From Competition to Collaboration: precisionFDA Challenges

By: Taha Kass-Hout, M.D., M.S., Zivana Tezak, Ph.D., and Elaine Johanson

Next week, we will announce the winners of the first precisionFDA challenge.

Taha Kass-Hout

Taha A. Kass-Hout, M.D., M.S., FDA’s Chief Health Informatics Officer (CHIO) and Director of FDA’s Office of Health Informatics

We set up precisionFDA as an online, cloud-based, virtual research space to allow scientists from academia, industry, health care organizations, and government to work together on creating tools to evaluate a method of “reading” DNA known as next generation sequencing (or NGS). The ultimate goal of precisionFDA is to foster innovation and develop regulatory science around NGS tests, which are essential to achieving the promise of President Obama’s Precision Medicine Initiative. So far, the response to precisionFDA has been gratifying, with participants calling precisionFDA “refreshing”, “innovative,” and “a new paradigm in regulatory science.” The community currently boasts more than 1,500 users from 600 organizations, with more than 10 terabytes of genetic data stored.

To engage users and encourage sharing of data and ideas, precisionFDA has offered two competitions to date. These competitions are motivating community members to demonstrate the effectiveness of their tools, test the capabilities of the precisionFDA platform, and engage the community in discussions and data analysis that will provide new insights and serve as a comprehensive source of information about reference data and software pipelines used to analyze sequencing results.

Zevana Tezak

Zivana Tezak, Ph.D., Associate Director for Science and Technology at FDA’s Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health

The first precisionFDA challenge, the Consistency Challenge, closed in April 2015, with 21 entries from 17 submitters. Participants were given two datasets of whole genome sequences from a known human sample, sequenced at two different sites and generously donated to precisionFDA by Garvan Institute of Medical Research and Human Longevity, Inc. Challenge participants were instructed to use the informatics pipeline (software) of their choice to identify genetic variants and check for consistency between results in the provided datasets. The top performers will be announced in person by FDA Commissioner Robert Califf on May 25, 2016. At the time of his announcement, we will post detailed information here on all the recognitions and how the top performers were selected. So stay tuned!

The second challenge, the Truth Challenge, closes on May 26, 2016, and was designed in collaboration with the Genome in a Bottle consortium and the Global Alliance for Genomics and Health. Participants are expected to identify genetic variants in one known and one unknown sample dataset. The goal is to see how close they come to the truth when analyzing data from a human sample with variant results unknown to them, which we will reveal at the end of the challenge. An exciting characteristic of this challenge is that the Genome in a Bottle consortium will release for the first time new high confidence variant calls for the unknown sample dataset (we refer to in this challenge as “truth dataset”) for the human sample at the end of the contest.

Elaine Johanson

Elaine Johanson, precisionFDA Project Manager and Deputy Director of FDA’s Office of Health Informatics.

The knowledge generation potential for precisionFDA is immense, and leverages the collaboration of the global community to help solve challenges that will ultimately provide insight to regulation to ensure the safety and efficacy of genetic tests. The platform offers users the ability to assemble and run apps, learn from other experts, share lessons learned, participate in competitions, and help to develop standards for assessing the effectiveness of genetic tests.

With new challenges and opportunities for ongoing discussions and collaborations between FDA and the global community, we look forward to the precisionFDA community facilitating and advancing development and assessment of new tools and tests in this fast growing field of genetic testing.

 

Taha A. Kass-Hout, M.D., M.S., is FDA’s Chief Health Informatics Officer (CHIO) and Director of FDA’s Office of Health Informatics

Zivana Tezak, Ph.D., is Associate Director for Science and Technology at FDA’s Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health

Elaine Johanson, is precisionFDA Project Manager and Deputy Director of FDA’s Office of Health Informatics

What We Mean When We Talk About EvGen Part II: Building Out a National System for Evidence Generation

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

In an earlier FDA Voice blog post, we discussed a pair of concepts – interoperability and connectivity – that are essential prerequisites for the creation of a successful national system for evidence generation (or “EvGen”). In this post, we take a look at how we would apply these constructs as we go about building such a system.

Building EvGen

Rachel Sherman

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

Creating knowledge requires the application of proven analytical methods and techniques to biomedical data in order to produce reliable conclusions. Until recently, such analysis was done by experts operating in centers that typically restricted access to data. This “walled garden” approach evolved for several reasons: the imperative to protect the privacy and confidentiality of sensitive medical data; concern about the negative consequences that could arise from inappropriate, biased, or incompetent analysis; and, the tendency to see data as a competitive asset. Regardless of the specific reason, the result has been the same: widespread and systemic barriers to data sharing.

If we are to reverse these tendencies and foster a new approach to creating evidence of the kind envisioned for EvGen, we must bear in mind several critical principles:

  1. There must be a common approach to how data is presented, reported and analyzed and strict methods for ensuring patient privacy and data security.
  2. Rules of engagement must be transparent and developed through a process that builds consensus across the relevant ecosystem and its stakeholders.
  3. To ensure support across a diverse ecosystem that often includes competing priorities and incentives, the system’s output must be intended for the public good and be readily accessible to all stakeholders.

What Would EvGen Look Like in Practice?

Robert Califf

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

What would a robust national platform for evidence generation look like? It may be helpful to envision EvGen as an umbrella for all activities that help inform all stakeholders about making treatment decisions.

The task of evaluating drugs, biologics, or devices encompasses different data needs and methods. However, all share a common attribute: the characterization of individuals and populations and their associated clinical outcomes after they have undergone diagnostic or prognostic testing or been exposed to a therapeutic intervention.

Moreover, when medical practice itself is part of the evaluation, characterization of the organization and function of delivery systems is critical. In other words, the kinds of evidence needed to evaluate medical products for safety and effectiveness and the kinds of evidence needed to guide medical practice overlap substantially.

Over the last decade, there has been enormous progress in the area of “secondary use,” in which data collected for one purpose (for instance, as part of routine clinical care) can be reused for another (such as research, safety monitoring, or quality improvement).

The Sentinel Initiative, launched in response to a Congressional mandate to develop an active postmarket risk identification and analysis system, is one example. Modeled after successful programs such as the Centers for Disease Control and Prevention’s Vaccine Safety Datalink, Sentinel allows FDA to conduct safety surveillance by actively querying diverse data sources, primarily administrative and insurance claims databases but also data from electronic health record (EHR) systems, to evaluate possible medical product safety issues quickly and securely.

Another example, the National Patient-Centered Clinical Research Network (PCORnet), is a national system that includes many of the attributes needed for EvGen. PCORnet includes participation from government, industry, academia, and patients and their advocates. Whereas FDA’s Sentinel system is built primarily on claims data repurposed for safety surveillance, PCORnet is designed to leverage EHR data in support of pragmatic clinical research.

The NIH’s Health Care Systems Research Collaboratory has demonstrated through its Distributed Research Network that the concept of secondary data use can be extended into the realm of prospective pragmatic interventional trials. The NIH Collaboratory program, which includes many of the same health care systems involved in Sentinel and PCORnet, has 10 active trials underway.

In addition, the Reagan-Udall Foundation Innovation in Medical Evidence Development and Surveillance (IMEDS) Evaluation Program is exploring governance mechanisms to ensure that private-sector entities, notably regulated industry, can collaborate with Sentinel data partners to sponsor safety queries about marketed medical products. Such measures have the potential to expand the involvement of private-sector partners beyond the arena of methodology, further helping to ensure that Sentinel continues its expansion into a national resource.

Similarly, efforts are underway to establish a National Device Evaluation System (NDES). As currently envisioned, the NDES would be established through strategic alliances and shared governance. The system would build upon and leverage information from electronic real-world data sources, such as data gathered through routine clinical practice in device registries, claims data, and EHRs, with linkages activated among specific data sources as appropriate to address specific questions.

As substantial work already is being done in all of these areas, valuable experience is being gained. The next step is to ensure that these pioneering efforts coalesce into a true national resource. More on that in future postings.

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

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

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

Continuous Manufacturing Has a Strong Impact on Drug Quality

By: Lawrence Yu, Ph.D.

If we used a time machine to transport a pharmaceutical scientist from the 1960s into a current pharmaceutical production plant of today, it might be surprising to learn that they would already be very familiar with most of the processes and production techniques being used. That’s because not much has changed in pharmaceutical production over the last 50 or so years.

Lawrence YuFor decades, most drugs have been manufactured using what is known as “batch” technology — a process whereby the ultimate finished product has been made after many stops and starts in a series of steps. Unfortunately each break in the process causes inefficiency and delay, as well as the increased possibility of defects and error.

Today, a new and exciting technology — continuous manufacturing — enables much faster production and more reliable products through an uninterrupted process. How much faster is continuous manufacturing?  In some cases, manufacturing that takes a month by batch technology might only take a day using continuous manufacturing techniques.

Of course, speed alone would not matter if continuous manufacturing compromised quality. But by eliminating breaks between steps and reducing opportunities for human errors during the stops and starts in the batch process, continuous manufacturing is more reliable — and safer. That’s a powerful combination.

There’s the added benefit that more efficient production of quality products can drive down manufacturing costs, possibly resulting in lower drug prices for consumers. Continuous manufacturing also allows manufacturers to respond much quicker to changes in demand, potentially contributing to prevention of drug shortages.

We are seeing a growing number of manufacturers working towards building continuous manufacturing into their processes. One manufacturer, Vertex, the maker of a cystic fibrosis drug called Orkambi (lumacaftor/ivacaftor) has been using the continuous manufacturing process for this drug since its approval date in July 2015.

Last Friday marked another significant step towards integrating continuous manufacturing into pharmaceutical production. FDA approved, for the first time, a manufacturer’s change in their production method from “batch” to continuous manufacturing. This new approval is for manufacturing Janssen Products, LP’s, medication for the treatment of HIV-1 infection, Prezista (darunavir). The company’s efforts in manufacturing advancement were facilitated by the use of FDA’s recently-released draft guidance to industry titled, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, a product of the agency’s Emerging Technology Team (ETT) designed to help manufacturers implement a variety of technological advancements.

Although it is not easy for drug manufacturers to transition from batch to continuous manufacturing, there are significant rewards. FDA encourages others in the pharmaceutical industry to consider similar efforts.

Progress comes at an opportune time. The medications we use are changing. We are entering an era of precision medicine, when drugs must be made with unique features and provided more quickly to patients in need. FDA will continue our efforts to encourage the advancement of continuous manufacturing as one of a variety of ways to enhance the quality of the medications used by the American public.

Lawrence Yu, Ph.D., is FDA’s Deputy Director, Office of Pharmaceutical Quality, 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

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

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

‘Leaning in’ on Combination Products

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

Medical products that combine drugs, devices, and/or biological products are known as combination products. These products present a number of regulatory, policy, and review management challenges because they include components from multiple regulatory categories (e.g., drug and device, drug and biologic, biologic and device, drug, device, and biologic) with distinct regulatory requirements, and review of a combination product generally requires involvement of more than one FDA Center.

Nina Hunter

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

However, as FDA continues to adapt to the rapidly evolving ecosystem of therapeutic development, it’s more important than ever to find ways to encourage innovation and support the development of these needed technologies.

To that end, FDA has been working on ways to improve the overall efficiency, consistency, and predictability of combination product review. We’ve already shared some of our progress with you in a recent blog post.

An important next step is launching the lean management process mapping approach to build a better system for combination products review – one that’s more cohesive, more collaborative, and more systematic.

What is lean management process mapping, you might ask? It begins with an analysis of what’s being done now, then designs a future state that eliminates waste and maximizes value.

We expect two significant outputs from this mapping:

  • A “current state” map that shows how we’re doing now. Importantly, this initial look will highlight existing sources of delay or redundancy. Creating this baseline map also will allow us to identify metrics for success and to assess the impact of improvements as they are put in place.
  • A “future state” map showing a streamlined, efficient process that will eliminate previously identified delays and redundancies.
Rachel Sherman

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

Has lean management already been successfully applied at the FDA? Yes!

Under the leadership of Kyle Hair, the Lean Management Team in the human drugs program in the Office of Strategic Programs has executed strategic work and communication plans for initiatives across the Agency.

For example, when the “Lean Team” consulted with the Office of Clinical Pharmacology within the Center for Drug Evaluation and Research, it helped establish project management staff functions, roles, and responsibilities for the Office’s core processes. The team also has applied its expertise to stand up the new Office of Pharmaceutical Quality, as well as apply its expertise to such topics as drug safety communications and risk evaluation mitigation strategy.

Lean management works. And we’re confident that applying lean management principles to combination product review will allow us to enhance communication and coordination among the groups that oversee the development, review, and approval of combination products.

Of course, we realize that success in this area depends upon meaningful interactions among all FDA Offices and Centers involved with combination products review. The active participation emphasized by lean management principles will ensure that the needed collaboration is present from the start.

Lean methods also encourage critical thinking and problem-solving, with a focus on reliable, efficient, timely, and reproducible evaluation and decision-making. In this case, our efforts will be focused on the ultimate goal of a combination product review system that is transparent, clear, and consistent.

But lean process mapping is only one piece of the puzzle. Stay tuned for more information about other key priorities and initiatives aimed at modernizing the review of combination products!

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

What is FDA Doing to Improve the Health of African-Americans?

By: Jovonni Spinner, M.P.H., C.H.E.S.

Every February, we celebrate Black History Month – a time to reflect, celebrate, and honor the contributions of African-Americans to our society. We know that achieving and maintaining good health is a long-standing issue for this group, many of whom may experience worse health outcomes in critical areas like heart disease and diabetes. But, we want to focus on the positive and provide consumers with health education materials to support healthy behavior changes!

Jovonni SpinnerIt’s true that the health equity gap has narrowed over time, but there is still significant room for improvement. Here are few things that the FDA and the Office of Minority Health (OMH) have done over the past year to reduce health disparities.

Public Engagement: More than 29.2 million blacks/African-Americans are on social media — and we want to meet consumers where they are. So we’re using Facebook, Twitter, and other social media platforms and electronic communications (e.g. our newsletter and e-blasts) to educate African- Americans on issues such as heart disease, diabetes, and sickle cell disease among others, and also provide tangible solutions to help manage these chronic conditions.

For example, to mark American Heart Month in February, we developed a social media toolkit to help our stakeholders engage with their members and partnered with the Association of Black Cardiologists to spearhead an #ILoveMyHeart social media campaign.

Stakeholder Engagement: We have cultivated relationships with a core set of partners to better understand their health needs, aligned our priorities to meet those needs, and worked together to leverage each other’s resources for the common good. By doing so, we’ve increased our stakeholder’s capacity to communicate with the agency on regulatory issues. For example, multicultural stakeholders are now better able to make their voice heard in FDA-sponsored public meetings and on open dockets.

Minority Health Research: We worked with academia to fund African-American-based research projects (e.g. HIV/AIDs and triple negative breast cancer) and research fellows working on topics like genomics and digital communications. This allows us to increase the knowledge base on these issues and ensure a diverse workforce is in place to solve these complex health problems.

Resources: We have taken care to tailor our health education resources, such as infographics and fact sheets, to African Americans. Our website has valuable information on sickle cell disease and lupus, both of which affect African Americans more than any other racial/ethnic group.

Clinical Trial Diversity: Did you know that sometimes minority populations may respond differently to medical products? One example is an FDA-approved heart failure medication that reduces the risk of death and hospitalization in people with certain types of long-lasting/chronic heart failure.

During clinical trials, it was found there was an increased risk of an allergic reaction called angioedema in blacks. In this trial, only 5% of the participants were black, even though blacks represent 13% of the U.S. population and experience heart failure at rates higher than the rest of the population. This is why we continue to work toward increasing clinical trial diversity, to ensure that medical products are safe and effective for everyone!

President Obama has said, “If you’re walking down the right path and you’re willing to keep walking, eventually you’ll make progress.” OMH will continue walking down the path to improving health equity and we want you to join us, because this work cannot be done alone.

Visit FDA’s OMH at: www.fda.gov/minorityhealth

Follow us on Twitter @FDAOMH

Jovonni R. Spinner, M.P.H., C.H.E.S., is a Public Health Advisor in FDA’s Office of Minority Health