FDA

Med Device Monday – De Novo Clearance of The Miris Human Milk Analyzer

Breast milk is often considered a “superfood” for babies; it contains the appropriate vitamins, minerals, and nutrients to support a baby’s growth and development (not to mention hormones and enzymes that promote maturation and digestion, and antibodies that help the baby resist infection!). It’s no wonder why breast milk is often referred to as “nature’s first health plan.”

Yet for infants born preterm (before 37 weeks gestation), or with certain health conditions, breast milk may not contain sufficient protein or provide enough energy. For these infants with increased nutritional needs, knowing the macronutrient content of the breast milk being provided could give vital information to the health care team and parents, allowing them to make informed decisions on how to fortify the breast milk based on the individual needs of the infant.

In December 2018, the U.S. Food and Drug Administration permitted marketing of the Miris Human Milk Analyzer (HMA) to Miris AB of Sweden. The Miris HMA uses an infrared spectroscopy system to analyze samples of human milk, and provides a quantitative measurement of fat, protein and total carbohydrate content, as well as calculations of the total solids and energy content contained in the milk. The prescription device is intended for use by trained health care personnel at clinical laboratories, providing healthcare professionals with a new tool to aid in the nutritional management of newborns and young infants at risk for growth failure due to prematurity or other medical conditions.

FDA reviewed the Miris HMA test through the De Novo premarket review pathway, a regulatory pathway for low-to-moderate-risk devices of a new type. Along with its granting, FDA established a list of special controls to provide for the accuracy and reliability of tests intended to measure the nutritional content of human milk to aid in the nutritional management of certain infants. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for tests of this type. As discussed in our previous blogs about the De Novo pathway, this action also creates a new regulatory classification; meaning subsequent devices of the same type and intended use may go through FDA’s 510(k) process.

Already on sale in over 25 countries worldwide, the Miris HMA is now available to analyze breast milk and guide the individual nutrition of preterm babies in the U.S. The new device supports Miris’ mission, “to make individual nutrition, based on human milk, available globally to improve neonatal health.” We’re excited to see a new device on the market that has the potential to help one of the most vulnerable patient populations. Go babies!


Additional Reading:

1.      FDA Press Release

2.      De Novo Letter for The Miris Human Milk Analyzer

3.      NIH: Do breastfed infants need other nutrition?

4.      CDC: Breastfeeding

5.      Miris Website

FDA Friday - Dulciana Chan, M.S.E.

This #FDAFriday series consists of mini-interviews with former FDA regulators. Our goals are twofold: (1) help students and professionals interested in Regulatory Affairs see what career paths are possible, and (2) talk about some of the various roles at FDA to demonstrate the diversity of responsibilities at the Agency. If you are a former FDA employee and would like to participate, please email us at info@acknowledge-rs.com.


A common mistake that manufacturers make in their Investigational Device Exemption (IDE) submissions is not having a plan to deal with missing data. It is important to have a plan upfront so that the data from all patients can be used.
— Dulciana Chan, M.S.E.
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Dulciana Chan received her B.S. in Biomedical Engineering from Johns Hopkins University in 2002, and her M.S.E. in Bioengineering from the University of Maryland in 2010. Directly following her undergraduate degree, Dulciana began her FDA career as a research associate in the Center for Devices and Radiological Health (CDRH), Office of Science and Engineering Laboratories (OSEL). A year later, she became a Biomedical Engineer at FDA, and for 14 years operated in various branches of the administration, including as a scientific reviewer and policy analyst in the Office of Device Evaluation (ODE), and as an OSEL principal investigator.

While working at FDA, Dulciana received numerous honors and awards, including the 2014 CDRH Honor Award and the 2014 FDA Scientific Achievement Award for Excellence in Analytical Science. Dulciana has extensive experience in the areas of electromagnetic compatibility (EMC) testing and electrical safety, and is an asset to Acknowledge Regulatory Strategies, where she is a Senior Regulatory Specialist.


Tell us a little bit about your time at FDA.

I started at the FDA as a research associate in the Center for Devices and Radiological Health (CDRH) in the Office of Science and Engineering Laboratories (OSEL). I worked on several research projects and gained skills including computational modeling and electromagnetic compatibility. One of my main projects focused on optical recording of cardiac myocyte monolayers to study cardiac arrhythmias. After my first year at FDA, I also became a scientific lead reviewer in the Office of Device Evaluation (ODE). Fortunately, I was able to continue performing research in OSEL while doing premarket reviews for devices in ODE for the next 14 years.

Can you tell us a little more about your research in the Office of Science and Engineering Laboratories (OSEL)?

The lab I was in began to use pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias. It was part of a larger program to predict drug proarrhythmic risk in cells prior to the clinical studies that are required for new drugs. This research was very rewarding in clinical relevance and scope.

You also worked as IDE staff while you were at FDA. What was one of the common mistakes you saw companies make when submitting their clinical study to FDA?

A common mistake that manufacturers make in their Investigational Device Exemption (IDE) submissions is not having a plan to deal with missing data. It is important to have a plan upfront so that the data from all patients can be used. The reality is that there will be missing data, whether from a patient missing a follow-up or a missing test or outcome. However, with preplanning, the data can still be interpreted correctly.

What was your favorite thing about working with a review team on a premarket notification/approval submission?

One of the benefits of working with a review team is being able to access the knowledge of an expert. Often there may be an aspect about a device that you only have high level knowledge about. The review team can quickly explain the technicalities to you in a meaningful way. Their expertise might also help in identifying potential problems.

What past experience or trait do you think helped you be a successful reviewer/during your tenure at FDA?

I think being a lifelong learner helped me be a successful reviewer. Some might see the process of reviewing medical devices as repetitive. However, I found that each product provided a unique learning experience due to the many types of devices, regulation pathways, and emerging public health issues to learn about. There were endless ways to learn new things at the FDA.

What were your favorite FDA submissions to work on and why?

My favorite FDA submissions were IDEs because I learned about the details of a clinical study and about an emerging technology or trend. It was also nice to ensure that all the aspects necessary for a successful clinical study were planned out. Although there was pre-clinical work performed before an IDE submission, it was interesting to see a device at the beginning of its regulatory path.

What's something that you learned from FDA that helped you in your current position?

Working at FDA helped me learn team communication and managing expectations. Everyone’s time is valuable and it is important to make the most of team meetings. When leading a team, I aim to let each member of the team know the goal, their responsibility, and potential outcomes.

How does your current role incorporate or benefit from your regulatory experience?

Many times, companies are not sure what to submit to the FDA so they submit everything (test report and data), which can be overwhelming to an FDA reviewer. I think my regulatory experience can help companies determine what to submit so that they clearly show they meet all FDA requirements.


More about Dulciana Chan, M.S.E.

For more information about Dulciana, please visit her LinkedIn page.

Med Device Monday: Recall of the Raindrop Vision Inlay Device

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In April 2017, we wrote about a new device called the Raindrop Vision Inlay, manufactured at the time by ReVision Optics. Approved in 2016, the device is basically a small implantable contact lens that reshapes the front of the eye and corrects presbyopia, more commonly known as farsightedness. A little over two years later, the Raindrop Vision Inlay was the subject of an FDA Safety Communication recommending patients not receive the device. After post-market research, FDA identified an increased risk of corneal haze, or the development of a cloudy layer within the eye that impairs overall vision. Shortly thereafter, in November 2018, FDA issued a Class I recall - the most serious type of recall - reserved for devices that may cause serious injuries.

So, what happened?

Going back to 2016, the Raindrop Vision Inlay was given FDA approval in large part due to a two-year clinical trial that yielded promising results, including high numbers of patients who could read smaller print at closer distance post-op. At the time of device approval, the clinical study showed that while 16.1% (60 of 373) of patients had central corneal haze of any severity at some point during follow-up, the percentage of patients with two or more lines of loss in vision on the eye chart caused by corneal haze was 1.1% (4 of 373 patients). The number of patients who had the device removed was 24 of 373 patients (6.4%) at the two-year follow-up visit, with 29% of those device removals (7 of 24 patients) being due to corneal haze.

The Raindrop Vision Inlay was marketed under the conditions that the device be restricted to prescription use and specifically labeled to define the training or experience practitioners needed in order to implant the device. Marketing of the device was also conditional on the reporting of results from two post-approval studies (PAS), one that followed patients enrolled in the original clinical study, and a second that tracked newly enrolled patients. Of the 373 patients from the original study, 150 were enrolled in the PAS. The most recent data from the ongoing study, including 5 years of follow-up in some patients, showed that the rate of central corneal haze, at any time during the study, was 42% (63 of 150 patients), and that the presence of haze at any location within the cornea was a whopping 75% (113 of 150 patients). The percentage of patients with two or more lines loss on the eye chart caused by corneal haze remained low at 2.0% (3 of 150 patients), however that was greater than what was observed during the original clinical study. After evaluation of the PAS data, the risks outweighed the benefits of the device and lead the company and FDA to initiate the recall.

It is awful that the Raindrop Vision Inlay caused any patients implanted with the device to suffer, and one might be quick to judge that FDA ‘screwed up’ by allowing an unsafe device to be sold. The whole story is quite a bit more complicated, however, and we feel the Raindrop Vision Inlay situation is an example of FDA working to uphold its mission. In this situation, FDA took responsibility for both helping speed innovation that would potentially improve patient’s lives, and for ensuring the safety and effectiveness of a medical device before and after market approval.

FDA closely monitors reports of adverse events and other problems with medical devices, and alerts health professionals and the public when needed to ensure their proper use. FDA has stated that it is currently working with the owner of the Raindrop Vision Inlay, Optics Medical, on a plan to collect any remaining devices already distributed. FDA will continue to gather and evaluate data related to the recalled device, and communicate new information as warranted.

Further Reading:

1. FDA Safety Communication

2. Raindrop Vision Inlay PMA Approval Letter

3. Summary of Safety and Effectiveness Data

4. Raindrop Vision Inlay Recall Notice

FDA Friday - Srinidhi Nagaraja, PhD

This #FDAFriday series consists of mini-interviews with former FDA regulators. Our goals are twofold: (1) help students and professionals interested in Regulatory Affairs see what career paths are possible, and (2) talk about some of the various roles at FDA to demonstrate the diversity of responsibilities at the Agency. If you are a former FDA employee and would like to participate, please email us at info@acknowledge-rs.com.


While working on a premarket approval (PMA) submission, I always enjoyed the diversity in skills and expertise within the team. It was a great opportunity to listen to and learn from medical officers, toxicologists, and veterinarians, and better understand their perspective of the risks and benefits of a particular device.
— Srinidhi Nagaraja, PhD
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Dr. Nagaraja received his Doctorate and Master of Science degrees in Mechanical Engineering from the Georgia Institute of Technology, following a Bachelor of Science degree in Mechanical Engineering from the University of Michigan. In his role at FDA, Srinidhi acted as a senior consultant for mechanical safety of premarket medical device submissions, including IDE, PMA and 510(k) applications. He also analyzed post market mechanical failures, with expertise in cardiovascular and orthopedic devices. Concurrent with his time at FDA, Srinidhi was an affiliate faculty member at the University of Maryland, and developed an active research program improving assessment and studying the integrity of cardiovascular and spinal devices.


Tell us a little bit about your time at FDA.

I spent 10 years at the FDA’s Office of Science and Engineering Laboratories (OSEL) in the Center for Devices and Radiological Health (CDRH). Not many in industry are aware that CDRH has facilities to perform device research and testing. During my time at FDA, my responsibilities spanned both the regulatory and science based mission of CDRH. For example, I was a technical consultant to the review teams in the Office of Device Evaluation (ODE) for various regulatory submissions. My area of expertise was mechanical safety and performance of medical devices. In particular, I was involved in evaluating the durability, corrosion resistance, and mechanics of various medical devices. I was also a principal investigator for research studies focused in areas such as spinal biomechanics, nitinol durability, and corrosion susceptibility of implants. These studies were performed to help ensure that CDRH was ready to evaluate emerging and innovative medical technologies. In addition, the research aided in the development of appropriate testing standards (e.g. ASTM or ISO standards) or acceptance criteria for use by the medical device community during design verification activities.

How did your research in OSEL inform your work as a reviewer?

One example of how my research informed regulatory review was a study to better understand in vivo corrosion resistance of nitinol implants. This was an important topic within the implant community as there was considerable debate regarding suitable acceptance criteria during an FDA workshop that I co-organized in 2012. We conducted an animal study to address the issues raised and provide scientific data to help determine acceptable limits for the corrosion of implants. The papers published on this topic have helped clients I work with in my current position as part of design verification testing activities, and also have been referenced by FDA during regulatory review.

What was your favorite thing about working with a review team on a premarket notification or approval submission?

While working on a premarket approval (PMA) submission, I always enjoyed the diversity in skills and expertise within the team. It was a great opportunity to listen to and learn from medical officers, toxicologists, and veterinarians, and better understand their perspective of the risks and benefits of a particular device. I also was fortunate to work on PMAs in many different product areas, especially in those where the use of nitinol was increasing. This really made the day-to-day work fun, as I needed to think critically about how to apply mechanics principals to various significant risk devices.

While at FDA, you were also affiliate faculty at the University of Maryland. How did you swing that sweet gig? What was it like having that joint appointment?

It was great having a faculty appointment at the University of Maryland while at FDA. The connection was beneficial for both FDA and the university’s Bioengineering Department. As a result of the joint appointment, I was able to advise PhD candidates and participate in seminars and collaborate on research studies at the university. My dual position also created opportunities for University of Maryland students to gain experiences in regulatory science and device approval process as FDA interns. Overall it was a wonderful experience, and allowed me to mentor undergraduates and graduate students pursuing biomedical engineering degrees.

What are you up to these days?

I left FDA over a year ago and started at G. Rau Inc., which is an independent medical device testing laboratory in the Bay Area. Our company provides standard and custom mechanical testing (e.g., durability, corrosion) and technical consulting to medical device companies. My role at G. Rau Inc. is to support device companies seeking approval/clearance of their device. In particular, we help establish testing strategies, conduct testing to characterize device safety and performance, and address FDA deficiencies during the approval/clearance process.

How does your current role incorporate or benefit from your regulatory experience?

I think there is a direct benefit to having regulatory experience. I apply my previous FDA regulatory and research experiences to help device companies with design verification testing and other scientific matters in order to demonstrate the mechanical safety and performance of their device. For example, my reviews of devices at FDA were focused on analyzing testing plans, reviewing mechanical test reports, and providing technical recommendations to device companies. Now, I use those experiences to help companies outline an approach to successfully establish safety and performance of their device.

What do you think is a common misconception about your current company?

One misconception is that our company provides testing and technical consulting solely for nitinol-based products. However, our testing capabilities and expertise are fairly broad, allowing for testing of devices manufactured from other materials (e.g. titanium spinal components).


More about Srinidhi Nagaraja, PhD

For more information about Srinidhi, please visit his LinkedIn page, and for more information on G. Rau Inc., please feel free to contact Dr. Nagaraja by email <srinidhi.nagaraja@g-rau.com> or click here.

FDA Friday: Reclassification

The longer you know someone, the more you learn about them. Well, the same goes for medical devices! As knowledge about a medical device increases, we inevitably have a better understanding on its benefits and risks. As our understanding of a device evolves over time, it is possible that the classification of the device might need a little update. There are two different ways for a medical device to be reclassified at FDA, both of which we review below.

First, there is a way for a medical device to be reclassified as described in the Food, Drug and Cosmetic Act (the Act). Under Section 513(e) of the Act, FDA may reclassify a device based on new information, whether it is discovered on their own, or in response to a petition from an interested person. In this case, “new information” is defined as publicly available, valid scientific evidence. If FDA or a petitioner proposes that a device be reclassified to a lower class (say from the higher risk Class III to a moderate risk Class II), sufficient and valid scientific evidence must be provided in order to support the determination. In July of 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) was created, which changed the reclassification process to an administrative order process instead of rulemaking. According to FDA’s website that discusses reclassification, in order to reclassify a device under this section of the FD&C Act, FDA must do the following before making the reclassification final:

§  Publish a proposed order in the Federal Register that includes proposed reclassification and summary of the scientific evidence supporting the reclassification

§  Have a panel meeting for the device classification before or after the proposed order has been published

§  Take comments from the public docket into account

Image from https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm378724.htm

Image from https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm378724.htm

There are also additional rules and guidelines that apply depending on the original class level, and the new class level for a device. For example, for devices being reclassified from Class II to Class III, the scientific evidence must indicate that the general and special controls are insufficient to provide reasonable assurance of safety and effectiveness. Conversely, if a device is being reclassified from Class III to Class II, the scientific evidence must show the opposite; that the general and special controls are sufficient to provide reasonable safety and effectiveness. Lastly, if a device is being reclassified to Class I from either Class III or Class II, the scientific evidence must show that the general controls alone are sufficient to provide reasonable assurance of safety and effectiveness.

 

The other route for devices reclassification is described in Section 513(f)(3) of the FD&C Act. This originates from the understanding that any device not available before the Medical Device Amendments in 1976 was automatically classified as Class III. This classification was determined regardless of any risk the device posed, and without undergoing any FDA rulemaking processes. These medical devices are more commonly known as postamendment devices. Unlike the process above, these devices may only be considered for reclassification if the initiative comes from FDA or a petition from a manufacturer or importer. Similar to the 513(e) process discussed in the previous paragraph, reclassification of a device can only be made when sufficient regulatory controls can provide reasonable assurance of safety and effectiveness. A device reclassification panel may also be called, should FDA receive a petition requesting reclassification. After all information has been considered, FDA will determine whether the reclassification petition is approved or denied. Following approval, the order describes both the reason for reclassification, as well as any of the device’s risks to patient health.

 

By the way, if you’re wondering where the whole de novo process fit here, you should check our previous blogs here along with the update here. Keep in mind, a de novo request (per 513(f)(2) of the FD&C Act) is a file where a submitter can request a new classification altogether. Therefore, we don’t really consider it a ‘reclassification’ per the definition of our subject in this blog.

 

To see a full list of medical devices that have been reclassified since 2013, visit this link. If you’re wondering why the list only goes back five years, it’s because it wasn’t until FDASIA was enforced in 2012 that FDA was required to annually post the devices reclassified in the year prior.

 

Additional Reading:

  1. Overview of Medical Device Classification and Reclassification

  2. Classify your Medical Device