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

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By: Robert M. Califf, M.D.

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

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

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

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

Robert Califf

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

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

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

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

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

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

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

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

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

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

FDA’s Science-based Approach to Genome Edited Products

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

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

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

Research is currently underway that would use these technologies to:

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

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

Robert Califf

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

Maintaining product-specific, risk-based regulation

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

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

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

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

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

Collaborating with Federal agencies

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

Ritu Nalubola

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

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

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

Scientific engagement and horizon-scanning

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

Working with international partners

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

Going forward

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

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

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

 

Introducing IMEDS, a Public-Private Resource for Evidence Generation

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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)

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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

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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.

A Review of CDER’s Novel Drug Approvals for 2016

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By: John Jenkins, M.D.

This past year was another successful year for the new drugs program in FDA’s Center for Drug Evaluation and Research (CDER).

John JenkinsCDER reviewed and approved 22 novel drugs, most of which have the potential to add significant clinical value to the care of thousands of patients with serious and life-threatening diseases.

Among the novel drugs approved in 2016 were the first treatment for patients with spinal muscular atrophy, the first drug approved to treat Duchenne muscular dystrophy, a new drug to treat hallucinations and delusions in people with Parkinson’s disease, another to treat patients with a rare chronic liver disease known as primary biliary cirrhosis, and two new treatments for patients with hepatitis C. There were also new oncology drugs to treat patients with ovarian cancer, bladder cancer, soft tissue sarcoma, and chronic lymphocytic leukemia — as well as two new diagnostic agents for detecting certain forms of cancer.

Nearly three out of four of these novel products – or 73 percent – benefitted from at least one of FDA’s programs to expedite drug development and review (i.e., Fast Track designation, Breakthrough Therapy designation, priority review designation, accelerated approval).

CDER’s review team also met the goal dates specified by the Prescription Drug User Fee Act (PDUFA) for 95 percent of 2016’s novel drug approvals. We also approved 95 percent of the novel products on the “first cycle,” meaning additional information was not requested that would delay approval and lead to another review cycle. Moreover, 86 percent of the novel drug approvals were approved in the U.S. before they were approved by any other regulatory authorities. The upshot of these efficiencies is that CDER is reviewing drugs as quickly as possible while continuing to uphold FDA’s traditionally high approval standards.

The total number of novel drugs approved in 2016 is lower than the 45 novel drugs approved the year before and below the average of 29 drug approvals per year on average over the last 10 years. There are several reasons for this. While the number of novel new drug applications received for review in 2015 was similar to our most recent 10-year average of 35 applications per year, the natural fluctuation of the timing of application submissions and their PDUFA goal dates, meant there was a smaller pool of novel drug applications to target action on than in recent years. For example, CDER approved five novel drugs in 2015 that had PDUFA goal dates in 2016. These early approvals benefited patients by making the drugs available sooner, but also decreased the total of novel drugs approved in 2016. Another factor was the number of Complete Responses (CR), which describe deficiencies in the application, precluding approval, with advice on what the sponsor needs to do for FDA to support resubmission of the application. CDER issued 14 CR letters for novel drugs in 2016, higher than in recent years.

Each application for a new drug must meet the statutory and regulatory standards for approval by demonstrating that the new drug is safe and effective for its intended use, and that the quality of the manufacturing of the product is high, before it can be approved. FDA reviews each application on its own merits. While we report on groupings of applications submitted and approved each year, given the expected variation in the quality of the data contained in any particular application it is not surprising that the ratio of approvals to CR letters tends to fluctuate from year-to-year. In examining the deficiencies cited in the CR letters issued to novel drugs in 2016 it is notable that the primary deficiency for several of the applications was failure to comply with FDA’s current Good Manufacturing Practice (cGMPs) regulations. These regulations are designed to control the quality of manufacturing procedures for drugs in order to ensure that patients receive drug products of a consistently high quality, which is an important component of the safety and efficacy of a drug. The number of CR letters that cited failure to comply with cGMP regulations was unusually high for a single year. By comparison, only four of the 47 novel drug applications for which a CR was issued from 2010 through 2015, included failure to comply with cGMPs as the primary deficiency. 2016 may serve as a reminder to sponsors that all of their manufacturing facilities must be in compliance with cGMP regulations if they wish to ensure approval of their application. Failure of manufacturing facilities to pass FDA inspection can unnecessarily delay patient access to novel new drugs.

Our annual Novel Drugs summary provides more details about CDER’s novel drug approvals for calendar year 2016.

On a personal note, I will retire from FDA on January 7, 2017, after nearly 25 years of service at FDA and nearly 32 years of service in the Federal government. It has been a great honor and privilege to serve with the dedicated public servants at FDA whose hard work, under often challenging circumstances, serves to promote and protect the public health of Americans and patients around the world. During my time at FDA we have seen the erasure of the “drug lag” of the 1980’s where drugs were approved in other countries years before they were approved in the United States. Today more than two-thirds of novel drugs are approved first by the FDA, providing patients in the U.S. with earlier access to new drugs that have the potential to significantly improve their quality of life, and in some cases to extend their lives. This remarkable change has been accomplished without compromising FDA’s standards for approval; in fact, we have also significantly strengthened and modernized our pre-market and post-market drug safety programs at the same time as we dramatically improved the efficiency of our new drugs review program. I am proud to have been a part of helping to make FDA the “gold standard” for drug regulatory agencies around the world. While I am leaving FDA, FDA will not leave me; its principles and high standards will help to guide me in my future work.

There are many new challenges and exciting opportunities for CDER in 2017 and beyond; I am confident that the highly professional and dedicated staff in the new drugs program will meet those challenges and have the experience and vision to translate the exciting and rapid advances in science into new safe and effective treatments for patients in need.

John Jenkins, M.D., is Director of the Office of New Drugs in FDA’s Center for Drug Evaluation and Research

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Learn More

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

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

Clacker Balls and the Early Days of Federal Toy Safety

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By: John P. Swann, Ph. D.

As many of us scramble to find the perfect toy for the children in our lives this holiday season, it’s interesting to note that at one time FDA could very well have been known as the Food Drug and Toy Administration.

John SwannThe 1966 Child Protection Act gave FDA authority to ban toys that had chemical, flammability, or radioactivity hazards and the 1969 Child Protection and Toy Safety Act further defined FDA’s responsibility for ensuring the safety of toys, which the agency pursued until the formation of the Consumer Product Safety Commission in 1973.

During FDA’s brief stint as toy regulator, the agency dealt with flammable dolls; infant and toddler playthings that posed serious puncture, laceration, and crushing risks; and the infamous lawn darts. To appreciate FDA’s role at the time, consider what happened with clacker balls. Their origin was unclear, but clacker balls were a veritable craze by January 1971, to the consternation of parents and school districts everywhere. Sold under a variety of other names such as Kerbonkers, Click-Clacks, and Bo-Los, they could vary somewhat in design but typically, they were plastic, wooden, or steel balls of about two-inches in diameter. The balls were attached at each end of a two-foot cord that had a ring or knot in the middle. By holding the cord in the middle and moving your hand up and down, you could cause the balls to strike each other at the top and bottom of an arc with great force and abundant noise. By the spring of 1971, over 100 manufacturers had sold millions of clacker balls, according to FDA’s Bureau of Product Safety, which oversaw such commodities. And it was not a uniquely American phenomenon. The village of Calcinatello in Italy held an international competition of clacker ball enthusiasts in August 1971. In lieu of a trophy the winner received a variety of local delicacies.

picture of clacker balls

Assorted clacker ball sets, including some that ruptured.

Many compared the sudden popularity of clacker balls with the Hula Hoop, but they posed considerably greater risk to the user, as FDA soon discovered. Though advertised to “teach skill and coordination” and to consist of “non-breakable plastic with strong cord,” some of those enthusiasts sustained serious eye and other injuries due to the design and action of the toy, prompting the Society for the Prevention of Blindness to raise an alarm.  The balls could rupture and spew fragments, or become wayward missiles through detachment from or fraying of the cord itself.

The 1969 Toy Safety Act had provided for the banning of toys that represented an electrical, mechanical, or thermal hazard, pending the agency’s publication of the hazardous nature of the item and, if applicable, means of eliminating the hazard. And the agency took that seriously, banning more than 300 individual toys in seven classes through 1971.

After learning  of several injuries to children and adults from clacker balls, FDA issued a public warning in February 1971 as it investigated these reports and studied the toy and its potential to hurt the user—or bystanders.

FDA Toy Review Committee

The recommendations of the Toy Safety Review Committee in the Bureau of Product Safety (pictured here), which included a pediatrician and two engineers, played a key role in FDA’s decisions to ban, further test, mandate product redesign, or create regulations to address the hazards.

With ongoing reports of clacker ball injuries, just two months later, in April, FDA published its intention to ban such toys unless they could meet detailed standards of safety that addressed the integrity of the balls, cords, and connections that held them together.  FDA’s notice stated that the manufacturer would have to carry out the prescribed tests on a proportional number of samples based on the size of the batch produced, maintain records of these results, and make them available to the agency upon request. FDA finalized this plan in November 1971, and all clacker balls marketed thereafter had to either abide by the new safety standards or be subject to the ban.

The rulemaking process rendered clacker balls a safer toy, and those that failed to follow the standards were seized. Over 300,000 sets were put into storage at the Port of Miami while the agency was developing its safety standards for the clacker balls (presumably because the manufacturer knew they wouldn’t pass the safety tests). After a manufacturer tried, unsuccessfully, to find a market for these in South America, a salvage dealer apparently purchased the lot late in 1972, but their subsequent history is unknown.

Ensuring safety was FDA’s goal – and later that of the CSPC. But the toy’s noise was quite another thing. The standards applied by the two agencies never addressed the click-clack-click-clack that tormented parents and others for all these years.

Enjoy the click-clack sound of clacker balls!

John P. Swann, Ph.D., is an FDA Historian

Academic Medical Centers and FDA – Working Together for the Future

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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

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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