A Curriculum for Medical Device Progress

By: Francis Kalush, Ph.D.

Horace, the greatest Roman poet of antiquity, spoke of the need to “seek for truth in the groves of Academe” — and in the last four years, my colleagues in FDA’s Center for Devices and Radiological Health (CDRH) and I took his advice. In scores of meetings and two large workshops, we consulted with hundreds of academics about a novel idea: a university-level program to address an important public health need by stimulating the development of new medical devices.

Francis KalushIn 2011, CDRH embarked on an Innovation Initiative to help accelerate and reduce the cost of the development and regulatory evaluation of safe and innovative medical devices. Through that and other programs, we learned that the delivery of new therapies to patients can be accelerated if medical device innovators — including entrepreneurs and university students and faculty — understand FDA’s regulatory processes. We then established the Medical Device Technology Innovation Partnership, and tasked it with developing an educational program that would explain FDA’s standards and procedures for evaluating and approving or clearing medical devices.

This learning tool grew from collaborations with Stanford University, University of Virginia, Howard University, The Johns Hopkins University, University of Maryland at College Park and at Baltimore, and University of Pennsylvania.

The program, called the National Medical Device Curriculum, will provide students at academic institutions and science and technology innovators with the core information about the regulatory pathway to market. This includes an understanding of the expertise needed to design, test and clinically evaluate devices; identify the root causes of adverse events and device malfunctions; develop designs for devices with repetitive functions; and, navigate FDA’s regulatory process.

The mode of the curriculum is a series of fictional case studies based on real-world medical device scenarios. The four learning tools developed so far cover the following subjects: the regulatory pathways for medical devices; safety assurance and risk management planning; and the regulatory pathways for novel devices and for devices that are substantially equivalent to already marketed predicate devices.

Each of these fictionalized case studies includes a student module and an instructor’s guide with ideas for exercises and discussion in class. The curriculum was tested at several universities and received high praise. For example:

  • William E. Bentley, from the University of Maryland James Clark School of Engineering found that the case studies “are of tremendous pedagogical value, and we are definitely incorporating them into our curriculum.”
  • ŸArthur L. Rosenthal, Ph.D., a professor at Boston University’s College of Engineering, used the case studies to teach advanced biomedical product design and development and reported that “the students found the material engaging as well as providing essential context for their projects.”
  • ŸYouseph Yasdi, Ph.D., MBA, executive director at The Johns Hopkins Center for Bioengineering Innovation and Design, found that the cases are “a good fit” for his program to train engineers to better understand regulatory issues.

More case studies are being planned to help train the next generation of entrepreneurs and keep the U.S. a leader in medical device innovation. Regulatory training is particularly important in the development of medical devices, as the industry is heavily populated by small companies that may not have the expertise to navigate FDA’s requirements.

The National Medical Device Curriculum is a step forward in our Agency’s efforts to encourage and facilitate the development of new medical products — drugs, biological products and medical devices — that has been made possible by the great scientific breakthroughs in the last two decades, such as the mapping of the human genome and the invention of nanotechnology. Those of us who worked on this novel curriculum hope it will encourage and advance the development of new devices for patients and help protect and promote the public health.

Francis Kalush, Ph.D., is a senior science advisor at FDA’s Center for Devices and Radiological Health

OpenFDA Provides Ready Access to Recall Data

By: Taha A. Kass-Hout, M.D., M.S.

Every year, hundreds of human and animal foods, drugs, and medical devices are recalled from the market by manufacturers. These products may be labeled incorrectly or might pose health or safety issues. Most recalls are voluntary; in some cases they may be ordered by the U.S. Food and Drug Administration. Recalls are reported to the FDA, and compiled into its Recall Enterprise System, or RES. Every week, the FDA releases an enforcement report that catalogues these recalls. And now, for the first time, there is an Application Programming Interface (API) that offers developers and researchers direct access to all of the drug, device, and food enforcement reports, dating back to 2004.

Taha Kass-HoutThe recalls in this dataset provide an illuminating window into both the safety of individual products and the safety of the marketplace at large. Recent reports have included such recalls as certain food products (for not containing the vitamins listed on the label), a soba noodle salad (for containing unlisted soy ingredients), and a pain reliever  (for not following laboratory testing requirements).

At present, FDA provides various ways to access the recalls data, including an RSS feed, a Flickr stream, and a search interface. This new API supplements these sources as the first, and one-call, access to the entire enforcements archive. The hope is that this API will be useful to developers and researchers interested in FDA enforcement actions. Developers can now call into the API to add recalls data to mobile apps or consumer websites. And researchers could use the API to study individual manufacturers, product categories, or specific foods or drugs.

The recalls database is the second dataset to be released on openFDA. Since openFDA debuted on June 2, 2014, the website has generated considerable interest. In the past five weeks, the site has had 34,000 sessions (two-thirds are new sessions) from 26,000 unique visitors worldwide that generated 80,000 page views.

The adverse events API has been accessed by 18,000 Internet connected devices, with nearly 2.4 million API calls since the launch.  At least one new website, http://www.researchae.com, has been created to allow any user to submit queries on the adverse events data, and several other companies are integrating the data into their products and services. It is also being accessed by researchers inside and outside FDA and by journalists as well.

More APIs will follow in the weeks ahead. OpenFDA is taking an agile (development in small chunks of iterations) approach in the creation and release of these APIs, with the objective of getting feedback from developers and researchers (as well as from industry and the public) at the GitHub and StackExchange forums that serve our project. We plan to incorporate some of the feedback into future iterations of the API. Accordingly, as we learn more about how the public might seek to use this data — and as a result of our agile and user-centered methodologies — the API structure may change in quite a bit in the coming months. It’s also important to note that this API, like all others on openFDA, are in beta and are not ready for clinical use. However, their contribution to FDA’s public health mission already now grows every day.

Taha A. Kass-Hout, M.D., M.S., is FDA Chief Health Informatics Officer and Director of FDA Office of Informatics and Technology Innovation

Developing new tools to support regulatory use of “Next Gen Sequencing” data

By: Carolyn A. Wilson, Ph.D.

When you’re thirsty, you don’t want to take a drink from a fire hose. And when scientists are looking for data they don’t want to be knocked over with a flood of information that overwhelms their ability to analyze and make sense of it.

Carolyn WilsonThat’s especially true of data generated by some types of both human and non-human genome research called Next Generation Sequencing (NGS). This technology produces sets of data that are so large and complex that they overwhelm the ability of most computer systems to store, search, and analyze it, or transfer it to other computer systems.

The human genome comprises about 3 billion building blocks called nucleic acids; much medical research involves analyzing this huge storehouse of data by a process called sequencing—determining the order in which the nucleic acids occur, either in the entire genome or a specific part of it. The goal is often to find changes in the sequence that might be mutations that cause specific disease. Such information could be the basis of diagnostic tests, new treatments, or ways to track the quality of certain products, such as vaccines made from viruses.

NGS is a complicated technique, but basically it involves cutting the genome into millions of small pieces so you can use sophisticated chemical tricks and technologies to ignore the “junk” you don’t need, and then make up to hundreds of copies of each of the pieces you want to study. This enables additional techniques to identify changes in the sequence of nucleic acids that might be mutations. NSG enables scientists to fast-track this process by analyzing millions of pieces of the genome at the same time. For comparison, the famous human genome sequencing and analysis program that took 13 years to complete and cost $3 billion could now be completed in days for a few thousand dollars.

Man with HIVE Computer

The Center for Biologics Evaluation and Research (CBER) supported the development of High-Performance Integrated Virtual Environment (HIVE) technology, a private, cloud-based environment that comprises both a storage library of data and a powerful computing capacity being used to support Next Generation Sequencing of genomes.

In order to prepare FDA to review and understand the interpretation and significance of data in regulatory submissions that include NGS, the Center for Biologics Evaluation and Research (CBER) supported the development of a powerful, data-hungry computer technology called High-Performance Integrated Virtual Environment (HIVE), which can consume, digest, analyze, manage, and share all this data. HIVE is a private cloud-based environment that comprises both a storage library of data and a powerful computing capacity. One specific algorithm (set of instructions for handling data) of HIVE that enables CBER scientists to manage the NGS fire hose is called HIVE-hexagon aligner. CBER scientists have used HIVE-hexagon in a variety of ways; for example, it helped scientists in the Office of Vaccines Research and Review study the genetic stability of influenza A viruses used to make vaccines. The scientists showed that this powerful tool might be very useful for determining if influenza viruses being grown for use in vaccines were accumulating mutations that could either reduce their effectiveness in preventing infections, or even worse, cause infections.

There’s another exciting potential to HIVE-hexagon research: the more scientists can learn about variations in genes that alter the way they work—or make them stop working–the more they can help doctors modify patient care to reflect those very personal differences. These differences can affect health, disease, and how individuals respond to treatments, such as chemotherapy and influenza vaccines. Such knowledge will contribute to advances in personalized medicine.

Team members at work in FDA's HIVE server room.

CBER scientists showed that HIVE might help scientists determine if influenza viruses being grown for use in vaccines were accumulating mutations that could either reduce their effectiveness in preventing infections or cause infections. Genome studies supported by HIVE will also contribute to advances in personalized medicine.

Because CBER’s HIVE installation has been so successful we are now collaborating with FDA’s Center for Devices and Radiological Health (CDRH) to provide a second installation with greater capacity and computer power that takes advantage of the high-performance computing capacity there. When ready and approved by FDA for use, we will use this powerful, CBER-managed, inter-center resource to handle regulatory submissions.

HIVE-hexagon and its innovative NGS algorithms are just one major step CBER has taken recently as it continues its pioneering work in regulatory research to ensure that products for consumers are safe and effective. I’ll tell you about other exciting breakthroughs in my next update on CBER research.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

For more HIVE photos go to Flickr

FDASIA at Year Two

By Margaret A. Hamburg, M.D.

Margaret Hamburg, M.D.Anniversaries are a time for stock-taking and today, on the second anniversary of the Food and Drug Administration Safety and Innovation Act or FDASIA, I’m pleased to report on the progress we’ve made implementing this multi-faceted law.

To date, we have completed nearly all of the deliverables we had scheduled for the first two years after FDASIA became law. And many of the new authorities under FDASIA are already having a positive impact on health. It’s difficult to cover all of our FDASIA work, but here are some highlights:

Preventing Drug Shortages: Drug shortages, which can have serious and immediate effects on patients and health care professionals, reached an all-time high in 2011, the year before FDASIA was enacted. In response to a Presidential Executive Order in December of that year, FDA issued an interim final rule to amend and broaden FDA regulations requiring certain manufacturers to give early notification of production interruptions that could cause drug shortages. FDASIA further broadened this requirement by requiring that other prescription drug manufacturers provide notification and also gave FDA additional authorities. In October 2013 FDA proposed a rule to implement these authorities and issued a strategic plan for addressing drug shortages. So far, with the help of early notifications, FDA was able to prevent 282 shortages in 2012 and 170 shortages in 2013. The number of drug shortages that did occur has also declined.

Promoting Innovation: FDASIA includes many provisions designed to encourage innovation. We have held meetings on the use of meta-analyses in drug applications; put in place a plan for implementing a benefit-risk framework for drug reviews, and issued a variety of guidance documents covering such topics as drug studies in children, abuse-deterrent drug development, antibacterial drug development and expedited review and development programs for serious diseases.

This latter guidance provided information that sponsors needed to know about our new Breakthrough Therapy designation that was part of FDASIA. This option exists for new drugs intended to treat a serious or life-threatening disease that, preliminary clinical evidence suggests, could provide a substantial improvement over available therapies. As of June 23, we had granted 52 requests for this designation, and of those, approved four new drugs and two new indications for previously approved drugs.

As part of our implementation of the FDASIA-related provisions related to medical devices, we proposed a strategy and recommendations for a risk-based health information technology (health IT) framework that would promote product innovation while maintaining appropriate patient protections and avoiding regulatory duplication; issued a proposed rule for implementing FDASIA’s streamlined new procedures for reclassifying a device; and published a final rule on a medical device unique identification or UDI with implementation in accordance with the timetable set in the law. UDIs will help the FDA identify product problems more quickly, better target recalls and improve patient safety. The riskiest medical devices will start bearing their UDI by September 24th.

Establishing and Strengthening User Fee Programs: An important element of FDASIA was reauthorizing user fees for prescription drugs and medical devices and creating new user fee programs for generic drugs and biosimilar biological drugs. User fees on some types of applications offer an important source of funding to support and maintain key activities, including FDA’s staff of experts who review the thousands of product submissions we receive every year. Since FDASIA took effect, review times for medical devices have been declining.  Our prescription drug user fee program is meeting or exceeding almost all of our performance goals agreed to with industry. We have acted on 54 percent of the generic drug applications, or amendments and supplements to generic drug applications which were pending in our inventory as of October 1, 2012. This helps ensure that consumers can have access to more low-cost drugs. And we have been able to provide advice concerning most of the 93 submissions from companies who are developing biosimilar biological drugs under a pathway that could also ultimately lower costs for consumers.

Enhancing Patient Engagement: A hallmark of FDASIA was a series of provisions intended to tap the patient perspective. Our Patient-Focused Drug Development Program allows us to more systematically obtain the patient’s perspective on a disease and its impact on the patients’ daily lives, the types of treatment benefit that matter most to patients, and the adequacy of the available therapies for the disease. In accordance with FDASIA, we have held patient meetings on eight diseases and have plans for meetings on 12 more. We have learned a great deal from patients in terms of their views of the symptoms of their condition, their feelings about how it affects their life, and their thoughts on ideal treatments and on participation in clinical trials to aid future drug development.  A FDA Voice blog post on patient reports captures these patient perspectives and much more.

Finally, Title VII of FDASIA provided FDA with numerous new authorities to protect the drug supply chain. We thought now was a good time to provide the public with a more detailed description of our work on Title VII, so we asked Howard Sklamberg, Deputy Commissioner for Global Regulatory Operations and Policy, to write a separate blog on that topic.

FDA laid out a three-year plan for implementing FDASIA and we’re on our way to achieving our stated goals. To help the public follow our progress, we set up a dedicated webpage—the FDASIA-Track. It provides useful links to each action and is updated on a regular basis.

Margaret A. Hamburg, M.D., is Commissioner of the U.S. Food and Drug Administration

A Blueprint for Helping Children with Rare Diseases

Editor’s Note: This blog has been updated to provide additional information about our use of expedited programs to speed rare disease medical product development.

By Jill Hartzler Warner, J.D.

Jill WarnerThe U.S. Congress and the Food and Drug Administration have long focused on bringing new therapies to patients with rare diseases, including children.

Two years ago this week, Congress made another contribution to this effort by enacting the Food and Drug Administration Safety and Innovation Act (FDASIA). The law directs our agency to take two actions to further the development of new therapies for children affected by rare diseases: (1) to hold a meeting with stakeholders and discuss ways to encourage and accelerate the development of new therapies for pediatric rare diseases, and (2) issue a report that includes a strategic plan for achieving this goal.

There are unique challenges when developing drugs, biological products and medical devices for the pediatric population. Not only is there the potential for children to respond differently to products as they grow but there are also additional ethical concerns for this patient population.

But these challenges are further compounded when developing therapies for pediatric rare diseases. For example, rare disease product development, by definition, means there is only a small potential group of patients available to participate in clinical studies that can help determine whether a product is safe and effective.

In our FDASIA meeting in January, we heard a variety of suggestions on clinical trial design and data collection from hundreds of the participating stakeholders from academia; clinical and treating communities; patient and advocacy groups; industry and governmental agencies.

These discussions helped inform our Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases, which we posted on our website today. It outlines how we plan to meet the following four objectives:

Enhance foundational and translational science. Our strategy is to fill essential information gaps through such measures as fostering the conduct of natural history studies for pediatric rare diseases and by identifying unmet pediatric needs in medical device development. We also plan to issue guidance for sponsors on common issues in rare disease drug development and to refine and expand the use of computational modeling for medical devices.

Strengthen communication, collaboration, and partnering. Robust cooperation within FDA, among agencies, governments and private entities is necessary to enable the exchange of information on the issues of developing treatments for pediatric rare diseases. Single entities by themselves usually don’t have sufficient resources or expertise to overcome the product development challenges posed by pediatric rare diseases.

Advance the use of regulatory science to aid clinical trial design and performance.  Regulatory science helps develop new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products. Of note, we plan to facilitate better understanding of biomarkers and clinical outcome assessments that are useful for the development of treatments for pediatric rare diseases. We also plan to further develop the expedited approval pathway for medical devices intended to treat unmet medical needs; and use FDA’s web-based resources to update and expand awareness of issues involving the development of medical products for pediatric rare diseases.

Enhance FDA’s review process. Our strategies include fostering efforts to learn patients’ and caregivers’ perspectives and incorporating this information into medical product development. We also plan to further develop and implement a structured approach to benefit-risk assessment in the drug review process and establish a patient engagement panel as part of the medical device advisory committee process.

The report notes our use of expedited programs to speed rare disease medical product development. For example, the accelerated approval program allows for approval of products to treat serious and life-threatening diseases based on an effect on a surrogate marker, such as blood test, urine marker, or an intermediate clinical endpoint, that is believed to be reasonably likely to predict clinical benefit to the patient. Under accelerated approval, further studies are required after approval to confirm that the drug provides a clinical benefit to the patient.

More than 80 new products have been approved under the accelerated approval program, and many of these have been for rare diseases. But it’s important to note that in some cases FDA exercises regulatory flexibility to approve drugs under the traditional approval pathway, rather than under the accelerated approval program. In fact, most of the recent new drug approvals for rare diseases have been approved under the traditional approval pathway because FDA has determined that the drug provides a clinical benefit to the patient. Such approvals make new drugs available to patients, and also mean that companies are not required to do confirmatory trials after approval.

FDA is committed to continuing its use of expedited programs and regulatory flexibility to speed development and approval of safe and effective drugs for all patients with rare diseases, and the strategies outlined in this plan will help us achieve a major goal of FDASIA and for our agency, which is to speed the development of therapies for children with rare diseases.

 

Jill Hartzler Warner, J.D., is FDA’s Associate Commissioner for Special Medical Programs

Empowering Consumers through Accurate Genomic Tests

By: Jeffrey Shuren, M.D., J.D.
We’ve come to recognize that almost every disease has a genetic component, and many consumers now are eager to know more about their genetic profiles. They need only send a sample of their DNA collected from their saliva or from a cheek swab to a company, and in exchange they’ll get back information about their genetic risk for development of future disease.

Jeffrey ShurenFDA understands and supports people’s interest in having access to their genetic information and believes such information can help them make more informed choices about their health – so long as that genetic information is accurate – that the results are correct, meaningful and written in a way that consumers can understand. FDA reviews genetic tests for medical conditions, whether they are intended to be ordered by a healthcare practitioner or directly by the consumer, to assure that consumers receive accurate test results.

Telling someone they are at high risk for a life-threatening cancer when they are not—or that they are at low risk for diabetes when they actually are at high risk for this chronic disease does not empower consumers. Consumers are not empowered by tests that tell them they need higher or lower doses of widely-used drugs, when the opposite is true. Moreover, some genetic tests have questionable value. Their impact on patient health is not known, and there are no guidelines for consumers or healthcare practitioners on how to interpret these test results, in part because the risk of getting a disease depends on a number of other factors such as age, sex, ethnicity, or environment and because genetic tests may only assess a limited number of genetic variations that only account for a small part of the risk.

Concerns about the need to demonstrate accuracy were at the heart of our five-year effort to work with the firm 23andMe that resulted last year in the company ceasing marketing its disease risk and drug dosing tests until it could demonstrate their accuracy.

These concerns were hardly theoretical ones. In 2010, at the behest of Congress, investigators from the U.S. Government Accountability Office purchased direct-to-consumer (DTC) genetic tests from four different companies—including 23andMe—and submitted two samples of their DNA to each company to receive risk predictions for 15 common diseases. The results varied across the four companies. One investigator was told that he was at below-average, average, and above-average risk for prostate cancer and hypertension. In some cases, the risk predictions conflicted with an investigator’s actual medical condition.

FDA is not standing in the way of 23andMe selling tests intended to help consumers trace their ancestry, identify relatives and tell them why they like or don’t like the taste of cilantro. Yes, that information can be fun. But Alzheimer’s disease, cancer and heart disease are serious matters. Our concern remains that genetic tests for diseases, just like other tests for medical conditions, such as hemoglobin A1C for diabetes (glucose control) should be accurate. Armed with that accurate information, consumers can take appropriate steps to take charge of their health.

Accurate information empowers. Consumers deserve no less.

Jeffrey Shuren, M.D., J.D., is Director of FDA’s Center for Devices and Radiological Health

Filling Information Gaps for Women in Medical Device Clinical Trials

By: David Strauss, M.D., Ph.D.

At FDA’s Center for Devices and Radiological Health (CDRH), results from clinical trials often serve as the foundation for our decisions to approve the most important medical devices—devices, such as implantable heart devices, that carry the greatest risk to patients and have the potential to save or sustain life.

David StraussWhile there is risk inherent with all medical devices and procedures, we look for potential gaps in that foundation—gaps that could be filled with more information or data.

One information gap is that there are not enough women enrolled in some clinical trials.

Why is that a gap?

Underrepresentation of women (or minority or ethnic groups) results in a lack of information for these patients and their physicians regarding risks and benefits of some medical products. Certain differences between women and men—including anatomy and physiology—can lead to medical devices performing better or worse.

FDA is actively trying to learn more about how to optimize the safe and effective use of medical devices in women.

With support from FDA’s Office of Women’s Health, CDRH recently performed an analysis of data from multiple clinical trials conducted in support of cardiac resynchronization therapy (CRT), a pacemaker therapy for patients with heart failure. Only 22% of the patients in the clinical trials were women. We combined individual patient data from multiple clinical trials to increase the number of women in the analysis.

We found that women benefit from CRT significantly more than men do. Patients of both sexes with a left bundle branch block (LBBB), an electrical conduction disorder in the heart, benefited most. However, women did so at a shorter QRS duration (time to complete electrical activation of the heart) than men. In the patients with LBBB and shorter QRS duration, women had a 76 percent reduction in heart failure or death, while there was no significant benefit in men. With LBBB and a longer QRS duration, both women and men benefitted from CRT.

We discuss this in greater detail in today’s Journal of American Medical Association: Internal Medicine. It was FDA’s first individual-patient data analysis involving medical devices from multiple companies.

Later this summer, FDA plans to take two additional steps to address this information gap.

One, CDRH intends to finalize a guidance document that provides a clear framework for how to analyze and communicate data on women in medical device clinical trials.

Two, FDA intends to release an Action Plan—mandated by Congress—that contains recommendations for improving the completeness and quality of analyses of data on women, as well as other populations, in summaries of product safety and effectiveness data and in labeling.

As illustrated in today’s publication in JAMA: Internal Medicine, combining individual-patient data from multiple clinical trials is an additional research tool that can help answer questions about patient groups underrepresented in clinical trials—and help us strengthen the foundation for all of medical devices on the market.

David Strauss, M.D., Ph.D. is a medical officer in FDA’s Center for Devices and Radiological Health.

FDA Encourages Medical Device Data System Innovation

By: Bakul Patel

Thanks to advances in digital health, doctors and their patients are more frequently using computer systems to collect medical data that can provide useful information on a patient’s health.

Bakul PatelSome of these systems, referred to as “medical device data systems,” are off-the-shelf or custom hardware or software products that transfer, store, convert format, and display medical device data without modifying it, and without controlling or altering the functions or parameters of any connected medical devices.

Medical device data systems can collect and store data from a variety of other medical devices, including glucose meters, blood pressure cuffs, and weight scales. This data can be used at home to track certain information or it can be stored for a doctor to review at a later time.

Medical device data systems can be used in hospitals to collect information and data from other medical devices including bedside monitors and infusion pumps. This information can then be stored in a patient’s electronic health record for a more complete review of a patient’s total health.

In 2011, FDA issued a regulation down-classifying medical device data systems. Since that time, FDA has gained additional experience with these types of technologies, and has determined that these devices pose a low risk to the public.

Today, given the low level of patient risk, we are proposing a compliance policy under which medical device data systems should see their burdens reduced.

Why would we do that?

Since our 2011 action, we’ve been working with two other federal agencies that oversee health IT – The Office of the National Coordinator for Health IT (ONC) and the Department of Health and Human Services, and the Federal Communications Commission (FCC) on a proposed risk-based regulatory framework for health IT that promotes innovation, protects patient safety, and avoids regulatory duplication. In the course of our work on the proposed framework, we sought extensive public feedback. And we listened.

In light of those discussions, we believe that medical device data system products pose little risk. While every medical device and procedure carries a certain level of risk, the health IT report proposes a risk-based framework – where we use our regulatory tools, resources, and expertise where they are most needed – and that’s with devices that carry  greater levels of risk.

This allows developers of medical device data systems to focus on making these products better able to operate amongst various devices and technology systems – resulting in stronger products.

Today’s proposed guidance for manufacturers of medical device data systems is thus consistent with the health IT report we issued earlier this year with ONC and FCC on the proposed framework. That report placed health IT products in three categories according to their risk to patients. FDA’s regulatory oversight of health IT products is focused on the devices that pose higher risk to patients.

Medical device data systems are critical to the success of digital health because they transfer, store, convert, and display a variety of information from medical devices critical to understanding an individual’s health. These systems are the foundation for intercommunication and interoperability among devices and between medical devices and other health IT.

Because they pose such a low risk, FDA does not intend to enforce compliance with the regulatory controls that apply to medical device data systems. FDA believes that this will encourage greater innovation in the development and maturation of these systems.

Bakul Patel is senior policy advisor in FDA’s Center for Devices and Radiological Health.

Life-Saving, Smart Regulation on Behalf of Patients with Aortic Stenosis

By: Jeffrey Shuren, M.D., J.D.

At FDA’s medical devices center, we have a vision—it’s what we strive for each day in our review and assessment of new medical technology. And patients are at the very core of that vision: “Patients in the U.S. have access to high-quality, safe, and effective medical devices of public health importance first in the world.”

Jeffrey Shuren

Our actions are focused on improving the health and enhancing the quality of life of patients. If a device is safe and effective, we want patients to have access to it as quickly as possible—especially if the patients suffering have little to no treatment options.

This week, we’ve taken steps to help those patients suffering from heart valve disease, which impacts more than 5 million Americans, many of whom have few treatment options and are fighting to survive.

Aortic valve stenosis is a serious, progressive, age-related disease that is commonly caused by calcium deposits on the aortic valve that cause it to narrow.. As the heart works harder to pump blood through the smaller opening, it can eventually weaken. Aortic valve stenosis can lead to fainting, chest pain, heart failure, irregular heart rhythms (arrhythmias), or cardiac arrest.

Of those 5 million Americans, 1.5 million suffer from aortic valve stenosis and some 500,000 of those have severe aortic stenosis. Patients with severe aortic stenosis will most likely need open-heart surgery to replace their aortic valve. Without such a replacement, progressive heart failure may result and 50 percent of patients may not survive more than an average of two years after the onset of their symptoms.

Until recently, aortic valve replacement required an open-heart surgical procedure, which involves accessing the heart through an incision between the ribs or through the breastbone, while the patient is supported by a heart-lung machine. Unfortunately, many of these patients are elderly and have additional conditions, such as extreme frailty or liver disease. This makes the surgical procedure either too risky to attempt (inoperable) or very risky for death and permanent complications (high-risk for surgery).

In the past few days, FDA has expanded patient access to the benefits of aortic valve replacement by approving the use of two transcatheter heart valve (THV) systems. These catheter-based therapies provide the only effective therapy for inoperable patients and are alternatives to open-heart surgery for patients at high risk for surgery. Both systems allow physicians to perform aortic valve replacement using catheters, so patients benefit from reduced symptoms of heart failure and improve their chances for survival.

Both THVs are typically implanted through an artery in the leg, without opening the chest or heart, or removing the diseased valve. The replacement valve is compressed into a thin, flexible tube called a delivery catheter. The delivery catheter and the replacement valve are inserted into the femoral artery and pushed up to the diseased valve. The replacement valve is then released from the delivery catheter to become immediately functional. If the femoral arteries are not suitable, the replacement valve can be directly inserted into the tip of the heart, other arteries, or the aorta itself, without using the heart-lung machine.

On June 12, 2014, FDA expanded the use of the CoreValve, a self-expanding THV manufactured by Medtronic, to include patients who are at high-risk for open-heart surgery. We had previously approved CoreValve only for inoperable patients. FDA based its approval of CoreValve on clinical data from a 795-patient randomized, clinical study conducted in the United States, comparing the safety and effectiveness of transcatheter aortic valve replacement using CoreValve with that of surgery in patients at high-risk for open-heart surgery. This study showed a lower mortality rate for patients treated with CoreValve.

And today, June 16, FDA approved the Sapien XT, a balloon-expandableTHV, manufactured by Edwards Lifesciences. The Sapien XT is a revised version of their earlier Sapien THV for use in patients with aortic valve stenosis who are either inoperable or at high-risk for open-heart surgery.

The Sapien XT THV uses a smaller profile delivery system than the previously approved Sapien THV. The smaller system helps patients with small or severely diseased vessels. The Sapien XT is also available with an additional, larger-size 29-mm valve, which helps patients with larger-size native aortic valves.

For the Sapien XT approval, FDA based its decision on clinical data from a randomized clinical study and several, single-arm nested registries, conducted in the U.S. The 560-subject randomized clinical trial showed that, for inoperable patients, the Sapien XT device was as safe and effective as the previously approved Sapien device, with better procedure outcomes and reduced vascular complication rates.

The agency also reviewed clinical data from the European SOURCE XT Registry, Society of Thoracic Surgeons /American College of Cardiology Transcatheter Valve Therapy (TVT) Registry, and peer-reviewed articles that showed the benefits of the Sapien XT device for high-risk patients outweighed the risks of the device.

We approved the Sapien XT THV despite observing certain quality system violations during a recent inspection at the Edwards manufacturing facility where the Sapien XT delivery systems and accessories are made. Quality system requirements govern the design, manufacture, and distribution of devices, and we conduct such inspections to assure that devices are safe and effective. When violations occur, according to federal law, we cannot approve a company’s medical device—unless, we allow deviation from quality system requirements through what is known as a “variance.”

This is a rarely used regulatory action that is employed only in special situations of public health need. FDA may grant a variance from any device quality system requirement when the agency determines that it is in the best interest of the public health and that the firm seeking the variance has alternate methods and controls in place sufficient to assure that the device will be safe and effective and otherwise in compliance with the Act.

We granted Edwards Lifesciences a variance from the quality systems requirements for two reasons.

First, we determined that there is an important, immediate need for these technology options and that Sapien XT demonstrates a reasonable assurance of safety and effectiveness for its intended use. This means patients who really need this technology could and should receive it.

And second, Edwards Lifesciences presented us with an appropriate variance plan for addressing its manufacturing problems—including specific controls to permit safe use of the Sapien XT while corrections are underway.

We are committed to flexible, smart regulation, and to working with companies and the clinical community to ensure that innovative new medical devices that demonstrate a reasonable assurance of safety and effectiveness are available for patients in a timely manner.

There is a clear and important public health need for both these devices. With the additional availability of two THV systems, physicians will now be able to treat the widest possible spectrum of patients with severe and symptomatic aortic stenosis. They will be able to choose the procedure or device that best suits each individual patient based on unique patient characteristics, anatomic constraints, implant procedure risks, device characteristics, and overall benefit-risk profiles.

After all, patients are at the core of what we do.

Jeffrey Shuren, M.D., J.D., is Director of FDA’s Center for Devices and Radiological Health

Report: CDRH on Track to Improve Device Submission Review Process

By: Jeffrey Shuren, M.D.

FDA’s Center for Devices and Radiological Health (CDRH) is committed to speeding innovative new medical devices to market and to improving the efficiency of our device submission review process. That’s critical for patients getting access to medical devices that treat often life-threatening conditions. It’s also important for industry’s ability to continue developing new products.

Jeffrey ShurenWhile recent data suggest we’re making solid progress in bringing down total review times for both 510(k) submissions and our higher risk premarket approval applications, it’s always useful to get a reality check.

That’s why, as part of the 2012 Medical Device User Fee Amendments (MDUFA III), FDA agreed with the medical device industry to participate in an independent and comprehensive assessment of our review process.

A third party consulting firm assessed CDRH’s review process, management systems, IT infrastructure, workload management tools, reviewer training programs and staff turnover. Key findings were released in December 2013, along with a list of high-priority recommendations for improvements.

Their Final Report on Findings and Recommendations, released today, affirms that CDRH is on a path to meeting many of the challenges that were flagged in the months leading up to the enactment of MDUFA III, including such topics as sponsor communication, IT infrastructure, reviewer training, reviewer attrition, and submission quality.

Initially, the contractor identified 31 unique issues related to the device submission review process. They concluded that CDRH had taken steps to address 21 of those 31 issues – either through the development and implementation of new MDUFA III provisions, updated systems, and/or processes for review staff – and that we had at least begun to address another nine of the issues. Only one issue – creating the tools and metrics to assess the consistency of decision-making across the program – remained. It was the driver for one of the contractor’s high-priority recommendations.

After the December report came out, we put together our own plan of action to implement the high-priority recommendations. These recommendations call for:

  • Developing criteria and establishing mechanisms to improve consistency in decision-making throughout the review process.
  • Providing mandatory full staff training for the three primary IT systems that support MDUFA III reviews.
  • Identifying metrics and incorporating methods to better assess review process training satisfaction, learning and staff behavior changes.
  • Adopting a holistic, multi-pronged approach to address five quality component areas to standardize process lifecycle management activities and improve consistency of reviews. This approach addresses such topics as corrective and preventive action and continuous process improvement, resource management, document management and system evaluation.

This action plan, also out today, has been divided into two stages. The first stage includes those actions needed to address specific recommendations identified in the December report, most of which will be implemented by 2016. The second stage covers longer-term actions to further enhance the efficiency of our processes beyond what the contractor recommended. We will now begin to execute this action plan. In addition, as we committed to do under MDUFA III, we will now develop an implementation plan for the new recommendations in this final report.

I encourage you to take a close look at the report and our plan of action. I think you’ll agree with me that sustained focus on these various management improvements will translate to more consistent and efficient reviews, advanced innovation and ultimately improved patient health.

Jeffrey Shuren, M.D., is Director of FDA’s Center for Devices and Radiological Health