Wednesday Wisdom: Article on Regulating Software as a Medical Device (SaMD)

AcKnowledge RS’s very own Michelle Rubin-Onur wrote an article that was published this past week. Check it out on the Regulatory Affairs Professionals Society (RAPS) website HERE. In the article she discusses the rise of software as a medical device (SaMD) and how the regulatory landscape is changing for these devices. Read the abstract below, and in case you missed it, HERE is the link again to read the full article!


Regulating Software as a Medical Device in the age of Artificial Intelligence

Posted 30 May 2019 | By Michelle Rubin-Onur, PhD

“This article summarizes the current and proposed regulatory landscape for software as a medical device (SaMD) with artificial intelligence and machine learning capabilities. The author provides definitions for SaMD, categorization and testing features and how to approach and adjust regulatory pathways for SaMDs that “learn” by using real-world evidence to continuously adapt and improve and, therefore, may need to be re-submitted for a new premarket approval due to changes to the device via its adaptations. Because the regulatory system does not currently take into consideration SaMDs using Artificial Intelligence (AI) and Machine Learning (ML) to continually adapt, FDA has initiated a conversation with SaMD stakeholders to develop an appropriate regulatory pathway to accommodate AI/ML SaMD continuous adaptation.”

Med Device Monday- Optimizer Smart system is a Breakthrough Device that aims to treat Chronic Heart Failure

Image from https://www.impulse-dynamics.com/int/patients/ccm-and-the-optimizer-system/

Image from https://www.impulse-dynamics.com/int/patients/ccm-and-the-optimizer-system/

In March, the Optimizer Smart system from Impulse Dynamics received Breakthrough Device designation. The device is intended to treat individuals suffering from moderate-to-severe Chronic Heart Failure, and for whom treatment with other heart failure devices is not suitable. FDA gave the Optimizer Smart system its Breakthrough Device designation because the device treats a life-threatening or irreversibly debilitating disease, and addresses an unmet medical need in patients who fail to get adequate benefits from standard treatments and have no alternative treatment options.

Chronic Heart Failure (CHF), also known as congestive heart failure, occurs when the heart is unable to pump enough blood through the body to ensure a sufficient supply of oxygen. As a result, individuals with CHF may experience breathlessness and exhaustion, as well as swollen ankles and legs. Chronic heart failure is a serious long-term condition that generally gets worse over time, however its progression is very unpredictable and individual prognoses can vary greatly. The causes of CHF are many, and often a number of problems will affect the heart at the same time. A heart’s reduced ability to pump blood can be caused by an inherited genetic defect, an infection, high blood pressure, heart rhythm problems, coronary heart disease, or other diseases that have caused the walls of the heart chambers to become stretched, thickened, or stiff.

Measuring how well someone’s heart is pumping blood can help to diagnose and track heart failure. Physicians will often measure the heart’s ejection fraction, or how much blood the left ventricle pumps out with each contraction. Normally, the ejection fraction will be 50-70%, but if that percentage dips below 50%, a patient may notice they become breathless during activities and are more easily fatigued. In patients with CHF, the ejection fraction percentage can often drop below 40%, with symptoms of heart failure being experienced while performing everyday tasks, and even while at rest.

The Optimizer Smart system was developed to alleviate symptoms in patients for whom other treatments are not suitable or have been shown to be ineffective. There are several different components to the medical device: the Optimizer Implantable Pulse Generator (IPG), the Optimizer Smart Charger system, the OMNI II Programmer System, and the Omni SMART Software. The IPG is implanted under the skin in the upper left or right area of the chest and connected to three leads that are implanted in the heart. After the device is implanted, a physician tests and programs the device, which delivers electrical impulses to the heart during regular heartbeats to help improve the heart’s squeezing capability, or ejection fraction. The IPG can be recharged on a weekly basis without any clinical guidance or supervision, and the OMNI II System and Software allow medical personnel to track and then modify the device to meet an individual patient’s needs. The circumstances surrounding each case of CHF are unique, and the software’s ability to tailor the treatment delivered by the device aims to improve the patient’s quality of life.

During two randomized, multi-center clinical trials, a total of 389 patients with moderate-to-severe heart failure received optimal medical therapy, with 191 of those patients also receiving an Optimizer Smart system implant. Patients receiving the implant showed improvements in the distance they were able to walk in physical fitness tests, as well as improvements on standard assessments to measure heart failure symptoms. Patients fitted with the Optimizer Smart system implant reported a decrease in how much CHF symptoms affected their quality of life and how much the symptoms impeded daily physical activities compared to those who received only medical therapy.

Chronic Heart Failure is unfortunately very common, affecting more than 25 million people worldwide, most of them over the age of 65. Drugs or implanted devices, including pacemakers and implantable cardiac defibrillators, are sometimes enough to treat the symptoms associated with heart failure, however these solutions do not always mitigate symptoms. For these patients, there has been little physicians can do to treat their CHF. With the introduction of the Optimizer Smart system, physicians can now offer these patients an implant with the potential to relieve symptoms, prevent a worsening of their condition, reduce time spent in the hospital, and improve the length and quality of their lives…all news that makes our hearts very happy!


Additional Reading:

  1. Impulse Dynamics Website

  2. Video explaining how Optimizer Smart works

  3. Optimizer Brochure

  4. FDA News Release

FDA Friday - Robert Allen, 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.


I really enjoyed working with FDA reviewers and managers. You might think that FDA employees are focused on just rules and red tape, however, people there are very passionate about public health, and creative in getting things done that benefit patients within the framework of rules and regulations.
— Robert Allen, PhD
2019_MCRA_Robert (1).jpg

Dr. Allen received his bachelor’s and doctorate degrees in Bioengineering from the University of Pittsburgh, Swanson School of Engineering. As a Ph.D. candidate, his research focus was in cellular and medical product engineering. In 2015, he began work at FDA as an American Institute for Medical and Biological Engineering (AIMBE) Scholar. After completing his tenure as an AIMBE fellow, Dr. Allen joined the FDA’s Center for Devices and Radiological Health (CDRH) as a biomedical engineer and staff fellow. Robert acted as a lead reviewer in the former Division of Cardiovascular Devices, coordinating the review of premarket regulatory submissions such as 510(k)s, Pre-Submissions, and various supplements for Investigational Device Exemption (IDE) and Pre-Market Application (PMA) submissions. He also worked as a biocompatibility consulting reviewer, evaluating the potential biological response patients could have to a medical device.


Start off by giving us some more detail about your time at FDA.

I spent three years at FDA. For the first nine months, I was an American Institute for Medical and Biological Engineering (AIMBE) Scholar, working on strategic projects for the Center for Devices and Radiological Health (CDRH). Afterward, I became a premarket device reviewer for CDRH. My titles included “Biomedical Engineer” and “Staff Fellow”, and my roles included Lead Reviewer and Biocompatibility Consulting Reviewer for the Division of Cardiovascular Devices (now referred to as DHT2B), Vascular Surgery Devices Branch (now known as the Vascular and Endovascular Devices Team).

Tell us a little more about being an American Institute for Medical and Biological Engineering (AIMBE) Scholar. Can you briefly describe the program and talk about your responsibilities in that role?

The AIMBE Scholars program is an opportunity for early career PhDs in biomedical engineering or related fields to serve as expert advisors to policy makers at CDRH. The first cohort of AIMBE Scholars started at FDA in 2014. To date, AIMBE Scholars have worked on a wide range of projects aimed at improving the review process, providing tools to support regulatory decision-making, and developing policies to promote innovation and public safety. More information on the program can be found at https://aimbe.org/scholars-program/.

My AIMBE Scholar appointment was with the Office of Device Evaluation (now known as the Office of Product Evaluation and Quality, or OPEQ), where I assisted with efforts to reclassify a large number of medical devices. Reclassification is a process that impacts the regulatory requirements for each reclassified device. It is a complex process involving multiple teams across CDRH. To coordinate this process, I needed to learn the details of the process, then guide each team through it. This involved project management and lots of internal written and verbal communication. Throughout the process I worked with upper management, middle management, and individual premarket reviewers.

In addition to our FDA projects, AIMBE Scholars also attended site visits to current and potential industry sponsors. We also presented our projects at the AIMBE Annual Meeting to academic and industry members of AIMBE. These were great opportunities to network and hone our regulatory communication skills.

What about your experience as an AIMBE scholar made it clear to you that you wanted to spend more time at FDA?

Two things: the public health impact of FDA’s work, and the people at FDA. Regarding public health impact, it was fulfilling to work on projects where the immediate goal was to benefit public health. Prior to this work, I was a graduate student developing early-stage technologies that might one day help patients. While such research could be important in the long-term, it takes many years to prove a new technology, and many more years to develop a medical product and obtain regulatory approval/clearance. In contrast, the work I did at FDA changed the regulatory requirements for each reclassified device, which directly impacts the speed and cost to develop and market new products in that device category. It was thrilling to be able to see how my work could have a positive impact on patients in the short term.

Regarding people, I really enjoyed working with FDA reviewers and managers. You might think that FDA employees are focused on just rules and red tape, however, people there are very passionate about public health, and creative in getting things done that benefit patients within the framework of rules and regulations.

You worked as a lead reviewer in the Vascular Surgery Devices Branch. Before your time at FDA, what was your experience with blood-contacting cardiovascular devices?

Prior to FDA, I helped develop a resorbable vascular graft, which is a blood-contacting permanent implant. This was part of my dissertation work as a graduate student at the University of Pittsburgh, under the mentorship of Dr. Yadong Wang. That work helped me to understand how device materials interact with blood. I also learned about the design requirements for implants that need to withstand and maintain blood pressure, and the various failure modes to watch for.

While this experience was certainly helpful to my work as a lead reviewer, it was not a prerequisite for the job. After starting as a reviewer, I learned that FDA considers a wide range of backgrounds for lead reviewers, though they are most commonly engineers or scientists. Additionally, most of what I needed to know I learned on the job. FDA review teams have a wealth of collective experience and scientific knowledge about their devices. Coming in as a fresh Ph.D., I certainly did not know even 10% of what it takes to review a device. But the review team did and they got me up to speed quickly.

What was your favorite thing about working with a review team on a premarket notification (510(k)) or premarket approval (PMA) submission?

I enjoyed “standing on the shoulders of giants”, so to speak. I had the privilege of working with seasoned scientists, engineers, medical officers, and veterinary officers. I learned so much from these FDA veterans over the course of my premarket reviews. Much of their insight comes uniquely from experience reviewing devices, so it felt like I was learning things I couldn’t learn anywhere else.

What does it mean to be a biocompatibility reviewer?

Here is my personal take on what a biocompatibility reviewer does: Biocompatibility reviewers focus on reviewing the potential biological response that a patient can have to a medical device. Practically speaking, this means that biocompatibility reviewers review a combination of in vitro and in vivo testing, risk assessments, and rationales for why testing is not needed. These tests, risk assessments, and rationales focus on the impact of the device, or chemicals that can leach out of the device; on the patient’s cells/tissues, blood, and organ systems.

Biocompatibility review is just one of many roles that a premarket device reviewer can play at FDA. For example, I served as both a lead reviewer and a biocompatibility reviewer for premarket device submissions.

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

When I started review work, I thought that my technical expertise would be my most valuable asset for day-to-day work. While it certainly came in handy, the skills that helped me most were actually my communication and consensus building skills. Review teams often include multiple experts with a range of technical backgrounds and communication styles. To complete a review efficiently, we all needed to find common ground regarding priorities, action items, and ultimately, the safety and effectiveness of the device.

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

I enjoyed reviewing 30-Day Notices for manufacturing changes. In reviewing these submissions I got to see some of the manufacturing steps for the device, then evaluate and/or question the thought process behind each manufacturing change. This was fun because I got to see how devices are made; there are a wide range of manufacturing techniques out there, and some of them are fascinating. For the techniques that I already knew well from graduate school, it felt satisfying to leverage my existing knowledge to expedite a review.

What are you up to now and how does your current role incorporate your regulatory experience?

I currently work as a Senior Associate within the Regulatory Affairs team at MCRA. MCRA is a leading advisory firm and Contract Research Organization (CRO) for the medical device industry, with a range of services including regulatory, reimbursement, clinical research, healthcare compliance, and quality assurance. As a Regulatory Affairs Senior Associate at MCRA, I help our US and international clients to write and submit regulatory submissions to achieve and maintain market approval/clearance. These submissions include US FDA submissions, such as 510(k)s, Investigation Device Exemptions (IDE), and Premarket Approvals (PMA). They also include international submissions such as Clinical Evaluation Reports (CER). We also help our clients to develop and execute long-term regulatory strategies.

My FDA experience translates well to my work as a regulatory consultant. I am constantly using my firsthand knowledge of FDA’s regulatory expectations when I write premarket submissions for MCRA’s industry clients. The translation is direct for cardiovascular devices and biocompatibility evaluations, since I worked on those two specific things at FDA. For other device types and different types of testing, I can extrapolate from what I know, while also leveraging the experience of other MCRA employees. One of the great things about working at MCRA is the depth of experience that MCRA has in a range of product areas. For example, if I’m working on an orthopedic device submission, I can ask any of our 5 former FDA orthopedic device reviewers for their firsthand knowledge. I can also borrow the experience of MCRA’s other seasoned regulatory consultants who have a long track record of developing successful orthopedic device submissions.

How is working in industry similar and/or different than working at FDA?

As a regulatory consultant, I’m writing rather than reviewing device submissions. However, the process of writing submissions is very similar to that of FDA review. For example, as a consultant I still think about things like technological characteristics, benefit/risk, and the appropriateness of predicate devices. I also frequently reference FDA Guidances and regulations, just as I did at FDA. In addition, I often change hats and “review” my draft submissions from the perspective of an FDA reviewer; this helps me to anticipate FDA questions and thereby strengthen the overall submission. So overall, writing a submission doesn’t feel too different from reviewing one.

Of course, there are some differences in consulting vs. FDA review. As a consultant at MCRA, I work on a larger range of project types than I did as an FDA reviewer. This includes both the types of devices and the types of work products. For example, at FDA, I worked only on cardiovascular devices without electrical components, also known as the “plumbing” devices. As a consultant with six months experience at MCRA, I have already worked on a larger range of technologies than I did at FDA, including cardiovascular, orthopedic, and wound care devices. Similarly, at FDA I mainly worked on US premarket reviews. As a consultant at MCRA, I do write US premarket submissions, but I also work on international submissions as well as developing overall regulatory strategy recommendations for clients, which consider not just the technology but also the regulatory time and costs of each potential pathway. I like the variety that comes with working as a consultant!


More about Robert Allen, PhD

For more information about Robert, please visit his LinkedIn page; and to learn more about MCRA, LLC, please visit their website.

Med Device Monday – CureMetrix “Triage” Service cleared to Screen Mammograms for Signs of Cancer

Image from https://www.sandiegouniontribune.com/

Image from https://www.sandiegouniontribune.com/

It is estimated that one in eight women will be diagnosed with breast cancer during their lifetime. Generally, the first noticeable symptom of breast cancer is a lump that feels different from the rest of the breast tissue. In fact, more than 80% of breast cancer cases are discovered when the woman (or man…men get breast cancer too!) feels a lump. Finding breast cancer early can mean improved chances that the disease can be successfully treated. Fortunately, mammograms are often able to detect breast cancers early, and involve a simple low energy x-ray of the breast.

The use of mammograms as a screening tool for the detection of early breast cancer in otherwise healthy women is not without controversy. A mammogram that generates a false positive can cause significant stress and lead to unnecessary surgical interventions, and mammography can also generate false negatives. It is estimated that the numbers of cancers missed by mammography is ~20%, either due to observer error or because the cancer is hidden by other dense tissue in the breast. While mammograms do save lives, improved mammography could lead to earlier and more accurate detection of breast cancer.

Which is why we were excited to see FDA clear CureMetrix to sell its software “triage” service to screen mammograms for signs of cancer. CureMetrix is based here in San Diego, and in March 2019, the company was given the green light to market cmTriage™, which according to the company’s website is “software intended to provide a notification triage code to the radiologist’s mammography work list based on the presence of a suspicious region of interest found by the underlying algorithm. This workflow optimization tool enables a radiologist to customize their mammography work list based on cases that may need immediate attention.”

According to CureMetrix CEO Kevin Harris, “the cloud-based service sends back the results in three to four minutes. What we’re seeing in preliminary studies is the triage software can help doctors read through their work list up to 40 percent faster.” In addition to having an impact on clinical efficiency, CureMetrix says radiologists can elect to get immediate notification of suspicious results, so patients can be made aware of a concern before they have even left the clinic.

We are definitely seeing more companies like CureMetrix, focused on leveraging artificial intelligence and deep learning to develop the next generation of medical image analysis technology, and FDA is working hard to keep pace. FDA recently published a Discussion Paper and Request for Feedback on the topic of Artificial Intelligence and Machine Learning in Software as a Medical Device. FDA is considering a total product lifecycle-based regulatory framework for these technologies that would allow for modifications to be made from real-world learning and adaptation, while still ensuring that the safety and effectiveness of the software as a medical device is maintained.

Artificial intelligence and machine learning technologies have the potential to transform health care by deriving new and important insights from the vast amount of data generated during the delivery of health care every day. Information is power…we just have to figure out how to harness it to better assist health care providers and improve patient care!

Further Reading:

  1. CureMatrix Website

  2. CureMatrix cmTriage™ Letter

  3. More Information on Breast Cancer – American Cancer Society

  4. What is a Mammogram – CDC

  5. Artificial Intelligence and Machine Learning in Software as a Medical Device



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