Strengthening Partnerships: FDA’s China Office Engages in Key Outreach with Chinese Provincial FDA, Academia, and Industry

By: S. Leigh Verbois, Ph.D.

独木不成林,单弦不成音

Dú mù bù chéng lín, dān xián bù chéng yīn

‘A single tree makes no forest, one string makes no music.’

“A single tree makes no forest, one string makes no music.”This old Chinese proverb inspired FDA’s China Office, as members of our staff embarked on a five-day trip to meet with provincial FDA regulators, industry, and academia in China’s Yangtze River Delta region.

FDA Staff with Zhejiang FDA

FDA Staff Meets with Zhejiang FDA
Hangzhou, China
Front Row, Left to Right: Gang Wang (FDA China Office), Bo Ju (Zhejiang FDA), Yuanchang Shao (Zhejiang FDA), Leigh Verbois (FDA China Office), Jue Chen (Zhejiang FDA), Chiang Syin (FDA China Office), William Sutton (CDRH),
Back Row, Left to Right: Jinfeng Liang (Zhejiang FDA), Wenhua Zheng (Zhejiang FDA), Yini Ye (Zhejiang FDA), Lixin Shen (Zhejiang FDA), Nicole Taylor Smith (FDA China Office), Lixia Wang (FDA China Office)

The Yangtze River Delta region is an economic area that encompasses the Shanghai municipality, Zhejiang and Jiangsu provinces. The commercial epicenter, which accounts for 20 percent of China’s gross domestic product, is home to a significant number of FDA-regulated medical product manufacturers.

We traveled more than 3,300 kilometers (1,980 miles) to meet with key leaders and experts to strengthen partnerships, share information, and build the foundation for future cooperative engagement. Our first stop was Shanghai, where I had the great fortune to be able to address hundreds of students and faculty at East China University of Science and Technology’s School of Pharmacy and China Pharmaceutical University.

My message to the students was that they are the future leaders who will be in charge of the next generation of pharmaceutical innovation and data integrity.

In Shanghai, we also had the opportunity to sit down with U.S. Embassy Consul General Hanscom Smith to compare notes and to talk about current FDA priorities underway in the region.

China Pharmaceutical University (CPU)

China Pharmaceutical University (CPU)
Nanjing, China
CPU Faculty and Students attending Dr. Leigh Verbois’s Presentation on “CDER’s Novel Drug Approvals and Priorities”

The team then rode a high speed bullet train to Nanjing to meet with Jiangsu FDA, the regional regulator. This type of information sharing between the provincial FDA and the FDA China Office supports our shared mission of assuring that medical products produced in China meet U.S. safety standards.

On day three, we traveled again by bullet train to Suzhou where we partnered with China’s Association for Medical Device Industry to hold a two-hour, town hall meeting with almost 200 of China’s big device manufacturers that export products to the United States.

Working with FDA’s Center for Devices and Radiological Health (CDRH), our team provided information on Unique Device Identification (UDI) requirements. In the greater China region, it is estimated that there are nearly 4,000 medical device establishments affected by these requirements.

Hangzhou, China

Hangzhou, China
One of the many bridges in Hangzhou to symbolize “Building Bridges” between the FDA China Office and our Chinese stakeholders

The next morning, we headed for Hangzhou. After about two hours by train, we arrived in Hangzhou ready to meet with provincial FDA officials. Our meeting focused on specific ways we could collaborate on future medical device and drugs outreach, and more effectively share information.

The final day of our weeklong journey started with an industry roundtable focused on pharmaceuticals, held in partnership with Zhejiang FDA. As fellow regulators, we joined together to engage in substantive discussion with representatives from major manufacturers located in the Zhejiang, Jiangsu, and Shanghai regions, many of whom were interested in recent data integrity efforts in China. The FDA team then boarded our last train back to Shanghai for a final meeting with local officials that focused on our mutual priorities, as well as ways to expand and leverage efforts going forward.

The team flew back to Beijing feeling very satisfied that we accomplished much and clearer than ever that continued collaboration with Chinese regulators, industry and academia will help to ensure that medical products manufactured for the U.S. market are safe and effective. After all, one tree alone does not make a whole forest.

Leigh Verbois, Ph.D., is Director of FDA’s China Office in the Office of International Programs

What We Mean When We Talk About EvGen Part I: Laying the Foundation for a National System for Evidence Generation

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

Rachel Sherman

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

Across the clinical research enterprise, there is a growing awareness of serious shortfalls in the current paradigm of generating the scientific evidence that supports medical product evaluation and clinical care decisions and the need to modernize methods and expectations surrounding this evidence base.

We know, for instance, that most clinical practice guideline recommendations are not based on high-quality evidence, typically derived from appropriately designed randomized controlled trials. We also know that adherence to standards supported by such high-quality evidence results in better outcomes for patients.

There is reason to believe that we’ve arrived at a tipping point where previously separate, “siloed” efforts can be linked to create a national system for evidence generation (EvGen). In this first of a series of posts, we’ll take a look at the elements required to build such a national system, beginning with a pair of foundational concepts—interoperability and connectivity.

Interoperability

Robert Califf

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

Put simply, interoperability is the idea that different systems used by different groups of people can be used for a common purpose because those systems share standards and approaches. To take one example: modern train tracks employ agreed-upon standards in terms of track gauge and other specifications so that many different kinds of vehicles can safely use the rail system.

In similar fashion, a national system for evidence generation that applied common data standards and definitions could “lay the track” for significant improvements in the exchange of biomedical data. Patients, consumers, professional groups, payers, the medical products industry, and health systems all stand to benefit from potential gains in efficiency and reductions in cost that would accompany standardized approaches to data collection, curation, and sharing, once up-front investments are absorbed. Then, with these standards in place, effort could be devoted to generating actionable knowledge rather than simply managing data.

Connectivity

Establishing interoperable systems is a critical step in building a national system for evidence generation. An equally important step is to enable collaboration among the many groups that generate data, for example patients, clinicians, hospital systems, health insurance organizations. Evidence is derived from high-quality data that often originates from many different sources or settings. We can create an interconnected environment that leverages all the available data to provide answers to important public health questions. A defining characteristic of such a network is the ability to leverage all available data for different tasks as needed, allowing the network to integrate complex relationships between data input and output. Coupled with interoperable standards, a national system for evidence generation based on these principles will be capable of generating very large quantities of data and enabling those data to flow among system components.

The result? Researchers will be able to distill the data into actionable evidence that can ultimately guide clinical, regulatory, and personal decision-making about health and health care.

These two core constructs represent the essential scaffolding that must be developed and put in place to support a national system for evidence generation. In our next posting, we’ll examine ways we can begin building and continuously improving such a system for the benefit of all stakeholders.

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

Engagement and Collaborative Problem Solving: Two Ingredients for FSMA Success

By: Michael R. Taylor and Stephen Ostroff

As we’ve developed the rules needed to implement the FDA Food Safety Modernization Act, we’ve done a great deal of outreach to explain the new requirements and obtain feedback from stakeholders.

group touring Florida citrus grove

Tim Dooley (top of photo, center right), vice president of Blue Goose Growers in Fort Pierce, Florida, leads a tour of the company’s citrus groves.

We’ve got to continue doing this with the people working on the nation’s farms–since the produce safety rule issued in late 2015 primarily involves them.

This was a lesson learned in our recent trip to southern Florida, where we toured citrus farmlands and took part in a public meeting on the final FSMA rules at the University of Florida’s Institute of Food and Agricultural Sciences (UF/IFAS). We found that growers want to meet the new standards in the produce safety rule but need greater clarity and understanding about how the rule can be applied to their specific farm setting.

Florida farmers are under a lot of pressure that has nothing to do with the FSMA rules. The citrus groves there have been hard hit in recent years by a disease called citrus greening that results in stunted, bitter, green fruit and drastically reduced harvests. The stark backdrop to our conversations is that these growers are fighting for survival–and every cost counts.

That makes it especially important that they, and all farmers covered by the produce rule, understand what will be required. And, just as important, what won’t be required.

For example, we talked to growers who have dozens of wells on their farms and are worried about the rule’s water testing requirements and associated costs. But in many cases, only a fraction of those wells are used to apply water in a way that is intended or likely to contact crops during growing, or for other uses that are  subject to the microbial water quality criteria in the produce rule.

Some growers pull surface water out of extensive canal systems where the water from any one canal may deliver water to many farmers. Other growers use seep irrigation systems in which the water seeps from a surface water source through the soil. The growers told us that the soil filters the water, which comes in contact with root vegetables like carrots, beets and radishes.

Their questions were: How are we covered by the produce safety rule and how do we achieve compliance? One of the growers produces beets and our answer to him was that beets are not covered because the produce rule exempts specific crops that FDA identified as rarely consumed raw, such as garden beets and sugar beets. We explained that water used in seep irrigation that contacts root crops covered by the rule does have to meet the applicable microbial standard. But farms have the option of establishing and using alternatives for certain agricultural water requirements if they have scientific evidence to support them.

Each region of the country has its own complexities, and Florida has a dramatically diverse landscape of crops, settings, and soils. The soil around Lake Okeechobee transitions from sandy at one end to densely dark muck at the other. Within the citrus industry, agricultural water can come from completely different sources, surface and ground water that have different testing requirements. We at FDA are constantly learning about the complexities that are part of everyday life for our nation’s food producers.

This trip highlighted how important it will be for us to be continually engaged at the local, state and federal levels in collaborative problem solving with growers and others in the food industry as we implement the FSMA rules.

We value the leadership of Florida Commissioner of Agriculture Adam Putnam, Deputy Commissioner Lisa Conti and others on their team. We have long been partners with Martha Roberts of UF/IFAS, an authority on food safety issues. And Florida itself is a pioneer in food safety, in 2008 establishing the first mandatory state regulatory program for produce with provisions for inspections and audits for tomato handling, production and packing.

Susan Turcovski, the director of FDA’s Florida District, and her team accompanied us on this visit. They are also on the front lines of implementation and their role will be critical in the months and years ahead. We were joined by Leanne Skelton, the U.S. Department of Agriculture’s liaison to FDA on FSMA issues, and spent time at USDA’s Horticultural Research Lab in Fort Pierce.

Education is an important part of our FSMA efforts. Another member of our group was Dr. Michelle Danyluk, one of the leads for the Southern Training, Education, Extension, Outreach, and Technical Assistance Center at the University of Florida. The center is one of four regional centers funded by USDA and FDA that will coordinate and implement FSMA-related training.

We’ve got our work cut out for us but every conversation brings us closer to the food safety system envisioned by FSMA that systematically takes steps to prevent the causes of foodborne illness. Working together, we’ll get there.

Michael R. Taylor is FDA’s Deputy Commissioner for Foods and Veterinary Medicine; Stephen Ostroff, M.D., formerly FDA’s Acting Commissioner, will be succeeding Mr. Taylor as Deputy Commissioner on June 1, 2016.

2015: An Important Year for Advancing Generic Drugs at FDA

By: Kathleen “Cook” Uhl, M.D.

Generic drugs allow greater access to health care for all Americans.

At FDA’s Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research, 2015 was an important year. It was our first full year of operation after vastly expanding our office’s scope and structure. This change allowed for the office to have greater prominence and allowed for additional staff to handle a growing workload and enhance our ability to advance the safety and availability of generic drugs in the U.S.

Kathleen "Cook" UhlConsider this: In 2014, generics saved the U.S. health system an estimated $254 billion – and FDA continues to work hard to advance the use of generic drugs to help improve public health.

Our increased capacity and expansion came at a critical time. In 2012, a new law called the Generic Drug User Fee Act (GDUFA) authorized additional funds for FDA for the review of generic drug applications, inspection of facilities and other regulatory actions. But with those additional funds came an FDA commitment to reach a variety of goals. These goals were articulated in a document that accompanied the GDUFA legislation, which was negotiated between FDA and industry and enacted by Congress. The additional funds help FDA efficiently handle thousands of applications for new generic products and reduce the time needed to review generic medications for approval.

We’re on track for meeting all of those goals. Today, to help the public understand our progress, OGD released our first annual report. It’s filled with detailed accounts of our work, which seeks to improve the generic drug program with more efficient reviews of applications, and by developing the science needed to help the generic drug industry demonstrate that their products are as safe and effective as their brand-name counterparts.

Among the highlights, the report notes that 2015 marked the highest number of generic drug approvals and tentative approvals ever awarded by FDA – more than 700 in all. Last year, in December, we granted the highest number of approvals and tentative approvals in a single month (99) since the generic drug program began.

Another major commitment of GDUFA was to take a first action, by 2017, on 90 percent of the “backlog,” those applications pending prior to GDUFA as of October 1, 2012. We had 2,866 abbreviated new drug applications (ANDAs) and 1,873 prior approval supplements (PASs), but by the end of 2015, we completed first actions on 84% of ANDAs and 88% of PASs – already close to the 90% goals set for 2017! We also approved 90 “first generics,” meaning that in 2015 we added a new cost-saving generic alternative for 90 brand name drugs.

Despite our progress, we have a lot more work to do. But we don’t expect to do it entirely on our own. Achieving goals that work for the public requires input from the public, including industry, the research community, lawmakers and other stakeholders.

As part of our effort to align with stakeholders’ visions, we’re holding a public meeting on May 20 to solicit valuable feedback on our regulatory science initiatives and help us chart directions forward. We invite all to attend and to contribute by providing your thoughts and ideas to our public docket.

We encourage you to read our annual report and to participate in our annual meeting. With our ongoing efforts and strong public input, we are confident that 2016 and beyond will be as successful as 2015.

Kathleen “Cook” Uhl, M.D., is FDA’s Director, Office of Generic Drugs in the Center for Drug Evaluation and Research

Developing a Consensus Voice: The Combination Products Policy Council

By: Nina L. Hunter, Ph.D., and Rachel E. Sherman, M.D., M.P.H.

We recently announced the launch of lean process mapping to build a better system for combination products review – one that is more cohesive, more collaborative, more systematic, and more predictable. We look forward to providing an update on this effort soon.

Nina Hunter

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

In the meantime, we’re delighted to announce the creation of FDA’s first Combination Products Policy Council. Building on successful cross-cutting efforts such as the Biosimilars Implementation Committee and the Medical Policy Counsel in the Center for Drug Evaluation and Research (CDER), the Council will be a senior-level, agency-wide forum for discussing, resolving, and implementing product and policy issues. Because of the multiple FDA organizations involved, this council will have decisional authority on issues relating to combination products, cross-labeled products, and medical product classification.

The different parts of a combination product and the different product types labeled for use together in premarket applications for combination products and cross-labeled products can create complexities for reviewers and require expertise from multiple centers.

Rachel Sherman

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

Currently, the lead center manages the review process using procedures associated with the center-specific application type and user fee goal dates. But differences in statutory and regulatory requirements for different application types, including evidentiary standards, data requirements, and review limitations, make it challenging to coordinate reviews and ensure alignment and consistency in addressing issues across centers.

In response to these complexities, we are creating a key component in the Office of the Commissioner that can convene parties across centers, foster understanding and consistent application of requirements, and develop a unified FDA position on issues that arise. Although this process will not replace the existing formal appeal process, we anticipate that many issues can be resolved before reaching that stage.

Council Mission

  • Modernize the inter-center consultation process and related aspects of combination product and cross-labeled product review;
  • Promote development of innovative, safe, and effective combination products and cross-labeled products; and
  • Promote alignment in addressing challenging medical product classification issues.

The Council will be composed of representatives from relevant centers and offices. In addition, experts from within centers and other FDA offices will provide expertise as needed for specific policy topics under consideration.

In addition to serving as a communications hub, the Council will be involved in the development of agency-wide and external communications such as draft guidances, publications, and blog posts on policy decisions. FDA envisions a variety of topics may be relevant for consideration by the Council, including such “front-burner” items as product jurisdiction and designation practices, application of evidentiary standards for clearance/approval to combination products and cross-labeled products, and regulation of novel products.

We’ve heard that many stakeholders desire a voice in modernizing the combination review program, and we’re listening! In addition to the topics listed above, one of the Council’s priorities will be to consider how best to seek input from external stakeholders on various issues. We would hope that such comments include policy issues recommended for discussion and recommendations on how the policy issue could be addressed or implemented.

We are confident that the Council’s efforts will ensure transparency and consistency in our approach to combination product policy development and implementation, ultimately helping to ensure that innovative combination products marketed to the American people are safe, effective, and appropriately labeled. We look forward to providing updates about the Council, as well as additional modernization efforts in this important area.

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

Rachel E. Sherman, M.D., M.P.H., is FDA’s Associate Deputy Commissioner in the Office of Medical Products and Tobacco and the Chairperson of the Council

FDA-State Partnership Propels FSMA Implementation

By: Michael R. Taylor and Stephen Ostroff, M.D.

Ever since the FDA Food Safety Modernization Act (FSMA) was enacted in 2011, we’ve said that successful implementation is not possible without a meaningful partnership between FDA and its counterparts in state government. This is especially critical in the new area of produce safety regulation.

Michael R. Taylor

Michael R. Taylor, FDA’s Deputy Commissioner for Foods and Veterinary Medicine

After years of rulemaking – of planning, discussing and revising – this partnership is no longer just an aspiration. Instead, it’s evolving into a real union of public health and regulatory colleagues at the state and federal levels who together are taking concrete steps to make the produce safety protections envisioned by FSMA a reality.

An example of this forward movement is a conference we both attended on March 22 in Orlando, Florida, where the National Association of State Departments of Agriculture (NASDA) unveiled its proposed framework for state participation in the implementation of FDA’s new produce safety rule. This rule—for the first time—establishes enforceable federal safety standards for the production and harvesting of produce on farms.

In 2014, FDA entered into a five-year cooperative agreement with NASDA to work with state partners to collaboratively plan implementation of the produce rule. The NASDA framework will help guide and inform states that are working to develop a state produce safety regulatory program that is aligned with the FSMA rule.

The NASDA framework was developed with the active involvement of 24 state departments of agriculture and five national public health organizations. Key areas addressed include education and compliance, information sharing, regulator training, accessing laboratory resources, technical assistance, and infrastructure.

Stephen Ostroff, M.D.

Stephen Ostroff, M.D., formerly FDA’s Acting Commissioner, will be succeeding Mr. Taylor as Deputy Commissioner on June 1

All 50 states were represented at the Orlando meeting to review and discuss the proposed framework, which is intended by NASDA to be a living document that can be refined and improved over time as experience is gained with implementation of the produce safety rule. The level of alignment and energy among participants at the conference – which included 46 agriculture departments and 19 public health departments – was inspiring and demonstrates that we are very much on the right path toward a sustained partnership with our state colleagues.

The states have always been clear in conversations with us, and we have been clear in conversations with Congress, that federal funding is necessary for the work ahead. State agriculture and public health personnel are the ones who have built relationships with and knowledge of local farming communities and practices and can often deliver oversight most efficiently. But almost all states will have to build produce safety programs largely or completely from scratch. We want to rely on them, not only to deliver education and technical assistance, but also to provide ongoing compliance support and oversight.

But this requires resources.

The President’s Fiscal Year 2017 budget request includes $11.3 million in new funds for the National Integrated Food Safety System. We have been building this system to fully integrate the more than 3,000 state, local and tribal government agencies involved in food safety in FDA’s work to meet the FSMA mandate. The FY 2017 funding, which Congress is considering, will be used primarily to support state produce safety programs through cooperative agreements and grants.

The FY 2017 funding builds upon resources for states that Congress provided for FSMA implementation in FY 2016. Earlier this month we took an important step toward distributing these funds – $19 million – to support state produce safety programs by soliciting applications for cooperative agreements with state regulatory agencies. These funds will make an important down payment on the capacity states need to be our full FSMA partners in produce safety. The FY 2017 funding request recognizes that more will be needed – both next year and beyond — to realize this goal.

There is a great diversity in where states are right now in planning and developing their produce safety programs. Some may already have developed multi-tiered plans and are ready to begin implementing. Others may just be starting to consider what’s ahead. This program is designed to give states the support they need at whatever stage they’re in.

Our goal is to get the initial funding to a number of states before the end of this fiscal year.

This has been a long road. But we are gaining real momentum toward the ultimate goal of having a food safety system in place in which government agencies at all levels are working in partnership with each other – and collaboratively with farmers – to ensure that we are doing everything we can to prevent or reduce the risk of foodborne illness. Safe and widely available produce is good for consumers, good for public health, and good for growers. That’s why we’re all in this together.

Michael R. Taylor is FDA’s Deputy Commissioner for Foods and Veterinary Medicine; Stephen Ostroff, M.D., formerly FDA’s Acting Commissioner, will be succeeding Mr. Taylor as Deputy Commissioner on June 1.

Priorities – Teamwork to Achieve Common Goals

By: Robert M. Califf, M.D.

With my appointment as Commissioner of Food and Drugs comes a rare and humbling opportunity—to make a positive difference at an institution that does vitally important work for the nation and its citizens. During my vetting process I received hundreds of emails and had almost as many conversations with a large and diverse group of stakeholders. Over the course of these discussions, a recurring theme emerged: namely, that setting priorities would be critical to success.

Robert M. Califf, M.D., Commissioner of the U.S. Food and Drug AdministrationThis is hardly surprising. FDA regulates about 20 percent of the nation’s economy and, given the vast number of options, it would be easy to get lost in an overwhelming swirl of activity. In fact, at times I have been (rightfully) accused of having an excessively lengthy to-do list! But my interactions with so many of the knowledgeable, dedicated, and mission-driven people here at FDA have helped foster a clear, realistic, and focused sense of priorities and have further heightened an already strong enthusiasm for helping this awesome organization reach these ambitious goals.

FDA makes decisions in a remarkably effective and responsible way. Guided by the lodestone of our mission to protect and promote the public health, and supported by the concerted efforts of dedicated and talented professionals who examine issues within team-based systems, FDA’s Centers that form the core of our organization are able to make an enormous number of decisions every day. The vast majority of these decisions, many of which are vital to the well-being of all Americans, are made possible by a system sustained by professionalism and a well-earned reputation for high-quality and impartial judgments—despite the fact that many decisions must ultimately disappoint (or at least not fully satisfy) one or more constituencies.

I strongly believe my most important responsibility during my time at FDA is to encourage and support a professional environment that enables our remarkably dedicated workforce to thrive and to reach its fullest potential. Dramatic advances in biotechnology and information sciences, as well as continuously accelerating trends toward globalization, are ushering in an era of rapid change. But amid this change, the key to success for the Agency in accomplishing its mission remains constant—sustaining and expanding our talented workforce and ensuring that we both hire the people we need for the future while we continue to enhance our environment to ensure that we retain existing staff. To that end, I will pursue a workforce initiative designed to 1) improve the hiring system, 2) ensure that the Agency has the best possible working conditions for staff, and 3) foster professional homes for the diverse professions that make up our teams so that we are able to recruit and retain them in a very competitive market.

My top programmatic priority will likely come as no surprise, given the astonishing changes that are currently rippling through society: we must do everything possible to rapidly adapt our national and global systems of evidence generation to meet the challenges and opportunities presented by technological advances. What does this mean? I’ve noticed that when high-quality evidence is available, FDA’s scientific decision making is often straightforward. But it can be particularly challenging for the Agency when it must make scientific decisions in the absence of optimal information. In such cases, opinions may carry greater weight, and there can be an increased likelihood of dissension both inside and outside of FDA, as well as a greater risk that we may fail to most fully protect or advance the welfare of patients and the public.

FDA is a science-based, science-led organization that focuses on the needs of patients and consumers; protecting their well-being is our charge as a public health agency. The state of the art as it pertains to understanding the needs and choices of patients and the public is progressing rapidly, and we must continue to keep pace by incorporating the best methods for taking patient preferences, experiences, and outcomes into account in every part of our work.

Biomedical science is nearing a tipping point where the amount of high-quality evidence available to support our decisions is likely to increase exponentially. As a nation, we have invested over $50 billion to provide an electronic health record (EHR) for almost every American. Further, computational storage capacity and analytical power are increasing by orders of magnitude from year to year. At the same time, the advent and wide diffusion of social media are enabling direct communication with patients and consumers on an unprecedented scale. When projects such as Sentinel and the National Medical Device Evaluation System are linked with the many complementary initiatives under way at our sister agencies and at organizations outside of the government, we can (and I believe in short order will!) build a robust foundation for a system in which both private and public sectors can produce much more useful knowledge at a fraction of the cost such efforts have previously required. Indeed, a major function of FDA is to support the continued development of an effective system for evidence generation, so that the private and academic sectors can make it happen.

Accordingly, FDA is thoroughly committed to working with the many partners in our ecosystem to help build and sustain an infrastructure that produces the high-quality scientific evidence needed to guide FDA’s decisions about the drugs, medical devices, tobacco products, and food products it’s charged with regulating, as well as the decisions that healthcare providers, patients, and consumers make about their health and well-being.

In addition to this overarching priority, a number of specific critical issues are on my front burner this morning and will remain there for the foreseeable future:

  • Pain. The present epidemic of opioid overdose deaths now exceeds deaths from automobile crashes. FDA cannot solve this problem on its own—and indeed, no single entity can—but we have a critical role to play, as described in our FDA Opioids Action Plan.
  • Tobacco product deeming. Much effort has gone into developing the framework for the approach to the regulation of the broad array of tobacco products. FDA is working hard to finalize the deeming rule, which in its proposed form would extend FDA regulation over virtually all tobacco products, including electronic cigarettes, either all cigars or all but premium cigars, pipe tobacco, certain dissolvables that are not “smokeless tobacco,” gels, and waterpipe tobacco.
  • Implementation of the FDA Food Safety Modernization Act (FSMA). This statutory directive to transform the food safety system is well on its way to being implemented, with critical regulations issued and more to come. The effort involves the complex development of a new control and risk-based system that includes the entire chain of food safety. Effective implementation of this system will require the application of cutting-edge analytical and biological science, as well as the most modern approaches to human systems management.
  • Antimicrobial resistance. Concerns about the proliferation of multidrug-resistant pathogens, as well as the sustainability of the product pipeline needed to meet this threat, continue to grow. We have a major responsibility in the federal plan, one that will involve many parts of the Agency and require that we work with the broad ecosystem, both to ensure that appropriate antimicrobials are used appropriately on farms, and that novel antimicrobials are developed, approved, and used responsibly within a framework of effective stewardship.
  • Interagency effectiveness. When we consider our mission to protect and advance the public health, as well as our duty to balance benefit and risk for patients and consumers of medical products, much of our success can be enhanced by coordinated effort across government. We have therefore continued the FDA-NIH Joint Leadership Council and the FDA-CDC meetings, and also initiated similar discussions with CMS. The Biomarkers, Endpoints and other Tools (BEST) Resource offers a powerful example of the ability of FDA and NIH to contribute to solving scientific and regulatory issues together.
  • Precision Medicine. President Obama’s Precision Medicine Initiative represents more than just a project. Rather, it is a window that provides a clear view of the future for biomedicine and agriculture, a future in which powerful new technologies and methods allow the precise targeting of interventions using an array of genetic, genomic, biological, clinical, social, and environmental data according to the scale needed to achieve improved health outcomes.
  • Cross-Cutting Issues. There are a great many other issues (truthfully, the number reaches triple digits) on my list of concerns. But those issues that cut across the Agency, including optimizing our approach to combination products, medical countermeasures, and improving product labeling, will benefit most from my attention and support.

A single introductory blog post is not suited for giving details about priorities or individual programs. However, I hope I’ve conveyed my enthusiasm for the work at hand, as well as my confidence that we will be able to make real and lasting improvements in many critical areas. I promise that we will follow up with frequent updates, as fostering effective communication is itself an overarching priority of immense importance to me. So expect to hear from me again soon!

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

Addressing Issues Relating to Combination Products: Human Factors

By: Jill Hartzler Warner, J.D., and Thinh Nguyen

Combination products represent an important and growing category of therapeutic and diagnostic products under the FDA’s regulatory authority. These products, which combine a drug, device, and/or biological product (referred to as “constituent parts”) with one another, do not fit into traditional categories for medical products.

Jill Warner

Jill Hartzler Warner, J.D., FDA’s Associate Commissioner for Special Medical Programs.

Combination products come in three basic configurations: their constituent parts may be physically or chemically combined; they may be co-packaged; or they may be separately distributed with specific labeling that provides instructions for their combined use.

The different constituent parts of a combination product can add complexity to the final product. For example, when a medical device is part of the combination product, issues that relate to how the product is used can be as important as the product itself.

Human factors engineering, and the closely related field of usability engineering, both study how people interact with technology, to understand how the design of user interfaces for technology affects the quality, experience, and outcomes of that interaction. The questions addressed by human factors studies overlap with those addressed by “medication error” assessments, another area of user-product interaction evaluation commonly applied to drugs. The understanding gained from these evaluations can be applied to the design and review of the user interfaces for FDA-regulated products to assure their safety and effectiveness.

Thinh Nguyen

Thinh Nguyen, FDA’s Director, Office of Combination Products

Because the design of a combination product can have a significant impact on whether a given product is safe and effective for its intended use, human factors evaluations are a central consideration for FDA when it assesses combination products, particularly those that include certain devices.

In February 2016, FDA published draft guidance for industry and FDA staff titled “Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development.” This draft guidance builds on principles articulated in earlier guidances that discuss human factors and medication error considerations for medical devices and drugs. When final, it will represent FDA’s thinking on when and how combination product manufacturers should perform human factors evaluations for investigational or marketing applications.

The draft guidance provides examples of combination products that include devices and describes recommendations for how to approach human factors studies for them, focusing on key challenges for developers such as:

  • The timing and sequencing of human factors studies in relation to overall development and study of a combination product;
  • How human factors studies compare with and relate to other types of clinical studies;
  • When changes to a combination product call for new human factors studies to be performed;
  • The role of simulated-use versus actual-use human factors studies; and
  • What information should be provided to the FDA, and when, to ensure timely feedback for a human factors study.

During the comment period on the draft guidance, FDA is seeking input on the overall guidance, as well as requesting that stakeholders submit examples of combination products in their comments and address whether they believe human factors studies are needed for them. The Agency is also seeking input on what challenges and development risks may arise if such studies are conducted before, in parallel to, or after major clinical studies for combination products. Input from stakeholders will help inform FDA’s final guidance in this important area. The comment period for this draft guidance closes on May 3, 2016.

Watch for more to come from FDA this year to further enhance transparency and predictability of combination products regulation. We are developing additional guidance for combination products, including current good manufacturing practices and a final rule on postmarket safety reporting. We also welcome your feedback regarding topics related to combination products that you would like us to address.

Jill Hartzler Warner, J.D., is FDA’s Associate Commissioner for Special Medical Programs

Thinh Nguyen is FDA’s Director, Office of Combination Products

Border Crossings: Working With Partners to Verify the Safety of Imported Produce

By: Michael R. Taylor

One of the vivid images that sticks with me from my tenure at FDA is of the port of entry at Nogales, Arizona. There, I saw large trucks from Mexico lined up as far as the eye could see, awaiting entry into the United States‎, many loaded full with fresh produce. I was told by our FDA team that, during the busy season, as many as 1,500 produce trucks enter the United States there daily, and Nogales isn’t even the busiest port of entry on the 2,000-mile U.S.-Mexico border.

Michael R. TaylorThat visit to Nogales was in the early phase of our food safety modernization initiative at FDA‎, but it had a lasting effect on me. It drove home the degree of difficulty we would face in fulfilling the produce safety vision embodied in the FDA Food Safety Modernization Act (FSMA).

With 50 percent of our fresh fruit and 20 percent of our vegetables coming from growers in other countries, the challenge was not only to establish produce safety rules that would be effective and workable across the hugely diverse produce sector, but also to verify with reasonable confidence that those standards are being met consistently, every day, regardless of where the produce is grown.

‎The FSMA produce ‎safety rule is now on the books, but implementation and the task of achieving and verifying compliance is just getting started. We know that success will take an enormous amount of education, training, and technical assistance to support the vast majority of farmers who will want to comply.

It will take a concerted effort by government and industry alike to verify that compliance is happening. And all of that demands active public-private collaboration and partnership to meet high consumer expectations.

‎‎Within the United States, this means working with our state government partners to build state produce safety programs that will provide our primary interface with U.S. growers on all aspects of produce safety. We will also work with growers and their customers to strengthen the reliability of private audits as a source of verification that can complement, but never replace, the essential role of government inspection.

‎But what about those 1,500 truckloads coming into Nogales daily from Mexican farms? How do we verify their compliance?

‎The answer is this: only by using every tool in our import tool kit‎, and, of course, by building partnerships.

‎I’m writing this while en route to Tubac, Arizona, for the annual Spring Policy Summit of the Fresh Produce Association of the Americas (FPAA). FPAA represents those producing and trading fresh produce across the U.S.-Mexico border. For good business reasons, FPAA and its members focus heavily on ensuring the safety of that huge volume of food.

At this meeting, my colleagues and I will be discussing implementation of the foreign supplier verification program (FSVP) final rule, which places new responsibility on importers to ensure the safety of the food they import. This responsibility includes ensuring and verifying that their foreign suppliers use processes and procedures that meet U.S. safety standards. The result is that importers’ private verification efforts will help ensure the public health. At the same time, they are accountable to FDA.

FSVP is the regulatory linchpin of FSMA’s historic paradigm‎ shift for imported food from reaction at the border to accountability for prevention at the point of production. But Congress recognized that FSVP alone is not enough. FSMA also mandates that FDA conduct more foreign inspections and work more closely with foreign governments to ensure the safety of imported food.

‎So‎ also gathering in Tubac are our regulatory colleagues from the two Mexican agencies responsible for produce safety on the farm (SENASICA) and after the produce leaves the farm (COFEPRIS).

In 2014, we formed the US -Mexico Produce Safety Partnership, through which we are collaborating with our Mexican colleagues – much the way we do with our state partners – on education and technical assistance, inspection and compliance, and response to outbreaks. We’ll be reviewing our progress and discussing our challenges in a partnership working group meeting and sharing our government perspectives with FPAA, which has formed its own working group to collaborate with the government effort.‎

‎This degree of collaboration on food safety is unprecedented‎. But it is necessary because neither government nor industry alone can provide the level of verification FSMA envisions and consumers demand.

And it is possible because of the deep alignment of strategic interests ‎on food safety that exists among industry, government and consumers. We all have a huge stake in seeing that modern preventive practices are being used consistently to make produce safe. That is the foundation for real partnership. We all have different roles to play, but we all have the same goal.

‎That’s why we are gathering in Tubac. And, that’s why I’ll be traveling to Mexico City in April with Dr. Stephen Ostroff, my successor at FDA when I leave the agency in June, to work with our Mexican colleagues and the Mexican industry on FSMA implementation. That’s why we’re holding a public meeting in Washington today to discuss import safety with consumer, industry, and foreign stakeholders.

‎And it’s why hundreds of my FDA colleagues are working tirelessly with partners across the food system to prepare for FSMA implementation. I’m grateful for the opportunity I’ve had to work with so many people dedicated to food safety.  I think we are all fortunate that Steve Ostroff and other leaders across the food system have their hands on the helm.

And I am confident that we are on the way to success in fulfilling the FSMA vision, from the farms of Vermont and California to that line of trucks at Nogales.

Michael R. Taylor is FDA’s Deputy Commissioner for Foods and Veterinary Medicine

FDA and NIH Release a Draft Clinical Trial Protocol Template for Public Comment

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

Enhancing important efforts around clinical trials continues to be a key scientific priority. Another way we can encourage clinical trials is to look for ways to help clinical investigators make clinical trials more efficient, potentially saving development time and money. Today we’re announcing a draft clinical trial protocol template developed by the Food and Drug Administration (FDA) and National Institutes of Health (NIH) that should help with that.

Peter MarksThe clinical trial protocol is a critical component of any medical product development program. It’s defined in the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practice: Consolidated Guidance, as describing “the objective(s), design, methodology, statistical considerations, and organization of a trial…[and] usually also gives the background and rationale for the trial”. Similarly, for medical devices, some direction has been provided in the International Organization for Standardization (ISO) Clinical Investigation of Medical Devices for Human Subjects — Good Clinical Practice (ISO 14155:2011). Although guidance provides information on the important content that should be included in a protocol to help ensure human subject protection and data quality, it does not describe a standardized format for presenting this information. Time spent identifying the specific elements that should be included in a protocol and how best to organize them can delay the start of a clinical trial, and lead to delays in getting important new treatments to patients. What’s more, because up to 85% of investigators have only participated in one clinical trial in their careers, many investigators lack significant experience in protocol development. It’s likely that investigators could benefit from additional help in this area.

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, realized this represents an opportunity to help improve the design of clinical trials. Now, the NIH-FDA Joint Leadership Council (JLC) has launched a project to develop a template that could be used by investigators developing a clinical trial protocol.

Representatives from the NIH institutes and FDA’s medical product centers collaborated to develop a template containing instructional and sample text for investigators writing phase 2 or phase 3 clinical trial protocols that require investigational new drug (IND) or investigational device exemption (IDE) applications. Our agencies hope that the availability of the template and instructional information enables investigators to prepare protocols that are consistent and well organized, contain all the information necessary for the clinical trials to be properly reviewed, and follow the ICH E6 Good Clinical Practice guidance. Better organized, high-quality protocols will also expedite the review process at both agencies.

We are aware of other efforts in this area, including one undertaken by TransCelerate Biopharma Inc. (TransCelerate), which has issued a common protocol template intended to be the basis for a forthcoming electronic protocol. Although our initial target audiences differ, we plan to collaborate with groups like TransCelerate to help ensure consistency for the medical product development community.

We see the template as a way to facilitate creativity and innovation, not inhibit it. In the words of our NIH colleague Dr. Pamela McInnes, “Our goal is to provide an organized way for creative investigators to describe their plans so that others can understand them.” Just as ICH E6 allows considerable flexibility in the actual operations of trials using quality by design principles, the template includes the appropriate elements to be considered, but does not dictate exactly how the trial should be done—that is the work of the investigators.

NIH and FDA are seeking public comment on the draft template, which is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-043.html. Comments are accepted through April 17, 2016. We welcome feedback from investigators, investigator-sponsors, institutional review board members, and other stakeholders who are involved in protocol development and review. We are particularly interested in hearing your views on the utility of the template and whether the instructional and sample text is useful and clear.

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

More information can be found at:

NIH and FDA Request for Public Comment on Draft Clinical Trial Protocol Template for Phase 2 and 3 IND/IDE Studies

Clinical Research Policy

Clinical Trial Protocol Template