Several new and final FDA Guidance Documents were issued for Medical Devices in the past month. Why so many?

As part of the Medical Device User Fee Amendments 2012 and the 510(k) Working Group committee report 2010, the FDA is working hard to improve predictability, increase transparency and raise the standard of 510(k) submission, demonstrating the agency’ commitment to reducing regulatory burden where practical, without compromising patient safety.

The agency is also adapting to the requirements of medical devices in a changing healthcare landscape of personalized healthcare, an aging general patient population pushing decentralized care, and more focus on helping people with chronic conditions live longer, more productive lives.

The guidance documents cover risk-benefit analysis for instances where the device technology characteristics differs from the predicate, guidance on the agency’s expectations when evaluating substantial equivalence, a list of 107 devices the FDA plans to exempt from 510(k) submissions, design considerations for home use devices, and guidance for IVD companion diagnostics. That’s a lot to read and digest easily, so I’ve summarized them below.

• (Draft) “Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics”, UCM404773, issued Jul 15, 2014 by CDRH and CBER

The “Benefit-Risk Factors” draft guidance document explains how the FDA will review submissions where the technology characteristics differ from the predicate. It is up to the submitter to identify an appropriate, legally marketed device, preferably with the same intended use and same technology characteristics. However, there is some criticism of the 510(k) process, claiming it stifles new technologies and innovation. Hence, the Agency has released this guidance to clarify their expectations for submission where the technology characteristics differ.

Essentially, the agency is seeking to determine that new devices do not raise any new questions on safety or effectiveness by undertaking a risk-benefit analysis, and indicates that performance data may be necessary to demonstrate efficacy and/or safety. For the risk-benefit analysis, valid scientific evidence may be required, preferably in the form of well powered scientific studies. If the device has a diagnostic capability, then the risks will also include false positive and false negative effects. The guidance document also gives several examples, ranging from a bone rongeur surgical instrument, to an ambulatory infusion pump.

• (Final) “The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]”, UCM284443, issued Jul 28, 2014 by CDRH and CBER

The Evaluating Substantial Equivalence guidance is the final version, in part instigated by the 2010 report from the 510(k) Working Group which sought to take into consideration Medical Device Industry concern on old predicates stifling innovation; Patient and User Group concerns for unsafe and ineffective devices receiving clearance, and FDA CDRH concern that the current program did not work well with complex devices and that submissions were often poor quality. In particular, the tendency to use ‘split predicates’, where a hypothetical device is offered as the predicate with technology characteristics of one stated device and indications for use from another, was criticized. The guidance indicates this is no longer permissible and that the predicate must have both same intended use and technology characteristics. Note the recent guidance document above on predicates with differing technology characteristics. A useful flowchart is provided which helps explain the agency’s thinking. Multiple predicates are permissible when combining features from several devices, and multiple examples are provided, but these will generally be considered on a case by case basis.

Finally, the guidance document discusses changes to Indications for Use and when they affect the Intended Use, which can affect predicate suitability. Essentially, changes from an indication to a treatment, change from a diagnostic to screening, change in patient population e.g. adult to paediatric, and change in use context such as hospital versus home or periodic to continuous monitoring all constitute different Intended Use. It is the authors’ belief that the FDA would like to make greater use of the de-novo process, particularly for lower risk, novel devices where no predicate exists, the technology characteristics raise too many questions on safety or effectiveness, or the product requires a change to the Indications for Use. This may be either after receipt of an NSE letter, or directly requesting classification through the de-novo process.

 • (Draft) “Intent to Exempt Certain Class II and Class I Reserved Medical Devices from Premarket Notification Requirements”, UCM407292, issued Aug 1, 2014, by CDRH

The Intent to Exempt draft guidance document downgrades several lower risk devices that are “sufficiently well understood and do not present risks” for them to require a 510(k), comprising certain lower risk class I, II and unclassified devices (which were grandfathered in before the 510(k) process came into effect, but were never officially classified) from the need to submit a 510(k).

In total, 107 devices are downgraded, such as portable air compressor, body fat composition tester, general clinical thermometer, and certain drapes, amongst others. Note that, although it is intended a 510(k) submission will not be required before marketing these devices, Good Manufacturing Practice (including Design Controls), compliance with consensus standards, medical device reporting is still required, and manufacturers of these 510(k) exempt devices will still be subject to FDA inspections. As this document is a draft, the FDA is accepting comments for 60 days.

 • (Final) “Design Considerations for Devices Intended for Home Use”, UCM331681, issued Aug 5, 2014 by CDRH and CBER

The FDA also published the final version of the Home Use Device design considerations. There already exists a consensus standard for electrical medical equipment intended for home use: IEC60601-1-11, and the guidance document refers to the ANSI version of the consensus standard several times. Both these documents exist because of the special precautions which must be taken for devices used in a non-clinical environment, often by lay people.

The guidance document has advice on labeling (i.e. clear, concise and easily understood, preferably with pictures), location usage considerations, contamination, operating environment (temperature, humidity, etc.) and travel, such as power supplies and use during transportation. The guidance also advises that specific risks of a device in a home use environment should be captured, and that lock-out mechanisms are not the sole risk mitigation measure. In addition, the document refers to several other consensus standards which should be complied with, such as Risk Management (ISO14971 2010), IEC62304 (2006) for software lifecycle process, ANSI ES60601-1 (2012) Basic safety and essential performance of medical electrical equipment, and ANSI ES60601-1-2 (2014) 4th Edition, EMC, and IEC62366 (2013) Usability, amongst others.

 • (Final) “In Vitro Companion Diagnostic Devices”, UCM262327, issued Aug 6, 2014 by CBER, CDRH and CDER

The FDA published the final version of the IVD Companion Diagnostics guidance document. Companion diagnostic devices are those which are used in conjunction with a primary therapeutic product, often a drug. The guidance notes this approach is becoming increasingly common in the era of personalized medicine, Ideally, the primary therapeutic and the IVD diagnostic would be developed in parallel, since the companion diagnostic may be essential for the primary therapeutic to achieve its safety and efficacy claims.

An example of an IVD companion diagnostic is a HER-2 test to determine whether a patient is a candidate for the drug Herceptin, indicated for treatment of metastatic breast cancer. Since Herceptin lacks effectiveness in those without a HER-2 marker, and has cardiac failure as a known adverse event, an IVD companion diagnostic is used to identify those patients who could benefit from the therapy.

Given these factors, the FDA requires that, for Novel Therapeutic Products, the IVD companion diagnostic is developed and cleared at least in time for when the therapeutic product is approved.  The therapeutic will not be approved until the IVD is cleared. The IVD companion diagnostic will also be included in the labelling of the therapeutic. Having said that, the guidance document discusses cases when the IVD companion diagnostic is not cleared, such as when the therapeutic is intended to treat serious or life-threatening injuries. However, it appears these are taken on a case by case basis, and the guidance notes that revisions to already approved therapeutics will not be approved until the companion diagnostic is cleared, unless a serious safety issue arises.

The agency is clearly working hard to respond to feedback on the 510(k) process, defining what they expect to see in a 510(k) submission, how they assess the submission, and discussing options when your device is novel. Note that more FDA Guidance Documents for abbreviated 510(k) and Special 510(k) submission are yet to come.  Stay tuned.