Advancing Policies to Promote Safe, Effective MedTech Innovation

By: Scott Gottlieb, M.D.

Advanced technologies, biomaterials and digital tools are offering us fundamentally better ways to develop new medical devices to advance human health. To build on these innovations and ensure patients have access to safe and effective advances in medical care, it’s crucial that FDA modernize its policy framework for the review of medical devices. We must provide more opportunity to enhance traditional products with new advances, and to use these same innovations to develop fundamentally novel devices altogether. This requires FDA to implement reforms that make the review process more benefit-risk based; allow us to efficiently adopt more modern tools for evaluating safety and benefits of new products; and to actively embed in our review patient-centric measures of risk and benefit.

Dr. Scott Gottlieb

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

We must do this all while taking steps to strengthen FDA’s gold standard for safety and effectiveness.

FDA already has taken steps to modernize its review pathways in recent years as device technologies have advanced. But there’s more we must do.  Early in the coming year, FDA’s Center for Devices and Radiological Health (CDRH) intends to advance several important new regulatory policy initiatives to further modernize the medical devices program and continue to foster new medtech innovation.

Background on the Current Framework

The Medical Device Amendments of  1976 set forth that manufacturers of new, moderate-risk devices – generally Class II and certain Class I devices – must demonstrate substantial equivalence to a similar device legally marketed in the U.S. in order for a new device to be cleared by FDA for use in patient care.  Under this construct, older devices that function as the comparators are referred to as predicate devices. This process is generally known as the 510(k) pathway. It’s designed to assess the safety and effectiveness of medical devices whose risks are well understood.

FDA’s regulatory process has remained largely unchanged since it was first implemented 40 years ago. As a consequence, there are an increasing number of cases where this basic framework isn’t well-suited to reflect the innovation that we see today in certain technologies, and how we must evaluate those technologies..

FDA’s existing framework also fails to realize the full potential of the FDA’s consensus standards program, which was established through the Food and Drug Administration Modernization Act of 1997, and will be refined and expanded as a result of provisions in the 21st Century Cures Act of 2016.

Through this program, CDRH has already recognized more than 1,200 national and international standards wholly or in part. CDRH typically incorporates these standards in guidance documents that provide recommendations on testing and performance standards. These guidance documents provide innovators with predictable, consistent, and least burdensome approaches for demonstrating that a new technology is safe, effective, and functions properly for its intended use.

Yet despite manufacturers being able to demonstrate that they meet these consensus standards, a manufacturer is required to demonstrate that a device is substantially equivalent to an existing, legally marketed device. But the predicate devices that new products must compare themselves to are sometimes 40 years old. FDA recognizes that such direct comparison testing creates burdens for 510(k) applicants, especially when many new devices are designed in novel ways, using more advanced technologies. It’s sometimes hard to identify sufficient, appropriate predicate devices in order to conduct testing. This can create an obstacle to certain kinds of innovation and lead to inefficiency in the review process with few, if any, benefits to patient safety. In fact, at times, it can make it less efficient for FDA to assure the safety of the device.

New Steps to Reform, Modernize 510(k) Review

To address these challenges, in the first quarter of 2018, FDA intends to publish a draft guidance outlining a voluntary, alternative pathway for demonstrating substantial equivalence. This pathway will allow more flexibility to use more modern criteria as the reference standard, and permit comparisons to standards that more closely approximate the kind of novel technology we’re being asked to evaluate.

Under this new framework, device manufacturers could demonstrate substantial equivalence by meeting objective safety and performance criteria. These can include FDA-recognized standards, FDA-developed guidance documents, or a combination of the two, which embody the safety and performance criteria that new devices could meet to be cleared under a 510(k).  This pathway would be available for pre-specified categories of mature devices – those for which safety and performance criteria that meet or exceed the performance of existing, legally-marketed devices can be identified. It will be outlined in new draft guidance that we are announcing today in the Federal Register and plan to issue in the first quarter of 2018. This approach will also make it easier for FDA to conform its framework for evaluating new products to international consensus standards where such standards exist.

The program will be voluntary, and manufacturers could continue to utilize the existing 510(k) pathways.  It would apply only to devices for which 510(k) clearance is the appropriate pathway to market and would not affect the scope of the current De Novo program for more novel devices that do not have a predicate. But imagine the benefits of a more efficient and transparent pathway for bringing to market well-understood technologies like ultrasound imaging machines, common in vitro diagnostic devices, and blood pressure monitors.

This regulatory innovation holds tremendous promise to further streamline device review for sponsors and FDA and allow new innovations to get to patients more quickly; to allow more advanced technologies to be efficiently incorporated into new devices; and to foster greater confidence in the FDA’s ability to efficiently evaluate safety and benefits of technologies cleared under this pathway – all while maintaining the same gold standard that we apply to existing review processes. By modernizing the benchmarks by which we evaluate the performance characteristics of cleared devices, we believe it will also enable us to put in place more modern criteria for assessing safety.

New Framework to Balance Pre- vs. Post-Market Requirements

For all medical devices that are subject to premarket review – whether through a premarket notification, premarket approval application (PMA), humanitarian device exemption application (HDE), or other type of marketing submission – FDA must determine whether probable benefits to health from use of the device outweigh any probable risk of injury or illness from its use.  As part of that analysis, FDA considers what level of uncertainty is acceptable about the product’s probable benefits and risks before the device is available to the public. To fully discharge any uncertainty, FDA requires post-market follow-up studies. These studies are a way to fully elucidate the long-term performance of new medical products.

But the balance between acceptable uncertainty in the pre-market setting, relative to a product’s benefits and potential risks – and, in turn, how much reliance FDA can place on post-market follow-up studies – has never been objectively defined in one, comprehensive policy framework.

FDA intends to publish a draft guidance, again in early 2018, setting forth factors that the agency may consider when assessing acceptable uncertainty. The guidance will outline how certain issues could be ultimately resolved in the post-market setting, rather than the pre-market setting, to allow patients to gain faster access to potentially life-saving devices, when appropriate. Under this form of more progressive review, FDA will outline how it makes judgments about when it’s appropriate to place greater reliance on post-market data in order to facilitate access to certain innovation, or when the agency needs to rely more on pre-market data collection because of certain issues related to a particular product or how it may be used.

This approach will be outlined in a new draft guidance that relates to the acceptable levels of uncertainty that FDA can accommodate in the pre-market setting relative to the public health benefits, and in turn rely on post-market data to answer certain questions. This balance is already a feature of product review across all of FDA’s programs. The new guidance is an attempt to make these considerations more transparent, consistent, and objectively-defined.

To further assess the impact of pre-market uncertainty, FDA may consider several factors.  One is the extent of the public health need. Factors that may influence these considerations are the seriousness of the illness that the device will treat or diagnose, the size of the population that could benefit from a new innovation, and the benefit-risk profile of alternative therapies or diagnostics (if any exist). Another factor is how likely uncertainty can be resolved pre-market versus the post-market.  FDA might accept greater uncertainty for a device where gathering extensive clinical evidence pre-market would not be feasible given the small patient population that the device is intended to treat.  The likelihood that uncertainty can be resolved by collecting data post-market, such as through the use of registries, is another consideration. FDA must have confidence that it’ll be able to acquire required post-market data.

This approach to evaluating uncertainty could be used in any one of the existing pathways that developers must follow to market new devices – 510(k), De Novo, PMA, or HDE.  That’s because these factors should guide our decisions about patient access to medical devices in any of the regulatory classifications. We’ll use our existing authorities to require more post-market data collection if we determine that’s the best way to resolve appropriate pre-market uncertainty for a specific device.  And in all cases when this approach is taken, we’ll uphold the same standards for safety and effectiveness.

Looking Ahead to Other Device Policy in 2018

Although I’ve highlighted only two upcoming guidance documents related to FDA’s medical device review program, additional important guidance is forthcoming over the next several months, as outlined in FDA’s list of pending device-related guidance documents being published today.  FDA publishes this list annually to provide transparency about our medical device regulatory priorities in the upcoming fiscal year. Several of the additional planned guidance documents, including the draft guidance documents regarding application of least burdensome and the Q-Submission Program, further demonstrate FDA’s commitment to advancing modern regulatory policies that are designed to promote medical device innovation, while continuing to assure the safety and effectiveness of new products.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

PEPFAR: FDA Approves 200th HIV/AIDS Therapy

By: Scott Gottlieb, M.D.

Since 1981, when the first case of AIDS was reported in this country, U.S. and foreign governments, scientists, grassroots and global community health organizations, patients, and their families have worked hard to address the impact of this virus.

HIV/AIDS is responsible for one of the most destructive pandemics in human history.

Dr. Scott Gottlieb

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

World AIDS Day is a time for us to honor the 36 million people who have died from AIDS and HIV infections, to rededicate ourselves to helping the more than 35 million people living with HIV/AIDS today, and to pay tribute to the caregivers, families, and communities who support them.

As we contemplate the enormity of these numbers and the far-reaching impact of AIDS and HIV on our world, we can also take some heart at efforts to combat the disease, through the development of more effective treatments, and efforts to expand access to these therapies.

The men and women of FDA remain dedicated to these efforts as a core part of our mission.

Earlier this week, FDA approved – or tentatively approved – the 200th antiretroviral drug application, including 30 solid formulations specific for children, under the President’s Emergency Plan for AIDS Relief (PEPFAR). The plan was launched in 2003 to address the global HIV/AIDS epidemic by stimulating the development of new HIV therapies, many of which were new combinations of generic medicines and were purchased with American funds at low cost, to expand opportunities in countries that lacked good access to treatment.

To implement the goals of PEPFAR, FDA used its expedited review process to provide review of life-saving antiretroviral drugs produced by manufacturers all over the world. Through guidance and an active outreach program to the pharmaceutical industry, FDA encouraged sponsors worldwide to submit U.S. marketing applications for single entity, fixed dose combination (FDC), and co-packaged versions of previously approved antiretroviral therapies. These new drugs were typically combinations of medicines that were being combined or packaged together to make their administration easier. FDA worked closely with manufacturers who had not interacted with FDA previously to help them develop an FDA application and to prepare for the requisite FDA inspections of their manufacturing facilities.

By combining medicines into once a day pills, or co-packaging drugs, it helped facilitate treatment in areas of the world, particularly in parts of Africa that lacked advanced health care infrastructure, and where a one-pill-once-a-day regimen helped expand access to treatment.

Under the program, these fixed dose combination drugs could be fashioned even in circumstances where there was still patent or exclusivity market protection for one or more of the components in the U.S. The sponsors agreed not to assert their patent rights, so long as the drugs were sold in markets that lacked the resources to otherwise make these drugs available. In recent years, subsequent legislation applied updated classifications for speed of review.

The process enabled developing markets that were hard hit by the virus to get more widespread access to effective treatments tailored to their health care needs, while making sure that these products underwent FDA evaluation and met the agency’s gold standard for safety, efficacy, and quality. These products could then be purchased with U.S. funds under the President’s PEPFAR Fund. Due to the significant public health impact of these products, FDA prioritized the review of these marketing submissions.

Over the years, FDA’s scientific and regulatory contributions have helped the U.S. respond with compassion and effectiveness to the needs of those who are living with AIDS throughout the world, including many children who face unique challenges getting appropriate treatments.

Since October 2016, the most recent date for which numbers are available, the PEPFAR program has provided life-saving antiretroviral (ARVs) treatment for nearly 11.5 million people in its global efforts to battle the HIV/AIDS epidemic.The FDCs helped enable more widespread treatment.

PEPFAR also has supported collaboration by FDA and HHS with the Department of State Office of the Global AIDS Coordinator; the United States Agency for International Development; the World Health Organization; the Global Fund to Fight AIDS Tuberculosis, and Malaria; and other organizations that help countries build and strengthen their health care systems and regulatory capacities.

This country’s response to the global HIV/AIDS crisis, through programs like PEPFAR, and through the dedicated work of both global and country partners, has created an opportunity to change the course of the HIV/AIDS pandemic, with a potential end to it as a public health threat firmly in sight. We are working to seize this opportunity.

The PEPFAR Strategy for Accelerating HIV/AIDS Epidemic Control (2017-2020) (“Epidemic Control Strategy”), released in September, sets a bold course for achieving control of the HIV/AIDS epidemic by the end of 2020 in 13 countries which represent the most vulnerable communities to HIV/AIDs.

This will be accomplished in partnership with and through attainment of Joint United Nations Programme on HIV/AIDS 90-90-90 framework – in which 90% of people living with HIV will know their status, 90% of people who know their status are accessing treatment, and 90% of people on treatment have suppressed viral loads – and an expansion of HIV prevention.

FDA remains fully committed to these efforts. By working closely with other governments and public and private agencies and organizations, we can build on the impact and success of the life-saving PEPFAR program, expanding transparency, accountability, and partnership, so that the world can finally overcome one of the most devastating public health challenges in history.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

 

 

 

FDA Takes Important Steps to Stem the Tide of Opioid Misuse and Abuse

By Scott Gottlieb, M.D.

 America is awash in immediate-release (IR) opioids. About 90 percent of all opioid pain medications prescribed – or 160 million prescriptions a year – are for IR formulations like hydrocodone and acetaminophen or oxycodone and acetaminophen combinations. Many people who are currently addicted to opioids became medically addicted. Their first exposure to opioids was from a legal prescription, and for many, that prescription was written for an IR formulation of these drugs. Many addicted patients may then move on to higher dose formulations or more accessible illegal street drugs.

At FDA, we believe it’s necessary to continue to take steps to address both ends of this continuum, the potential gateway to addiction that is often the IR formulations, and the higher dose, extended-release formulations, both of which carry a significant risk of overdose and mortality. We are taking several actions to address these challenges. This week, we issued letters notifying 74 manufacturers of IR opioid analgesics intended for use in the outpatient setting that their drugs will now be subject to a more stringent set of requirements under a Risk Evaluation and Mitigation Strategy (REMS). The REMS requires that training be made available to health care providers who prescribe IR opioids, including training on safe prescribing practices and consideration of non-opioid alternatives.

Dr. Scott GottliebFDA also will soon issue a final guidance document that will assist potential applicants who plan to develop, and submit to FDA, an application to seek approval of a generic version of abuse-deterrent formulations (ADFs) of opioid drugs. Most of the currently approved opioids with labeling describing abuse-deterrent properties are extended release/long-acting (ER/LA) formulations of opioids. These drugs are generally formulated to be more resistant to the sort of manipulation that would otherwise make them amenable to snorting and/or injecting. Addicted patients who start by using the IR drugs will sometimes migrate onto the ER/LA formulations, and then try to manipulate those higher-dose formulations in ways that can provide a more immediate “high” through injection or snorting. But there are currently only brand name ADF formulations. These steps that FDA is taking are aimed at addressing each end of the spectrum of abuse and addiction.

With respect to the new REMS measures to address the safer use of the IR opioid pain medications, these short-acting drugs will now be subject to the same regulatory requirements as the ER/LA opioid analgesic formulations. Since 2012, manufacturers of ER/LA opioid analgesics have been subject to a REMS, which requires, as its primary component, that training be made available to prescribers of those products. To meet this requirement, the sponsors of the ER/LA opioid analgesics have been providing unrestricted grants to accredited continuing education providers for the development of education courses for health care professionals based on content outlined by FDA, which the agency calls the “Blueprint.” FDA is now extending these REMS requirements to the IR manufacturers.

While some of the ER/LA manufacturers also make IR opioids, today’s action will greatly expand the number of products covered by the REMS. The existing REMS currently includes 64 ER/LA opioid analgesic products. Once the action is finalized, an additional 277 IR opioid analgesics will be subject to these REMS requirements.

In addition to expanding the REMS to include IR products, FDA is modifying the content of the educational “Blueprint” required under the REMS. The agency is adding content on pain management, including non-opioid alternatives. This includes principles related to the acute and chronic pain management; non-pharmacologic treatments for pain; and pharmacologic treatments for pain (both non-opioid analgesic and opioid analgesic). The revised Blueprint will also cover information about the safe use of opioids, and basic information about addiction medicine and opioid use disorders.

For the first time, this training will also be made available to other health care professionals who are involved in the management of patients with pain, including nurses and pharmacists, which is in addition to prescribers of opioid analgesics. FDA believes that all health care professionals involved in the management of patients with pain should be educated about the safe use of opioids so that when they write or dispense a prescription for an opioid analgesic, or monitor patients receiving an opioid analgesic, they can help ensure that the product is properly indicated for the patient and used under appropriate clinical care.

FDA’s new Opioid Policy Steering Committee is also considering whether there are circumstances when FDA should require some form of mandatory education for health care professionals, and how the agency would pursue such a goal. The agency’s purpose is to reduce overall exposure to opioids by making certain that prescribing doctors are properly informed about appropriate prescribing recommendations, that providers understand how to identify the risk of abuse in individual patients, and know how to get addicted patients into treatment. In fact, today, the agency issued a public notice to solicit input on a detailed series of questions related to these goals. FDA has also been scheduling meetings with provider organizations and sponsors engaged in dispensing drugs – including health systems and pharmacy chains, in an effort to solicit additional input on new strategies.

Sending out the manufacturer notification letters is the first step in extending the REMS to the IR drugs. This process could take about a year to finalize. The modified REMS will continue to include a requirement for patient Medication Guides, patient-counseling documents, and plans for assessing the effectiveness of the revised REMS. The crisis of opioid addiction is a public health tragedy of enormous proportions. By putting in place safety measures for IR opioid analgesics, and creating a more robust path to converting the high dose opioids to formulations that are more resistant to manipulation, we are addressing both ends of this crisis. Our hope is that we can help prevent new patients from becoming addicted, and keep some individuals from experiencing the serious adverse effects associated with these medications.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Working Together to Reduce the Devastating Effects of Opioid Misuse

By Robert M. Califf, M.D.

The public health crisis of opioid misuse, addiction and overdose is one of the most challenging issues the U.S. Food and Drug Administration has faced during my time as FDA commissioner.  Solving this issue is critical to our future.

The issues cut across every socioeconomic level and geographic boundary. It would be difficult to identify any community in America that has not been touched by friends, family members or colleagues suffering from addiction, and far too often, losing their lives to it. As I leave the agency as part of the presidential transition, I have reflected on what I have seen, how far the nation has come, and the important work that remains for both the public and private sectors.

Robert CaliffI’ve made it a point to see affected communities, first-hand, because interventions and national policy solutions work best when they are well informed by what communities actually need. Just last week, I visited Baltimore to better understand how our cities are being affected – in this case, by an inflow of illicit fentanyl, a synthetic opioid that is about 100 times more potent than many other prescription opioids, and can be deadly on its first use. I have also visited the neonatal intensive care unit, or “NICU” of a Tennessee hospital where babies were screaming and shaking in the pain of withdrawal because they were born with Neonatal Opioid Withdrawal Syndrome. I have met people in West Virginia who did back-breaking work in power plants or in coal mines; after suffering on-the-job injuries they were first afflicted with pain, then by addiction. They got prescription pain relief but, too often, it wasn’t accompanied by the proper support and counseling. In Kentucky, I spoke to spouses and families whose lives have been forever changed by addiction, even as the community rallied together to fight it. And, much closer to home, I have heard personal stories from FDA employees and providers in local health care facilities, whose families and friends are not immune.

We have taken a number of actions at the FDA over the past several years to help reduce the number of people who become addicted, or who ultimately overdose from prescription opioids. We’ve improved product labeling, pushed for prescriber education, and encouraged the development of abuse-deterrent formulations. In addition, we have approved new intranasal and auto-injector forms of naloxone — products to reverse opioid overdoses, which can be administered by laypersons and are, therefore, better available able to save lives.

I’m also proud of the partnerships we have formed with other federal Agencies and the work that has resulted from them. But the latest data, including data from the Centers for Disease Control and Prevention (CDC) remind us that while some progress is being made, there is more to do. For example, it is promising to see that the nationally estimated number of outpatient prescriptions dispensed for Schedule II opioids decreased by 10 percent in 2015 compared to the previous year, according to IMS Health. However, the CDC reports that while the rate of overdose deaths associated with prescription opioid use increased by just 4 percent instead of by 9 percent the previous year, deaths associated with heroin use have skyrocketed. Clearly, more work needs to be done.

As I prepare to turn over the awesome responsibility of FDA commissioner to the next Administration, I feel compelled to point out that public and private sector efforts in this area must be continued and strengthened. In particular, I want to call on the pharmaceutical companies that manufacture and sell these drugs to dig deeper into their expertise and resources to prioritize finding solutions to this public health problem. I have consistently been impressed that the motivation to cure disease and improve quality of life for patients is shared across the spectrum of federal agencies, public health workers, health care providers and scientists within the pharmaceutical industry. However, the financial incentives in the industry can lead to a focus on short-term profits instead of patient well-being.This is the time for both branded and generic drug companies  to go beyond marketing and distribution plans and instead commit their expertise and resources to  confronting  the devastating negative consequences of a class of drugs that brings much needed pain relief, when used appropriately.

Specifically, I urge us all to focus on the following priorities:

  1. Encouraging appropriate prescribing by healthcare practitioners. Too many people become addicted from unnecessary prescriptions for minor pain or injury. And even appropriately prescribed opioids can lead to addiction, so careful monitoring of patients prescribed these powerful drugs is needed. While there are situations where opioids are appropriate, there are also situations where other alternatives can be effective. Therefore, conversations between provider and patient about the pain treatment plan are imperative. If an opioid is appropriate, CDC guidelines and FDA labeling emphasize the need to start on the lowest dose and minimum time necessary, and carefully monitoring patients for signs of addiction and inadequate pain control.
  1. Considering the family as well as the patient. Pain treatment, and use of opioid drugs, will be more successful when the family is involved. It will result in fewer drugs diverted from the medicine chest, fewer babies born addicted to opioids and better treatment of pain. Women who use or abuse opioids, or who are in treatment for opioid addiction, should talk to their health care provider before considering pregnancy.
  1. Finding better ways to treat pain with new medications and with more holistic pain management. It’s time to put more resources into the development of non-opioid, non-addictive medications to help people who are in serious, debilitating pain. We need more research to define the most effective non-medication approaches to pain and how to deliver them in a complex and financially constrained healthcare system.
  1. Improving how companies, professional societies and academics communicate about their activities in this area. I urge companies to commit to transparent and appropriate company communications and to work with government and others in the community to do a better job in educating the medical professionals responsible for treating our nation’s pain, as part of the overarching effort to do everything possible to help prevent addiction. Professional societies and academic medical centers also need to continue their efforts at educating their members and examining their practices to find ways to improve. For example, the education of the next generation of physicians about how best to manage pain is critical.
  1. Finding new ways to curb diversion and misuse of opioids. In addition to our continuing efforts to help support the development of abuse-deterrent formulations, the FDA is exploring potential packaging, storage, delivery, and disposal solutions that companies and other stakeholders might consider that would prevent opioids from being diverted to those without a legitimate prescription for these powerful drugs. I implore companies to conduct research and offer their creative ideas and resources to innovate in this area.
  1. Increasing pragmatic research to better understand how to implement appropriate pain therapy in general and use of opioids in particular. Post-market requirements from FDA that mandate industry-funded studies and recent pragmatic research efforts by the Patient-Centered Outcomes Research Institute and the NIH and Department of Defense are expected to provide important data, but we need more robust evidence to better guide practice. Pain is a vexing issue that seems to fall between the cracks in research funding; we need to keep the pressure on funding entities to move pain to the forefront as a research issue.
  1. Treating addiction as a disease, not as criminal behavior. We have the tools to treat addiction and reverse overdose from opioids and are working to develop more of them. But there’s a lot we don’t know about the drivers for drug abuse, and scientific knowledge will help us make better decisions. This is one reason why we need companies with products on the market to monitor the safety of those drugs and make their data public. We have mandated post-market studies to define major questions about chronic use of opioids, and it is essential that industry fulfills these requirements.

I am proud to have been part of the effort that’s changing the tide on this epidemic, but the nation has a long way to go.Government, companies, healthcare systems and healthcare providers all have important roles to play. The most recent data reminds us it’s time to double down on these efforts. While I won’t have the good fortune of leading this fight in an official capacity, I’m proud of the work the FDA and others have done so far. I leave FDA’s efforts to the many leaders at the agency who have been working tirelessly on this issue — and will continue doing so — and look forward to supporting public and private efforts to bring this epidemic to an end.

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

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

FDA’s Science-based Approach to Genome Edited Products

By Robert M. Califf M.D., and Ritu Nalubola, Ph.D.

Recent scientific advances now make it possible to more efficiently and precisely alter the genome of plants, animals, and microorganisms to produce desired traits. These genome editing technologies are relatively easy to use and can be applied broadly across the medical, food and environmental sectors, with potentially profound beneficial effects on human and animal health. However, there are also potential risks ranging from how the technology affects individual genomes to its potential environmental and ecosystem impacts. Additionally, genome editing has raised fundamental ethical questions about human and animal life.

Genome editing technologies can be used to introduce, remove, or substitute one or more specific nucleotides (letters in the DNA code) at a specific site in the organism’s genome, and is achieved with the use of protein-nucleotide complexes. Several classes of these complexes exist, the most recent discovery is known as CRISPR/Cas9.

Research is currently underway that would use these technologies to:

  • Treat HIV, cancer or rare diseases by genetically altering specific types of cells;
  • Control or alter organisms that carry infectious diseases (for example, mosquitoes that are vectors of viruses/parasites causing dengue fever, Zika or malaria; or mice that transmit bacteria causing Lyme disease);
  • Improve the health and welfare of food producing animals, (for example, hornless cattle, pigs resistant to African swine fever or porcine reproductive and respiratory virus); and
  • Alter specific traits of food plants or fungi (for example, non-browning mushrooms).

Accompanying the enthusiasm about these promising technologies are questions about whether FDA is prepared to ensure the safety of regulated products that use this technology. Providing appropriate and balanced regulatory oversight for applications involving an emerging technology is not a new or unique challenge for FDA, but the potential breadth of applications and the fundamental nature of altering the genome call for the participation of multiple constituencies in considering the most effective regulatory policies to address any potential risks.

Robert Califf

Robert M. Califf, M.D., FDA Commissioner

Maintaining product-specific, risk-based regulation

Genome editing applications are relevant to three main FDA-regulated product classes. The specific regulatory approaches for each of these classes vary, reflecting differences in underlying statutory authorities. FDA is maintaining a product-focused, science-based regulatory policy, in accordance with specific legal standards applicable to each type of product and consistent with overarching U.S. Government policy principles.

Human medical products that apply gene editing to exert their therapeutic effect are regulated under our existing framework for biological products, which include gene therapy products. “Gene editing” here refers to non-heritable situations somatic cell gene therapy only, and not to heritable conditions (germ line gene therapy). The FY16 appropriations bill restricted use of federal funds “in research in which a human embryo is intentionally created or modified to include a heritable genetic modification.” FDA’s Center for Biologics Evaluation and Research (CBER) has a well-established program and policies in place to evaluate gene therapy products. Although different types of gene editing have potential clinical applications, currently only one type of gene editing, zinc finger nuclease- (ZFN) mediated, has been announced by their sponsors as being applied in clinical trials underway in the United States. Proposals for NIH-funded human gene therapy clinical trials are discussed and reviewed for scientific, clinical, and ethical issues by the NIH’s Recombinant DNA Advisory Committee (RAC). The RAC recently discussed (and did not find any objections to) the first clinical protocol to use CRISPR/Cas9-mediated gene editing. The potential for “off-target” effects such as insertions or deletions at unintended genetic loci has been identified by experts in the field as a key concern.

Similarly, FDA’s Center for Food Safety and Applied Nutrition and Center for Veterinary Medicine have in place programs to adequately address foods derived from plants produced using genome editing and animals produced using genome editing. In these two product areas, we are issuing documents to clarify our current thinking and seek scientific information. With respect to foods derived from plants produced using genome editing, FDA has a longstanding program for foods derived from new plant varieties, including those developed by recombinant DNA (rDNA) techniques. We are requesting information on whether human and animal foods derived from genome edited plants pose additional risks compared to those from traditionally bred plants. FDA’s decades of experience providing oversight of foods from new plant varieties, coupled with scientific evidence and data received, will help inform our thinking on risk considerations going forward.

When animals are produced using genome editing, FDA has determined that, unless otherwise excluded, the portion of an animal’s genome that has been intentionally altered, whether mediated by rDNA or modern genome editing technologies, is a drug because it is intended to alter the structure or function of the animal and, thus, subject to regulation under our provisions for new animal drugs. We have updated our existing guidance for genetically engineered animals to include genome editing within its scope, and are issuing it in draft form for public comment. We are also seeking input on whether certain types of genome editing in animals pose low or no significant risk, and we may modify our regulatory approach based on this input.

Our efforts to gather necessary scientific data aside, industry remains responsible for ensuring that its products meet all applicable requirements, including safety standards. FDA has historically made itself available to meet with developers and we encourage them to engage with us to help ensure they meet their statutory and regulatory obligations. And we will continue to provide technical advice and guidance for industry, as necessary.

Collaborating with Federal agencies

The White House Office of Science and Technology Policy (OSTP), FDA, the U.S. Environmental Protection Agency (EPA), and the U.S. Department of Agriculture’s Animal and Plant Health Inspection Service (APHIS) initiated an effort in 2015 to ensure public confidence in the regulatory system for biotechnology products and improve the transparency, predictability, coordination, and, ultimately, efficiency of that system. After reviewing public comment to a docket and holding three public meetings, the agencies produced A National Strategy for Modernizing the Regulatory System for Biotechnology Products, to help ensure that the federal regulatory system is prepared to assess future biotechnology products, issued in September; and, earlier this month, a 2017 Update to the Coordinated Framework for the Regulation of Biotechnology (CF Update), to clarify each agency’s role.

Ritu Nalubola

Ritu Nalubola, Ph.D., Senior Policy Advisor, FDA’s Office of Policy

APHIS is proposing to revise its regulation regarding genetically engineered organisms that may pose plant pest or noxious weed risks. As FDA, APHIS, and EPA formulate policies, there may be differences in approaches, reflecting differences in the scope of their authorities and the types of risks addressed. Under the CF Update, interagency coordination and cooperation will continue, including on appropriate terminology, identification of hazards, and approaches to addressing risks, within the constraints imposed by regulatory paradigms for different product areas.

FDA also has a longstanding collaborative relationship with the NIH office that oversees the RAC. FDA serves as a non-voting liaison on the committee, hears the discussions first-hand, and receives the written recommendations.  These recommendations may be considered during our overall review of investigational new drug applications (INDs) submitted to FDA.

Scientific engagement and horizon-scanning

Being ready to evaluate innovative emerging technologies is a top FDA regulatory science priority. FDA is co-sponsoring two studies, conducted by the National Academies of Sciences, Engineering, and Medicine (NASEM). Both are expected to be completed this year. FDA is also conducting its own horizon-scanning through its Emerging Sciences Working Group, an FDA-wide science-based forum, and opened a public docket to receive input on emerging technologies.

Working with international partners

Scientific advances do not adhere to national boundaries and therefore it is critical that we understand the evolving views of our international counterparts. Given the leadership role of the United States in biomedical and biological sciences, we cannot afford to fall behind in this exciting scientific frontier. As expected, international regulatory agencies, too, are currently working in this area. FDA’s CBER is an active member of the International Pharmaceutical Regulators’ Forum (and its Gene Therapy working group), which provides a forum for members to identify and exchange information on issues of mutual concern and undertake targeted regulatory cooperation activities.

Going forward

FDA is committed to fulfilling its mission to safeguard public health, while encouraging innovation and competitiveness. The actions we have taken to date, including release of the CF Update, National Strategy, and FDA’s documents – are steps in a series of ongoing activities. We will continue to collaborate with our federal and international partners, and actively communicate with stakeholders to help ensure confidence in FDA’s regulatory system. However, oversight provided by FDA is one aspect of broader governance necessary for safe and responsible research and development of genome editing applications. Moreover, the expansive scope of intentional genomic alterations using modern genome editing technologies has triggered debate on fundamental ethical and social issues, which will continue to influence public opinion and acceptance of genome editing applications. Even as FDA implements necessary steps for effective regulation to ensure the safety of products, the role of broader, inclusive public discussion involving multiple constituencies (e.g., scientists, developers, bioethicists, and public interest and community groups) to address the larger societal considerations should not be overlooked.

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

Ritu Nalubola, Ph.D., is a Senior Policy Advisor in FDA’s Office of Policy

 

Managing Medical Device Cybersecurity in the Postmarket: At the Crossroads of Cyber-safety and Advancing Technology

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

Protecting medical devices from ever-shifting cybersecurity threats requires an all-out, lifecycle approach that begins with early product development and extends throughout the product’s lifespan.

Today, we’re pleased to announce that industry now has advice from FDA across this product continuum with the release of a final guidance on the postmarket management of medical device cybersecurity. It joins an earlier final guidance on medical device premarket cybersecurity issued in October 2014.

suzanne-schwartz-new-dec-2016To understand why such guidance is so important for patients, caregivers and the medical device community, we need to take a step back and look at how cybersecurity fits into the medical device ecosystem.

In today’s world of medical devices that are connected to a hospital’s network or even a patient’s own Internet service at home, we see significant technological advances in patient care and, at the same time, an increase in the risk of cybersecurity breaches that could affect a device’s performance and functionality.

The best way to combat these threats is for manufacturers to consider cybersecurity throughout the total product lifecycle of a device. In other words, manufacturers should build in cybersecurity controls when they design and develop the device to assure proper device performance in the face of cyber threats, and then they should continuously monitor and address cybersecurity concerns once the device is on the market and being used by patients.

Today’s postmarket guidance recognizes today’s reality – cybersecurity threats are real, ever-present,  and continuously changing. In fact, hospital networks experience constant attempts of intrusion and attack, which can pose a threat to patient safety. And as hackers become more sophisticated, these cybersecurity risks will evolve.

With this guidance, we now have an outline of steps the FDA recommends manufacturers take to remain vigilant and continually address the cybersecurity risks of marketed medical devices. Central to these recommendations is FDA’s belief that medical device manufacturers should implement a structured and comprehensive program to manage cybersecurity risks. This means manufacturers  should, among other things:

  • Have a way to monitor and detect cybersecurity vulnerabilities in their devices
  • Understand, assess and detect the level of risk a vulnerability poses to patient safety
  • Establish a process for working with cybersecurity researchers and other stakeholders to receive information about potential vulnerabilities (known as a “coordinated vulnerability disclosure policy”)
  • Deploy mitigations (e.g., software patches) to address cybersecurity issues early, before they can be exploited and cause harm

This approach enables manufacturers to focus on continuous quality improvement, which is essential to ensuring the safety and effectiveness of medical devices at all stages in the device’s lifecycle.

In addition, it is paramount for manufacturers and stakeholders across the entire ecosystem to consider applying the National Institute of Standards and Technology’s (NIST) core principles for improving critical infrastructure cybersecurity: to identify, protect, detect, respond and recover. It is only through application of these guiding principles, executed alongside best practices such as coordinated vulnerability disclosure, that will allow us all to navigate this uncharted territory of evolving risks to device security.

This is clearly not the end of what FDA will do to address cybersecurity. We will continue to work with all medical device cybersecurity stakeholders to monitor, identify and address threats, and intend to adjust our guidance or issue new guidance, as needed.

Digital connections power great innovation—and medical device cybersecurity must keep pace with that innovation. The same innovations and features that improve health care can increase cybersecurity risks. This is why we need all stakeholders in the medical device ecosystem to collaborate to simultaneously address innovation and cybersecurity. We’ve made great strides but we know that cybersecurity threats are capable of evolving at the same pace as innovation, and therefore, more work must be done.

Learn More

For more information about medical device cybersecurity, visit the FDA’s Center for Devices and Radiological Health web page.

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

FDA’s Opioids Action Plan: A Midyear Checkup

By: Robert M. Califf, M.D.

As FDA works to address the opioid epidemic of abuse, misuse and addiction, it’s valuable to see firsthand some of the ways the crisis is affecting our communities.

This summer, I toured areas hard-hit by the opioid crisis in Tennessee, West Virginia, and Kentucky, visiting  with survivors of opioid addiction and overdose as well as community activists, government officials, and health care providers, all of whom are working diligently and creatively to address and overcome this crisis.

Robert Califf

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

My visit to the nationally-recognized neonatal intensive care unit at East Tennessee Children’s Hospital was deeply moving and set the stage for the rest of my tour and underscored the urgency of fighting this epidemic. More than a third of the babies admitted to the NICU have neonatal opioid withdrawal syndrome (NOWS), a condition which can be life-threatening if not recognized and treated

Watching a nurse treat a fretful baby suffering from NOWS underscored the complexity of the opioid problem.  Many women taking opioids haven’t planned their pregnancy, don’t immediately know they are pregnant and may not be aware of the risk that opioids pose to their unborn child. This includes those women who are taking medication as part of medication-assisted treatment (MAT) which also includes counseling and behavioral therapies. For women on MAT, the risk of NOWS must be balanced against the additional dangers of untreated opioid addiction during pregnancy.

How best to prevent NOWS and treat opioids use disorder was a continued theme of my trip, and among the issues we grappled with during a roundtable at the University of Tennessee’s Medical Center hosted by Surgeon General Vivek Murthy, who is traveling the country to discuss solutions to opioid abuse as part of his TurnTheTideRx campaign. I’m pleased that expanding access to and the use of evidence-based MAT is a key focus area for the Administration, is a part of the HHS-wide opioid initiative, and is an approach supported by a recent FDA advisory committee.

In Charleston, WV, I met with several patients who are reclaiming their lives with the use of MAT including “Dave.” Like so many others, Dave became addicted to opioid pain medication after being treated for an injury. As a result of his addiction, his marriage failed and he lost contact with his children. But with treatment, he has reunited with his family and next spring will graduate from college and hopes to taper off of his treatment.

Throughout my tour, I heard that opioid education – including training during medical school and residency and greater public awareness far and wide – is a key component in fighting the opioid epidemic. At a roundtable in Charleston, Gov. Earl Ray Tomblin and U.S. Sen. Joe Manchin singled out their state’s model mandatory education program for prescribers and they told me the state is leading an effort to implement the CDC’s Guideline for Prescribing Opioids for Chronic Pain as a best practice for their state-run Medicaid program.

At a firehouse in the town of Williamson, WV, I met with those on the frontlines of the opioid epidemic – the firefighters and first responders who carry life-saving naloxone to help reverse an overdose. They told me more education about naloxone was needed and told me that they appreciate our efforts to help make naloxone more available to the general public.

My last stop this summer was to Kentucky where I toured the emergency room at the Pikeville Medical Center and participated in a roundtable with physicians, pharmacists, and state policy and community leaders brought together with the help of the regional organization Operation UNITE. UNITE coordinates treatment for those with substance use disorder as well as support for their families and friends, and educates the public about the dangers of drug use. These measures, combined with a recent state law requiring prescribers to register with a prescription drug monitoring program are working, we were told.

Throughout my travels, I listened and learned more about how FDA can help end this crisis. I also had the chance to share what FDA has been doing this year to implement a multipart plan to address the opioid epidemic.

Our milestones so far include:

  • Developing warning and safety information for immediate release opioids and requiring that prescription opioid analgesics and opioid-containing cough product labels include strengthened warnings about the risk of using benzodiazepines at the same time.
  • Working to better understand the long-term safety of using extended release/long acting opioids. Sponsors must now conduct a number of studies to generate postmarket data on these products.
  • Issuing draft guidance for industry to support the development of generic versions of approved opioids with abuse-deterrent formulations.
  • Seeking advice from the National Academy of Science Engineering and Medicine on how to balance both the needs of patients with pain and the need to address opioid misuse and abuse.
  • Supporting increased access to naloxone; for instance, by awarding a contract to conduct consumer behavior studies based on model product labeling for a potential OTC version of the antidote and by launching a competition to create a mobile app that could help find the closest available naloxone treatment in an emergency.
  • Approving the first implantable treatment for the maintenance treatment of opioid dependence.

The community-based successes I observed on my three-state tour reinforced my view that we are making important progress in addressing this crisis.  But continued hard work, creative ideas, and collaboration — across government, with the medical profession, health care providers, industry, and, most importantly, patients and their families, is still required.

We at FDA will continue to work with all of these groups, using all the resources at our disposal, to improve the judicious and responsible use of opioids and to help bring an end to this epidemic.

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

 

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

Evaluating FDA’s Approach to Cancer Clinical Trials

By: Richard Pazdur, M.D.

Since the announcement of the FDA Oncology Center of Excellence (OCE) two months ago (June 29, 2016) as part of the White House’s Cancer Moonshot, we’ve been working to further FDA’s efforts to get new oncology products into the hands of patients. We are committed to meet the needs of patients and health care communities by driving progress in the prevention, diagnosis, and treatment of cancer.

Dr. Richard PazdurAt the core of the OCE’s work – and of the Cancer Moonshot – is taking a new look at what we have been doing in the past so we can operate more efficiently in the future. The OCE will leverage the combined skills of oncologists and scientists with expertise in drugs, biologics, and devices to employ the best and most innovative approaches to bring forth safe new oncology products.

The vision set forth by the Vice President underscores our commitment to optimally designed clinical trials that efficiently provide answers to important questions. Given the recent advances in our understanding of cancer and our improved technological capabilities, we are now placing an emphasis on evaluating how we design clinical trials to make the system more efficient to more rapidly deliver safe and effective products for patients.

We are working with stakeholders across government and industry to revisit the criteria used for determining whether a patient is eligible to participate in a trial. Modifying the eligibility criteria could expand the number of people who qualify and therefore open new opportunities for participation and enhance the generalizability of what we learn. Of course, regardless of adjustments, patient safety will remain paramount.

We recently published our perspective on shifting away from the conventional phase one, phase two, and phase three drug development paradigm to a more seamless approach that could expedite the regulatory pathway, providing earlier access to highly effective therapeutic drugs. Adopting this approach could complement FDA’s expedited regulatory programs such as breakthrough designation and accelerated approval to get products to patients in the most efficient manner possible.

Another initiative is the use of common control trials. These trials, sharing a common control arm, involve multiple different drugs for the same indication and may involve different companies. When a common control arm is used, it decreases the overall number of patients that need to be recruited and enrolled, optimizing clinical trial resources and potentially decreasing the time it takes to get a new study off the ground.

Encouraging the use of large simple trials is another way to make more efficient use of clinical trial resources. These trials generally use easily-measured endpoints that are well understood, optimizing the collection of data for safety or secondary efficacy endpoints and thus reducing the amount of data needed compared to conventional randomized trials.

As befits the Center of Excellence, one of our top goals is striving for excellence both in drug and device regulation and in emerging oncology science. To achieve that goal we must also collaborate with academia, industry, patient groups, professional societies, and other international regulators. We have already begun this work by scheduling several public meetings that will provide a forum to interact with patients and other stakeholders.

These initiatives will allow us to expedite drug development and approval of truly novel agents that will have a major impact on our patients, while allowing us to make thoughtful decisions regarding the risk-benefit of oncology drugs.

Richard Pazdur, M.D., is FDA’s Acting Director, Oncology Center of Excellence