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

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

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

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

CBER’s Laboratory Quality System Management Helps Keep Biological Product Standards High

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

Part of the vision of the Center for Biologics Evaluation and Research (CBER) is to strengthen the Center as the preeminent regulatory organization for biologics. One way CBER is achieving this: Through the work of the Office of Compliance and Biologics Quality (OCBQ) and the Office of Vaccines Research and Review (OVRR).

Peter MarksThese offices play a major role in helping to ensure the safety and quality of products regulated by CBER. Their work shows that CBER isn’t just talking the talk about its vision, it’s also walking the walk to demonstrate the expertise needed to fulfill that vision.

That walk leads directly to OCBQ’s Division of Biological Standards and Quality Control (DBSQC), OVRR’s Laboratory of Immunobiochemistry (LIB), and the Center’s Laboratory Quality System (LQS) Program.

LQS is the coordinated structure, procedures, processes, and resources that the Center uses to evaluate and test CBER-regulated biological products. LQS product testing supports biological product licensing, Lot release and surveillance of licensed biological products, and other Center actions. The LQS program also is critical to the development and evaluation of reference materials, standards, and manufacturers’ assays. This extensive responsibility makes LQS an important link in the chain of regulatory actions that support CBER’s mission to help ensure the safety, purity, and potency of biological products.

CBER is authorized by law to create regulations that authorize OCBQ and OVRR to oversee facilities that manufacture CBER-regulated biological products and the biological products they make. CBER leaders wanted to go further in demonstrating the Center’s commitment to quality systems, and decided to voluntarily submit the LQS program to accreditation by an unbiased, non-governmental, nonprofit third party: the International Organization for Standardization (ISO).

ISO sets laboratory accreditation standards for academic and industrial organizations worldwide. Laboratories that receive ISO accreditation can rightly state their test results are precise and reproducible. OCBQ and OVRR accepted the challenge to ensure that their work meets high, internationally recognized standards.

The particular standards CBER sought to meet, called ISO/IEC 17025:2005, are used by testing and calibration laboratories. In the United States, industry laboratories can get accredited to ISO standards by one of many accrediting bodies. CBER turned to the American Association for Laboratory Accreditation (A2LA).

In 2010, CBER received accreditation from A2LA for six methods to test influenza vaccines, including those for sterility and potency, and seven methods for evaluating blood donor screening kits that detect the presence of HIV, HBV, HCV, HTLV-I/II, Trypanosoma cruzi, and West Nile virus.

Additional methods have been accredited since then. CBER’s recent accreditation renewal in October 2015, demonstrated the Center’s competence in 32 test methods previously accredited and added a new laboratory test: evaluating a cELISA allergen test used by CBER for cat hair, ragweed, and dust mites in the newly accredited Laboratory of Immunobiochemistry.

These laboratory accreditations signify that this program is an international leader in biological product regulation based on demonstrated expertise in these laboratory techniques. And they offer more evidence that CBER’s goal of being a preeminent regulatory organization isn’t just a vision, it’s a reality that CBER and FDA, can be proud of.

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

Clarifying What We Mean When We Talk About Biomarkers: An NIH/FDA Joint Leadership Council Success

By: Melissa A. Robb, B.S.N., M.S. (RegSci), and Robert M. Califf, M.D.

What if there was a more uniform way to convey key technical terms to help advance scientific progress? Thanks to the Biomarkers, Endpoints, and other Tools (BEST) Resource, we’re one step closer to that goal.

Melissa Robb

Melissa A. Robb, B.S.N., M.S. (RegSci), FDA’s Associate Director for Regulatory Affairs, Office of Medical Policy, Center for Drug Evaluation and Research

Now available on the National Center for Biotechnology Information’s Bookshelf, the BEST Resource was developed through a collaboration of the Food and Drug Administration (FDA) and the National Institutes of Health (NIH). It includes a glossary of terms and definitions that will ensure the consistency and clarity needed to drive progress in biomedical research and clinical care.

Why is this textbook so important? In the spring of 2015, the FDA-NIH Joint Leadership Council identified a problem: Confusion about the definitions and inconsistent use of key terms–including biomarkers, surrogates, and clinical outcome assessments. This can deter progress in developing medical products and thereby potentially compromise efficiency in achieving public health benefits.

Accordingly, the council identified a high priority: harmonizing terms—or making sure that everyone is “speaking the same language”–that describe and categorize types of endpoints.

Members from multiple FDA Centers and NIH institutes formed a working group to focus on creating a glossary. This was the first step to a publicly available and open access textbook that could be continuously updated and expanded.

Robert M. Califf, MD, MACC; Commissioner, U.S. Food and Drug Administration

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

As the basis of their work, the group considered existing terminology and definitions. Those include FDA guidance documents and other literature, especially a seminal FDA-sponsored Institute of Medicine study.

The use of biomarkers has recently expanded widely to include fields such as mechanistic biomedical research, clinical trials, drug discovery, medical product development, clinical care, and regulatory science. Recognizing this broad influence and the accepted vernacular of these varied fields, the group sought to first reach consensus around biomarker taxonomy.

For example, there’s misunderstanding about the various types of biomarkers and the distinction between biomarkers and surrogate endpoints. One challenge was to settle upon definitions that were broad enough to be used by diverse communities, including biomedical scientists, translational researchers, clinical researchers, medical product developers, and clinicians, and also across diverse types of products.

Where possible, to provide more context and insight into important terms, examples are given alongside many definitions in the BEST Resource. NIH and FDA intend to use the definitions included in this glossary when communicating on topics related to its contents (e.g., biomarkers) to ensure a consistent use of the terms and therefore, a common understanding of the issues. FDA’s Biomarker Working Group, with representation from all of our Centers, contributed to developing these definitions.

Now we need your help. We need your feedback and comments on the glossary. You can provide them at the BEST (Biomarkers, EndpointS, and other Tools) Resource.

In the meantime, we’ll continue to work on adding context to terms related to regulatory science, clinical trials, and laboratory science.

Effective, unambiguous communication is essential for efficient translation of promising scientific discoveries into approved medical products. Once we are all speaking the same language, we can tackle other challenges to bring the promises of biomedical research and clinical care to fruition.

The FDA-NIH Biomarker Working Group members include: from FDA – Shashi Amur, Robert L. Becker, Robert Califf, Aloka G. Chakravarty, David S. Cho, Nina L. Hunter, Ilan Irony, Christopher Leptak, Kathryn M. O’Callaghan, Michael A. Pacanowski, Elektra J. Papadopoulos, Vasum Peiris, Melissa Robb, Hobart L. Rogers, Rachel E. Sherman, Robert J. Temple, Ann Marie Trentacosti, and Sue Jane Wang; and from the NIH – Holli Hamilton, Pamela McInnes, Lisa M. McShane, and Monica R. Shah.

Melissa A. Robb, B.S.N., M.S. (RegSci), is FDA’s Associate Director for Regulatory Affairs, Office of Medical Policy, Center for Drug Evaluation and Research

Robert M. Califf, M.D., previously FDA’s Deputy Commissioner for Medical Products and Tobacco, became FDA’s Commissioner of Food and Drugs on Feb. 25, 2016

2016: The Year of Diversity in Clinical Trials

By: Robert M. Califf, M.D.

Controlled clinical trials provide a critical base of evidence for evaluating whether a medical product is effective before the product is approved for marketing. One challenge that remains for FDA is ensuring that research participants are representative of the patients who will use the medical product.

Robert M. Califf, M.D., MACC, FDA's Commissioner of Food and DrugsMoving from the result of a clinical trial to applying it in practice is complex. But it’s generally agreed that the composition of the population enrolled in a trial should help FDA reviewers, clinicians, or policy makers to have confidence that the trial results will apply to future practice.

Furthermore, a wide range of people should have the opportunity to participate in trials, both for access to new therapies and to have the chance to contribute to better treatment of everyone, an important altruistic goal for many Americans.

Historically, the elderly, women (in some therapeutic areas), and racial/ethnic minorities have been underrepresented in trials. A substantial body of literature has documented this under-representation in recent years, particularly for women in some cardiovascular trials and general inclusion of black/African-American and minority participants in clinical trials. In response to these concerns, Congress included Section 907 in the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, giving FDA direction to evaluate this issue and take action.

FDA has responded in multiple ways, including the creation of Drug Trials Snapshots that give the public readouts of the demographic profile of people participating in clinical trials for approved drugs. While progress has been made, we’ve learned from this program that we still have work to do. An evaluation of the Snapshots since the program began more than a year ago shows that some groups, especially ethnic and racial groups, aren’t always well represented in clinical trials.

These data are critical, because certain groups of patients may respond differently to therapies. For example, studies for a recently approved schizophrenia drug found that one side effect – the urge to move constantly – was seen more often in black/African-American patients. Two important classes of blood pressure drugs were found to work less well in black patients. And a drug for heart failure works very well in black patients but not in white patients. We also have seen labeling changes due to differences in dosing requirements between men and women, such as the recent labeling change with a sleep medication. These few examples show the importance of improving diversity in clinical trials, so medical products are safe and effective for everyone.

Increasing diversity in clinical trials is a priority for FDA. To that end, in 2016, the Agency is planning a variety of activities to push for greater inclusion, including more minority participation. For example:

  • FDA’s Office of Minority Health has developed a variety of tools to support clinical trial participation, including collaboration with the National Library of Medicine to help consumers and patients find clinical trials, educational materials on trials, as well as a multi-media campaign highlighting the importance of clinical trial participation. These materials are designed to urge those underrepresented in clinical trials to find out more information, and consider enrolling.
  • FDA’s Office of Women’s Health launched its Diverse Women in Clinical Trials initiative. Developed in collaboration with the National Institute of Health’s Office of Research on Women’s Health, this multipronged effort will raise awareness and share best practices about clinical research design, recruitment, and subpopulation analyses.
  • Our biostatisticians, trial design experts, and quantitative scientists will continue to work with the research community to develop methods to refine our approach to the conduct and analysis of trials to provide the best estimates of treatment effects for diverse populations.
  • We will continue our commitment to include patient advocacy groups to engage patients in clinical trial design, feedback and evaluation from a patient’s perspective. By engaging patients early in the trial design process, feasibility and participation may be improved.
  • Finally, our Office of External Affairs plans to publish a consumer update describing what it is like to participate in a clinical trial and encouraging the public to enroll in trials, if possible.

As mentioned above, these activities – and, indeed, the Snapshot program itself – were conceived as part of FDA’s response to Section 907 of FDASIA. This provision directed FDA to conduct an inventory of how well various population groups were being represented in clinical trials of FDA-regulated medical products and whether these data were publicly reported. Once that was done, FDA was directed to develop an action plan, which we published in August 2014. And we’ve been diligently working toward implementation and sustainability ever since.

As you heard from Barb Buch, M.D., Associate Director for Medicine at CBER, earlier this month, the public meeting at the end of next month will continue the dialogue with important stakeholders –like you – to continue this momentum.

And there’s more to come.

We want to make 2016 the year of more diversity in clinical trials. But we can’t do it alone. Stay tuned in the coming months for how we can work together to make this critical goal a reality.

Robert M. Califf, M.D., previously FDA’s Deputy Commissioner for Medical Products and Tobacco, became FDA’s Commissioner of Food and Drugs on Feb. 25, 2016