FDA Advisory Committees: Independent, Informed, Essential, and Evolving

By: Robert M. Califf, M.D.

One of the most common concerns raised when I meet with medical leaders is the need to improve the function of FDA’s Advisory Committees (ACs). ACs play a key role in FDA’s decision-making process by providing independent expert advice on extraordinarily complex issues. Just as importantly, they offer a forum for open and transparent discussion about these processes. As their name suggests, ACs are only advisory, but they can yield unique insights into understanding the balance of benefits and risks of products.

Not every product is brought to an advisory committee — when the answers are clear, the FDA makes decisions without consulting an AC. But when products present challenging issues or involve developing areas of science, the views of experts in relevant fields can provide essential perspective needed to make good decisions.

They also provide a barometer for the public on Agency thinking in a given field and offer insight into Agency decision-making and requirements for successful product development in a particular setting. The views expressed and votes taken can have financial impacts on companies and can lead to changes in how investments are made in therapeutic areas. So it is not surprising that the deliberations and views of ACs often receive significant media attention.

ACs have been the subject of ongoing discussions concerning their impartiality, their transparency, and how they affect decisions made about FDA-regulated products. In response to these concerns, the FDA is taking a closer look at the AC meeting process to determine what changes may be needed to ensure that ACs remain able to provide crucial expert advice relevant to the uncertainties that prompt such meetings.

Robert Califf

The process of engaging the expertise needed for ACs requires careful consideration, and the goal of ensuring that such a critical function leads to the best advice with optimal public trust by eliminating or managing conflicts is embedded in both law and culture at FDA. Experts who comprise ACs generally are classified as “special government employees” (SGEs) of the FDA. As such, they must declare any potential conflicts of interest and undergo a rigorous financial screening to ensure that they do not have a conflict or apparent conflict that could preclude their participation. SGEs are also expected to be free of intellectual bias that may foreclose their ability to consider the data and questions with an open mind.

Sometimes, a compelling interest can justify allowing a SGE with a potential conflict to participate. In such a case, the prospective AC member must be granted a waiver or appearance authorization, which provide a mechanism for clearly delineating the reasons for allowing that person to participate and requires disclosing the conflict. This aspect of the AC process has evolved over time, becoming increasingly complex and burdensome.

In 2007, the Food and Drug Administration Amendments Act (FDAAA) restricted the FDA’s ability to use waivers for SGEs as part of an effort to reduce bias among AC members by allowing minimal or no financial conflicts. This led to concerns from multiple stakeholders about whether the FDAAA provision was in fact discouraging the most qualified experts from serving on ACs and thus depriving FDA of the best possible guidance on important scientific issues.

In response to these concerns, Congress included a provision in the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) that encouraged FDA to weigh an AC member’s conflicts against the need for that participant’s scientific expertise. However, despite this added flexibility, there are many who believe FDA has not been aggressive enough in advocating for waivers — a circumstance that they believe has sometimes resulted in difficulty obtaining the optimal expertise needed to address the complex problems typically brought to ACs. And some outside the Agency have wondered whether this means FDA is moving to reduce use of ACs.

The process for AC participation itself has led to other criticisms. Across academia, the AC system is seen as overburdened with unnecessary paperwork. Additionally, FDA has faced criticism that the concept of an “imputed interest” is interpreted so that academic leaders with significant experience and insight are considered to have conflicts relating to grants and contracts held by faculty members at the same institution — even if they themselves have no involvement with the project. The proliferation of roadblocks to serving as an SGE has led some within FDA and key leaders in various scientific fields to question the value of ACs in their current form.

After indepth discussion with the medical product and tobacco Centers, OMPT initiated a process improvement evaluation using Lean concepts, which comprise an industrial engineering toolset used for process improvement. These tools were applied to the AC process to fully understand the administrative requirements for planning meetings and screening potential SGEs. We are confident that administrative processes, both inside FDA and for SGEs, will be streamlined as a result.

The next step will be to evaluate current policies and identify areas where the evaluation of conflicts of interest for SGEs can be modernized. We must consider questions such as the criteria for disqualifying AC members from specific activities, the appropriate scope of “imputed interests,” and the interrelationship between the advisory role of AC members and the decisional role of Agency employees.

Even more importantly, we must engage in wide-ranging discussions inside and outside FDA about the best ways for the Agency to get the advice it needs to make critical decisions that protect and promote the health and safety of all Americans. To obtain the best expertise possible, we must optimally configure and administer our ACs.

There is no question that we must appropriately address potential conflicts for our SGEs.  However, we must also ensure that experts working in their fields are not unnecessarily foreclosed from participation in the AC process. As we continue to improve the mechanics of ACs and to reduce unnecessary administrative burdens, we must also address the appropriate mix of expertise on committees, so that FDA scientists and staff get the advice they need to make the best decisions on behalf of the American public.

Robert M. Califf, M.D., is Commissioner of the U.S. Food and Drug Administration

Better Tool to Help Assess LASIK Patients

By: Malvina Eydelman, MD

LASIK (laser-assisted in situ keratomileusis) eye surgery is an alternative for patients who need glasses or contacts to see well. Some 600,000 to 800,000 patients undergo LASIK in the U.S. each year, and a very high number of those patients are satisfied with their surgical outcomes.

Malvina EydelmanHowever, some patients develop unwanted visual symptoms following surgery, symptoms that can have a significant impact on their daily lives. Patients who see starbursts, glare, ghosting, or halos—or those who experience severe dry eye—may have their daily lives change in negative ways.

While there are risks with all medical procedures – and the risks associated with LASIK are well known – FDA teamed up with the National Institutes of Health (NIH), and the Department of Defense (DoD) to more fully capture the patient experience with LASIK. Through the LQOLCP (LASIK Quality of Life Collaboration Project) and the Patient-Reported Outcomes with LASIK (PROWL) studies, we have developed a valid web-based questionnaire that can be used to assess LASIK patients before and after surgery. The questionnaire is available on FDA’s website.

The new scientifically validated questions can help assess patient expectations, symptoms, and satisfaction, and includes definitions of the visual symptoms and images depicting the range of the symptom to facilitate patients’ reporting. These questions can be used for a variety of purposes, such as being used by eye care providers to monitor symptoms before and after LASIK surgery. Additionally, manufacturers may wish to include such information in future LASIK product submissions along with other clinical and nonclinical evidence for FDA’s benefit-risk determination.

The LQOLCP focused on patient-reported outcomes (PROs)—which are reports of the status of a patient’s health condition that come directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. Using well-developed PRO measures, everyone can better understand the impact that visual symptoms associated with LASIK treatment have on the patient’s life.

The newly-developed questions in the PROWL questionnaire can facilitate discussions between eye care providers and patients considering LASIK surgery. In the PROWL studies, patients were more than twice as likely to report their visual symptoms when filling out a questionnaire, than to tell them to their health care provider.

With this improved collection tool of patient experiences, the development of debilitating symptoms was uncommon. Less than 1 percent of study participants experienced difficulties performing their usual activities following LASIK surgery due to any one symptom in each of the PROWL studies. The PROWL questionnaire can be used in future research to more accurately estimate the prevalence of visual symptoms in LASIK patients and identify the predictors of visual symptoms and dissatisfaction.

By listening to the patient’s perspective during the development, evaluation, and use of medical devices, FDA and manufacturers can work together to better assure that LASIK devices marketed in the United States are safe, effective and meet the needs of the patients for whom they are intended. The patient perspective is so important to us that it is one of FDA’s Center for Devices and Radiological Health’s strategic priorities.

Read more information about the LASIK Quality of Life Collaboration Project.

Malvina Eydelman, M.D., is the Director of the Division of Ophthalmic, and Ear, Nose, and Throat Devices, Office of Device Evaluation, at FDA’s Center for Devices and Radiological Health

21st Century Cures Act: Making Progress on Shared Goals for Patients

By: Robert M. Califf, M.D.

Today, President Obama signed into law the 21st Century Cures Act, which, I am pleased to report, builds on FDA’s ongoing efforts to advance medical product innovation and ensure that patients get access to treatments as quickly as possible, with continued assurance from high quality evidence that they are safe and effective.

Robert CaliffCures will greatly improve FDA’s ability to hire and retain scientific experts. One of our ongoing challenges has been recruiting and retaining the experts we need in specialized areas to allow us to get our work done and meet our growing responsibilities. This is an especially important need given the tremendous advances in biological sciences, engineering, information technology and data science. Preventive, diagnostic and therapeutic strategies will become more complex with much greater potential for benefit and in some cases greater risk if used without adequate evidence to exclude risks that exceed potential benefits.

This new law rightly recognizes that patients should play an essential role in the development of drugs and devices to diagnose and treat their disease, since patients are in a unique position to provide essential insights about what it is like to live with and fight their disease. That’s been our perspective as well, and it’s why FDA has continued to advance the science of patient input through our patient-focused drug development program and our partner with patients program for medical devices. As it is, Cures will enhance these ongoing efforts to better incorporate the patient’s voice into FDA’s decision-making.

Cures will also support our efforts to modernize and improve efficiency in clinical trial design. This has been an important FDA priority for decades, but exciting new approaches are now available, and we need to develop a common understanding of which designs should be used for which clinical issues. In cancer, for example, we’re already weighing the use of common control trials, which share a control arm, involve multiple different drugs for the same indication, and may even involve different companies. One of the benefits of using a common control arm is that the overall number of patients who need to be recruited and enrolled decreases, thereby optimizing clinical trial resources and potentially shortening the time it takes to get a new study off the ground

Even without the benefit of Cures, patients have been well-served by FDA’s program efficiencies, emphasis on early meetings, and use of expedited pathway programs to speed approval and delivery of new drugs and devices to patients. Rather than passively processing product applications, FDA works to advise companies and inventors from the earliest stages of the development process on the kinds of medical products needed, how to do the necessary research, and how to viably and effectively translate from concept to product. This not only means that important new products will be developed as efficiently as possible but also that medicines and devices with no chance of success are identified much earlier so that money isn’t wasted on futile development. These programs have been embraced by developers of medical products in this country, and they are making a real and positive difference.

In the United States, the FDA uses expedited programs (fast track, priority review, accelerated approval, and breakthrough therapy) for drugs and biologics more than comparable drug and biologic regulators in other countries use theirs and as a result FDA is the first to approve a majority of novel drugs compared to our foreign counterparts.

For devices, this past year was the first full year of operation for FDA’s expedited access pathway (EAP) program, which helps speed the development and availability of certain medical devices that demonstrate the potential to address unmet medical needs for life-threatening or irreversibly-debilitating diseases or conditions. So far, we have granted 24 devices access to this program. Cures builds on EAP by creating the breakthrough device pathway.

The law establishes other new programs as well. For instance, the Limited Population pathway will help streamline the development programs for certain antibacterials and antifungals intended to treat targeted groups of patients suffering from serious or life-threatening infections where unmet need exists due to lack of available therapies. Approvals of these antimicrobials are expected to rely on data primarily targeting these limited populations. The statement “Limited Population” will appear prominently next to the drug’s name in labeling, which will provide notice to healthcare providers that the drug is indicated for use in a limited and specific population of patients. The limited population statement, additional labeling statements describing the data, and FDA review of promotional materials, will help assure these drugs are used narrowly to treat these serious and life-threatening infections while additional evidence is generated to assess safety and effectiveness for broader use.

Cures also creates a new program for  the development of regenerative medicine products, an important and exciting new field that deserves this special focus. The program designates drugs as regenerative advanced therapies and takes appropriate actions to improve the efficiency of development and to enhance the exchange of information among FDA, researchers and developers. An especially important element of this program is the creation of a research network and a public-private partnership to assist developers in generating definitive evidence about whether their proposed therapies indeed provide clinical benefits that are hoped for.

Looking ahead, much still needs to be done to spur product development. There have yet to be successful therapies identified for certain diseases, such as Alzheimer’s disease, where underlying scientific knowledge is still lacking.  In addition, we are only at the early stage in building a national evidence generation system based on registries, claims data, and electronic health records that will be a rich source of post-market data and an avenue for conducting more efficient research. Last week we published a consensus of FDA leadership on the use of real world evidence in the New England Journal of Medicine, focusing on the misperception that randomized trials and real world data are incompatible.  In fact, the use of randomization within the context of clinical practice will constitute a major advance in evidence generation and we are actively encouraging proposals with this combination of randomized trials conducted in real world practice. Cures provides support for continued exploration of the use of real world evidence in the regulatory context.

The law also addresses drug firms providing healthcare economic information to payers and formulary committees. This complex area will require careful delineation of principles to guide information exchange to enable these entities to appropriately assess the value of drugs.

With Cures, great progress has been made towards our shared goal of advancing regulatory science so that we can continue to speed the discovery, development, and delivery of medical products to prevent and cure disease and improve health while sustaining the evidence framework that enables assurance to the public of the safety and effectiveness of medical products. We are excited about the major advances in NIH funding, and welcome the increasing focus on rigorous translational science and data sharing reflected in the bill. Furthermore the funding of opioid addiction treatment and mental health services is a major positive element for our country and consistent with tremendous needs that we recognize.

FDA now stands ready to work with Congress, our sister federal agencies and the medical products ecosystem to implement these important provisions as we continue to work on behalf of all Americans to protect and promote public health and promote innovation in this exciting time.

Robert M. Califf, M.D., is Commissioner of the U.S. Food and Drug Administration

Combination Products Review Program: Progress and Potential

By: Nina L. Hunter, Ph.D., and Robert M. Califf, M.D.

Nina Hunter

Nina L. Hunter, Ph.D., FDA’s Associate Director for Science Policy in the Office of Medical Products and Tobacco

About a year ago, we shared with you our Combination Product Review, Intercenter Consult Process Study Report, which was developed by FDA’s Office of Planning. The report’s findings were derived from focus group studies with reviewers from FDA’s different Centers and included input from industry. Since then, we have built on foundational policies and processes to address many of the issues identified in the report.

The team has made tremendous progress toward the goal of modernizing the combination products review program by improving coordination, ensuring consistency, enhancing clarity, and providing transparency within the Agency as well as with all stakeholders. We are excited to share our progress with you now. The table below summarizes some key achievements from the past year, including publication of draft guidances, a variety of new processes, and a look at future goals.

Robert Califf

Robert Califf, M.D., is Commissioner of the U.S. Food and Drug Administration

As technologies advance across multiple fields, the distinctions that previously allowed combination products to be neatly categorized by FDA’s medical product centers are blurring or even vanishing.

Combination products account for a growing proportion of products submitted for review, and FDA will continue to pursue new approaches to collaboration that ensure safe, effective and innovative medical products are made available to patients as quickly as possible. Continued collaboration with you, our stakeholders, will be critical as together we continue to make progress in this important area.

We are still listening and have much more work to do!

Combination Products Review Table

This table summarizes key Combination Product Review Program achievements from the past year. Click on table for PDF version.

The PDF version of the table is also located here: combination-products-review-program

Nina L. Hunter, Ph.D., is FDA’s Associate Director for Science Policy in the Office of Medical Products and Tobacco

Robert M. Califf, M.D., is Commissioner of U.S. Food and Drug Administration

Trade Alert: FDA Issues New Import Data Requirements

By: Howard Sklamberg, J.D.

One of FDA’s many responsibilities is to review imported products regulated by the agency to determine admissibility. This job has become increasingly challenging with growing volumes of imports of FDA-regulated products each year — from six million import entries in 2002 to 35 million in 2015.

Howard SklambergTo help meet that challenge in a way that benefits both government and the trade community, import entries of products regulated by FDA are submitted through an electronic system called the Automated Commercial Environment (ACE). A final rule published on November 29 in the Federal Register specifies certain data that must be submitted in ACE when an FDA-regulated product is offered for import into the United States. The effective date of the rule is December 29, 2016, 30 days from the date of publication.

The trade community helped us pilot ACE, which is operated by U.S. Customs and Border Protection (CBP), from August 2015 to May 2016. In July 2016, ACE became the sole CBP-authorized system for electronic submissions of entries that contain FDA-regulated products.

The rule also includes technical revisions to certain sections of FDA regulations:

  • The owner or consignee of an FDA-regulated product is now defined as the importer of record. This brings FDA regulations up to date with previous revisions to customs laws. (21 CFR 1.83 and 21 CFR 1005.2)
  • FDA will now directly provide a notice that an FDA-regulated product is to be sampled, rather than having to go through CBP to provide that notice. (21 CFR 1.90)
  • FDA may now provide written notices electronically to the importer of record about FDA actions to refuse FDA-regulated products and/or subject certain drug products to administrative destruction. (21 CFR 1.94)
  • The rule clarifies that FDA can reject an entry for failure to provide through ACE the complete and accurate information required by the rule.

As a result of the more streamlined import process for FDA-regulated products provided by ACE, the rule is expected to lead to an efficient use of FDA and importer resources, and more effective enforcement of laws and regulations enforced by FDA.

FDA will continue to provide assistance to filers working to properly submit the required data. Some of the measures we have instituted:

  • We are offering telephone meetings with importers, customs brokers, and other stakeholders, in real-time, while they are filing entries in ACE. Request a meeting by emailing ACE_Support@fda.hhs.gov.
  • An ACE Support Center is staffed 24/7. Reach FDA staff by email at ACE_Support@fda.hhs.gov or by phone at a domestic toll-free line (877-345-1101) or a local/international line (571-620-7320).
  • Upon request, FDA will assist in a filer’s first ACE submission, or for filers who import various commodities, FDA will assist with every first submission of a particular commodity.
  • Additional assistance for general import operations and policy questions, including FDA product codes and entry requirements, is available via email at FDAImportsInquiry@fda.hhs.gov or by calling 301-796-0356.

ACE replaces the Automated Commercial System, an older electronic submission system. Additionally, ACE provides an efficient single window for importers. Prior to the development of ACE, importers of products regulated by multiple government agencies could in some cases be required to submit information more than once.

ACE has already shown promise in accomplishing the dual goal of protecting public health while also serving the needs of the trade community by facilitating a more efficient review for admissibility of compliant products. FDA processing times for both automated and manual review have already been substantially reduced, by approximately 75% and 93% respectively, compared with the agency’s processing times in the previous system.

The ACE system serves to protect public health by allowing FDA to focus its limited resources on those FDA-regulated products being offered for import that may be associated with a greater public health risk.

Howard Sklamberg, J.D., is FDA’s Deputy Commissioner for Global Regulatory Operations and Policy

National Cyber Security Awareness Month: Understanding the Interdependencies of Medical Devices and Cybersecurity

By: Suzanne B. Schwartz, M.D., M.B.A.

October is National Cybersecurity Awareness Month. Proclaimed by President Obama each year, Cybersecurity Awareness Month encourages the public and industry to understand the importance of cybersecurity and to be vigilant when it comes to the technology we rely on every day, including helping patients remain confident in the safety of their medical devices.

Suzanne SchwartzMany medical devices are “life critical systems”—meaning they play a crucial role in monitoring and protecting human life. As more and more of these systems use technology to interconnect, we must be dedicated to securing them from hackers and cyber-attacks.

Here at FDA, we work with hospitals, health care professionals, and patients to provide medical device manufacturers with guidance for monitoring, identifying, and addressing cybersecurity vulnerabilities in their devices before and after they have entered the market. To further counter threats, FDA has been making a deliberate effort to work with outside groups—including those we have previously not engaged with—such as security researchers.

This outreach has allowed our guidance to evolve. While manufacturers can incorporate controls in the design of a product to help prevent these risks, it is essential that manufacturers also be proactive and on guard for potential vulnerabilities and emerging threats throughout the lifecycle of devices, and be prepared to devise solutions—points made in FDA’s draft guidance on postmarket medical device cybersecurity, issued in January 2016.

A life cycle approach requires creating, evolving, and maintaining a comprehensive cybersecurity risk management program starting from early product development and extending throughout the product’s lifespan. A key component of such a program is what should be done after a product’s potential risks and vulnerabilities have been identified. A life cycle approach should include manufacturers collaborating with entities that discover threats or vulnerabilities to a medical device’s cybersecurity in order to understand and assess the identified risks. It should also include manufacturers developing appropriate solutions prior to the vulnerabilities being publicly disclosed, which is an added protection for patients.

But, our work alone won’t achieve safety if all stakeholders do not recognize and remain vigilant against potential threats. Medical device manufacturers, government agencies, health care delivery organizations, health care professionals, and patients all share this responsibility.

In recognition of this shared responsibility, FDA has entered into a partnership with the National Health Information Sharing and Analysis Center (NH-ISAC), and the Medical Device Innovation, Safety, and Security Consortium (MDISS) to foster rapid sharing of medical device vulnerabilities, threats, and mitigations within the hospital and health care ecosystem. Doing so will help to proactively address cybersecurity threats and vulnerabilities that may impact patient safety.

Digital connections provide great power to innovate—and security must keep pace with that innovation. Safeguarding our sector’s—Healthcare and Public Health (HPH)—critical infrastructure therefore includes first identifying, and then addressing previously unforeseen medical device cybersecurity vulnerabilities. As National Cybersecurity Awareness Month rolls on, we encourage everyone to be aware, vigilant, and committed to upholding and strengthening cybersecurity. Through a joint approach encompassing the public and several government agencies, we are beginning to see the necessary change in culture within the medical device ecosystem, accompanied by progress in the management of medical device cybersecurity. FDA’s January 2016 workshop “Moving Forward: Collaborative Approaches to Medical Device Cybersecurity” highlighted some of the progress that has been made. Moreover, recent examples of coordinated vulnerability disclosure between medical device manufacturers and security researchers demonstrate the promise of partnership in addressing medical device cybersecurity. But there is still work to be done, and we must remain committed to working collaboratively to address our goal of protecting the public health.

Learn More

For more information about National Cybersecurity Awareness Month including tips on cyber safety, visit the Stop.Think.Connect.™ campaign website. You can also find more information about medical device cybersecurity on FDA’s Center for Devices and Radiological Health web page.

Suzanne B. Schwartz, M.D., M.B.A., is Associate Director for Science and Strategic Partnerships at FDA’s Center for Devices and Radiological Health

FDA is working with hospitals to modernize data collection about medical devices

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

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

America’s hospitals and their dedicated staff helps us fight disease and suffering by delivering life-saving and life-enhancing care every day in an astounding variety of ways.

From helping set a broken leg or responding to an emerging viral threat, to assisting and performing delicate heart surgeries on tiny newborns, these hospital personnel are the front line of surveillance, vigilance, and intervention.

Throughout their work day, hospital staff use a variety of medical devices: imaging machines, EKGs and in vitro tests to make diagnoses; infusion pumps, ventilators and robotics to provide treatment, and an array of implants to replace diseased joints and organs. And, as the nation’s hubs for real-time health care data, hospitals are uniquely positioned to help identify new safety problems with devices as well as changes in the frequency of already known safety problems because they use these technologies in the real-world setting of clinical practice, outside of the more controlled setting  of a clinical trial.

FDA is looking to improve the way we work with hospitals to modernize and streamline data collection about medical devices.

Jeffrey Shuren

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

Given the greater diversity and complexity of medical devices today; the rapid technological advances and iterative nature of medical device product development; the interface between the technology and the user – including the learning curve associated with adopting new technology; and, in some cases, a relatively short product life cycle that can be measured in months, not years; FDA’s evaluation of medical device safety presents unique challenges not seen with drugs and biologics. Therefore, assuring the safety of medical devices depends on many factors and should a problem arise, it could be due to a variety of causes.

At the time of premarket evaluation, however, it is not feasible to identify all possible risks or to have absolute certainty regarding a technology’s benefit-risk profile. Among other reasons, studies required to do so would likely be prohibitively large in order to capture less frequent and more unpredictable effects or consequences. In addition, such larger studies still may not reflect the true benefit-risk profile of the device. Once a device is on the market, for example, doctors may use it beyond the FDA cleared intended use. In addition, subsequent modifications to the device or changes in how the device is used in practice can result in new safety risks or greater frequency of known risks.

FDA has several tools for watching devices once they are on the market, also called postmarket surveillance, all of which have inherent limitations. For one thing, we can require that a manufacturer conduct a post-approval or postmarket surveillance study that focuses on identifying potential longer-term issues noted at the time of clearance or approval or specific safety concerns that may arise after clearance or approval. However, conducting studies on a product after it’s already on the market can be challenging because patients often have little incentive to enroll in a study when the device is already available to them.

Likely the most well-known of FDA’s postmarket surveillance tools is medical device reporting, which FDA requires from certain entities, including device manufacturers and device user facilities, such as hospitals. Federal law requires hospitals and other user facilities to report when they become aware of information reasonably suggesting that a medical device has or may have caused or contributed to a death or serious injury to a patient.  They must report these medical device-related deaths to both FDA and the manufacturer, if known; and device-related serious injuries to the manufacturer, or to FDA, if the manufacturer is not known.  Such passive surveillance has important limitations because it relies on people to identify that a harm occurred or a risk is present, recognize that the harm or risk is associated with the use of a particular device, and take the time to report it.

Congress mandated this reporting by user facilities in 1990 to complement similar adverse event reporting by manufacturers. But then, in 1997, Congress required that FDA establish a reporting program that could limit user facility reporting to a subset of representative user facilities. As part of our efforts to develop this  reporting program, FDA set up a large-scale network of about 300 hospitals, called MedSun (the Medical Product Safety Network), with whom we work interactively to better understand and report on device use in the real-world environment. Even with MedSun, all hospitals were required to continue reporting until FDA implements by regulation a program limiting user facility reporting to a subset of facilities.

Although FDA has recognized that requiring all hospitals and other user facilities to report may provide limited added value and could entail unnecessary costs that take away from patient care, we have not yet established the program limiting reporting to a subset of user facilities. In the past, we have not enforced universal reporting requirements for hospitals and other user facilities.

In light of several high-profile device safety issues occurring in hospitals, FDA, in December 2015, initiated inspections at 17 hospitals, chosen because there were reports of events at these facilities related to the spread of uterine cancer from the use of morcellators or the spread of infections associated with contaminated duodenoscopes. While these events appeared to be the kind that would have fallen under our current medical device reporting requirements, we did not see corresponding adverse event reports in our adverse event (MAUDE) database. From those inspections, we learned three important lessons:

  • First, some hospitals didn’t submit required reports for deaths or serious injuries related to devices used at their facilities, and in some cases, they did not have adequate procedures in place for reporting device-related death or serious injury events to FDA or to the manufacturers.  Based on the number of user facilities in the United States and the number of reports we receive, we believe that these hospitals are not unique in that there is limited to no reporting to FDA or to the manufacturers at some hospitals.  We want to work with all hospitals to address these issues.
  • Second, hospital staff often were not aware of nor trained to comply with all of FDA’s medical device reporting requirements.
  • Third, we feel certain there is a better way to work with hospitals to get the real-world information we need, and we should work with the hospital community to find that right path, especially in light of developments in the creation and evaluation of electronic health information.

In order to effectively address these issues, we will work with the hospital community on what role they should play in assuring the safe use of medical devices. This work will include how they can effectively participate in  the National Evaluation System for health Technology (NEST), and whether or not current reporting requirements should remain, be modified, or eliminated in light of more effective modern tools, such as software tools to conduct active surveillance of electronic health information that contains unique device identifiers.  In many cases, our inspections of these 17 hospitals turned up violations of FDA’s medical device reporting regulation. For some hospitals with significant violations of the regulation, FDA received a response that we determined was not adequate to address those violations, and we engaged with these facilities to facilitate an effective path to compliance. These hospitals indicated their willingness to work with us and address the violations, and at this time, we do not believe any additional action with regard to these hospitals is necessary.  Some hospitals also expressed willingness to work with us on more efficient and effective ways to collect the information we need.

On December 5, FDA will hold a public workshop to solicit input and advice on improving hospital-based surveillance systems and the broader role of using hospitals to evaluate how well devices work in the clinical setting. We encourage all hospital stakeholders—from clinicians to IT system managers—to attend and discuss current hospital-based surveillance efforts, the role of hospitals in evidence generation and future opportunities for hospital-based surveillance. We’d also like their input on the incorporation of unique device identifiers (UDIs) into electronic health records to aid in the future development of evidence generation efforts, including the support of better device development, surveillance and health care delivery.

We are already working directly with the Association of American Medical Colleges and the American Hospital Association to prepare for this workshop and help develop improvements to our systems.

Hospitals are our partners in building the infrastructure for NEST. Together we can build a state-of-the-art system that not only quickly identifies life-threatening problems caused by medical devices but also expedites patient access to crucial life-saving devices. Armed with such information, health care providers can help patients make more informed medical decisions that improve their health.

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

precisionFDA’s Next Challenge? Conduct an App-a-Thon!

By: Zivana Tezak, Ph.D., and Elaine Johanson

FDA is increasingly harnessing the power of supercomputers, the creative and collaborative culture of the scientific community, and novel approaches to technology to help achieve advances in diagnostics, therapeutics, and analytics that will ultimately benefit patients.

Zevana Tezak

Zivana Tezak, Ph.D., is Associate Director for Science and Technology at FDA’s Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health

Perhaps no program personifies these efforts more than the online research portal precisionFDA, which was developed by FDA scientists with the help of leading minds from Silicon Valley as part of President Obama’s Precision Medicine Initiative (PMI).

The goal of the PMI is to help translate scientific knowledge about genomics into clinical care. As part of this initiative, precisionFDA’s task is to advance the use of a core technology behind the PMI known as next generation sequencing or NGS, which is capable of mapping the entire human genome. To achieve that, precisionFDA is drawing upon the latest computing and storage technologies to provide an open source cloud-based space where experts can share data, ideas, and methodologies. Today, it boasts more than 1,600 participants, including researchers, test developers, industry, academics, statisticians, and clinicians.

One way we’ve been learning and growing is through contests designed to spark the creative thinking of members on behalf of important NGS questions about data, analytics, and sequencing tools.

We are happy to announce the next challenge: an “App-a-Thon,” inviting software developers to get together with their peers, collaborators, and friends to add NGS software apps to the precisionFDA app library. Apps in this case are executable commands using the Linux operating system that are “wrapped” around NGS software.

Elaine Johanson

Elaine Johanson, is precisionFDA Project Manager and Deputy Director of FDA’s Office of Health Informatics

Apps can be existing, modified, or completely new. Ultimately this challenge, which closes Oct. 28, 2016, is a contest to engage the NGS community in the development of new genome sequencing analytical tools for use on precisionFDA. These apps can do a variety of useful activities such as simulations, benchmarking, data integration, mapping portions of the genome, or identifying genetic variants. Members of precisionFDA are encouraged to try out these apps by running them on the platform.

Our goal is to build a robust reference library of apps and files so that precisionFDA can provide developers with everything they need to support development work on their software pipeline or tests.

If you’d like to set up an App-a-Thon, FDA provides the framework and all the materials, storage, and compute capacity to hold an App-a-Thon on precisionFDA. We encourage you to choose a timeframe, invite your researcher/developer friends, and follow the directions in FDA’s ‘App-a-Thon in a Box’ toolkit. This toolkit even contains video and results from a precisionFDA App-a-Thon held at Stanford University.

The results of this challenge will be highlighted by FDA Commissioner Robert Califf at the World Precision Medicine Congress on Nov. 14, 2016 in Washington D.C. Participating will benefit the entire NGS community, but most importantly, it will advance public health and benefit the patients we collectively serve.

Zivana Tezak, Ph.D., is Associate Director for Science and Technology at FDA’s Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health 

Elaine Johanson, is precisionFDA Project Manager and Deputy Director of FDA’s Office of Health Informatics

Using Symbols to Convey Information in Medical Device Labeling

By: Antoinette (Tosia) Hazlett, MSN, RN, and Scott Colburn CAPT, USPHS

Symbols convey important messages for navigating everyday life; whether it’s a traffic sign or a graphic image indicating that no smoking is allowed in a building. Symbols in medical device labeling can also convey important information. However, to be an effective means of communicating information, it’s critical that symbols on medical devices are understood by the individuals who use them.

Tosia Hazlett

Antoinette (Tosia) Hazlett, MSN, RN, Senior Policy Analyst at FDA’s Center for Devices and Radiological Health

In June, FDA issued the Use of Symbols in Labeling final rule, which describes the circumstances in which manufacturers can use a stand-alone symbol in device labeling without any adjacent explanatory text. For example, if certain requirements are met under the final rule, manufacturers of sterile syringes could opt to use the symbol for “do not reuse” on a syringe package without adding the actual words “do not reuse” to the package.

Using Symbols

The “Use of Symbols in Labeling” final rule which went into effect on September 13, 2016, does not mandate the use of stand-alone symbols in device labeling. Under the final rule, device manufacturers have three options. They can choose not to use symbols, use symbols with adjacent explanatory text, or use stand-alone symbols that have been established in a standard if certain requirements are met, including providing an explanation of the symbols in a symbols glossary that is included in the labeling for the device.

Adding the option of stand-alone symbols is expected to reduce design costs for manufacturers because it is more consistent with how devices are currently labeled in Europe and other foreign markets. Replacing small and difficult-to-read text with a symbol will also help make some labeling more user-friendly and understandable. That is critical in medical device labeling, where space may be limited. The use of stand-alone symbols on a global scale may help promote better understanding through consistent labeling across products distributed in the U.S. and foreign markets.

Scott Colburn

Scott Colburn CAPT, USPHS, FDA’s Director, Center for Devices and Radiological Health Standards Program

Before this rule, FDA recognized five consensus standards that address the use of stand-alone symbols. On the same day this rule was issued, FDA updated its currently recognized consensus standards list and added three new standards containing more symbols in a published standards-recognition notice.

Symbols Glossary

The required symbols glossary is intended to help users become familiar with the meaning of the stand-alone symbols and serve as a reference for users to look up any definitions they may not recall.

The symbols glossary may be in a paper or electronic format as long as it is included in the labeling for the device. Additionally, the labeling on or within the package that contains the device must bear a prominent and conspicuous written statement identifying the location of the symbols glossary.

Symbol Statement “Rx Only” or only”

The rule also allows for the use of the commonly used symbol statement “Rx only” or “℞ only” in the labeling for prescription devices.

Learn More

On Monday, July 25, 2016, FDA conducted a webinar to help industry and patient groups learn more about this final rule and the new standards recognition notice. The slides, recording and transcript from the webinar entitled, “Final Rule: Use of Symbols in Labeling” is available on the CDRH Learn  and Webinar webpages.

Antoinette (Tosia) Hazlett, MSN, RN, is a Senior Policy Analyst at FDA’s Center for Devices and Radiological Health

Scott Colburn CAPT, USPHS, is FDA’s Director, Center for Devices and Radiological Health Standards Program

Making Continuous Improvements in the Combination Products Program: The Pre-RFD Process

By: Thinh Nguyen and Rachel E. Sherman, M.D., M.P.H.

One question that sponsors often ask FDA is whether their medical product will be regulated as a drug, a device, a biologic, or as a combination product, and in the case of the latter, which FDA component will regulate it.

Thinh Nguyen

Thinh Nguyen, FDA’s Director, Office of Combination Products

One way sponsors may determine how their product will be classified is to submit a Request for Designation (RFD) to the Office of Combination Products (OCP). This request requires FDA to provide a written determination of product classification and/or which agency component will regulate the product if it is a combination product. Sponsors have also been able to obtain less formal feedback regarding product classification through communications with OCP.

We are pleased to announce that the Agency is making some changes to our internal procedures for responding to communications from sponsors regarding preliminary product classification assessments from OCP. The Pre-Request for Designation (Pre-RFD) process is the result of cooperative efforts by OCP, the Office of Medical Products and Tobacco, and CDER Lean, including a formal internal evaluation that incorporates current state process mapping and identifies and integrates process improvements.

Rachel Sherman

Rachel E. Sherman, M.D., M.P.H., FDA’s Associate Deputy Commissioner for Medical Products and Tobacco

The Pre-RFD process shares some similarities with the RFD process. In both cases, FDA’s assessment depends on sponsors providing a complete, clear, and detailed product description, which includes the product’s indication for use, its composition/ingredients, and an explanation of how it works. In most instances, both processes also require input from the product jurisdiction officers in the relevant Centers and, if necessary, legal perspectives from the Office of Chief Counsel.

Once OCP has received the necessary input, the Office makes its assessment of the classification and/or Center assignment for the product. OCP’s goal for Pre-RFDs is to respond to sponsors within 60 days following receipt of all information needed to initiate the review—the same timeline for responding to RFDs. During this review period the office will communicate with the sponsors as needed.

When may this Pre-RFD process be useful?

The Pre-RFD process can be used at any point during medical product development. It may be preferable to the more formal RFD process when a sponsor would like to engage FDA using a more interactive approach—a course that may be especially helpful when a medical product is at an early stage in its development, or when a sponsor is contemplating whether to develop a specific product, or what configuration of that product to pursue. In such cases, sponsors may find the Pre-RFD process beneficial for the following reasons:

(1) Sponsors are not required to provide a recommendation for classification and assignment of their product along with a corresponding rationale (e.g., bench studies; clinical studies) for that recommendation;

(2) Sponsors are not required to discuss the classification of currently marketed products that they believe to be similar to their product; and,

(3) Sponsors can receive preliminary feedback and information from the Agency that is derived from a structured and efficient process. The feedback will ultimately help lead to better decision-making and development of products for the sponsors.

Pre-RFD flow chart

FDA’s Pre-RFD Process Flow: To view, click on the image.

Because our feedback will be based on the information submitted, sponsors should bear in mind that the speed and quality of any review, whether Pre-RFD or formal RFD, is highly dependent on the quality of the submitted data.

The Agency is developing a draft guidance about the Pre-RFD process, which provides details about information sponsors should include in a Pre-RFD and describes the procedure for FDA’s review. In addition, the Agency plans to publish a list of product classifications for various types of products. We believe this list will offer additional transparency and clarity to sponsors that will ultimately foster innovation and promote better health for patients. We welcome your feedback regarding the Pre-RFD and RFD Programs, as well any other thoughts regarding the jurisdictional assessment of products.

A sponsor who wishes to submit a Pre-RFD or an RFD for a product can find detailed information at the OCP website or contact OCP at combination@fda.gov for further assistance.

Thinh Nguyen is FDA’s Director, Office of Combination Products

Rachel E. Sherman, M.D., M.P.H., is FDA’s Associate Deputy Commissioner for Medical Products and Tobacco