2017 Was Another Record-Setting Year for Generic Drugs

By: Kathleen “Cook” Uhl, M.D.

In 2017, FDA’s Center for Drug Evaluation and Research’s generic drug program marked several major accomplishments on behalf of the American people.

Kathleen "Cook" UhlOur Office of Generic Drugs (OGD) marked another record-setting year for generic approvals at FDA with 1,027 new generic drugs, 214 more than our previous record of 813 set in 2016. Of those, 843 were full approvals and 184 were “tentative” approvals, that is, applications that are ready for approval from a scientific perspective, but cannot be fully approved due to patents or exclusivities on the brand-name drug.

Also in 2017, we helped establish the first reauthorization of the Generic Drug User Fee Amendments (known as GDUFA II)  ̶  an important law that Congress passed to authorize the continued collection of user fees from generic drug manufacturers. GDUFA I, enacted in 2012, allowed OGD to hire additional staff, so that from 2012 to 2017 FDA had additional resources to approve the record numbers of generic drug applications. Reauthorization is helping facilitate continued advances in generic drugs, including complex drug products – such as some inhaled or injectable products.

FDA-approved generic drugs account for 89% of the prescriptions dispensed in the United States. Over the last decade, these FDA-approved generic drugs have saved consumers more than $1.67 trillion. While it’s exciting to see the number of approvals continue to rise year after year, and to exceed 1,000 annual approval actions for the first time, our attention remains focused on public health by ensuring the effectiveness and quality of approved generic drugs.

2017 Generic Drug ApprovalsIn 2017, we approved 80 “first generic” drugs. These are the first generic alternatives to a brand-name product. First generic drugs spur cost-saving competition that helps lower prescription drug costs. Lowering the cost of drugs is a public health priority, so FDA expedites the review of first generic applications to open the market to generic competition. In addition, multiple generic versions of the same drug lead to more competition, resulting in even more cost savings. In 2017, we updated our policy to prioritize the review of generic applications up to the third generic approval of a drug, helping to maximize savings for the public.

Another FDA initiative designed to foster competition focuses on complex drugs. OGD’s regulatory science work and guidances helped advance scientific knowledge about generic drugs to assist industry. OGD’s efforts provide the critical information needed to develop and meet our standards for equivalence to the brand-name drug. But traditional methods and standards for assessing generic drugs may not apply to more complex generics. Health care professionals use complex drugs to treat a wide range of diseases, from hormone replacement therapy in post-menopausal women to type II diabetes. In 2017, OGD provided guidance to industry on developing products from tiotropium bromide inhalation powder (the generic of Spiriva Handihaler), used to treat COPD, to EpiPen (epinephrine) alternative Adrenaclick, used for emergency treatment of anaphylaxis.

It’s important to note that even as FDA continues to meet the GDUFA performance goals, there will be occasional variations in generic drug approvals. Approval numbers can be impacted by a number of external factors, including the number of ANDAs submitted for review over a given time period and changes in legal requirements that come into effect that generic applicants must address to meet the standards for approval.

FDA’s continued work under GDUFA II will help ensure that safe and effective generic versions of brand-name drugs continue to be made available by giving industry clear guidelines on the science behind developing a quality generic drug and clearly identifying what is needed in an application to make it approvable.

The 2017 annual report provides more details on how OGD’s work benefits public health. We look forward to continuing our work with industry, the research community, physicians, health care providers, lawmakers, and other stakeholders to make generic drugs available for the benefit of the American public.

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

The One-Year Anniversary of the Oncology Center of Excellence

By: Richard Pazdur, M.D.

One year ago, Jan. 19, 2017, FDA officially launched the Oncology Center of Excellence to leverage the combined skills of regulatory scientists and reviewers with expertise in drugs, biologics and devices (including diagnostics).

Dr. Richard PazdurIn doing so, we hoped to help expedite the development of oncology and hematology medical products and support an integrated approach to the clinical evaluation medical products for the treatment of cancer.

Significantly, OCE is the first center to focus on a specific disease rather than FDA’s traditional orientation toward centers that focus on specific products. In this new era of cancer therapeutics development, biologic products like gene and cellular therapies and vaccines, and devices like next-generation sequencing in vitro diagnostics, are increasingly being integrated with drug therapies into patient care.

Looking back over the past year, it is clear that FDA — and patients — have benefited from this unique disease-specific center. To get started we established procedures for collaboration across the centers. We created disease-specific interest groups so that experts across the various FDA review divisions can talk about cutting-edge science. We also created an internal scientific council to advise the OCE. By breaking down traditional silos and focusing on a specific disease, we increased our communication and collaboration, creating best practices to integrate our reviews of these exciting new technologies.

Altogether in 2017, we approved 16 new drug and biologic applications, including the first two cell-based gene therapies. We also approved 30 supplemental drug and biologic applications, two biosimilar applications in oncology, and cleared or approved several in vitro diagnostics.

And we used creative approaches for approval. For example, last May, FDA granted the first approval of a cancer treatment based on a tumor’s biomarker without regard to the tumor’s original location. Pembrolizumab is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker known as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), abnormalities that affect the proper repair of DNA inside the cell. Rather than requiring separate development programs for each disease site, we created a single therapeutic approach for patients with different tumor types, allowing extrapolation of the observed treatment effect to diverse tumors.

Notable Oncology Products Approved in 2017

Drugs and Biologics

  • The first two cell-based gene therapies – chimeric antigen receptor (CAR) T-cell immunotherapies for the treatment of advanced hematologic malignancies – tisagenlecleucel for pediatric precursor B-cell acute lymphoblastic leukemia and axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. To treat a serious adverse event known as cytokine release syndrome associated with tisagenlecleucel, tocilizumab was concurrently approved with that drug.
  • The first cancer drug product label update describing how certain patients could STOP taking nilotinib once their cancer,  Philadelphia chromosome positive chronic myeloid leukemia, had responded after at least three years of taking the drug.

IVDs

  • The Oncomine DX Target Test that detects mutations in 23 genes, including BRAF, ROS1 and EGFR mutations in non-small cell lung cancer
  • Memorial Sloan Kettering Cancer Center’s IMPACT next-generation sequencing (NGS) tumor profiling test that detects mutations in 468 unique genes that can identify a higher number of genetic mutations (biomarkers) that may be found in various cancers than any test previously reviewed by the agency
  • FoundationOne CDX, an NGS test that detects genetic mutations in 324 genes, two genomic signatures and tumor mutational burden in solid tumors for use as a companion diagnostic to identify patients with specific mutations who may benefit from certain FDA-approved treatments for non-small cell lung cancer, melanoma, breast cancer, colorectal cancer or ovarian cancer—extending beyond the previous “one test for one drug” model

Outreach and Collaboration

In addition to product review, the Oncology Center of Excellence is also tasked with external outreach and the academic development of our staff. To be effective, we must collaborate with our stakeholders to develop discussions and conferences that will have an impact on drug regulation. In the past year, we held more than 30 symposiums bringing academics and key therapeutic leaders to FDA. We also held a workshop for patient advocates to discuss the important role they can play in oncology product development. Often these conferences were conducted jointly with oncology professional societies, patient groups, and leading cancer centers.

Now that we have been in business for a year, it is time to ask our stakeholders about the new center. We have scheduled a public listening session on March 15 to hear recommendations from stakeholders regarding their expectations of the OCE, specifically, what stakeholders desire of the OCE in terms of structure, function, regulatory purview, and activity.

We are planning other public meetings as well, including a public workshop on Jan. 29 to seek input from experts and patients to discuss how to best implement genetic sequencing data in patient management, and later this year workshops on trial designs for early stage lung cancer and how best to combine immunotherapy and radiation therapy.

The OCE also must be a leader in the development of regulatory science in oncology. Some of our recent initiatives include:

  • Re-evaluating clinical trial eligibility criteria to ensure patients who enter clinical trials will reflect patients treated in the community. Our work with the American Society of Clinical Oncology and Friends of Cancer Research was detailed in the Journal of Clinical Oncology.
  • Encouraging the development of site-agnostic indications. Our perspective on this topic was published in the New England Journal of Medicine.
  • Advocating for the use of master protocols, umbrella protocols, and the use of common controls. We have worked with sponsors to use seamless design trials that eliminate the conventional division of phase 1, 2, and 3 trials that may delay drug development. Working with professional groups and sponsors, we have promoted the use of these innovative designs to reduce redundancy and inefficiency of clinical trials.
  • Devoting resources to the use of real-world evidence for potential regulatory decision-making. This emerging area will in the future provide important safety and efficacy information and a window on how drugs are actually used.
  • Working with colleagues across FDA, at the National Cancer Institute, and the HHS Office of Human Research Protections, as well as many other external stakeholders to foster research into patient-reported outcomes measurement and generating science-based recommendations for regulatory policy.

Looking to 2018 and beyond, I am optimistic about the outlook for the future of oncology drug development. Maintaining the OCE’s emphasis on excellence in regulatory science will ensure the rapid development of highly effective and less toxic therapies for patients with cancer. At the end of the day, patients with a life-threatening disease want to live longer, with a better quality of life. We can never lose sight of our dedication toward progress against this disease.

Richard Pazdur, M.D., is Director, FDA Oncology Center of Excellence

Charting Our Course for 2018-2020

By: Jeff Shuren, M.D., J.D.

Since 2012, we at the Center for Devices and Radiological Health have set as our North Star the vision of patients in the U.S. having access to high-quality, safe, and effective medical devices of public health importance first in the world. “First in the world” is not about a competition between countries but rather a measure of timely patient access.  Since then our strategic priorities have been laser focused on achieving this aim, continually building on one another, with measurable goals that we report on to the public.

Jeff ShurenToday, I’m pleased to report that we achieved our goals and met or exceeded all our individual targets for our three 2016-2017 strategic priorities. Our actions include, but are not limited to the following:

Establish a National Evaluation System for Medical Devices (NEST): We developed the foundation for the National Evaluation System for health Technology, including giving a $3 million grant to the Medical Device Innovation Consortium in 2016 to establish a NEST Coordinating Center, and developed a framework for the incorporation of real-world evidence into regulatory decision making.

Partner with Patients: We established the Patient Engagement Advisory Committee, had over 96% of our employees participate in patient engagement events with 48 patient groups, increased the use of patient reported outcomes in device clinical studies, and increased the conduct and use of patient preference studies in our decision making.

Promote a Culture of Quality and Organizational Excellence:  More than 900 CDRH staff enrolled in formal quality training; 46 received new auditor certifications, 120 new quality associate certifications, and 18 new lean six sigma certifications. We also launched the Pre-market Approval (PMA) Critical-to-Quality Pilot Program to streamline the pre-market approval process while assuring a company’s quality system includes controls for features and characteristics considered critical to the safety and effectiveness of the device. As a result, FDA will be able to conduct a post-approval inspection rather than a pre-approval inspection where appropriate.

It is important to note that innovation and safety are two sides of the same coin: FDA fosters innovation in order to spur the development of safer, more effective technologies and assure timely patient access. New devices make less-invasive treatments possible and provide new options to patients whose conditions would have been considered untreatable in the past.

Our actions have already produced tangible, meaningful results. For example, between 2009 and 2017 the annual number of devices CDRH has approved has steadily increased almost 4-fold – from 24 to 95 – to reach an all-time high during the user fee era.

Now it’s time to look ahead to the next three years. So today I am announcing the three strategic priorities for 2018-2020, which we have laid out in more detail in our roadmap for this period. The new plan is based on internal input and feedback about goals, targets, and actions, and builds on the actions of our past priorities which we will continue to work on.

The three priorities are:

Employee Engagement, Opportunity, and Success. The dedication, expertise, and innovative spirit of our people are the bedrock of the Center and of our success. This priority recognizes the connection between taking care of our employees and achieving our vision. When our staff is engaged, they are the most productive, creative, motivated, less likely to leave, and committed to the mission and vision. However, we recognize that engagement requires work-life balance, open dialogue, and opportunities to succeed. We are grateful to our staff for their deep and abiding commitment to ensuring U.S. patients have access to high-quality, safe and effective medical devices and believe that by making this one of our strategic priorities, we are not only making a formal commitment to our staff but also supporting their ability to deliver on their commitment to patients.

Simplicity. Our issues are often complex; this priority acknowledges that our solutions and processes do not necessarily have to be, and that this complexity can sometimes serve as an impediment to ensuring that patients have access to the safest and most innovative products. Simplicity means that in everything we do, we continually streamline our policies, processes, programs, and approaches, as appropriate, to more effectively, efficiently, and quickly achieve our mission and vision.

We are already striving to streamline and modernize CDRH into a better aligned Center that enables us to work more efficiently. Our Total Product Life Cycle approach and reorganization, which integrates our pre-market, post-market surveillance and quality-compliance management Offices and functions, is an example of this. By having our teams look at products throughout the entire life cycle, we’re enhancing their understanding of the products and their impact on patients. Additionally, we are expanding the application of the Least Burdensome principle to reduce unnecessary burdens on industry and leaning our processes to reduce unnecessary burdens on ourselves.

We have one of the most rigorous regulatory standards for protecting public health – reasonable assurance of safety and effectiveness. And simplicity does not in any way mean sacrificing our commitment to these standards. In fact, we believe that applying an approach of simplicity will enhance our decision making and allow us to make better use of our resources to focus more on what matters most to patients.

Collaborative Communities. This priority acknowledges that we serve the American public better and achieve our vision when stakeholders in the medical device ecosystem, including CDRH, proactively work together to solve problems. The hallmark of a Collaborative Community is a continuing forum where public and private sector members proactively work together to solve both shared problems and problems unique to other members in an environment of trust and openness, where participants feel safe and respected to communicate their concerns. The role of CDRH will be to foster a community spirit and responsible choice through the creation of Collaborative Communities with broad and fair representation to solve problems and proactively build for the future. We will enable our customers to take a more active role in the advancement of smart regulation and the rise of Patient Scientists — those scientists, health care professionals, engineers and others who focus on serving the unmet and developing needs of patients and who incorporate their own experiences as or with patients into their work in industry, health care, and government.

Admittedly, these goals take a more holistic approach to improvement than our priorities of the past. They will require holding ourselves accountable to setting our employees up for success, streamlining processes and policies, and fostering collaboration between members of the public and private sectors.

By applying these three approaches more systematically we believe we will arrive at the threshold of achieving our vision in the next three years. Therefore, as a measure of success, we aim to have more than 50 percent of manufacturers of novel technologies for the U.S. market intend to bring their devices to the U.S. first or in parallel with other major markets by December 31, 2020.

I am convinced we can do this with the dedicated work of our excellent staff and the support of our customers – while continuing our ongoing efforts with NEST, our work with patients and our pursuit of quality and organizational excellence.

In addition to our strategic priorities, we will soon unveil our “Medical Device Safety Plan,” which among other objectives helps chart a path to a future state where the medical device ecosystem is inherently focused on device features and manufacturing practices that have the greatest impact on product quality and patient safety. We look forward to providing more information about this plan in the coming weeks.

Jeffrey Shuren, M.D., J.D., is Director of FDA’s Center for Devices and Radiological Health

Reflections on a Landmark Year for Medical Product Innovation and Public Health Advances and Looking Ahead to Policy in 2018

By: Scott Gottlieb, M.D.

Dr. Scott GottliebAs we look ahead to 2018, I’d like to take a moment to reflect on an inspiring year of advances in both medicine and public health for FDA — from groundbreaking medical products brought to market this year, to a record number of generic drug approvals that will promote competition, and to the agency’s ongoing efforts to advance policies that promote safe and effective product innovation, and keep Americans safe from food-related illnesses.

Today, new medical breakthroughs are profoundly altering how we view and treat disease in ways that seemed inconceivable just years ago. In this modern medical setting, FDA is evaluating all aspects of its policies to make sure we’re protecting consumers, while promoting beneficial innovation that has the potential to effectively treat disease for human and animal patients, and improve public health.

A Record Year for New Innovation

As scientific understanding of disease advances and the practice of medicine becomes more tailored to individual patient needs, we also are modernizing how we work with innovators throughout the development process to bring products to patients more efficiently, using the best available science.

For example, FDA recently coordinated the approval of a novel diagnostic device that can detect hundreds of genetic mutations in a single test with the Centers for Medicare & Medicaid Services’ proposed coverage of the test, thereby facilitating earlier access to this innovative product.

Also, in the rapidly advancing field of individualized medicine, the Agency advanced new draft guidance that addresses better ways to develop treatments that address the underlying molecular changes (e.g., genetic mutations) that often cause or contribute to diseases. This includes uncommon molecular changes that are present in only a small subset of patients. The guidance proposes an approach for drug developers to enroll patients into clinical trials for targeted therapies based on the identification of rare mutations,  when reasonable scientific evidence suggests the drug could be effective in patients with these genomic findings. The new guidance discusses the evidence needed to demonstrate effectiveness for a variety of molecular subsets within a particular disease. The framework could lead to more consistent development and approval of targeted therapies for patients who are likely to benefit from them.

This past August we also saw the practical advent of a whole new way to treat disease with the approval of the first gene therapy product in the United States. We have since approved two more gene therapy medicines. Innovations like these are creating a turning point in the treatment of serious illnesses. With this technology also comes greater potential to cure intractable and inherited diseases.

2017 saw a number of other similar, historic milestones with regard to new innovation. This collective progress reflects a fundamental shift in science that’s enabling us to attack more diseases with novel platforms. We’re increasingly able to identify patient benefit earlier in the development process because of the ability to better target medicines to the underlying mechanisms of disease. At the same time, in many cases these identical tools also allow us to surface safety issues earlier and more effectively.

pie chart of approvals

FDA approved a modern record number (56) of novel drugs and biologics in 2017.

Owing in part to these advances, FDA approved a modern record number (56) of novel drugs and biologics in 2017. Of these 56 novel approvals this past year, 46 were new molecular entities approved by our Center for Drug Evaluation and Research – of which 28 were approved using one or more of FDA’s expedited review programs. Ten of these 56 novel approvals were biological therapeutics that were approved by our Center for Biologics Evaluation and Research. We also had a record number of drugs with orphan indications approved. At the same time we eliminated the entire backlog of pending orphan drug designation requests. We also broke records, with the highest number of generic drugs approved in a single month multiple times in 2017, and we recorded the highest annual total of generic drug approvals (1,027) in the agency’s history. We believe that, if current trends continue, we’ll exceed this record number of generic drug approvals in 2018.

2017 generics approvals

Both full approvals and tentative approvals, which do not allow the applicant to market the generic drug product and postpones the final approval until all patents/exclusivity issues have expired.

Our science-based and patient-centered regulatory approach also extends to medical devices, where we’ve focused on a life-cycle approach to product development. This has allowed us to streamline clinical development protocols without compromising on our commitment to rely on rigorous evidence. By carefully considering when clinical data can be better gathered through post-market, as opposed to pre-market, studies, patients are waiting less time to access some breakthrough devices without conceding one bit FDA’s gold standard for demonstrating reasonable assurance of device safety and effectiveness.

Chart of device approvals

In 2017, the agency approved a record number of novel devices — 95. This was more than four times the number of novel devices that received market approval in 2009.

Our commitment to applying the “least burdensome standard” for generating information critical for device approval was strengthened and advanced by provisions in the 21st Century Cures Act. This policy approach is a hallmark of our efforts to help innovators generate high quality evidence that can support marketing approval as efficiently as possible. Our embrace of these principles has resulted in remarkable advances in access for patients. In 2017, the agency approved a record number of novel devices — 95. This was more than four times the number of novel devices that received market approval in 2009.

Modernizing FDA’s Regulatory Programs

These new advances also present new challenges. At FDA, we’re being confronted with the need to regulate highly novel areas of science like gene therapy, targeted medicine, cell-based regenerative medicine, and digital health; where our traditional approaches to product regulation may not be as well suited. To meet these new challenges, we’re taking a fresh look at how we can adapt our customary approaches to regulation. We need to make sure that we’re allowing beneficial new technologies to advance, while continuing to protect consumers as part of our product review processes.

To promote these efforts, we advanced a new policy framework allowing certain diagnostic tests to undergo review by accredited third parties. This new framework will reduce the burden on test developers and streamline the regulatory assessment of these types of innovative products. This approach more readily accommodates the highly iterative nature of these technologies, where tests often undergo routine modifications to improve their precision and clinical utility.

Over the past summer, we also launched a pilot program exploring a new way of regulating digital health devices so that these fast-evolving technologies can similarly undergo the rapid product evolution that’s the hallmark of software tools like medical apps, while FDA maintains the ability to make sure that these digital health tools are being reliably produced. We followed these actions with a suite of guidances that clarify how we intend to regulate certain digital health technologies in a way that encourages innovation.

More broadly, we provided more clarity for manufacturers of low- to moderate-risk medical devices which will reduce unnecessary submissions to FDA for minor modifications that could not significantly affect device safety or effectiveness. As a result, patients will benefit from upgraded products more quickly.

This effort to properly match our policies to the unique attributes of the new technologies we’re being asked to review was also evident in new steps we took across other programs; from our comprehensive policy on regenerative medicine aimed at spurring safe and effective innovation in these potentially transformative products, to our draft guidance for manufacturers of 3D printed medical devices.

We know that the public health benefits derived from our efforts to modernize our regulatory approaches are not confined to the pre-market review process. Advances in our post-market tools and policies can yield meaningful advances for patients in the form of safer products, better information to guide medical decisions, and more opportunity to more efficiently move products to market – if we can have confidence in our post-market oversight. This is why we’re always looking for ways to reform and improve this oversight, and advance the ways that we share this information with patients and providers.

For example, last fall we launched a new searchable database to better inform patients and health care professionals of adverse events reported with drug and biologic products. We’ll be taking other steps soon to improve on the ways that we share important clinical information with patients and providers. These goals also include new efforts to step up our post-market oversight of potentially risky products, and warn consumers earlier of potential problems we find. As an example, we’ve taken decisive action to protect the public from risky stem cell products offered by unscrupulous clinics. We’ll pursue similar actions in 2018.

In 2017, we also took new steps to warn companies making false claims that their unapproved products can treat or cure life-threatening diseases; we advanced a new draft guidance describing FDA’s approach to regulating homeopathic products based on the risk they can pose to consumers; and we took steps to alert the public to the dangers of other unproven and untested products, such as certain body-building products, contaminated dietary supplements and kratom. Among other efforts, we also took new steps to facilitate faster patient access to needed compounded medicines, while protecting the public from poorly compounded drugs. There will be additional enforcement steps in 2018. And we continue to promote work that will enable FDA to use real world data to better inform our regulatory decision-making.

Promoting Drug Competition

Many say that FDA has no role in drug pricing, but I disagree. While we don’t have the authority to regulate prices, we do have the authority — and the responsibility — to ensure that the agency’s policies are not impeding competition that could ultimately be a check to rising drug prices and patient access.

Our role as gatekeeper of cost-effective, high-quality generic drug products is a foundational part of fostering human and animal drug competition. We’re advancing new ways that FDA can help enable patients to get access to more affordable medications. We shared some of the steps the agency is taking with our launch in June 2017 of the Drug Competition Action Plan — from prioritizing our review of generic drug applications, to working to stop companies from finding loopholes in the system that delay the entry of generic drugs to market, to making substantial progress on the generic drug review backlog, to ensuring that low cost drugs get to the patients who can benefit from their effectiveness and more affordable price.

New Steps to Combat Addiction

I’ve noted many times that among my highest priorities as Commissioner is addressing addiction crises facing the nation, principally with respect to nicotine and opioids. In 2017 we announced new plans for how we address these crises. In July, we announced a comprehensive plan that proposes to lower nicotine in combustible cigarettes to minimally or non-addictive levels. At the same time, we took new steps to enable development of innovative delivery systems that could be potentially less harmful than cigarettes for adults who still want to get access to satisfying levels of nicotine. As part of that plan, we formed a new Nicotine Steering Committee. It’s charged with modernizing FDA’s approach to development and regulation of nicotine replacement therapy products that can help smokers quit and stay quit

FDA also unveiled new actions to confront the staggering human and economic toll created by opioid abuse and addiction, starting with my first major action as commissioner to establish an Opioids Policy Steering Committee. Under the leadership of this committee, FDA is reevaluating how drugs that are already on the market are used, both for legitimate purposes and misuse and abuse.

The committee will recommend new policy steps to address this crisis. FDA also is taking immediate action where needed, as we did with FDA’s first-of-its-kind request to remove a currently marketed opioid pain drug from sale due to the public health consequences associated with the product’s abuse and misuse. We’ve also worked to identify ways to decrease exposure to opioids, prevent new addiction, and support the treatment of those with opioid use disorder; for example, through new Risk Evaluation and Mitigation Strategy requirements for makers of immediate-release opioids, and requiring labeling changes to add important clarifying information regarding the use of medication-assisted treatments for patients suffering from opioid use disorder. We’re continuing to pursue other creative ways to address the crisis, such as leveraging different forms of packaging, storage and disposal of opioid medications.

Protecting and Empowering Consumers

It’s not only medical products and policies where FDA can innovate to better serve the public – we’ve also made much progress in the implementation of the Food Safety Modernization Act, which was designed to keep the American public safe from food-related illness. Implementing the most comprehensive food safety reform in 70 years requires a massive commitment from federal, state and local governments to food producers, farmers and other stakeholders that are working to protect the public health in new and innovative ways. That’s why in July we announced more than $30 million in funding for states to help implement new produce safety requirements. We also launched an innovative software tool called the Food Safety Plan Builder that assists food manufacturers in creating a food safety plan to help prevent foodborne contamination and ultimately protect public health. And we’re looking at other ways to empower farmers and producers to ensure the law’s modernized requirements are effectively fulfilled.

I also believe in empowering people to make better choices. This is reflected in our continued efforts to pursue the practical implementation of the menu-labeling rule. We listened to public feedback and have proposed practical solutions to make it easier for industry to meet obligations in these important public health endeavors, while ensuring restaurant patrons have access to the nutrition information they need.

Empowerment also is critical for patients facing life-threatening or debilitating illness. This year we held our first-ever patient engagement advisory committee meeting. This is a pioneering effort that seeks to strengthen our engagement with patients and secure the patient voice in our regulatory decision-making.

We also understand that in many serious diseases, patients want earlier access to experimental treatments. We’ve taken new steps to improve the expanded access resources we have to serve patients, including enhancing our online Expanded Access Navigator Tool and simplifying the process for approving a patient’s request for access to an investigational treatment. Last month, as part of our commitment to expediting drug development for rare diseases, we issued draft guidance that describes a possible new approach for companies to collaborate and test multiple drug products in the same clinical trials for a specific ultra-rare pediatric disease, thereby reducing the number of patients that need to be treated with placebo. This framework can be applied more widely to other ultra-rare diseases.

In everything we do at FDA, our top priority is to protect the public health. Perhaps nowhere was this more evident in 2017 than in the areas of the United States that were impacted by last year’s hurricanes.

The devastation caused by Hurricanes Harvey, Maria and Irma brought to public view some of the critical work FDA does in overseeing the safety of the food and medical products. We worked around the clock to ensure that farmers in Texas and Florida could safely handle their crops affected by flooding. We remain deeply committed to the recovery in Puerto Rico and that island’s long-term success. We worked closely with drug and medical device manufacturers in Puerto Rico to take steps to address potential and apparent shortages of medical products that resulted from the devastation left by Hurricane Maria.

Although we’re seeing progress in Puerto Rico owing to the hard work of federal and local authorities — and primarily because of the resilience of the American people who are affected — our work and commitment to hurricane victims and patients in need of critical medical products will continue into 2018.

Improving our Stewardship of Vital Drugs

Antimicrobial resistance continues to be a major public health challenge. Addressing this problem requires adoption of a “one health” approach that involves new efforts to use antibiotics more responsibly in both human and animal medicine. To better manage antibiotic usage in food animals, in 2017 FDA completed its implementation of a groundbreaking Guidance for Industry (GFI #213). This new guidance document eliminates the use of medically important antimicrobials for food production purposes and brings the remaining therapeutic uses of antibiotics in animals under veterinary oversight.

A total of 292 approved drug applications were impacted by this new guidance; with 84 drug applications withdrawn, 93 applications for oral dosage form products intended for use in water converted from over-the counter (OTC) to prescription, and another 115 applications for products intended for use in feed converted from OTC to Veterinary Feed Directive. This is a major accomplishment. It represents a milestone in our efforts to promote judicious use of antibiotics in animal health. We will take additional steps in 2018 to build on these successes, and improve stewardship over medically important antibiotics.

A look ahead to 2018

When I look back at my eight months as Commissioner, since coming aboard at FDA in May, I’m humbled by the many accomplishments of the agency’s dedicated professional staff.

We’ve achieved a great deal in 2017. We’re committed to making even more progress this year. 2018 holds promise in even more areas where the agency will take steps to advance beneficial innovation by adopting new measures to make sure our processes are efficient, human and animal products are safe, and practical solutions are implemented that protect and promote the public health. The launch of our Unified Agenda highlights some of our priorities. These include advancing biosimilar policies, modernizing how we advance over-the-counter products, and better informing women about health issues and risk factors.

Nobody innovates in a silo. Advancements in medicine, biotechnology, food science, and the whole of public health are possible only because of the collaboration of the public health community. FDA is in a unique position to bring together stakeholders from across the sector — patients, industry, academics, providers, other government agencies — to ensure innovation translates into successful outcomes that protect and benefit the public. That’s what drives us at FDA. It’s what we’ll pursue in the year ahead.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

You Spoke, FDA Listened: New Patient Engagement Collaborative, Call for Nominations

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

The FDA is committed to collaborating with patients, caregivers, and advocates, as well as incorporating the various perspectives from these groups into the FDA’s regulatory decision-making processes. And we know that patients and other stakeholders agree with the agency’s commitment to improving and increasing patient involvement in FDA matters. In fact, members of the patient and stakeholder communities commented in public feedback on Section 1137, Patient Participation in Medical Product Discussions, of the Food and Drug Administration Safety and Innovation Act (FDASIA). Stakeholders recommended that the FDA create an outside group to provide input on patient engagement across the agency. We are pleased to announce that in response to that feedback and to accelerate the FDA’s efforts in this area, today the FDA published a request for nominations to join the FDA’s Patient Engagement Collaborative (PEC).

Nina Hunter

Nina L. Hunter, Ph.D., FDA’s Deputy Director for Medical Programs, Office of Medical Products and Tobacco

The PEC will be coordinated by the FDA and the public-private partnership, the Clinical Trials Transformation Initiative. FDA is seeking a group of diverse representatives from the patient community to participate in the PEC including:

  • Patients who have personal disease experience
  • Caregivers who support patients, such as a parent, child, partner, other family member, or friend, and who have personal disease experience through this caregiver role
  • Representatives from patient groups who, through their role in the patient group, have direct or indirect disease experience

The PEC will provide an ongoing forum to discuss how to achieve more meaningful patient engagement in medical product development and other regulatory discussions. Topics to be discussed may include making patient engagement more systematic; how to improve transparency, education and communication; new strategies for enhancing patient engagement; and new models for patients to collaborate as partners in the medical product development and FDA review process.

The PEC builds on the agency’s existing patient engagement efforts, such as the Patient Focused Drug Development meetings (for drugs and biologic products) and the Patient Preference Initiative (for medical devices).

Rachel Sherman

Rachel E. Sherman, M.D., M.P.H., FDA’s Principal Deputy Commissioner

The new collaborative will be modeled after the European Medicines Agency’s Patients’ and Consumers’ Working Party (PCWP) which “has enabled the Agency to build upon its existing interactions with patients and consumers.” Examples of PCWP accomplishments include having patients review information on medicines ahead of publication to ensure that the information is “clear and relevant,” deciding on the eligibility criteria for patient and consumer groups who will be working with EMA, and involving patients as experts in EMA regulatory activities.

The PEC will be spearheaded by the FDA’s new Patient Affairs Staff (PAS) in the Office of Medical Products and Tobacco (OMPT), which is responsible for the coordination of agency-wide and cross-center projects related to patient engagement. The PAS will work closely with the medical product centers, the Office of External Affairs (OEA), and other offices across the agency to complement and support ongoing patient engagement efforts. Specifically, the PAS will focus on the following key areas:

  • Creating and assisting with public and private collaborations and partnerships with external groups of patients to discuss topics around medical product development and regulatory policies
  • Coordinating cross-cutting programs and activities to leverage best practices and enhance patient engagement
  • Facilitating consistent cross-center policy-making and common standards to enhance integration of patient perspectives into the regulatory and scientific process
  • Building a framework for hosting and maintaining a shared database of patient engagement information
  • Providing navigation services to triage inquiries from patients and patient organizations
  • Establishing a centralized point of entry into the FDA for patients and their advocates (existing FDA interactions will not be affected)
  • Enhancing our external communication platform to create awareness of the FDA’s patient engagement activities and regulatory processes

The PAS will be led by longtime FDA staffer and patient advocate Andrea Furia-Helms, who is currently the Acting Director of the PAS. Ms. Furia-Helms spent the past ten years in the FDA’s Office of Health and Constituent Affairs where she directed the FDA Patient Representative Program. Ms. Furia-Helms has been joined by Samir Shaikh, who is currently the Acting PAS Deputy Director. Mr. Shaikh has been a part of OMPT, supporting efforts in organizational development and process improvement that have had impacts across the agency. Ms. Furia-Helms and Mr. Shaikh will work closely with the centers to complement and support the FDA’s ongoing patient engagement efforts.

This new Collaborative is also facilitated by provisions in both the 21st Century Cures Act of 2016 and the Food and Drug Administration Reauthorization Act of 2017. Both sought to foster patient participation and incorporate patient experiences in the regulatory process. The goal of the nomination process announced today is to identify individuals interested in serving as members of the PEC. For more information about joining the PEC, read today’s announcement.

For more information about Patient Affairs and the new Patient Engagement Collaborative, visit the For Patients webpage. 

Nina L. Hunter, Ph.D., is FDA’s Deputy Director for Medical Programs, Office of Medical Products and Tobacco 

Rachel E. Sherman, M.D., M.P.H., is FDA’s Principal Deputy Commissioner

Looking ahead: Some of FDA’s major policy goals for 2018

By: Scott Gottlieb, M.D.

Twice a year the federal government publishes the “Unified Agenda of Federal Regulatory and Deregulatory Actions” (Unified Agenda), which provides the American public with insight into regulations under development or review throughout the federal government. For the U.S. Food and Drug Administration (FDA), it gives us an opportunity to outline some of our efforts to modernize our approach to our work and improve our efficiency, while fulfilling our mandate to protect and promote the public health and uphold FDA’s gold standard for regulatory decision-making. While many of FDA’s policies are advanced through guidance documents and other proposals, this annual list of proposed regulations provides one element of our policy agenda.

Dr. Scott GottliebPatients and consumers across our country depend on us to regulate products in a predictable, efficient, science-based manner. We also serve the public health by efficiently advancing innovations and therapies that improve patient care, enhance choice and provide competition; by aggressively taking action against serious threats to public health, such as opioid addiction and addiction to the nicotine in cigarettes; by empowering patients, consumers and healthcare providers with accurate and up-to-date information; and by recognizing when scientific innovations warrant new, more flexible regulatory approaches in order to make sure advances in care can reach patients. In addition to these goals, we must continually adapt our regulations to enhance efficiency, improve our effectiveness, and update old and out-of-date requirements.

FDA’s contributions to the Fall 2017 Unified Agenda address a number of these areas of policymaking under way at the agency, and are directly aligned with our key priorities:

Addressing the Nicotine Addiction Crisis

To reduce the morbidity and mortality associated with combusting tobacco, we are proposing meaningful actions to advance our new, comprehensive approach to nicotine and the regulation of combustible cigarettes. These efforts include an Advance Notice of Proposed Rulemaking asking critical questions related to our pursuit of regulation that would result in a targeted reduction of the nicotine levels in combustible cigarettes to eliminate or dramatically reduce their addictive value. At the same time, FDA is taking new steps to facilitate innovation in products that can deliver satisfying levels of nicotine to adults who want or need such access without the same health risks associated with combustible tobacco.

As part of this plan, FDA will also be issuing an Advanced Notice of Proposed Rulemaking to look at how to best regulate flavors in tobacco products to limit their appeal to youth, while considering the potential role that some flavors may play in helping users transition away from combustible products. Further, FDA will be issuing an Advance Notice of Proposed Rulemaking to solicit information that may inform regulatory actions FDA might take with respect to premium cigars, asking certain questions related to how we might define and regulate “premium cigars,” taking into consideration the health effects of these products and their patterns of use.

Advancing Drug Safety

FDA will issue several regulations on drug compounding to help ensure the quality of medicines that patients need. We want to make sure that outsourcing facilities clearly understand which drugs they may compound and allow these firms to adopt more efficient, streamlined manufacturing standards, while ensuring they observe necessary safety and quality measures.

Focusing on the safety of prescription drugs, FDA is also pursuing a proposed rule to establish national standards for the licensing of prescription drug wholesale distributors and third-party logistics providers, as part of track-and-trace requirements. By establishing national standards for all State and Federal licenses issued to key parts of the supply chain, these regulations will allow for the effective and efficient distribution of prescription drugs throughout the U.S.

Promoting Food Safety

FDA continues to take steps to improve its oversight of food safety. To address critical issues related to the overall safety of the food we eat, FDA intends to propose a rule on lab accreditation, which would establish a program to accredit labs to do food safety testing and to require that these accredited labs be used in certain situations.

Additionally, in the Unified Agenda, FDA committed to pursuing a rulemaking that will clarify registration requirements for food facilities to better align how facilities and farms that perform similar activities are treated under the preventive controls rules and the produce safety rule.

Empowering Consumers

Many of our agenda submissions are part of a broader effort to empower consumers and patients to make more informed and effective health decisions and ensure they have appropriate autonomy over their choices, while continuing to ensure the products they consume and use are safe and effective. Consumers tell us that they want this information. We also know that consumers who have access to more diverse, safe and effective options – and who have improved information about those choices – make better, more cost-effective decisions. 

  • Providing Better Information on Drugs: We have included a rulemaking that proposes a new type of patient medication document that would help ensure that patients have access to clear, concise, and useful written information about their prescription drugs or biologics, delivered in a consistent and easily understood format, each time they receive a medication from the pharmacy. We want to give patients the ability to make high value decisions about the medicines they take, and help them use drugs safely and effectively.
  • Broadening Access to Nonprescription Drugs: We are considering innovative action in the nonprescription drug area to expand the scope of drug products that can be made available to consumers without a prescription. We will be proposing to allow certain innovative approaches for demonstrating that a drug product can be used safely and effectively in a nonprescription setting. This will allow some drugs that would otherwise require a prescription to be marketed without a prescription through the use of innovative technologies and other conditions that will ensure appropriate self-selection and/or appropriate actual use of the nonprescription drug product by consumers. Examples of such conditions could include use of self-selection questions on a mobile medical app prior to permitting access to the drug, or other innovative technologies to improve safety. Through use of these types of additional conditions, we hope to create a new paradigm of drug safety with greater flexibility that will benefit patients and public health. We are committed to advancing this new framework to enable a potentially broader selection of nonprescription products for consumers, empowering them to self-treat more common conditions and chronic conditions. This also could help lower costs by increasing the availability of products that would otherwise be available only by prescription.

Modernizing Standards

Importantly, we also are working to ensure efficiency of existing regulations – a key focus of the Unified Agenda – by making sure that our standards are clearly defined, that they advance our public health goals and help promote the protection of consumers, and achieve these goals in an efficient way that does not place unnecessary burdens on those we regulate. We also want to ensure that our standards and regulations are modern and reflect the latest science, and have not become outdated, obsolete or otherwise not applicable to the current environment.

  • Harmonizing Global Standards: We will be updating FDA’s requirements for accepting foreign clinical data used to bring new medical devices to market. While helping to ensure the quality and integrity of clinical trial data and the protection of study participants, this rule should also reduce the burden on industry because it will harmonize with the standards currently used in drug regulation.
  • Modernizing Mammography Standards: We will be proposing a rule to modernize mammography quality standards that will improve women’s health. Our aim is to recognize advances in technology and help to ensure women get the most relevant, up-to-date information about their breast density, which is now recognized as a risk factor for breast cancer. This information can help doctors and patients make more informed decisions about further imaging.
  • Embracing Electronic Submissions: We will propose a new framework that will allow FDA and product developers to take greater advantage of the efficiency of electronic, rather than paper, submissions for devices and veterinary drugs.
  • Removing Outdated Rules: We will propose to remove an outdated inspection provision for biologics and outdated drug sterilization requirements to remove barriers to the use of certain sterilization techniques.

Looking to the Future

FDA serves Americans by delivering on the critical mission of protecting and promoting the public health. The more than 70 actions we have identified, as part of the Fall 2017 Unified Agenda, will help us even better deliver on this mission. But regulation is only one way in which we can foster our mission and improve American health.

Over the next year, we will also tackle many additional priority areas through guidance documents and other policy efforts. These areas will include efforts to reduce the cost of drugs by encouraging competition, spur innovation across medical products, give consumers access to clear and consistent nutrition information, create greater regulatory efficiencies in bringing products to market, and put a dent in the opioid addiction crisis facing our country.

Further, just because a previously identified regulation does not appear on this Unified Agenda submission does not necessarily mean the agency does not consider it a priority or will not continue to consider it moving forward. Look for additional information about the many initiatives identified in the Fall 2017 Unified Agenda as we advance all of these goals.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

New Steps to Facilitate Beneficial Medical Device Innovation

By: Scott Gottlieb, M.D. and Jeffrey Shuren, M.D., J.D.

In recent days, the Food and Drug Administration (FDA) has committed to several new policies that will modernize the agency’s approach to regulation in the medical device system.

Dr. Scott Gottlieb

Scott Gottlieb, M.D., Commissioner of the U.S. Food and Drug Administration

For instance, we announced our intention to propose an alternate approach to the traditional 510(k) clearance process, which will involve the use of modern, science-based, consensus standards and FDA-developed performance criteria as the comparator for device review for certain well-understood technologies. FDA currently compares new devices to predicate devices that can in many cases be as much as 40 years old. By modernizing the standards that FDA uses to assess some new devices, it will make it easier to innovate these products, and adopt more up-to-date and rigorous benchmarks for evaluating their safety and effectiveness.

Today, FDA is taking another step to modernize its regulatory framework and make its review processes more efficient. FDA is issuing a new, draft guidance that describes how it intends to implement provisions enacted by Congress to pursue the “least burdensome” means of assuring the safety and effectiveness of new devices so that innovations that benefit patients can reach them more efficiently.

medical device image

Through the application of the least burdensome approach, we’ve moved much closer to achieving our vision of patients in the U.S. having access to high-quality, safe and effective medical devices of public health importance first in the world.

Timely patient access to high quality, safe and effective medical devices requires that FDA reduce or reform those outdated, unnecessary burdens in our regulatory approaches that can add to development costs or forestall beneficial innovation without also enhancing device safety and effectiveness.

The least burdensome approach is not new; however, recent legislation, as well as the opportunities offered by advances in science, call for updating this framework.

Since the passage of the Food and Drug Administration Modernization Act (FDAMA) in 1997, FDA has been required to take a least burdensome approach to premarket review of devices that are subject to a premarket approval application (PMA) or premarket notification (510(k)). FDA issued guidance and began to train staff on the least burdensome requirements shortly after FDAMA’s enactment.

While these initial efforts first established the principles of this least burdensome framework for device premarket review, subsequent agency efforts – and especially new laws such as the 21st Century Cures Act in 2016 — clarified and expanded the least burdensome concept. As a result, the concept has been increasingly integrated into FDA’s culture and operations, and has become a guiding principle for the device center’s efficient, science-based regulation.

Jeff Shuren

Jeffrey Shuren, M.D., J.D., Director of FDA’s Center for Devices and Radiological Health

Today, in new draft guidance on the Least Burdensome Provisions, FDA defines least burdensome to be the “minimum amount of information necessary to adequately address a regulatory question or issue through the most efficient manner at the right time.” The new draft guidance also explains FDA’s regulatory approach and delineates guiding principles that we propose to apply across the total product lifecycle – beyond what Congress has required – including all device-related applications and interactions with medical device industry.

By making sure our processes are efficient and our regulatory frameworks are better tailored to  technology type and patient needs, we believe we can garner information about the safety and effectiveness of new devices in the pre- and post-marketing setting with less time and cost. Because we believe the application of these least burdensome principles will help drive the development of, and timely patient access to, safe and effective devices, we are committed to training all device center staff on the implementation of these principles, not just those involved in pre-market review as required by the Cures Act.

This balanced approach will allow for FDA to focus its resources on issues of highest public health concern. In just the past few years, we’ve seen notable results of our application of the least burdensome principles on medical device review, including reduction in review times and improved quality of applications. At the same time, we’re advancing FDA’s gold standard for safety by taking additional steps such as enhancing our pre- and post-market safety tools, including the establishment of a new pre- and post-market evaluation system (NEST).

The Cures Act extended the least burdensome provisions and their application to the pre-market review process in new ways. It streamlined FDA’s ability to remove the 510(k) submission burden where no longer needed for certain lower risk devices. This allowed the agency to free up review resources to focus on higher risk devices. The application of the goals of the least burdensome approach also has resulted in new efforts to implement risk-based compliance policies. For example, through the implementation of a variety of new digital health policies since 2013 – including those involving mobile medical apps and medical device data systems – the agency generally does not oversee low risk products that are part of the fitness/wellness industry.

The successes in the pre-market arena have encouraged FDA to apply the least burdensome approach in many other device policies and programs. This includes the development of a more flexible framework for making benefit-risk determinations in support of PMA approvals and De Novo classifications; a new policy on early feasibility studies; and the wider use of Real-World Evidence, such as data gathered as a part of routine clinical care, such as in electronic health records and registries. We’ve also developed and incorporated new regulatory science tools in our review process, such as computer models to make device development, assessment and review safer, faster and more efficient.

Each of these exemplifies the advances we’ve made in creating a more efficient regulatory process – and incorporating more modern evaluative tools and approaches – while enabling our scientists to get the safety and effectiveness information that they need to inform their decisions.

In extending these same principles, FDA has embraced and led international harmonization efforts to identify areas where regulation is not achieving its intended goal, and may be adding undue burden and presenting an obstacle to beneficial innovation. For example, FDA is a founding member of the International Medical Device Regulators Forum and led the forum’s working group that established the Medical Device Single Audit Program. Under this program, participating countries share their own inspections and rely on surveillance inspections conducted by or on behalf of other participating countries. The program potentially eliminates the need for participating device companies to prepare for multiple inspections while allowing government agencies to make better use of their limited resources. It shows how adopting the most efficient approach has set FDA on a course to generate high quality information at a potentially lower cost and burden to product developers and to the agency.

The resulting impact on public health from FDA’s implementation of these and similar principles has been significant. In 2016, we approved 91 innovative devices as compared to 24 in 2009, the highest number since the start of the user fee program in 2003. This year, we may achieve a modern record when it comes to the number of innovative medical device approvals. In 2016, we also saw an increase in the number of high quality, safe and effective devices of public health importance approved in the U.S. as the first commercial market, meaning that U.S. patients now have early access to critically important technologies, such as the first “artificial pancreas.”

Through the application of the least burdensome approach, we’ve moved much closer to achieving our vision of patients in the U.S. having access to high-quality, safe and effective medical devices of public health importance first in the world. At the same time, we’re setting FDA on a modern framework for making sure it continues to strengthen and secure its gold standard for medical product review.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Jeffrey Shuren, M.D., J.D., is Director of FDA’s Center for Devices and Radiological Health

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Treating Infections – FDA is Forging a More Efficient Path to Help Healthcare Providers Treat their Patients

By: Edward M. Cox, M.D., M.P.H.

When a patient has an infection, healthcare providers often order a test to help them select a drug that is likely to work against that infection. This testing is performed by laboratories and is called antimicrobial susceptibility testing.

bacteria image

Over time, bacteria (in the image) and fungi change and may become less susceptible to some drugs. When this happens, breakpoints may need to be changed so that laboratories are using the most up-to-date information to help healthcare providers choose an appropriate treatment.

The criteria used to determine whether bacteria or fungi are considered “susceptible” or “resistant” to a particular drug are referred to as “breakpoints” or more formally, as Susceptibility Test Interpretative Criteria (STIC). Over time, bacteria and fungi change and may become less susceptible to some drugs. When this happens, breakpoints may need to be changed so that laboratories are using the most up-to-date information to help healthcare providers choose an appropriate treatment.

Up-to-date breakpoints are also an important part of the public health response to address antimicrobial resistance. For example, antimicrobial susceptibility testing results are used to monitor for antimicrobial resistance in hospitals and determine if additional infection control procedures should be put in place to reduce the chance of spread.

Ed CoxToday, we took an important first step in implementing a more streamlined process of updating breakpoints for antimicrobial drugs. FDA launched new web pages that contain Susceptibility Test Interpretive Criteria (www.fda.gov/STIC). Our new online system identifying FDA-recognized breakpoints will help laboratories report the most up-to-date information to healthcare providers. This important step is a result of the recently-passed  21st Century Cures Act, which FDA and other agencies are now implementing.

Before the Cures Act, the process was laborious, duplicative, and time-consuming. It began with each manufacturer updating its drug labeling with new breakpoints. Only then could-up-to date breakpoints be incorporated in the antimicrobial testing devices used by laboratories. Updating and re-updating labeling for hundreds of drug and device products was inefficient, and delayed healthcare providers receiving the most current information.

Now under the Cures Act, FDA will leverage the work of Standard Development Organizations (SDOs) who keep up with the ever-changing standards needed to run laboratories. FDA assesses any changes in breakpoints made by SDOs and retains full authority to decide whether any changes should be recognized. This new approach will take advantage of online tools to modernize how we update breakpoints.

By keeping Susceptibility Test Interpretive Criteria up-to-date:

  • Healthcare providers will have the information they need to pick an antimicrobial drug to treat a patient’s infection.
  • Patients are more likely to get the treatment they need to get well.
  • Healthcare staff are more likely to know if a patient is carrying a drug resistant infection and may be better able to take enhanced infection control measures to reduce its spread.

In the Cures Act Congress recognized the importance of improving the process of updating breakpoints. The Cures Act created a system to expedite the recognition of these breakpoints so that up-to-date information is provided to healthcare providers. Transitioning this information from drug labeling to an online source is a first step in this new updating process. FDA has published a guidance to assist drug manufacturers with this transition. We look forward to working with the healthcare community to improve and further streamline this process.

Edward. M. Cox is the Director of FDA’s Center for Drug Evaluation and Research’s Office of Antimicrobial Products

Bringing Early Feasibility Studies for Medical Devices Back to the United States

By: Maureen L. Dreher, Ph.D., Andrew Farb, M.D., and Owen Faris, Ph.D.

Ten years ago, when medical device manufacturers wanted to gain early clinical experience with their new devices they often went overseas to conduct first-in-human or small clinical studies. Moving a device from bench to bedside for use in patients is a critical step along the development path. However, going overseas delayed access to potentially beneficial devices for American physicians and patients.

Medical Device image

The Early Feasibility Studies (EFS) Program is supporting medical device innovation and enhancing early patient access to new technologies.

Today, FDA’s Center for Devices and Radiological Health (CDRH) has an Early Feasibility Studies Program (EFS) that provides a route for innovators, sponsors, FDA review teams, and clinicians to work together to facilitate the early clinical evaluation of medical devices in the United States under the investigational device exemption (IDE) regulations.

An EFS is a limited clinical study on a device early in its development, typically before the device design has been finalized, for a specific indication. It may be used to evaluate the device design concept with respect to initial clinical safety and device functionality. The EFS Program includes enhanced opportunities for collaboration, increased regulatory flexibility, and consideration of benefit-risk principles, while maintaining appropriate patient protection measures.

Maureen Dreher

Maureen L. Dreher, Ph.D., Research Biomedical Engineer in the Office of Science & Engineering Laboratories and Early Feasibility Study Program Representative in FDA’s Center for Devices and Radiological Health

Since the release of our EFS guidance document in October 2013, and our  promotion of the EFS Program as part of the 2014-2015 Strategic Priorities, we’ve seen more early clinical studies on devices inside the United States. Specifically, the number IDEs submitted for EFS has more than doubled with 26 submitted in the first year after the EFS guidance document was finalized as compared to 57 submitted in fiscal year 2017.

More importantly, most of these studies have received timely FDA approval. During the last two years, 75% of the IDE submissions which are required to conduct any clinical study on an investigational device, have been either approved or approved with conditions by FDA within one 30-day review cycle.

There are many examples of how the EFS Program is supporting device innovation and enhancing early patient access to new technologies. One is Mitralign, Inc., which is developing a novel treatment for tricuspid regurgitation (TR). TR occurs when the heart’s tricuspid valve does not open and close properly. Many TR patients are not candidates for open heart surgery due to high risk comorbidities. But the Mitralign valve repair system may expand treatment options for these patients through the use of minimally-invasive transcatheter technology. Mitralign’s IDE approval in only 28 days enabled them to conduct a U.S.-based EFS that saved time, money, and the human resources to conduct the study:

Andrew Farb

Andrew Farb, M.D., Medical Officer in the Division of Cardiovascular Devices, Office of Device Evaluation in FDA’s Center for Devices and Radiological Health

“The EFS program has given Mitralign the opportunity to advance our Tricuspid program clinically, technologically and also from a regulatory pathway perspective. It is a clear example of the FDA striking the right balance between the need to advance healthcare technology for the US population and the need to protect the patients who may one day benefit from that advancement.” —Rick Geoffrion, President & CEO, Mitralign. 

Enabling medical device innovation with EFS has a direct and positive impact on all medical device developers, and may be particularly important for small manufacturers. About half of the EFS IDEs are submitted by medical device manufacturers, most of which are small companies for whom early clinical experience is crucial for obtaining financial resources. This was true for Enspire DBS, a startup medical device company, which used the EFS Program to begin a first-in-human study of their Deep Brain Stimulation technology in combination with physical rehabilitation to restore function in stroke patients:

The FDA was engaged and quite interested in working with us to find a mutually acceptable way to move forward with our early feasibility study. We were happy with the interactive review and having an approved IDE significantly helped the company in securing funding.” —Enspire DBS.

Owen Faris

Owen Faris, Ph.D., Director of the Clinical Trials Program, Office of Device Evaluation in FDA’s Center for Devices and Radiological Health

An important lesson learned from the EFS Program so far is that the enhanced opportunities for collaboration between the sponsor and FDA’s review team are crucial for success. Martha Murray, M.D., at Boston Children’s Hospital found this to be a significant advantage of the EFS Program when she approached FDA about translating her novel bridging scaffold, invented at an academic medical center, to treat anterior cruciate ligament injuries:

“Participating in the Early Feasibility Studies Program opened up the door for us to see how collaborative working with the team at CDRH could be. The program gave us access to a team of experts as we tested our device in the preclinical studies. Knowing we had that depth of expertise behind us made us more confident we had done as much as possible to ensure the safety of the subjects in our First-in-Human trial.” —Martha Murray, M.D., Orthopedic Surgeon, Boston Children’s Hospital.

The success of the EFS Program requires stakeholder collaboration beyond FDA. The Medical Device Innovation Consortium (MDIC) is a non-profit, public-private partnership whose mission of advancing medical device regulatory science for patient benefit is aligned with CDRH’s EFS program. MDIC EFS working groups are identifying opportunities to improve the EFS ecosystem by increasing administrative and clinical efficiencies and developing resources for device innovators, such as tools that increase efficiencies in contracting between developers and clinical sites.

We invite manufactures to visit our new webpage devoted to Early Feasibility Studies. With the availability of this webpage, we hope to expand awareness of this important pathway and provide the medical device community with a one-stop shop for EFS resources.

The program represents a critical component of CDRH’s larger efforts to streamline the clinical trial initiative, to increase access for patients in the U.S. to high-quality, safe and effective medical devices as quickly as possible.

Maureen L. Dreher, Ph.D., is a Research Biomedical Engineer in the Office of Science & Engineering Laboratories and Early Feasibility Study Program Representative in FDA’s Center for Devices and Radiological Health

Andrew Farb, M.D., is a Medical Officer in the Division of Cardiovascular Devices, Office of Device Evaluation in FDA’s Center for Devices and Radiological Health 

Owen Faris, Ph.D., is the Director of the Clinical Trials Program, Office of Device Evaluation in FDA’s Center for Devices and Radiological Health

FDA-Required Studies of Approved Drugs Make a Big Difference for Public Health

By: Peter Stein. M.D.

Drugs are approved by FDA based upon substantial evidence from clinical trials that the medicine will be both effective and safe for use if prescribed according to its labeling. However, there may be issues that need additional evaluation after approval. For example, post-approval studies may be needed to confirm clinical benefit when a drug is approved under accelerated approval provisions. Additionally, post-approval studies can allow for further evaluation of a potential safety issue or better characterize risk factors for a known safety issue. Once a drug is approved, a larger population and wider range of patients will use the drug than were studied before approval. With this larger experience, new potential safety issues may emerge that were not seen in the studies prior to approval, and such issues may require additional evaluation.

Peter SteinFDA’s ability to require post-approval studies, referred to as post-marketing requirements (PMRs), has evolved over time. Prior to 2007, FDA could require post-approval studies for the few drugs approved under the accelerated approval pathway, for the rare drugs approved based solely on animal studies and, in certain cases, for drugs that may be used in pediatric populations. If FDA wanted other types of post-approval studies, it would seek an agreement with the manufacturer, called a post-marketing commitment or PMC. The FDA Amendments Act of 2007 (FDAAA) was a major step forward for drug safety in the United States. It gave FDA authority to require safety-related PMRs when the agency becomes aware of new safety information.

FDA is committed to making sure industry fulfills their PMRs and PMCs and that the post-market studies are transparent to the public. Certain information about PMRs and PMCs is made available to the public in a searchable database on the agency’s website. Additionally, FDA monitors the progress of PMRs and PMCs to ensure they are conducted in a timely manner. Each year, FDA issues a report via a Federal Register (FR) Notice on the status of PMRs and PMCs. Our most recent FR report shows that, overall, the majority of PMRs and PMCs are progressing toward completion according to the original agreed-upon schedule (85 percent of PMRs and 77 percent of PMCs).

FDA also informs Congress on the status of a subset of PMRs and PMCs, referred to as the “backlog.” FDAAA required FDA to review the PMRs and PMCs that were in place (open) at the time the Act passed in 2007, to determine which ones needed to be revised or eliminated, and to establish completion dates for these PMRs and PMCs. FDAAA also required that FDA report annually to Congress on the progress being made on the backlog. The 9th Annual Report to Congress, which covered fiscal year (FY) 2016, showed that the number of the number of open PMRs and PMCs in the backlog has markedly decreased from 1,636 to 143.

Many factors influence the timely conduct of a study including low use of a product or changes in the standard of care which can reduce the number of patients that can be studied. FDA assesses the justification for any delays and if the justification is appropriate monitors adherence to a revised timetable. The agency can also take enforcement actions if a post-marketing requirement is not met or, depending on the violation, may give a manufacturer the opportunity to voluntarily take prompt, corrective action.

It’s important to note that in the years after a drug’s approval, a great deal more information about the drug, and about the disease it treats, often becomes available. FDA carefully reviews this emerging scientific information—and may conclude that the original post-approval study needs to be revised, with a new schedule for completion, or may be “released,” (no longer required or committed to) if FDA concludes that the new information indicates that the study is no longer needed.

But the important thing for the public to know is that most post-approval studies are on track. When studies are delayed, FDA works with manufacturers to identify the reasons for the delays and ensures that the studies are completed in a timely way. These post-approval studies are vital to enhancing patient safety and public health. The results from completed studies provide additional information that can lead to safety labeling changes, support expanded use of a drug, or alleviate concerns about a potential drug risk. FDA will continue to work to ensure PMRs and PMCs are conducted as promptly as possible.

Peter Stein, M.D., is Deputy Director, Office of New Drugs, at FDA’s Center for Drug Evaluation and Research