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

Introducing IMEDS, a Public-Private Resource for Evidence Generation

By: Robert M. Califf, M.D.

FDA has been working to establish a national resource for FDA-approved medical products that can be used by public and private-sector entities, including regulated industry, to conduct large scale evaluations of safety issues in an environment that is secure and protects patient privacy. These evaluations include epidemiologic studies of medical products in collaboration with multiple healthcare data partners and the analytic center utilized by FDA through the agency’s Sentinel System. This new resource is called the Innovation in Medical Evidence Development and Surveillance System, or IMEDS.

Robert CaliffOne of the unique aspects and advantages of IMEDS is that it was launched on January 1, 2017 as a public-private partnership by the Reagan-Udall Foundation for the Food and Drug Administration, a not-for-profit organization created by Congress in 2007 to advance regulatory science. The IMEDS framework specifically provides governance that allows private-sector entities to gain access to the system with appropriate oversight. As a result, the FDA Sentinel System’s distributed data as well as scientific methods and tools will now be available for entities outside of FDA who want to conduct important research to advance patient safety. Through Sentinel, FDA routinely utilizes information from large amounts of electronic healthcare data to better inform regulatory decisions.

IMEDS policies and procedures were adopted with broad stakeholder input and FDA concurrence over the past year. The program was tested with a pilot project sponsored by Pfizer. Epidemiologists and other staff from participating Sentinel Data Partners, the analytic center at Harvard Pilgrim Healthcare Institute, which operates FDA’s Sentinel’s activities and Pfizer studied two drug safety questions using rapid query templates known as modular programs. Lessons learned from the pilot have been incorporated into the full scale IMEDS program, which will now offer researchers nationwide access to modular programs as well as customized epidemiologic studies. IMEDS provides several important advantages for both regulated industry and regulators, including FDA:

  • First, the large underlying distributed database offers privacy-protected information about medical products used by millions of patients. The data are quality checked to FDA standards and formatted using the same common data model used by FDA.
  • Second, modular programs incorporate epidemiologic methods and computer software templates which are routinely used by FDA.
  • Third, years of collective experience with distributed drug safety analyses amassed by analytic center and data partner staff provides critical context for new IMEDS users.
  • Finally, IMEDS ensures transparency with detailed descriptions of analytic decisions and publication of results in sufficient detail to promote replication by others.

Using modular programs, the system is capable of rapidly evaluating important safety issues that are of concern to patients, healthcare providers, industry, and regulators. The size of the IMEDS distributed database enables identification of even small exposed populations, and it also allows rare adverse events to be captured. If initial case reports of adverse events cause concern, the system can focus on defined populations, taking a drug or biologic and determine rates of adverse events on a national scale. These investigations can be extended to include comparative studies assessing risk using appropriate adjustment for risk factors, which is critical when using observational data. In addition, it is possible to perform descriptive analyses of off-label use, appropriate use, medication errors, health outcomes after branded and generic drug use, and product uptake patterns before and after regulatory risk management actions.

Modular Programs form the backbone of FDA’s use of Sentinel for what we call Active Risk Identification and Analysis (ARIA). On those occasions when ARIA is not sufficient to address a safety signal, FDA may impose a post marketing requirement (PMR). With IMEDS, enhancements to a modular program or customized epidemiologic studies could reduce the logistical steps and resources necessary to initiate a PMR. IMEDS allows industry to address pharmacoepidemiology and risk management responsibilities in an efficient and effective manner, but it does not make regulatory decisions or alter the existing relationship between FDA reviewing divisions and regulated industry.

Because it relies on common and transparent procedures and infrastructure that can be understood by all participants, IMEDS appropriately shifts the focus from debates over differing methods and data to the underlying clinical and public health questions of concern. And IMEDS also has the potential to create economies of scale for all participants.

At the core of IMEDS’ innovative approach is the fact that it embraces and enables a long term partnership between FDA and the public and private sector. As new tools and methods leave the development pipeline and enter production for FDA use, they also are incorporated into IMEDS. For example, FDA is working to incorporate patient-provided data as well as randomization into Sentinel infrastructure to support clinical research in a real world setting. Such work could be accelerated through support from sponsors working through IMEDS.

And sponsors will surely have other new ideas for expanded uses of the system. Indeed, FDA is confident that IMEDS sponsors will play a key role in shaping the future of evidence generation to help answer outstanding questions about the safe and effective use of medical products in a broad range of populations. The governance process for IMEDS enables other stakeholders such as medical specialty societies, healthcare delivery systems, healthcare payers, and patient organizations to sponsor studies that will help accomplish this. We have a strong foundation in place. Organizations interested in partnering with IMEDS and building on this foundation should email IMEDS@reaganudall.org for additional information.

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

National Medical Evidence Generation Collaborative (EvGen Collaborative)

By: Rachel E. Sherman, M.D., M.P.H., and Robert M. Califf, M.D.

Readers of FDAVoice may have noticed that we’ve been talking a lot lately about the topic of evidence generation (for example, see here and here). Scientific evidence—how it’s created, how it’s interpreted, how it’s used to protect the health of Americans—is at the heart of all that we do at FDA.

Rachel Sherman

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

Over the course of your career, you’ve probably experienced the feeling of being visited by an important insight, but you’ve lacked the kind of clear, unequivocal evidence needed to feel confident that what you were proposing would actually work. Well, you aren’t alone. There has long been a chronic shortage of the information needed to inform decisions affecting health and healthcare, regardless of whether those decisions are being made by patients, physicians, regulators, payers, or other stakeholders.

For this reason, we’re especially pleased to share with you some of the efforts underway this past year to build a National Medical Evidence Generation Collaborative, or EvGen for short. We have a new website devoted to this collaborative, where you can watch videos on the EvGen vision and learn more about the many stakeholders involved.

A key EvGen goal is to leverage previously isolated data systems in a way that ensures that available information collected during healthcare-related activities (e.g., medical research, medical product development, clinical care) can be brought to bear for the benefit of all. As outlined in a recent publication, by combining insights, expertise, and technologies from across the spectrum of federal and private health sectors, we can build a new healthcare environment, one in which, for example, clinical research is embedded seamlessly within real-world clinical practice to create a cycle of improvement in care and outcomes, what is known as a continuously learning healthcare system.

Robert Califf

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

The vision for EvGen put forward by its many supporters is a momentous opportunity to transform how we approach the myriad decisions that affect different parts of the healthcare ecosystem. For instance, patients would benefit from a more comprehensive, patient-centered and evidence-driven approach that engages them as active participants in care and research. At the same time, practitioners and other healthcare professionals would have access to constantly growing sources of scientific evidence that would enable them to more confidently determine which treatments work best for which patients. And payers would have the information needed to identify which treatments truly provide value to those they cover.

Although the activities described on the EvGen website are a major step forward, much remains to be done. Working together, we can help build a healthcare world in which patients, clinicians, and policymakers have access to the high-quality scientific evidence to support the best choices for individual patients and populations.

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

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

FDA-Patented Invention Earns 2016 Patents for Humanity Award for Impact on Global Public Health

By: Carolyn A. Wilson, Ph.D., and Alice Welch, Ph.D. 

In 2003, two scientists in FDA’s Office of Vaccines Research and Review within the Center for Biologics Evaluation and Research (CBER) developed a pivotal step in the manufacture of a vaccine now called MenAfriVac. This vaccine has since protected more than 235 million lives against recurring meningitis outbreaks in sub-Saharan Africa. The patented chemical method devised by these two researchers, Dr. Robert Lee and Dr. Carl E. Frasch, enabled the production of the inexpensive and highly effective MenAfriVac vaccine, earning FDA a 2016 Patents for Humanity Award from the U.S. Patent and Trademark Office.

Carolyn A. Wilson

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

FDA’s scientific research doesn’t often grab headlines. But FDA’s research program is a critical part of the work we do to protect public health and speed innovations that make safe and effective medicines available. And sometimes FDA scientists make significant discoveries that are patentable inventions. When they do, FDA’s Technology Transfer program facilitates the transfer of such technologies to the private sector so they can become useful solutions to public health challenges. The MenAfriVac vaccine is a stellar example of such an FDA invention.

So it was with particular pride and satisfaction that we joined Drs. Lee and Frasch this past November as the U.S. Patent and Trademark Office honored them with a Patents for Humanity Award, in recognition of the critical contribution the patented technique made to the development of the MenAfriVac vaccine.

The story began in late 2003, when Dr. Lee devised a set of chemical reactions for a technique called “conjugation.” It is a method for efficiently linking one ingredient of a potential vaccine with a molecule that supercharges that ingredient’s ability to stimulate the immune system. That chemical joining, along with the collaboration with Dr. Frasch, became the basis of the FDA patent.

At the time, it was just another quiet development in the quest to make the production of certain types of vaccines more efficient. Little did the two researchers know that this patent would later help the Bill & Melinda Gates Foundation-supported non-profit PATH save tens of thousands of lives in the African meningitis belt.

Alice Welch

Alice Welch, Ph.D., Director of FDA’s Technology Transfer Program.

Just a couple of years earlier in 2001, the Meningitis Vaccine Project (MVP), a World Health Organization (WHO) and PATH partnership, had received Gates Foundation funding. Their goal was to produce an inexpensive, safe, and effective vaccine so that the affected countries could afford mass group A meningitis vaccination programs.

But MVP lacked access to a technique that was simple, efficient, and produced meningitis vaccines inexpensively. Thanks to the scientific accomplishment of these two scientists, CBER was able to provide its new technique to MVP via PATH, through a technology transfer agreement made with help from the National Institutes of Health. CBER also developed reagents to evaluate the performance and safety of the vaccine as well as methods to monitor the manufacturing process. And in December 2003, scientists from the Serum Institute of India Limited came to CBER to learn how to use the technique to make the vaccine on MVP’s behalf. The resulting vaccine didn’t need to be refrigerated, which greatly simplified deployment of this product in sub-Saharan Africa.

Awards Ceremony

Alice Welch holds the 2016 Patent for Humanity Award from the US Patent and Trademark Office.
Also in attendance for the ceremony were (left to right) Carolyn Wilson, Carl Frasch, and Robert Lee.

Early in December 2010, MVP initiated its vaccination campaign using MenAfriVac, first in Burkina Faso, then Mali, and then Niger. A year later, MVP extended the campaign to Cameroon, Chad, and Nigeria.

WHO is now helping countries transition from mass campaigns to routine immunization to establish sustainable disease control in the region. By 2020 the vaccine is expected to have protected more than 400 million people, preventing 100 million cases of meningitis A, 150,000 deaths, and 250,000 cases of severe disability.

In an era when established and emerging infectious disease outbreaks affect the lives of more people worldwide than ever before, the American public and the global community will increasingly depend on FDA to provide the kind of scientific research and expertise that have led to the successful development of medical countermeasures and vaccines like MenAfriVac.

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

Alice Welch, Ph.D., is Director of FDA’s Technology Transfer Program.

Academic Medical Centers and FDA – Working Together for the Future

By: Robert M. Califf, M.D.

FDA and the nation’s academic medical centers (AMCs) have a rich history together. Many of us at FDA trained and worked at AMCs, and many of us will go back to AMCs when we leave FDA. AMCs are where much of the basic science of medicine is advanced, and where the fundamental concepts for many of the tools to test for and treat illnesses are initially developed. Increasing numbers of AMCs have regulatory science programs, FDA has memoranda of understanding with numerous AMCs, and we are pleased to host a number of fellows from AMCs annually. All of these intersections advance our shared goals of protecting and promoting public health while also helping to speed innovation. Together, we push the boundaries of the known and possible, and ensure that in doing so the health and safety of patients is the primary concern.

Robert CaliffMany of these intersections have been coincidental or ad hoc – people reaching out to each other as needed and as helpful.  To better understand our interactions, and to find ways to make those interactions more deliberate and strategic, I spent part of this fall on a college tour of sorts, visiting eight states across three time zones. I spent time at some of the nation’s leading AMCs which are increasingly becoming integrated economic and medical systems that play a key role in the development of solutions to health care challenges for the American public, and are therefore an essential partner for FDA.

During my meetings with professors, students, researchers, administrators, and academic partners, I saw many different ways in which people were engaged in remarkable science, policy analyses and discussions to advance the human condition. From university undergraduates to experienced researchers and clinicians, the men and women with whom I met share a commitment to ameliorating and curing disease for individual patients and promoting public health. Several themes and common challenges emerged from our discussions and laid the foundation for a positive course of action.

AMCs have evolved from “ivory tower” teaching hospitals with associated basic research labs to multi-billion dollar enterprises that own an array of entities in a common corporate structure. These entities, usually not for profit, include the traditional teaching hospitals and labs, as well as community hospitals, large and small physician practice groups, hospice, long-term care, extended living and social services organizations. In addition, AMCs are spinning off biotech startups and working directly with private corporations, state and federal partners, and entrepreneurs.

These AMCs are often part of larger complexes that cross state lines and international borders and they have the increasing ability to take on unprecedented health care. In the past they could claim to be separated from the responsibilities of health care delivery, population health and the success of the medical products industry as a key part of our economy. Now they are large employers, economic engines and the critical elements of strategies to develop new ideas and technologies for the future and they are accountable for the healthcare for most Americans.

An increasing proportion of large healthcare delivery systems include a medical school and other healthcare professions schools. And in many states major universities are partners or owners of such systems. This concentration of economic and intellectual talent, combined with the entrepreneurial spirit and stated mission of innovation, demand our attention and strategic thought.

Consider the Texas Medical Center (TMC) in Houston. With eight million patient interactions a year, TMC is the eighth largest business district in the United States; they deliver more than 25,000 babies a year and have $3 billion in construction projects underway. I met with researchers and academic leaders at TMC, and was introduced to a group of young entrepreneurs working in a medical tech incubator housed in what was once a Nabisco cookie factory, a facility funded by a mix of public, private, and corporate donors.

One area of focus everywhere I went is how to collect, manage, and use the unprecedented amount of data now accessible on the human genome, human behavior, how much people earn and spend, the environmental conditions, and other subjects. With information such as this at the societal and individual level, clinicians and health system leaders will ultimately be able to chart precise treatments for each person and evidence driven policies for populations. To be useful, we expect these data to accurately measure what they claim to measure and to be connected to the medical condition to which they claim to be connected.

And as much as possible, these datasets must be accessible and shared. To succeed, researchers at Southern Illinois University need to be able to combine their observations with data in Morgantown, Birmingham, New York, and Des Moines. The best minds must be brought to bear on the best data, no matter where those people happen to live or where the data happens to be stored. It can be tempting to wall-off data, protecting it as one does a garden. But just as the “walled garden” was a failed model for the internet in the 1990s, the walled garden is a failed model for the data needed for precision medicine to succeed.

FDA can be an important partner in this effort. Scientists, whether at FDA, in academic institutions across the nation, or in private industry, share the goal to protect and promote public health. Together we can ensure that researchers, patients, and health care providers can trust the data and ensure that as many people as possible have access to it. It is also true that even those of us with the best motivations are human. We make mistakes, get sloppy, and occasionally let things slide. That’s where FDA can play such an important role, by helping to maintain and hold everyone to a high standard while driving innovation forward.

In addition to raising the bar, standards can help products stand out in an increasingly crowded marketplace. In Cambridge, for example, I met a young innovator who said he was having trouble attracting venture capital to fund his idea in part because potential investors saw an unregulated marketplace into which competitors whose products sounded similar but with no proven positive effect, could begin marketing immediately and undercut him. Requiring FDA approval essentially freezes out fly-by-night companies more interested in quick profits than developing and disseminating technologies with evidence for benefits to individuals and populations.

Make no mistake, FDA has room to improve. During my trip I heard directly, without equivocation, how FDA could do a better job.  As someone who spent most of my career at an academic medical center, I understand those concerns up close and personal, and I also know that there is room for improvement on both sides.

That means I also know firsthand the challenges, and opportunities, presented by both AMCs and this important scientific regulatory agency. After my tour, I am more convinced than ever that FDA and the academic medical center enterprise need each other, must continue to communicate and engage with each other, and, where appropriate, must collaborate to advance their shared missions.

This is not a short-term project. This engagement must continue long after I leave FDA.

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

FDA’s Naloxone App Prize Competition Celebrates Innovation In Search of Technological Solutions to the Opioid Epidemic

By: Peter Lurie, M.D., M.P.H.

The epidemic of opioid dependence and abuse has had an impact upon communities both large and small across the United States. Since 1999, rates of overdose deaths involving opioids, whether prescription painkillers or street drugs like heroin, have nearly quadrupled. In 2015, 91 Americans died from an opioid overdose each day.

Dr. Peter LurieMany local, state, and federal agencies have worked to prevent these tragic deaths by expanding access to naloxone, a prescription medication that can rapidly reverse the effects of an opioid overdose. Supporting increased access to naloxone is also a key objective of the multifaceted Opioid Action Plan released by FDA earlier this year. In addition, FDA has sponsored two national meetings on the topic and in recent years has approved two naloxone products that facilitate use by laypeople.

These efforts and others by federal partners, state and local governments, and by community-based organizations have increased the availability of naloxone in many communities, enabling both first responders and laypeople like friends and families of drug users to carry this life-saving medication. From 1996, when a community-based organization first distributed naloxone, to mid-2014, these organizations are reported to have reversed over 26,000 overdoses.

For naloxone to reverse an opioid overdose, however, it must be administered as quickly as possible. That’s why the agency launched the Naloxone App Competition, an effort to develop innovative solutions to the problem of how to rapidly connect naloxone carriers to a person experiencing an opioid overdose.

Through this prize competition, FDA aimed to engage with creative communities outside the agency who may not have traditionally focused on public health issues. We invited computer scientists, researchers, health care providers, patient advocates, academics, and entrepreneurs to form teams and submit concepts for a crowd-sourced mobile phone app that could help accelerate delivery of naloxone to a person experiencing an overdose.

While we didn’t know what to expect from this first-of-its-kind competition for the agency, public health-focused innovators responded with enormous enthusiasm. Over 150 teams registered for the competition, and more than 100 individuals participated, either in-person or virtually, in a two-day code-a-thon hosted on the FDA’s White Oak campus. The teams were eager to learn more about the opioid epidemic and began to develop compelling concepts to bring technological solutions to bear on a real-world problem.

A total of 45 submissions were reviewed by our team of judges from FDA, the National Institute on Drug Abuse, and the Substance Abuse and Mental Health Services Administration. While we received many thoughtful and innovative submissions, a single winning team was selected to take home the cash prize of $40,000. We are pleased to announce that the winner of the 2016 FDA Naloxone App Competition is OD Help by Team Pwrdby, a small startup based in Venice, California.

OD Help’s concept is a simple, easy-to-use mobile app designed to connect potential opioid overdose victims with a crowd-sourced network of naloxone carriers. OD Help can easily be tailored for use in rural or urban areas by expanding or contracting the radius within which naloxone carriers are sought. An additional innovative feature of OD Help is the optional interface with a breathing monitor to detect when a victim’s breathing rate is dangerously low, a sign of an opioid overdose. Hence, if the victim is alone and unable to call for help, OD Help will detect the diminished breathing and alert a naloxone carrier of the potential overdose. Other features of OD Help include: only alerting people in one’s support network and allowing naloxone carriers to disable alerts when they are unable to respond. The app also provides instructions on how to correctly diagnose an overdose and administer naloxone and helps contact emergency medical services when help is required.

Team Pwrdby was represented by the multi-disciplinary team of: Jared Sheehan, Dr. Talib Omer, Daniel Bouganim, Chris Rovin, Suresh Mohan, Ben Dukes, Andress Anantharaju, Oumayma Raimi, and Courtney Crockett. View the OD Help app video here: https://www.youtube.com/watch?v=wiiNvSLbUgo&feature=youtu.be.

FDA also congratulates Team MIT on their app concept, NalNow, which the judges recognized as a second high-performing submission. Team MIT receives an honorable mention as the team with the second-highest score in the Competition. Team MIT is represented by Dr. Hattie Chung, Grace Young, Sinchan Banerjee, Rodrigo Ipince and Emily Zhao. View the NalNow app video here:  http://bit.ly/nalnow_video. App developers interested in further developing their concepts are encouraged to seek support through NIDA’s Small Business Innovation Research grant program.

By enabling FDA to tap into the creativity, energy, and knowledge base of communities that do not regularly engage with the federal government, prize competitions expand the pool of smart, talented individuals committed to tackling the problems that face us as a society – and in this case that was a win for public health. We sincerely thank everyone who participated in the 2016 FDA Naloxone App Competition, and we congratulate Team Pwrdby on their winning concept, which has the potential to make a real difference in the fight against opioid overdose.

Peter Lurie, M.D., M.P.H., is FDA’s Associate Commissioner for Public Health Strategy and Analysis

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

Introducing FDA’s Emerging Sciences Idea Portal: Please Help Us Predict the Future

By: Donna L. Mendrick, Ph.D.

Gazing into the future to predict the next new things in science and technology is not just the work of a science fiction writer.

Donna MendrickGovernment and business engage in this forward thinking too– it’s called “horizon scanning,” a fairly recent practice that involves systematically gathering a broad range of information about emerging trends to help organizations develop the capabilities they need to deal better with an uncertain and complex future.

FDA set up its own intra-agency horizon scanning group in April 2015 called the Emerging Sciences Working Group, which I chair. Our 15-member group meets regularly and includes representatives from FDA product and research centers as well as relevant offices.

With the mission of leveraging scientific expertise and resources to conduct long-range horizon scanning, we advise Agency and product center leadership on how emerging issues and cross-cutting scientific advances may affect FDA preparedness and activities across government agencies.

The fact is, FDA’s ability to achieve its mission relies on awareness and preparing pro-actively to address emerging issues and scientific advances that will affect the products FDA regulates five or more years in the future – well in advance of formal FDA regulatory submissions.

What kinds of new science and technology will alter the way FDA does its work? We are not focused on evolving areas such as nanotoxicology, since nanoparticles are already in some approved products even though the field is still being developed and understood.  Our goal is to identify areas not yet addressed in current products like hibernation for surgery and brain-computer interfaces.

Once we have such information it can be used for science-based planning, programs, policies, reporting, and communication within and outside FDA.

It’s no surprise that FDA can’t possibly employ experts in every subcategory of scientific and technological knowledge. To cast a wide net, we are also seeking the advice of other government agencies that fund research, evaluate patent submissions, and develop scientific policy for the U.S. government — and that process has begun.

But it is clear that to fully horizon scan we must turn to experts in the private sector. That’s why today we are issuing a Federal Register notice asking science and technology experts outside of the government to submit their predictions on the next new things in their field of specialization.

To be clear, we’re not looking for advances that are already under discussion. We’re seeking information about scientific and technological advances that are so unknown they don’t show up – or barely show up – on a web search.

Your electronic submissions to our Emerging Sciences Idea Portal will be public so all confidential information should be submitted in writing. And there is no guarantee we’ll get back to you with a response – but we might if we’re sufficiently intrigued and want more information.

We look forward to your submissions. With your help, FDA will be ready to provide advice and to promptly review applications for products that truly represent the next new thing.

Donna L. Mendrick, Ph.D., is FDA’s Associate Director for Regulatory Activities at the National Center for Toxicological Research