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

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

A ‘Roadmap’ for Navigating Patient Advocacy

By: John J. Whyte, M.D., M.P.H.

So, you and your organization have a passion for helping people and you want to work with FDA to advance your advocacy work. Are you unsure of the most effective way to enable patients to gain greater access to safe and effective drug therapies?

John WhyteWe know government agencies can be big and confusing. That’s why we’re working on a roadmap to help make your navigation easier.

And you can get involved.

FDA’s Center for Drug Evaluation and Research (CDER) is sponsoring a daylong public workshop on March 31, 2016, titled Navigating CDER: What You Should Know for Effective Engagement. Our presentations will help patient advocates gain a better understanding of FDA and provide specific resources to help you and your colleagues learn ways to effectively advocate and engage with the Agency on behalf of the patients you serve.

We’ll provide a broad overview of patient engagement with various offices within CDER, and drill down into key specifics such as:

  • Who and when to call;
  • How to set up a meeting at FDA;
  • Provide tips on making the most out of your meeting; and,
  • How to prepare an effective presentation for FDA staff.

We’ll also discuss topics such as understanding labeling, generic drugs, and how patients can effectively interact and provide input to FDA. And, we’ll look at some programs including different drug approval processes, expanded access, and FDA’s role in patient focused drug development (PFDD). These are only a few of the many important areas we’ll tackle.

For several years, FDA has been working to focus on the needs and goals of the patient as the Agency makes decisions about drug therapies for the advancement and protection of public health. These efforts can only be as effective as our ability to connect with the patients and their representatives we seek to engage.

Join us if you can. If you can’t, we’ll be making information about the meeting available on our website. We look forward to a productive and informative day!

John J. Whyte, M.D., M.P.H., is Director of Professional Affairs and Stakeholder Engagement at FDA’s Center for Drug Evaluation and Research

‘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

Launching a New Natural History Grants Program: Building a Solid Foundation for Rare Disease Treatments

By: Katherine Needleman, Ph.D. and Gumei Liu, M.D., Ph.D.

Today, on Rare Disease Day 2016, FDA’s Office of Special Medical Programs/Office of Orphan Products Development (OOPD) is proud to announce the launch of a new grants program to fund natural history studies with the hope of bringing new and important diagnostics and therapeutics to patients with rare diseases.

Kathy Needleman

Katherine Needleman, Ph.D., is the Director of the Orphan Products Grants Program of FDA’s Office of Orphan Products Development

A rare disease, by definition, affects fewer than 200,000 individuals in the United States. Its impact, however, is far from rare. Altogether, about 7,000 known rare diseases affect about 30 million Americans. Yet the vast majority of rare diseases do not have adequate diagnostic tools or treatments.

Developing such diagnostics or treatments — whether it’s a drug, biologic, or medical device — has been compared by many to building a house. Both require a solid, sound foundation. For any rare disease treatment development program, that foundation consists of having a thorough understanding of the natural history of a disease.

How do you define the natural history of a disease? Think about it as the course a disease takes – from the time of its onset, progressing through its pre-symptomatic phase and clinical stages, to the end of the disease. Insight into a disease’s natural history can help lead to better, more well-designed trials that can accelerate the development of life-saving diagnostics and therapeutics.

Gumei Liu

Gumei Liu, M.D., Ph.D. is a reviewer and grant project officer in FDA’s Office of Orphan Products Development

A lack of understanding of the natural history is often a major obstacle to developing life-saving products for patients with rare diseases. Without it, it becomes very difficult to decide what to study, know what to look for within a study, and capture the data necessary for approval of a treatment or even a cure.

OOPD’s new Natural History Grant Program is intended to provide much needed support and complement ongoing efforts to help change the trajectory of rare disease product development. The funded studies should help characterize the natural history of a rare disease or condition, identify genotypic and phenotypic subpopulations, and develop and/or validate clinical outcome measures, biomarkers, and companion diagnostics.

There are several ways to conduct natural history studies. They can look back in time (retrospective), look ahead (prospective), or be a survey study (collection of data through questionnaires). Each has its pros and cons and the method will to a great extent depend on what we know about a specific rare disease and the currently available treatment options.

Patient advocacy groups can and do play a critical role in collecting natural history data as is highlighted in FDA’s video discussion (watch video below) on natural history studies featuring perspectives from patient advocates. Often what prevents organizations, like patient advocacy groups, from conducting natural history studies is funding. And that’s where the grants program can make a difference.

The Orphan Products Natural History Grants Program is open to funding all types of natural history studies that are appropriate for the rare disease being studied and can aid in development of diagnostics and treatments. There are two funding levels and durations that will be offered:

  • A maximum of $400,000 in total costs per year for up to five years for prospective natural history studies involving clinical examination of affected individuals; and
  • A maximum of $150,000 in total costs per year for up to two years for retrospective natural history studies or survey studies.

The Orphan Products Natural History Grants Program is built upon OOPD’s Orphan Products Grants program that was established by the Orphan Drug Act more than 30 years ago and which has typically funded clinical trials. OOPD has successfully utilized its budget to help bring over 50 products to market with that clinical trial grant program.

We hope that this new Orphan Products Natural History Grants Program will help build the important foundation necessary to accelerate the development of life-saving diagnostic and treatments for the many rare disease patients who need them.

Katherine Needleman, Ph.D., is the Director of the Orphan Products Grants Program of FDA’s Office of Orphan Products Development

Gumei Liu, M.D., Ph.D. is a reviewer and grant project officer in FDA’s Office of Orphan Products Development

Strengthening our Regulatory Relationships in India

By: Mathew T. Thomas and Dean Rugnetta

India’s economic expansion is in part due to the tremendous growth in the pharmaceutical industry. The United States is a large consumer of medical products, and India is one of the largest suppliers of its drug products. And our important work together remains an FDA priority.

Investigator Daniel Roberts

Investigator Daniel Roberts (FDA India Office) and an Indian Regulator sharing inspectional approaches for current good manufacturing practices for pharmaceuticals during the workshop in Ahmedabad

We are working with our counterparts in the Indian government to ensure the medical products manufactured there, especially those for export to the U.S., meet FDA’s safety and quality requirements. FDA established an office in India in 2008, in part to promote government-to-government interactions like these and to keep pace with rapid developments and innovations in the pharmaceutical sector.

In November 2015, representatives from FDA’s India Office, our Center for Drug Evaluation and Research (CDER), Office of Regulatory Affairs (ORA), and Office of International Programs (OIP), partnered with the India Government’s Central Drug Standards Control Organization (CDSCO), to share inspectional techniques and guidance for conducting current good manufacturing practices of pharmaceutical facilities.

Carmelo Rosa and Denise DeGiulio

Carmelo Rosa (CDER), Denise DiGiulio (CDER), and an Indian Regulator discuss Quality By Design guidance with the workshop participants in Ahmedabad

Training sessions were provided in two cities (Ahmedabad and Bengaluru) for about 200 Indian regulators representing CDSCO and some of the State drug control agencies. The training was an example of the cooperation by both agencies to increase knowledge and skills, thereby contributing to the health and welfare of citizens in both countries.

The collaboration resulted in representatives from both agencies learning more about the regulatory perspectives of the other – and doing so first-hand. It was clear from the interactions that the Indian inspectors had extensive knowledge of FDA and of the international techniques for conducting inspections. The FDA representatives at the sessions benefited from input regarding the differences between FDA and Indian legislation and regulations. And as new inspectors comprised the majority of attendees, there was the opportunity for learning on both sides.

FDA Workshop Team in India

FDA Workshop Team in Bangaluru. Front Row – Denise DiGiulio (CDER), Carmelo Rosa (CDER), Leslie Ball (Office of International Programs), Mathew Thomas (India Office), Thomas Cosgrove (CDER), Thomas Arista (ORA). Back Row: Shiva Prasad (India Office), Daniel Roberts (India Office), Solomon Yimam (India Office)

Senior officials from the Government of India attended both events and affirmed their goals of ensuring patient safety and of collaborating with FDA to make sure that products from India are safe and meet appropriate quality standards.

FDA and Government of India regulators will continue leveraging knowledge and strengths to ensure patient safety in India and product quality of FDA-regulated pharmaceuticals.

Mathew T. Thomas is the Director of FDA’s India Office in New Delhi, India

Dean Rugnetta is the Deputy Director in FDA’s India Office in New Delhi, India