45 minutes were painful but immensely revealing: we basically asked the FDA what we needed to do. The general response of the 10 people was ‘hire a consultant’ coupled with ‘Read the Regulations’, which with hindsight was obvious. Since then, the strategy for pre-IDE meetings has been to use presentation mode, whereby one describes the device, explains how it is substantially equivalent to the chosen predicate, then proposes the planned clinical investigations in order to demonstrate efficacy. The more you can site other recent 510(k) submissions for similar technology, then the more comfort this gives. The FDA will then agree, disagree or modify, but the scope of the regulatory activities will at least be fleshed out. It’s up to you to drive the discussion: asking direct questions work best; don’t ask open ended questions which can go in unexpected direction. Finally, don’t ask questions where someone has to go out on a limb by giving an opinion without checking with their boss. You will probably get a very conservative answer that becomes the final answer.

7. Be Nice!
Remember that FDA reviewers are normal people with huge workloads, and are not necessarily the highest paid regulatory specialists in the world, so cut them some slack. It’s human nature to be adversarial if someone gives you flack; treat them with respect. Put yourself in their position: they are not experts in your product, they probably have four other cases currently being worked on, their boss is asking when they will be ready, and they can get fired if they sign-off a device which then injures someone. So making their job easier and more pleasant can only be a good thing.

An often used quote, “By failing to prepare, you are preparing to fail”, originally by Ben Franklin, is particularly relevant here. It is not in the FDA’s interest to have to constantly bounce back applications for more information as they have their own metrics to meet. A well planned submission from an early stage containing all the necessary information is a good way to set your reviewer at ease. The No 1 tip on making adequate resource available may not be practical for all companies, so discussing your case with experienced Regulatory Consultants earlier in your development process, rather than at the end, is essential. If you have other tips for Medical Device 510(k) submissions, I would be delighted to hear them.