Mission Possible: Moving the Needle Forward to Advance Health Equity

By: CAPT Richardae Araojo

Every April our country observes National Minority Health Month to spotlight what we’re doing to eliminate health disparities among minority populations. A health disparity is a particular type of health difference that is closely linked with social and economic disadvantage, discrimination, or exclusion. We strive for what we call health equity―the attainment of the highest level of health for all people―by enlisting a range of approaches to remove the social and economic obstacles to health faced by racial and ethnic groups.

CAPT AraojoAs the Director of FDA’s Office of Minority Health (OMH), I lead cross-agency efforts with my team to protect, promote, and advance the public health of our country’s most vulnerable and underrepresented populations. OMH does this in many ways. For example, we:

  • Conduct and fund research on diseases that disproportionately affect minorities, like HIV/AIDS, diabetes, and heart disease.
  • Work to diversify the public health workforce by training principal investigators and pharmacists from diverse backgrounds, such as African Americans, Hispanics, American Indians/Alaska Natives, and Asian Americans and other Pacific Islanders, who can relate to research volunteers and patients from underserved communities. Research shows that people want their health professionals to look like them, so a workforce that reflects the demographics of the community it serves is vital.
  • Help minorities make better informed health decisions by creating culturally and linguistically tailored health education materials for use across different social media platforms.
  • Engage with minority-serving institutions of higher learning to protect and improve the health of the populations they serve.
  • Serve as a voice for those in need by encouraging all our constituents to participate in the work that we do. One example is the inaugural FDA Rural Health Symposium, a cross-Agency effort among OMH, the Office of Health and Constituent Affairs, and the Center for Tobacco Products, with participation from other FDA product centers. The symposium offered stakeholders from rural and tribal communities a forum to discuss how we can work together to address rural health challenges that range from the opioid crisis and tobacco use among youth to the need for telemedicine.

In the spirit of this year’s theme for National Minority Health Month, Partnering for Health Equity, I’d like to share a couple of other ways we’ve been partnering with private- and public-sector organizations to further equity on all fronts.

Getting culturally sensitive messages out to minority communities

My office conducts robust communications and outreach activities to share research and information on FDA-regulated products and to promote public health. For instance, Asian Americans, African Americans, and Latinos have lower immunization rates for adult vaccinations like herpes zoster, whooping cough, hepatitis B, and influenza. To better understand these disparities, OMH is supporting a study to assess the impact of advertising and promotional labeling as it relates to vaccine health disparities. OMH has message-tested FDA’s communications with consumer panels, among others, and we’re using the information from this research to shape FDA’s health education materials and outreach to minority communities.

Ensuring minority representation in clinical trials

Ensuring minority representation in clinical trials is crucial to improving minority health because we need to understand how different racial and ethnic groups respond to medical products before they are approved for use in the broad population. To that end, FDA developed guidance for industry and FDA staff. This guidance provides recommendations on using a standardized approach for collecting and reporting race and ethnicity data used to support marketing applications for FDA-regulated medical products.

OMH also works collaboratively with organizations whose mission includes encouraging more minorities to participate in clinical trials. We’ve partnered with the Veteran Health Administration’s Office of Health Equity to launch two videos featuring veterans talking about why diverse representation is so important. These veterans will also appear in the first installment of our new podcast series on health equity and disparities to share their experiences as participants in clinical trials.

Another important partnership involves our newly formed memorandum of understanding (MOU) with Yale University. Under this MOU, we’ll be working to advance scientific collaborations, outreach, and educational initiatives. Especially exciting is the cultural ambassador’s program, which will engage community members to get more involved in clinical research.

In sum, to create a world where health equity is a reality for all we must involve all stakeholders in new ways of thinking and working. And that requires the kind of teamwork, partnerships, and collaboration across disciplines, experiences, and sectors that I’ve shared with you here.

Visit www.fda.gov/minorityhealth for more information on FDA’s Office of Minority Health, and follow us on Twitter @FDAOMH for updates.

CAPT Richardae Araojo is FDA’s Associate Commissioner for Minority Health

New CDER Report Highlights Ongoing Drug Safety Initiatives and Priorities

By: Janet Woodcock, M.D.

At FDA’s Center for Drug Evaluation and Research (CDER), drug safety is among our highest priorities. Before we approve a drug, we make every effort to ensure its benefits outweigh its risks. After approval, we keep a careful watch for new safety issues that can arise once new therapies are prescribed for a broad population of patients.

Janet WoodcockIt’s a complex and ever-changing responsibility. As drug therapies become increasingly advanced, so too must our methods to prevent and/or manage risks related to their use. These risks come in many forms – including adverse events (side effects), problems arising from inappropriate or incorrect use, manufacturing issues related to sophisticated new production techniques, criminal tampering or counterfeiting, and the devastating effects of addiction, like that of the opioid epidemic. And, as innovative study methods provide new information, new safety issues can emerge for drugs that have been on the market and widely used for decades. For these reasons, we focus our efforts both on newly approved drug therapies and those already on the market.

Our annual report, Drug Safety Priorities 2017, provides updates on our ongoing initiatives, discusses new work, and highlights last year’s safety-related milestones and achievements.

Protecting the American public from risks associated with medications requires teamwork from many scientific and medical specialists at FDA working together to inform decisive regulatory action. Key efforts include the Safe Use Initiative to reduce preventable harm from medications; the FDA Adverse Event Reporting System (FAERS), which collects vast amounts of data about side effects and medication errors from medical products reported by patients, health care professionals, and manufacturers; and the Sentinel System, our state-of-the-art electronic drug safety surveillance system. We also collaborate with health care professionals, academia, researchers, and other health and science agencies in studying the effects of medications before and after approval to help ensure that the benefits of these therapies outweigh their risks.

Our report describes many ways CDER worked in 2017 to enhance drug safety for the American public. These include:

  • Safety surveillance and oversight of marketed drug products: In 2017, CDER’s Office of Surveillance and Epidemiology (OSE) conducted 7,446 safety reviews. Of those, 2,860 were initiated as a result of ongoing OSE surveillance.
  • The importance of real-world evidence to help advance drug safety science: Although randomized clinical trials (RCTs) are the gold standard for medical and scientific evidence needed to support FDA drug product approval decisions, they are often conducted in specialized and controlled research settings and are time-consuming and costly. And at the end of a drug development program, RCTs can leave critical questions unanswered, particularly about the effects or impacts of a drug after it gets into the “real world,” and is used by hundreds of thousands of people over an extended period. CDER safety scientists are using powerful new scientific computing and data storage technologies to enhance our capabilities of gaining valuable information from “real world evidence.”
  • New tools and new approaches for fighting our Nation’s opioid crisis: Our report emphasizes that in 2016, an estimated 11.5 million people misused prescription opioids — and that each day of that year, an estimated 116 people died from an opioid-related overdose. FDA actions taken in 2017 in response to the opioid epidemic align with our current four key priorities in this area: 1) decreasing exposure and preventing new addiction, 2) safely treating those with opioid addiction, 3) developing safe and effective novel alternative therapies to opioids, and, 4) improving enforcement of safety measures and assessing benefit-risk ratios.
  • Safety oversight for generic drugs: The report explains how we evaluate generic drugs to ensure they meet quality standards and deliver the necessary amount of active ingredient, and how we monitor generic drug use in the marketplace to flag early safety concerns. CDER’s Clinical Safety Surveillance Staff (CSSS) is addressing post-marketing safety concerns related to complex generic drug-device combination products. In 2017 a generic drug had two intravenous (IV) bag ports (rather than a single IV bag port used by the brand name drug). This difference raised concerns for potential confusion, risk of incompatibility issues, and potential adverse events in patients. The CSSS’s collaboration activities led to the development of a new process for managing review of similar IV bags with different port configurations.
  • Efforts to reduce preventable harm from medications: More than a million Americans are injured or killed each year due to preventable medication errors. FDA’s Safe Use Initiative works to reduce preventable medication-related errors, such as medicines dispensed in error, medicines taken for too long or not long enough, or medicines inappropriately mixed with other medicines or with foods that can increase risks of side effects. Among many other efforts, our work through the Safe Use Initiative in 2017 included making recommendations to enhance the safety of fluoroquinolone antibiotics, identifying “high-risk” prescribers (those who write prescriptions for high doses or co-prescribe with medications which increase the risk of adverse events) and educating them about safer prescribing practices, and identifying which diabetic patients may be at high risk of hypoglycemia (low blood sugar).
  • Compounded drugs – continuing regulatory and oversight efforts: FDA has taken many steps to strengthen safety measures for compounded medications since the 2012 outbreak of fungal meningitis associated with contaminated compounded drugs. Among other actions, the agency conducted 140 inspections, sent 55 warning letters, and issued 40 recalls related to compounding.
  • Diverse strategies, tools, and services for communicating drug safety: Effectively communicating what we do is an essential component of our work to protect the public. In 2017, we responded to 57,094 inquiries from the public (39,883 by phone, 16,269 by e-mail, and 942 via written letters), each an opportunity to help a patient ensure they are safely using their medication. Our Drug Safety Podcasts reached an estimated 350,000 listeners each week. These and many other communication efforts, such as our Drug Safety Communications that alert consumers and health care professionals about new or potential safety issues, serve to keep the public informed of important drug safety concerns that may impact them.

The report also details a variety of ways we keep pace with the rapid evolution of technology. For instance, we are evaluating the use of technologies, such as machine learning methods and other advanced computation techniques, to help our analytics systems contribute to more predictive safety and risk data. We are also exploring ways to leverage mobile apps, social media, and electronic prescribing data while ensuring patient privacy. As we pursue a wide-ranging safety agenda, CDER Drug Safety Priorities 2017 offers a deeper dive into FDA’s drug safety research, surveillance, and regulatory activities. We hope this report serves to demonstrate CDER’s ongoing commitment to protect the American public.

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

Ironed Out

By: Vanessa Burrows, Ph.D.

During the early part of the 20th century, the growing scientific knowledge that certain diseases were caused by vitamin and mineral deficiencies sparked public interest in products that touted these substances. But the public had little understanding of this emerging health care field and, as a result, was often easy prey for unscrupulous marketers who used phony claims that their products had therapeutic value.

Vanessa BurrowsOne such charlatan was a man named E. Virgil Neal, whose past schemes included palm-reading and hypnotism performed under the name Xenophon LaMotte Sage; a mail-order health and self-improvement program, which earned him a conviction for mail fraud; and a French cosmetics company that marketed false hair regenerators and bust enhancers.

Operating at the dawn of the modern advertising age, Neal employed a sophisticated and misleading marketing campaign to sell Nuxated Iron pills, which included iron and nux vomica, a derivative of the strychnine tree, which is highly toxic to humans and other animals. Beginning in 1917, Neal’s advertisements used celebrity endorsements that touted the product’s invigorating and strength-building qualities, promising to alleviate “that tired feeling.” However, the pills contained so little iron that their health impact was questionable, and so much strychnine that, in at least one case, they caused the fatal poisoning of a young boy.

Neal’s fraudulence was exposed by the American Medical Association and journalists in the early 1920s, but FDA was unable to prosecute him because the misbranding provisions of the 1906 Pure Food and Drugs Act did not outlaw misleading promotional material of the type that Neal distributed. Neal’s product actually contained some iron, albeit negligible amounts, and only made therapeutic claims in promotional materials. It wasn’t until 1944, after the passage of the 1938 Federal Food, Drug, and Cosmetic Act, when FDA was able to take action against the product on new types of misbranding grounds, which forbid, among other things, misrepresenting the quantity of ingredients contained in the product.

Today, FDA continues to play a critical role in protecting consumers from fraudulent, adulterated, and misbranded products like Nuxated Iron.

We hope you enjoy your visit to the History Vault.

Vanessa Burrows, Ph.D., is an FDA Historian

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

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.

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

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.

RECALL CLASSIFICATIONS
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

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