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

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

Consumer expenditure on FDA regulated products: 20 cents of every dollar

By: Sheri Walker, Ph.D., and Clark Nardinelli

Sheri Walker

Sheri Walker, Ph.D., is an FDA Senior Economist

One of the much-cited statistics about FDA is this: that FDA-regulated products account for about 20 cents of every dollar of annual spending by U.S. consumers. Add up 20 cents of every dollar and it amounts to more than $2.4 trillion in annual consumption that includes medical products, food and tobacco.

Our staff of 34 economists comes up with this estimate of FDA’s impact every year. We think it helps the public put in perspective the sheer scope of FDA’s responsibilities, especially when you recognize that FDA is only one of dozens of governmental agencies.

We largely rely on personal consumption expenditure data collected by the Bureau of Economic Analysis (BEA) every year to calculate total consumer spending in each of the major FDA product categories. These product categories include food (except alcohol and meat products regulated by USDA), drugs, medical devices, cosmetics, dietary supplements, and (since 2009) tobacco products.

Clark Nardinelli

Clark Nardinelli is FDA’s Chief Economist

Some BEA expenditure categories include more than one FDA product area. For example, biologics and dietary supplements are included in the expenditure for pharmaceutical and medical products (although, legally, dietary supplements are food). Cosmetic products are captured under the BEA expenditure category for personal care products. Pet food and animal drugs are estimated as a percentage of the pet-related products category. The estimate for medical device products is derived using data from the therapeutic equipment products category from the BEA and data from the Annual Survey of Manufacturers collected by the U.S. Census Bureau.

Food products represent the largest share of spending on FDA products, accounting for approximately 11 cents of every dollar of consumer spending. Without the addition of tobacco products, spending on FDA-regulated products would be slightly less than 20 cents per dollar.

20 cents pie chartWe know that some people say FDA oversees 25 cents of every consumer dollar. Maybe it’s an urban legend – or maybe it harkens back to decades ago. The 20 cents (or 20 percent of spending on consumer goods and services) has held steady over the past 5 years. Americans used to spend a much higher proportion of their income on food – with over 25 cents of every dollar going to food during World War II. But since then the share of food and tobacco in total consumer spending has been falling steadily while the share of consumer spending devoted to medical products has been steadily climbing. Whether those trends will continue, and whether FDA’s 20 cents will hold steady for the next 5 or 50 years, is impossible to predict.

Sheri Walker, Ph.D., is an FDA Senior Economist, and Clark Nardinelli is FDA’s Chief Economist

Key Facts about “Abuse-Deterrent” Opioids

By: Douglas C. Throckmorton, M.D.

Here at FDA, we work diligently to be part of our nation’s solution to the opioid abuse epidemic. While there is no single solution to this complex problem, we continue to encourage efforts to develop new opioid formulations with abuse-deterrent properties that make it harder to abuse these powerful medications.

Douglas C. Throckmorton, M.D.Knowing there are some 100 million Americans with significant pain each year, we need to help ensure that patients in need continue to have appropriate access to pain medications, including opioids. At the same time we must work to ensure that these powerful medications are used as safely as possible.

To date, FDA has approved seven opioid formulations with abuse-deterrent properties consistent with FDA guidance, and there are more in the development pipeline.

What does it mean to be abuse-deterrent? Opioids with abuse-deterrent properties are tablets or capsules that are designed to deter abusers from crushing them into a powder for swallowing, snorting or injecting to create a faster, more intense high.

Each manufacturer has its own proprietary technology for deterring abuse. Some abuse-deterrent formulations consist of tablets with a hardened surface that is difficult to crush and some turn the crushed medicine into a gooey substance that is difficult to inject.  Other current approaches combine the opioid with naloxone or naltrexone, drugs that block the effects of the opioid in the body that are activated when the opioid is crushed.  Additional approaches are currently under development.

The manufacturers of the seven FDA-approved opioids with abuse-deterrent properties to date have all submitted study data demonstrating that the products are expected to deter abuse. This work was guided by the 2015 final guidance for industry, Abuse-Deterrent Opioids — Evaluation and Labeling. As a result of FDA’s review, FDA-approved product “labeling” (prescribing information) for these medications clearly states the product’s abuse-deterrent properties. Other manufacturers have chosen to add what they may intend as abuse-deterrent properties to their product, but FDA has not seen sufficient evidence that these properties are effective and therefore the FDA-approved labeling for these products does not identify them as having abuse-deterrent properties. Prescribers and patients can look to our web site for the list of FDA-approved products with abuse-deterrent properties in their labeling.

It’s important to recognize that FDA refers to these drugs as “abuse-deterrent” not abuse-proof. There will always be some potential for abuse of these products. For instance, a patient can orally ingest a quantity beyond what is prescribed. It’s also true that people intent on abusing an opioid may find ways to overcome the abuse-deterrent properties of the drug that were not identified during premarketing research. With this in mind, FDA requires that any drug approved as having abuse-deterrent properties be further evaluated by its manufacturer after it is marketed. The manufacturer is required to conduct studies to evaluate the impact of the product on abuse in the community. If necessary, we may approve updated product labeling that describes the drug’s abuse deterrent features after approval.

Still, abuse deterrent technology certainly helps. That’s why FDA is looking at ways to encourage the development of abuse-deterrent generic versions of an opioid since none currently exist. We released draft guidance for industry in March and we’re looking forward to an interesting public discussion of the topic next Monday and Tuesday.

The FDA opioid action plan we issued in February involves a multi-faceted approach to reducing opioid misuse and abuse. And we continue to look for ways to make a difference. We recently announced we would help fund the development of assessment tools to evaluate packaging, storage, delivery, and disposal solutions, as well as product formulations, designed to prevent or deter misuse and abuse of opioid analgesics.

Support for abuse deterrent formulations is one important part of a strategy to help prescribers and patients make the best possible choices about how to use these powerful drugs. Our goal is to find the balance between appropriate access to opioids for patients in pain and the need to reduce abuse and misuse of these medications.

Douglas C. Throckmorton, M.D., is Deputy Center Director for Regulatory Programs in FDA’s Center for Drug Evaluation and Research

SCORE at Six Months: Meeting the Challenge of Complex Recalls

By: Stephen Ostroff, M.D., and Howard Sklamberg, J.D.

When a potentially contaminated food is on the market, time is of the essence to keep people from becoming ill. Yet there are times when it is difficult to determine what actions should be taken. This can happen when we do not have enough information to reach a clear decision.

Stephen Ostroff, M.D.

Stephen Ostroff, M.D., is FDA’s Deputy Commissioner for Foods and Veterinary Medicine

To better address these situations, in April FDA established a team of senior leaders that is brought in to make decisions in the most challenging cases. The team is called SCORE, which originally stood for Strategic Coordinated Outbreak Response and Evaluation, but it soon became clear that the scope of its work is broader than outbreaks. The team looks at cases in which recalls and other actions may be needed, even when there are no reports that people have fallen ill. So SCORE now stands for Strategic Coordinated Oversight of Recall Execution.

And we’re happy to report that SCORE is already making a difference, helping to overcome obstacles and streamlining processes to get potentially harmful foods off the market as soon as possible to reduce further consumer exposure.

In the last six months, SCORE has reviewed and directed operations in cases that include flour contaminated with peanut protein, (a major food allergen), facilities contaminated with Listeria monocytogenes, pistachios in which Salmonella was detected, and baby food that was not manufactured in compliance with infant formula regulations. All of these cases resulted in recalls and announcements issued by the firms and FDA.

Howard Sklamberg

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

SCORE was launched, in part, in response to concerns raised by the Department of Health and Human Services’ Office of the Inspector General about FDA’s ability to ensure that companies initiate voluntary recalls in a prompt and effective manner. While FDA staff were already helping to facilitate thousands of prompt and successful voluntary recalls, we recognized the need for an enhanced response in certain, more complex cases.

In the cases brought to the team, we believe that SCORE has helped determine the right course of action and shorten recall timeframes, getting the products off the market faster. SCORE has helped improve tactical planning, leading to additional inspections and sampling assignments, and to getting the word out to more consumers about potentially dangerous products. In one case, FDA suspended a food facility’s registration after a reinspection and additional sampling requested by SCORE showed continued contamination. Suspension of registration effectively shuts a facility down until FDA determines that there is no longer a reasonable probability that foods produced there will cause serious illnesses or death.

We set individual deadlines and got prompt results in these, and other, instances. FDA staff are seeing these actions as a model for their efforts going forward.

FDA has been evolving over the past few years into an agency that speaks with one voice in its oversight of food safety. SCORE’s membership includes leaders from within the directorates of Foods and Veterinary Medicine and Global Regulatory Operations and Policy, in addition to the Office of the Chief Counsel. The spectrum of expertise covers inspections and investigations, compliance and enforcement, policy, legal, communications, outbreak response and, most important, science.

This team is in its infancy but the results it has achieved thus far signal an integrated approach to food recalls that will help ensure a swift response no matter what obstacles arise. The arrival of the compliance dates for the FDA Food Safety Modernization Act rules overseeing the safety of domestic and imported foods are putting additional food safety controls in place to help reduce food contamination. And the work of SCORE and its colleagues will continue.

SCORE’s goals for the next year include identifying and closing gaps that slow the process of determining whether a food is a threat to public health or interfere with identifying the right actions to take in response to potential contamination. Our ultimate goal is to continue to improve our ability to protect consumers from contaminated food.

Stephen Ostroff, M.D., is FDA’s Deputy Commissioner for Foods and Veterinary Medicine, and Howard Sklamberg, J.D., is FDA’s Deputy Commissioner for Global Regulatory Operations and Policy.