‘Radiating Shoe Sales’

By: Vanessa Burrows

Since the discovery of X-rays in the late 19th century, the technology has enhanced health care in a variety of ways. Like many cutting-edge scientific developments, however, it also has inspired uses of uncertain therapeutic value. That was the case with the shoe-fitting fluoroscope, the subject of the latest episode of FDA’s history video series.

Vanessa Burrons

Vanessa Burrows, FDA Historian, next to a shoe-fitting fluoroscope

Marketed as a scientific method for optimizing shoe fit, the fluoroscope appeared in shoe stores nationwide from the 1920s to the 1960s. But the machines not only didn’t do what they promised, they also exposed children, their parents, and store clerks to unhealthy doses of radiation.

In the late 1940s, scientists and regulators began to raise serious concerns about the dangerous levels of radiation. Over the next two decades, individual states gradually took action to either ban or restrict the use of the device.

By the 1970s, concerns grew about radiation emitted from common appliances, such as televisions and microwave ovens. And in 1971, FDA was given authority to regulate radiation-emitting devices. The agency continues this oversight, working to protect consumers from harmful novelty devices like the shoe-fitting fluoroscope. FDA also sets standards for medical imaging, surgical and therapeutic equipment, security systems, and consumer products – all for the protection of the health of American consumers.

We hope you enjoy your visit to FDA’s HistoryVault.

Vanessa Burrows is an FDA Historian

FDA and NIH Release Final Template for Clinical Trial Protocols

By: Peter Marks, M.D., Ph.D.

A little more than a year ago, FDA and NIH announced the availability of a draft template for investigators to use when organizing clinical trial protocols, which are essentially roadmaps for conducting a clinical trial.

Peter MarksToday, we are excited to announce that the NIH-FDA Joint Leadership Council has issued a final version of the template, a development which is likely to contribute important efficiencies to the process of protocol development, saving medical product development time and money.

The final version is intended for clinical investigators who are writing protocols for phase 2 and phase 3 NIH-funded studies requiring investigational new drug or investigational device exemption applications, but could also be helpful to other investigators conducting studies of medical products that are not regulated by FDA. It provides both instructional and sample text and reflects input from the public, consisting of nearly 200 comments from over 60 individuals. Importantly, it also has been harmonized with a separate protocol template that was recently developed by the private sector organization, Transcelerate Biopharma, for industry-sponsored research.

Clinical trial protocols are critical components of any medical product development program, describing trial objectives, trial design, methodology, statistical considerations, and trial organization.

Having a standard protocol format will facilitate review of protocols by regulators and others (e.g., institutional review boards). We believe that the template will help investigators prepare protocols that are consistent and well organized, contain all the information necessary for the clinical trial to be properly reviewed, and follow the International Conference on Harmonisation (ICH) E6 Good Clinical Practice guidelines. By clarifying expectations, the template will contribute important time and money-saving efficiencies.

Guidance is available from FDA on the content that should be included in a protocol to help ensure human subject protection and high data quality, but the guidance does not describe a standardized format for presenting this information. Placing relevant information in a standardized location in a clinical trial protocol can expedite the development and review of protocols thus enabling a quicker start of a clinical trial, potentially leading to more timely completion of studies and getting important new treatments to patients more quickly. What’s more, with the increased complexity of clinical development, such as use of combinations of different medical products, it is more important than ever that investigators understand protocol development expectations and capture important components right from the start.

NIH, which supports and conducts biomedical research, and FDA, which evaluates the safety and effectiveness of medical products and depends on high-quality research to inform its decisions, agreed that developing a protocol template would be an excellent opportunity to help improve the design of clinical trials. Our agencies believe that the availability of this template and accompanying instructional information will be very useful to investigators in creating well-organized, high-quality protocols — a benefit to everyone involved in medical product development.

Peter Marks, M.D., Ph.D., is the Director of FDA’s Center for Biologics Evaluation and Research

Working to Raise Awareness and Reduce Health Disparities

By: Jonca Bull, M.D.

Minority Health Month imageApril is National Minority Health Month and this year’s theme is “Bridging Health Equity Across Communities.”

FDA’s Office of Minority Health (OMH) is committed to the HHS mission of advancing health equity, and our office works year-round to advance FDA’s message of ensuring the safety and efficacy of our nation’s food supply and medical products to all communities, but with a focus on minority groups. The first HHS Office of Minority Health was established nearly three decades ago and FDA’s own office came into being in 2010.

Jonca Bull, M.D., is Director of FDA’s Office of Minority HealthIn the intervening years, we have made significant progress. But we are reminded daily that there is still more to be accomplished in the fight to reduce and eliminate health disparities.

Today, minority communities and those at the lower socioeconomic rungs still remain disproportionately burdened by chronic disease and are much more likely to succumb to certain illnesses.

Within the past year, we have worked diligently to connect our communities to resources to help educate and raise awareness about these issues. Highlights from our two programmatic teams include:

Outreach and communications –

Released English and Spanish language videos to encourage minority participation in clinical trials, with the most recent video being released this month;

  • Worked closely with the health fraud team in the Office of Regulatory Affairs to raise awareness about tainted and fraudulent products that target some ethnic groups;
  • Exhibited and presented at nearly a dozen conferences throughout the year; and,
  • Spearheaded the agency’s Language Access plan to help ensure that FDA materials are available to all consumers in their native language.

Research and Collaboration –

  • Worked with FDA centers and external partners to support research studies around minority health and health disparities. Projects included: Racial Disparities in Multiple Myeloma, Underutilization of Generic Medications in Underserved Patients, and Advertising and Promotional Labeling in Adult Immunization Disparities.
  • Funded multiple Centers for Excellence in Regulatory Research Science and Innovation (CERSI) projects with Georgetown University (Targeting triple negative breast cancer in African American women), University of California San Francisco/Stanford (Safer Labeling of Pediatric Medications: Reducing Literacy-related Health Disparities among Chronically Ill Adolescents), Johns Hopkins University (Workshop Clinical Trials: Assessing Safety and Efficacy for a Diverse Population);
  • Supported a genomics and health disparities fellow at Harvard University School of Medicine; and,
  • Hosted more than half a dozen fellows and pharmacy students from Howard University, the University of Washington, and Florida Agricultural and Mechanical University, among others.

In addition, last fall, OMH issued a draft guidance document titled, Collection of Race and Ethnicity Data in Clinical Trials-Guidance for Industry and FDA Staff with the goal to ensure that subpopulation data is collected consistently by industry. This document outlines FDA’s expectations for, and recommendations on, the use of a standardized approach for collecting and reporting race and ethnicity data in submissions for clinical trials for FDA regulated medical products conducted in the United States and abroad. We also hosted a webinar to walk through the document.

Working collaboratively within FDA and with external stakeholders, we will continue promoting and protecting the health of diverse populations through research and communicating of science information that addresses health disparities.

Jonca Bull, M.D., is FDA’s Assistant Commissioner for Minority Health, Office of Minority Health

For more information read: The FDA Supports Research to Reduce Health Disparities

America’s Got Talent – Regulatory Science Style

By: Stephen Ostroff, M.D.

Veni Vidi Vici. It translates into English as “I came, I saw, I conquered.” It also happens to be the name chosen by one of the winners of the recently held America’s Got Regulatory Science Talent Competition.

America's Got Regulatory Science Event

Dr. Ostroff and FDA staff discuss projects with students from the University of Maryland CERSI.

FDA recognizes that young scientists are our future. Now in its fifth year, America’s Got Regulatory Science Talent is one of a number of initiatives FDA supports to encourage young scientists to pursue careers in the rapidly maturing field of regulatory science.

Each year, teams from the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (CERSI), and the University of Rochester’s Clinical and Translational Science Institute (CTSI), compete by presenting their proposed solutions to a current challenge in regulatory science. The students identify the needs by consulting eight priority areas identified in FDA’s Strategic Plan for Regulatory Science.

Winners are decided by a panel of judges after evaluating each presentation for its quality and novelty, and the proposed solution’s potential significance and feasibility. The winning teams come to FDA to formally present their ideas and have discussions with Agency scientists who are working in their project area. The event, held on April 12th, was sponsored by the Office of Regulatory Science and Innovation (ORSI) which is located in the Office of Chief Scientist. The winning teams certainly came, saw, and conquered.

This year’s winners are:

University of Maryland CERSI

Dr. Ostroff with the University of Maryland teams

Dr. Ostroff with the teams from the University of Maryland CERSI

1st Place Team – Veni Vidi Vici

A high-visibility universal labelling system to communicate risks of hazardous drugs. Wonder if your prescription medication has some dangerous side effects that may be noted in “fine print” – or even nowhere – on the label? A universal symbol in red and yellow in a prominent place on the label is the “Veni Vidi Vici” Team’s solution.

2nd Place Team – Biomarker Boys

Platform to improve transparency for biomarker integration in Accelerated Approval pathway. Tackling a challenge experienced in this growing area of biomedical innovation, the “Biomarker Boys” created a form that facilitates transparent and structured integration of biomarkers into rare disease state drug development.

University of Rochester CTSI

Dr. Ostroff with the University of Rochester teams

Dr. Ostroff with the teams from the University of Rochester CTSI

1st Place Team – Simple English Explanation Directive (SEED)

Making clinical trial results more accessible and functional. Team “SEED” takes the incredibly complicated language that is often found when describing a clinical trial, and puts it in easy-to-understand form.

2nd Place Team – 3-Defining Patient Matched Implants

A streamlined process to test 3-D printed personalized implants. The “3-Defining Patient Matched Implants” Team decided that a quality systems approach is needed to streamline the process of validating the integrity of individual patient-matched 3-D printed implant systems. Their proposal introduces an alternative approach to the current method used in 3-D printing to ensure implants are safe for implantation.

This competition reminds us that good science makes for good regulation. And it was great to see the outside-the-box thinking and innovative approaches these contestants took in addressing some of the challenges that FDA faces with the products we regulate. It’s also a good reminder that the future of regulatory science depends on training and education – and we cannot underestimate the importance of educational activities like these.

The innovative approaches from this year’s teams also show the power of collaboration, mirroring the collaborative approach FDA takes in leveraging the brainpower of our teams of scientists, engineers, statisticians, social and behavioral scientists, medical officers, communicators, and others. The teams from the University of Maryland and the University of Rochester demonstrate just how teamwork produces great results.

Congratulations to the schools for organizing the competitions and to the FDA mentors who encouraged the competitors. Each year the quality of the work improves and I’m certain it will benefit patients and consumers over the coming years. Please check out this year’s talent –including a presentation from a freshman at Maryland. Who knows? Maybe one of these students will be FDA Commissioner some day!

To see the finalists present their innovative solutions to regulatory science challenges, visit FDA’s America’s Got Regulatory Science Talent web page.

Stephen Ostroff, M.D., is currently Acting Commissioner of the U.S. Food and Drug Administratio

FDA flickr photos from FDA’s America’s Got Regulatory Science Talent 

FDA: Helping Small Businesses Get Big Results

By: Brenda Stodart, Pharm.D., and Renu Lal, Pharm. D.

It is well known that small business is vital to the success of the American economy. Less known, though, is how instrumental it has been to the growth and innovation in drug development.

Brenda Stodart

Brenda Stodart, Pharm.D. Captain, United States Public Health Service, Program Director at the FDA’s CDER Small Business and Industry Assistance Program, Division of Drug Information

We may think of the pharmaceutical industry in terms of giant corporations, but the fact is that there are hundreds of small firms – with very few employees – that are developing many of the important drugs that we use every day. FDA defines a small business as one with fewer than 500 employees (including employees of affiliates), but many are much smaller.

Industry sources indicate that, over the past decade or so, more than half of the novel drugs (i.e., those not previously marketed in the United States) developed in this country and approved by FDA, have been developed by small companies. Small companies also impact the generic drug industry creating market choice, competition, and increased access. According to FDA data, of the 2,176 new and generic drug applications submitted to the agency in 2014-2015, at least 639, or about 29 percent, were submitted by firms with fewer than 500 employees.

Small companies have certain advantages. They can be nimble with decision-making and can quickly progress with new ideas. A smaller drug development pipeline allows them to focus on a single or few products. But they also have unique challenges. A small workforce tends to require employees to wear multiple hats, as opposed to their larger counterparts who typically employ teams of specialists. And because many small companies are focused on developing one drug at a time, they often operate on a “high reward-high risk” model. There is a smaller margin for error for a small company that has invested all its resources in developing one drug than for a large company that is able to spread its risk across several products it is developing simultaneously.

Renu Lal

Renu Lal, Pharm.D., pharmacist at FDA’s Division of Drug Information, CDER Small Business and Industry Assistance Program

For many years, to help level the playing field, FDA has been assisting small pharmaceutical companies to maximize their opportunities for success. The Generic Drug Forum on April 4-5, 2017, is one example of the work we do to support small businesses. Organized by FDA’s Center for Drug Evaluation and Research Small Business and Industry Assistance (SBIA) staff, representatives from a wide range of pharmaceutical companies will gather to learn about the development, testing, review, and approval of generic drugs. CDER SBIA holds at least four meetings a year as part of a series called the Regulatory Education for Industry (REdI) conferences.

REdI conferences typically attract significant international attendance (in-person or via webcast). This global reach is important, as about 80 percent of active pharmaceutical ingredients used in U.S-manufactured drugs come from more than 150 different countries. The map below shows the geographic distribution of our most recent REdI conference registrants. Thirty percent of registrants were from outside the U.S., representing 55 countries worldwide.

CDER SBIA Conference Map

International participation at CDER SBIA REdI Conference [September 2016]

Many of these companies have never submitted an application for approval to FDA. Whether new or experienced, many are very early in the drug development process. In CDER’s SBIA program, 43 percent of the companies we work with have fewer than 100 employees, and 17 percent have fewer than 10 employees.

Although the mission of CDER SBIA is to help small business, our educational products are available to the entire pharmaceutical industry. In addition to REdI conferences, SBIA also offers webinars with live question and answer sessions by FDA subject matter experts on timely topics of interest to small companies.

SBIA recently held a half-day live webinar, which featured CDER experts from the Office of Pharmaceutical Quality (OPQ) discussing specific microbiology issues. CDER SBIA also provides a variety of helpful resources including a bimonthly electronic newsletter, CDER SBIA Chronicles, an audio podcast, CDERLearn, and online tutorials developed by CDER subject matter experts. We also interact with our constituents through our presentations and exhibits at conferences, and we are always available to help out via phone and e-mail. All slides, webcasts, and documents that we develop to help small companies are posted on the CDER SBIA Learn webpage after the event. REdI conferences and all other SBIA services are available at no cost to all who wish to attend and participate, which is particularly helpful to smaller companies with limited resources.

At a time when quality manufacturing and the safety and effectiveness of drugs in development is as important as ever, CDER understands that providing support to small businesses through education and resources is vital to advancing innovation and protecting public health.

Brenda Stodart, Pharm.D., Captain, United States Public Health Service, is a Program Director at FDA’s CDER Small Business and Industry Assistance Program, Division of Drug Information

Renu Lal, Pharm.D., is a pharmacist at FDA’s Division of Drug Information, CDER Small Business and Industry Assistance Program

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

By: Robert M. Califf, M.D.

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

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

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

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

Robert Califf

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

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

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

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

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

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

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

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

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

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

Better Tool to Help Assess LASIK Patients

By: Malvina Eydelman, MD

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

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

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

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

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

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

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

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

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

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

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

By: Robert M. Califf, M.D.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Combination Products Review Program: Progress and Potential

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

Nina Hunter

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

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

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

Robert Califf

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

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

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

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

Combination Products Review Table

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

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

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

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

Trade Alert: FDA Issues New Import Data Requirements

By: Howard Sklamberg, J.D.

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

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

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

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

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

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

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

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

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

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

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

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