FDA is Using Innovative Methods to Prevent Illegal Products with Hidden Drug Ingredients from Entering the United States

By: Scott Gottlieb, M.D., Melinda K. Plaisier, M.S.W., and Michael Kopcha, Ph.D., R.Ph.

One of the Food and Drug Administration’s important public health functions is to closely monitor the FDA-regulated products arriving at the nation’s international mail facilities (IMFs) every day to prevent unsafe, counterfeit, and unapproved products from entering the country. This sometimes includes interdiction of illicit products, in support of the U.S. Customs and Border Protection (CBP).

Dr. Scott Gottlieb

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

Given the volume of mail, the increasing sophistication of bad actors, and the amount of time it takes to inspect just one package, this is an increasingly challenging task. FDA is taking new steps to increase the scope and effectiveness of this mission. One tool that FDA has deployed is advanced screening technologies that can allow FDA inspectors to screen packages containing suspected drug products more efficiently and reliably.

According to a January 2018 report by the U.S. Senate Permanent Subcommittee on Investigations, in just three years from 2013 to 2015, the number of packages processed by the nation’s nine IMFs nearly doubled. Today, these combined facilities receive more than 275 million packages a year. Most of the mail arrives without advanced or specific identifying information. As a consequence, we have no way of knowing exactly how many packages contain FDA-regulated products.

What we do know is that every year thousands of packages are found to contain FDA-regulated products and a surprising percentage of those products are illegal. These products come in all different shapes and forms – some with sophisticated packaging and others in nondescript plastic bags.

They include unapproved products; counterfeit or substandard drugs; and purported dietary supplements being sold for weight loss, sexual enhancement, bodybuilding or pain relief. Many products promoted as dietary supplements contain potentially dangerous undeclared drug ingredients. Any package initially suspected of containing controlled substances is immediately referred to the U.S. Drug Enforcement Administration. Still, FDA is seeing an increase in the number of packages containing opioids including tramadol, codeine and morphine, making FDA’s investigators the last line of defense for drugs that may not be easily identified as narcotics.

Melinda Plaisier

Melinda K. Plaisier, M.S.W., FDA’s Associate Commissioner for Regulatory Affairs

Last year, FDA increased the number of investigators it has in the IMFs from 8 to 22 full time employees; taking the number of packages FDA is able to open and screen from 10,000 a year to 40,000. These are packages that our partners at CBP have flagged for additional screening in order to intercept and detail what are believed to be nefarious products prior to refusal of admission and possible destruction.

To do so, based on current laws, FDA must first establish that the products are drugs based on their intended use, then determine if the drug is subject to refusal of admission. This requires documenting the contents, which can be a labor-intensive process. Some of the packages may contain loose pills without any packaging or contain hundreds of small internal packages. Screening a single package can take about 20 minutes, while packages that contain multiple products or large quantities can take much longer. This limits the number of packages that FDA is able to inspect. CBP will only pull for inspection the number of packages that FDA is able to complete in a given day. CBP and FDA target the highest risk packages for physical inspection. This is where good intelligence work is key. But packages that can’t undergo a physical inspection will typically be sent on to their recipient. The more that FDA can improve the efficiency of its process, its authorities, and the tools that it uses to evaluate products; the more higher-risk packages that the agency is able to subject to vetting.

Although the agency’s professional staff works hard to examine and document suspicious contents, FDA investigators are only able to inspect a fraction of the incoming international mail packages. It’s estimated that FDA is able to physically inspect less than 0.06 percent of the packages that are presumed to contain drug products that are shipped through the IMFs. Recognizing these hurdles, we’re doing all we can by increasing our existing resources, working more efficiently and identifying innovative ways to extend our efforts.

In addition to tripling the size of our staff, we’ve invested in, and would like to enhance, our screening equipment at the IMF locations and laboratory equipment for the forensic confirmations needed – all of which serves to increase efficiency and strengthen our ability to more quickly identify and assess suspect products entering through IMFs. FDA’s current analytical process requires sending samples to an FDA laboratory for analysis. It can take days or weeks to get results and during that time products would have to be held within the IMF’s limited space, restricting the number of products that can be tested by FDA.

Michael Kopcha

Michael Kopcha, Ph.D., R.Ph., Director, Office of Pharmaceutical Quality at FDA’s Center for Drug Evaluation and Research

One of the most promising technical developments is the successful use of various portable screening devices that will allow us to rapidly test for unsafe ingredients at the IMFs with similar reliability and accuracy as the current laboratory methods. FDA recently concluded a successful six-month pilot at two IMFs, testing whether we might be able to increase the number of packages we screen by making use of a portable screening device called an ion mobility spectrometer. This is the same technology used by airport security to swipe your luggage for explosives and by prisons to screen visitors for illegal narcotics. The device works by comparing the chemical signature of the unknown substance against the chemical signatures of known compounds in a process that takes less than 30 seconds.

For the pilot, the device was loaded with a custom-built library of pharmaceutical compounds to test whether products marketed for weight loss and sexual enhancement contained undeclared drug compounds such as sibutramine, phenolphthalein and sildenafil. These compounds have significant safety concerns and are often counterfeited; and are commonly found within packages coming into the IMFs. When criminals secretly spike products with these compounds, consumers do not know that they are at higher risk of harm from the products.

An astonishing 65 percent of the samples we screened tested positive for the presence of undeclared pharmaceutical ingredients, results that were confirmed in a FDA laboratory. Based on these results, we’re able to demonstrate that the device was reliable, efficient, and produced valid results. As a result of this pilot, we’ve decided to expand the use of this new technology and add devices at two additional IMFs. Our aim is to refine our use of this device, and eventually install it in all nine of our IMF facilities so that our staff can more quickly determine whether products contain undeclared drug ingredients.

This is a significant milestone.

The scanner’s methods are flexible enough to be used to detect the presence of an active ingredient in a drug product or to identify active ingredients in counterfeit drug products, simply by adding new pharmaceutical libraries developed by FDA laboratories. This will allow the agency to more quickly identify and respond to emerging issues. Already we’re actively working on developing an opioid screening method for the device. We hope to initiate a pilot study using this method very soon.

As we advance the science behind rapid, deployable, screening methods, we aim to shift the paradigm of how FDA screens products; increasing the effectiveness of our oversight. It’s an example of the creative measures we’re taking to keep harmful products out of the U.S. marketplace.

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

Melinda K. Plaisier, M.S.W., is FDA’s Associate Commissioner for Regulatory Affairs

Michael Kopcha, Ph.D., R.Ph., is Director, Office of Pharmaceutical Quality, at FDA’s Center for Drug Evaluation and Research

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Read more: U.S. Food and Drug Administration and the International Mail Facilities

Visit FDA’s Flickr photo album: FDA and the International Mail Facilities

FDA’s New Pilot Program Aims for More Transparency about New Drug Approvals

By: Janet Woodcock, M.D.

When FDA approves a new drug, it has been found safe and effective when used under the conditions described in the label. Although this concept seems simple, the execution can be complex. Many factors are involved in weighing the benefits a drug can provide against the risks associated with its use. To that end, after we approve a new drug, we also want to make sure the scientific community and the public can understand why we approved it. This can help inform future drug development and, in turn, may facilitate the approval of additional safe and effective medicines.

Janet Woodcock, M.D.One way we explain the “why” behind a drug approval is by sharing information from the clinical trials that supported the approval decision. This information is usually discussed in FDA review documents authored by our physicians and other scientists. But often there is no complete description of the important efficacy trials, including the trial protocols, descriptions of any modifications made during the trial itself, and an explanation of all of the results. That’s why we launched the Clinical Data Summary Pilot in January. During the pilot, we will post key portions of the Clinical Study Reports (CSRs) – documents that sponsors create for FDA on each of their clinical studies. These portions would contain complete summaries of the study results, the protocol and protocol amendments, and the statistical plan. FDA plans to release these portions of the CSRs for the pivotal studies that supported the approval. The reports will be redacted by FDA to exclude confidential commercial information, trade secrets, and personal privacy information. FDA will not release patient-level data. Our goal is to share more directly complete summaries of the clinical trial information we have evaluated to determine whether a drug is safe and effective.

Currently FDA posts its review documents on line – material we call drug approval action packages. While the action packages include a significant amount of information pulled in from the sponsor’s application, that information is frequently separated into different sections and does not provide a complete summary of the results of any given study. This makes it difficult for academic researchers, regulators in other agencies, and other stakeholders to gain an in-depth understanding of the studies supporting approval. By providing the CSRs we hope to:

  • Enhance the accuracy of information used in scientific publications;
  • Increase stakeholders’ understanding of the basis for FDA’s approval decisions; and,
  • Inform physicians and other healthcare providers about the detailed results that regulatory decisions were based on.

The pilot will post the CSRs from up to 9 approved new drug applications of participating sponsors. We hope that reviewing the CSRs will help the scientific community better understand the information FDA used to evaluate an application and make an approval decision. At the end of the pilot we plan to seek comment from the public through a Federal Register notice to hear first-hand how the information was accessed and used. We hope to hear from a wide variety of stakeholders!

Our first pilot participant is Janssen Biotech for the approval of Erleada (apalutamide), the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer, as well the first to use the clinical trial result, or endpoint, of metastasis-free survival. Today we posted the CSR of the pivotal study with the regular action package. It’s a novel drug and we believe the CSR information, together with the FDA review, label, and other supporting documents, will facilitate a deeper understanding of how we reached our approval decision.

As an added benefit, our pilot program can help with global alignment, as our counterparts at the European Medicines Agency are similarly working to make information about their approvals more accessible and easier to understand.

The Clinical Summary Pilot is one of many efforts underway that require FDA working with industry to advance science. Now that it’s launched, we look forward to collaborating with sponsors who have an active or forthcoming NDA at FDA and who wish to participate in the pilot. For more information, visit the Center for Drug Evaluation and Research’s new pilot program page on our website.

Janet Woodcock, M.D., is Director of FDA’s Center for Drug Evaluation and Research

Predicting Stem Cell Activity to Ensure Safe and Effective Therapies

By: Steven R. Bauer, Ph.D.

We can admire an individualist for being independent and self-directed. But these traits can be disruptive and troublesome when they’re shared by cells called mesenchymal stem cells (MSCs). When these cells (also called human multipotent stromal cells, or MSCs) are being prepared for use as therapies to treat human diseases or medical conditions, what’s important is predictability.

Steve Bauer

Steve Bauer, Ph.D., chief of the Cellular and Tissues Therapy Branch, Division of Cellular and Gene Therapies, in the Office of Cellular, Tissue and Gene Therapy at CBER.

MSCs are called ‘multipotent’ because they can produce more than one type of specialized cell of the body, but not all types. For example, they will respond to various types of substances called growth factors by differentiating − or specializing − into cartilage, bone, or fat. MSCs may also help the body control inflammation by suppressing immune cell functions. These processes, immunosuppression and differentiation, justify MSC use in regenerative medicine clinical trials investigating their use to protect, restore, or repair tissues in the body.

But there’s a catch. As of January 2018, no MSC-based clinical trials have resulted in FDA-approved treatments. One significant challenge is ensuring that the MSCs will work together to perform the same desired function when they are administered to patients. So FDA scientists have been developing ways to predict whether specific populations of MSCs intended for use as a therapy are made up of individualists or sufficient numbers of team players. It turns out that MSCs are very responsive to their environment. In a lab-based manufacturing process, MSCs are exposed to an environment very different from the body — one that could change the way they respond to growth factors and one that could result in MSC preparations with lots of unexpected – and undesirable – individualism. Additionally, this might change the way the cells behave after they are put into a patient. For example, they might not suppress inflammation very well, might form tissue where it isn’t wanted, might form the wrong tissue, and even form tumors.

Recognizing these potential issues, FDA’s MSC Consortium is trying to develop methods that would predict with more certainty how manufactured or isolated MSCs will behave in patients.

My own laboratory has been developing ways to predict the behavior of MSCs that have been stimulated by growth factors. Our study has involved identifying changes in the size and shape (or morphology) of stimulated MSCs that may predict their future behavior. We call this approach functionally-relevant morphological profiling. It’s made possible by powerful imaging technologies that make it practical for us to routinely monitor and analyze the changes in the size and shape of many thousands of cells in a matter of hours.

Stem Cell lab photo

Human multipotent stromal cells undergo morphological changes after being stimulated by growth factors. FDA scientists have demonstrated that these changes can predict the ability of the cells to develop specialized properties that might support their use in regenerative medicine clinical trials.

Why are sizes and shapes so important to predicting MSC activity?

Think of it this way: you can tell the difference between basketball players and baseball players by looking at their uniforms. And you know what kind of behavior you can anticipate when they’re playing their respective games. Likewise, morphological profiling can help scientists predict whether stimulated MSCs are going to differentiate into specific cells that do specific tasks.

We’ve used this approach to follow MSCs that were stimulated to undergo a process called mineralization, the laying down of minerals that support bone growth. Previously, we had to wait for over a month to see if stimulated MSCs would mineralize. But, by using our profiling method, we can predict with over 90 percent certainty on day three whether the stimulated cells would mineralize by day 35.

In another study, we measured more than 90 morphological features — including their sizes and shapes, and the shapes of internal structures — of stimulated MSCs. Based on our knowledge of the changes in the size and shapes of MSCs that go on to develop immunosuppressive activity, we could predict which MSCs would suppress a certain type of immune cell (T cell). Immunosuppression makes these stimulated MSCs potentially effective treatments for inflammatory diseases, such as Crohn’s disease (chronic inflammation of the intestine), and multiple sclerosis (loss of nerve cell signaling).

In short, this type of profiling allows us to measure the extent to which there are similarities or differences in these cell preparations and to compare our findings with the profile of specific cell types associated with the biological functions we are seeking. That may help us predict whether the cells will perform the function we want if they are administered to patients.

MSC-based therapies are not available yet. But the ability to predict specific functions of different preparations of MSCs in the lab may be a big step toward getting safe and effective FDA-approved treatments to patients. We think our work is widely applicable to a variety of potential stem-cell based products, and it will help us determine if new techniques for stimulating MSCs to differentiate will produce safe and effective therapies.

Steven R. Bauer, Ph.D., is the chief of the Cellular and Tissues Therapy Branch, Division of Cellular and Gene Therapies, in the Office of Cellular, Tissue and Gene Therapy at FDA’s Center for Biologics Evaluation and Research.

The FDA Grand Rounds on March 8 features Steven Bauer discussing his research.

Brain Implant for Some Blind People Shows Benefits of FDA’s Breakthrough Device Program

By:  Malvina Eydelman, M.D.

FDA’s Breakthrough Devices Program is beginning to show important results for patients since it was established in late 2016 under the 21st Century Cures Act to help patients gain timely access to breakthrough technologies.

Malvina Eydelman

Consider Second Sight Medical Products Inc.’s Orion Cortical Visual Prosthesis System, which recently qualified for the FDA’s voluntary Breakthrough program.

Eligible technologies must provide more effective treatment or diagnosis for life-threatening or irreversibly debilitating diseases. In addition, there must be no approved or cleared treatment, or the device must offer significant advantages over existing approved or cleared alternatives.

The Orion is a brain implant for patients with blindness caused by damage to the optic nerve. With the designation, Second Sight qualified for interactive and timely communication with FDA, even before the Sylmar, Calif., company embarked on a clinical trial to study the device in patients. These early interactions resulted in the development of a flexible study design, review team support, and senior management engagement, all of which may allow a sponsor to evaluate complex, innovative technologies more efficiently.

And, when the development and evaluation of a technology or device is more efficient, beneficial medical devices may be able to reach the patients who need them sooner, even though they may be more complex or challenging to study because they are breakthrough products.

For Second Sight, early interaction meant that specialists across disciplines such as ophthalmology and neurology, representing the sponsor and FDA, could pose questions and solve problems. Oftentimes, early interaction can be especially helpful in solving any potential stumbling blocks – for instance, how best to go about measuring the benefits or risks of devices.

diagram of eye nerves

In normal vision, the optic nerve connects the eye to the brain. The optic nerve carries the electrical impulses (signals) formed by the retina (specialized nerve tissue at the back of the eye) to the visual cortex.

In normal vision, the optic nerve connects the eye to the brain. The optic nerve carries the electrical impulses (signals) formed by the retina (specialized nerve tissue at the back of the eye) to the visual cortex. The brain processes these impulses into the images that we perceive when we “see.”

There was no standard way to evaluate the benefits or risks of a device like the Second Sight Orion, which mimics the perception of light through a miniature video camera worn by a patient that transmits signals to an implant in their visual cortex.

Thanks to the breakthrough program, which builds on the FDA’s Expedited Access Pathway program, FDA was able to work closely with the company on a novel way to measure benefit and risk, clearing the way for the company to proceed with a small clinical trial, a necessary step before the company could seek approval for their device.

The Second Sight trial, approved by FDA’s Center for Devices and Radiological Health (CDRH), involves five patients at two sites, Baylor College of Medicine and the University of California in Los Angeles. The first patient received the implant on Jan. 30, 2018.

The Orion isn’t the only device to take advantage of the Breakthrough program. Since the Cures Act was passed, CDRH has received 94 requests for breakthrough status for devices treating a variety of conditions and granted 54, with patients as the ultimate beneficiaries.

In FDA’s Breakthrough Device Program, the interaction among specialists across disciplines representing the sponsor and FDA, could lead to devices that have the potential to change patients’ lives, without compromising safety or effectiveness.

In short, it shows FDA at its best, committed to patient access and willing to balance benefits and risks in a scientifically robust manner led by compassion and respect for the perspective of patients.

Malvina Eydelman, M.D., is the Director of the Division of Ophthalmic, and Ear, Nose, and Throat Devices, Office of Device Evaluation, at FDA’s Center for Devices and Radiological Health

Taking New Steps to Meet the Challenges of Rare Diseases — FDA Marks the 11th Rare Disease Day

By: Scott Gottlieb, M.D.

Today 30 million people in the United States – or one out of every 10 Americans – lives with at least one of more than 7,000 rare diseases. These conditions include rare cancers to inherited metabolic disease. And tragically, half of those affected by rare diseases are children.

Dr. Scott GottliebThis week, the U.S. observes the last day of February as Rare Disease Day to raise awareness about rare diseases and their impact on patient’s lives. Unfortunately, finding treatments for these conditions does not become easier or less costly with the rarity of a disease.

In many cases, developing a treatment for a rare disease can be especially hard and present unique challenges. Each success is the end of a long uphill climb. It requires the concerted efforts of many stakeholders, including scientists, product developers, regulators, policy makers, and of course, the energy and organization from patient advocacy groups.

For FDA, Rare Disease Day offers an opportunity to take measure of the progress we’ve made to help people affected by rare disease; and evaluate what more we can do to meet our commitment to advance the needs of patients with rare diseases and their families.

Thirty-five years ago there were few drugs and biologics for rare diseases and even fewer devices. Enacting the Orphan Drug Act in 1983 with its financial incentives and other inducements was an important start to enabling more investment and development of treatments targeted to rare diseases. Also important was legislation passed in 1990, creating a rare disease path for medical devices; known as the Humanitarian Device Exemption (HDE).

Rare Disease Treatment GraphSince 1983, we’ve seen significant progress in treating rare diseases. FDA has approved more than 650 therapies for rare indications. This includes new molecular entities and biologics, as well as new rare disease indications for drugs approved for another indication. We’ve also seen progress in the development of devices for rare diseases. Since 1990, the FDA has approved 72 medical devices for an orphan indication under the agency’s HDE program.

In recent years, the increasing emphasis on personalized medicine, including genetically targeted drug development, has enabled even more opportunities to develop treatments aimed at rare diseases. As a result, during the past five years, the number of requests to have a drug designated as serving an orphan population has steadily increased. In 2017, there were over 700 requests for designation. This was more than double the number of requests received in 2012. Last year we also saw 80 treatments approved by FDA for rare indications, the highest number ever.

FDA’s orphan drug program focuses its efforts on the full range of rare diseases, including relatively more rare or ultra-orphan diseases. In 2010, Miles Braun and other FDA researchers used data from 1983-2008 to show that there’s substantial effort with regard to the rarest diseases. The categories with the most orphan drug designations and the most approvals had very low prevalence levels. New analysis of more recent data shows this trend has been maintained. This experience suggests that the orphan drug program may continue to grow in importance as medicine becomes increasingly personalized, and better able to target the underlying molecular and genetic basis of even very uncommon disorders.

Despite these successes, we recognize that thousands of rare diseases still have no approved treatments. Indeed, FDA’s recent needs assessment survey, done in collaboration with the NIH’s National Center for Advancing Translational Sciences, identified a major public health need for innovative medical devices to care for children and adults with rare diseases.

FDA is committed to doing its part to facilitate continued progress toward more treatments and even potential cures for rare diseases. New scientific opportunities enabled by advances in cell and gene therapy hold out more opportunities to develop these potential cures. With efficient regulation, proper incentives for product development, and the continued support of patients, providers, and innovators; we’re more able to pursue these opportunities than ever before.

In June, I announced FDA’s Orphan Drug Designation Modernization Plan. Our aim was to create a more efficient, scientifically advanced, predictable, and modern approach to the approval of safe and effective treatments for rare diseases. Since then, we’ve eliminated the backlog of orphan drug designation requests. In addition, we’re fully implementing a 90-day timetable for processing new designation requests. We also established an FDA Orphan Products Council to further address scientific and regulatory challenges pertaining to orphan products.

Through our long-standing Orphan Products Grants Program we recently provided $17 million in funding to directly support 15 new clinical trials on products for rare diseases and to fund natural history studies for the first time. These four natural history studies, and an additional two studies funded through an NCATs partnership, could provide key information about how rare diseases develop and progress. This information can be vital for product development.

Of note, I also recently communicated our desire to expand upon these efforts to help foster investment and innovation in, and medical product development for, rare diseases by developing clinical trial networks to create an understanding of the natural history (such as individual patient experiences and progression of symptoms) and clinical outcomes of rare diseases. FDA’s 2019 budget includes a request for resources to make additional investments in rare disease natural history models. It’s clear more work can be done to advance these efforts.

Today I’m pleased to announce several new actions FDA is taking as part of our ongoing commitment to support and expedite the development of rare disease products. They include:

  • A new pilot for more efficient orphan designation requests, including a new fillable form that will make the submission process easier for sponsors to complete designation requests; and make it more efficient for FDA to review. This also includes an on-line tutorial to guide sponsors through the submission process. We’ve also developed a new inter-center consult process to streamline and standardize our communications process.
  • We are entering into a new Memorandum of Understanding with the National Organization for Rare Disorders to conduct outreach with our new Patient Affairs Staff on ways to enhance the incorporation of patient experience into regulatory discussions. As part of this process, we’re planning a joint series of pilot listening sessions on rare diseases. We recognize that early and iterative engagement can improve clinical and regulatory understanding of diseases and conditions; provide a common understanding of the most urgent patient needs; and inform drug development programs.
  • We’re planning a public meeting that will help us prepare for the changing landscape of orphan drug development posed by the growth in targeted therapies and molecularly defined diseases. At an upcoming meeting, we’ll seek input on complex scientific and regulatory issues related to cancer drugs and biologics that target a tumor’s specific genetic features rather than its location in the body (i.e., tissue agnostic approvals). We’ll also consider the appropriate application of orphan incentives to this new paradigm of drug development, and how we apply designations to these indications.

To provide the public with a more complete discussion of the scope of FDA’s rare disease activities, we’ve also created a new, enhanced web page that features videos from our three center directors plus other materials. I invite you to take a look.

Over the course of 2018 we’ll continue our efforts to increase the consistency and efficiency of our reviews of rare disease products. We remain committed to supporting rare disease research on diagnostics, therapies, and potential cures. We’ll also continue to evaluate how to best support investment in rare diseases; and to encourage the development of drugs that target rare, unmet patient needs. A lot of devastating and rare conditions still lack approved therapy. During this Rare Disease Week, it’s gratifying to review the steps we’ve taken, and to commit to more progress in the future, and making sure that our framework supports the needs of patients.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

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.


  • 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

FDA to Expedite Release of Recall Information

By: Douglas Stearn, J.D.

When FDA identifies that a product it regulates violates the law, it protects the public by working with the manufacturer and distributors to facilitate the product’s recall (i.e., removal from the marketplace or product correction). Among other actions, FDA assures that the public is warned when products present the most significant public hazards, including those recalls associated with an outbreak.

Douglas StearnNow, as part of a larger effort to increase transparency, empower consumers, and enhance public health, the FDA is working to alert the public sooner whenever a product has been recalled.

The public’s primary source for recall information is FDA’s weekly, web-based Enforcement Report. Historically, only recalls that have already been classified into one of three categories based on the severity of the hazard have been listed in the report. Through classification, FDA indicates the relative degree of health hazard presented by the recalled product. This enables consumers to better understand the severity of the problem posed by a recalled product so they can take appropriate action. FDA also provides guidance to companies on their recall strategies, taking into account the seriousness of the hazard presented by the recalled product.

However, recall classifications can sometimes take weeks – or even months when FDA needs to conduct a complex evaluation. Such analysis can involve determining whether any diseases or injuries have already occurred, the likelihood that a hazard might occur, or whether vulnerable segments of the population, such as children, are more at risk.

FDA has decided that the public would benefit by having recall information about FDA-regulated products as soon as possible, even though further evaluation remains to be done. Moving forward, FDA will include “not-yet-classified” recalls of human drugs, foods, and veterinary products in the weekly Enforcement Report, even while classification work is still ongoing.

As an example of how this will work, FDA recently posted a “not-yet-classified” recall of a certain lot of animal feed that contained monensin, which can be toxic to cattle at certain levels and could result in cardiovascular illness or death to cattle.

Posting “not-yet-classified” recalls will not affect current FDA protocols for working with companies to ensure that they quickly alert entities in the supply chain as soon as they have identified a problem with their marketed product. Also, FDA will continue to monitor the recalling company’s actions to correct or remove products held by retailers, pharmacies, grocery stores, and hospitals.

In addition to adding “not-yet-classified” recalls of human drugs, food, and veterinary products to the Enforcement Report, FDA recently began posting early summaries of correction or removal actions involving serious problems with medical devices in the Medical Device Recalls Database. FDA has also enhanced the website’s search capabilities. Returning to the site after viewing “not-yet-classified” recalls is recommended because more information is often made available once a recall has been classified.

Classification Risk Definition Examples
Class I Highest Reasonable probability that use/exposure will cause serious adverse health consequences or death. Defective pacemaker, food contaminated with salmonella, defective anesthesia products
Class II Intermediate Use/exposure may cause temporary or medically reversible adverse health consequences, remote probability of serious adverse health consequences. Failure to declare the presence of monosodium glutamate (MSG) in a food product
Class III Lowest Use/exposure is not likely to cause adverse health consequences. Undeclared colors on food product label, sub-potent dandruff shampoo

The public should recognize that recalls are almost always voluntary. Sometimes a company discovers a problem and recalls a product, while at other times a company acts after the FDA raises concerns. Whether FDA or the company discovers the problem, in every case FDA oversees a company’s recall strategy and assesses the adequacy of the recall.

If a product is believed to pose an immediate, serious hazard, FDA will also act quickly, even before classification is complete, to widely publicize a recall. FDA’s publicity efforts may include press releases, advisories, distribution of alerts to subscribers, and updates to the FDA web site. This outreach has proven effective in bringing exhaustive TV, radio, and newspaper coverage about recalls. Increased coverage has occurred in recent years, for example, with certain brands and batches of medicines, injection pens, and contaminated foods such as smoked fish, peanut butter, spinach, frozen vegetables, and ice cream.

The FDA Consumer Update provides more details about the process. Subscribe to the Enforcement Report mailing list at Enforcement Report email subscription. To comment, e-mail enforcementreports@fda.hhs.gov.

Douglas Stearn, J.D., is FDA’s Director, Office of Enforcement and Import Operations, Office of Regulatory Affairs

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

Many “Firsts” for CDER’s 2017 Drug Approvals Reflect Innovation and Enhanced Patient Care

By: Janet Woodcock, M.D.

In 2017, FDA’s Center for Drug Evaluation and Research (CDER) approved many new drugs never before marketed in the United States, known as “novel” drugs, to help improve people’s health.

Janet WoodcockNovel drugs often represent innovative therapies for advancing patient care. 2017 was no exception. We approved new treatments for patients with rare diseases such as Batten disease, Chagas disease, and hemophilia A with inhibitors. We also approved new cancer therapies, new antibiotics, and new therapies for patients with multiple sclerosis, Parkinson’s disease, tardive dyskinesia, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis (often called Lou Gehrig’s disease), among many others.

For the past six years, we have summarized our novel drug approvals in an annual report. This year, we expanded the report beyond novel approvals to show a wide range of other drug therapy approvals that help improve health. For example, we approved many new uses for drugs already on the market, extending their benefits and expanding their reach into new populations, such as children. We have also approved new dosage forms for drugs already available. These are the kinds of actions, separate from approving a novel drug, that can also provide important medical value.

How valuable are these other approvals? Let’s look at an answer in terms of “firsts.” There are many. For instance, there was the first approval of a drug to treat liver cancer in almost a decade, and the first approval of a drug to treat sickle cell disease in almost 20 years. Other firsts for approvals in 2017 will benefit certain patients affected by a wide range of medical conditions, including:

  • Giant cell arteritis, a dangerous condition that results in inflammation of blood vessels;
  • Cytokine release syndrome – a condition related to a reaction caused by a treatment called chimeric antigen receptor (CAR) T cell therapy;
  • Chronic graft versus host disease after a bone marrow transplant;
  • A type of blood cancer called marginal zone lymphoma;
  • Eosinophilic granulomatosis with polyangiitis, a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body; and,
  • Erdheim-Chester Disease, a rare cancer of the blood.

Other firsts for CDER’s drug therapy approvals that are not novel drug approvals include the first:

  • Biosimilars to treat certain cancers;
  • Immediate-release opioid product with properties intended to deter abuse;
  • Once-monthly injectable buprenorphine product to help patients struggling with opioid addiction;
  • Cancer treatment based on a genetic feature of the cancer rather than the location of the body where the tumor originated;
  • Treatment to help prevent recurrence of renal cell carcinoma (kidney cancer);
  • Complete regimen to treat HIV-1 that contains only two drugs, neither a nucleoside reverse transcriptase inhibitor, which can be detrimental to a patient’s kidneys, bones, and heart;
  • Drug approved in the United States with a sensor embedded in the pill that enables a patient to create an electronic record that the medication was taken; and,
  • Short-acting “follow-on” insulin product to treat patients with diabetes.

Our report Advancing Health through Innovation: New Drug Approvals and Other Drug Therapy Advances of 2017 tells the story of these and other important drug therapy approvals that occurred last year. The report also shows the variety of regulatory methods we used to efficiently execute our review and approval of novel drugs, while always prioritizing safety over speed. For example, CDER used at least one “expedited” development and review method for 61 percent (28) of the 46 novel drug approvals of 2017.

In part, as a result of CDER’s efficient methods, 78 percent (36 of 46) of the novel drugs approved in 2017 were approved in the United States before any other country, and 100 percent were approved within their targeted user fee date for application review, as per the goals of the Prescription Drug User Fee Act.

The increasingly vital role patients play in drug development and approval is very important to new drug regulation. CDER collaborates with a wide range of patient advocates and patients to ensure that patients’ perspectives are considered when the agency reviews development plans and drug applications that meet previously unmet needs. We also work with stakeholders in manufacturing, scientific, and medical organizations across the globe to help advance the science needed to develop and evaluate new drug therapies. Our report highlights some of the many public-private partnerships and consortia that CDER leads or participates in to support innovation and improved public health.

Finally, the 2017 report describes CDER’s response to the devastation inflicted by the 2017 hurricane season, working with hospitals and pharmaceutical manufacturers to limit drug shortages and keep those affected safe.

We hope our new report provides a deeper understanding of the many ways CDER works to support innovation and access to medications for improved public health.

Janet Woodcock, M.D., is Director of FDA’s Center for Drug Evaluation and Research