Rare Diseases at FDA: A Successful Year for Orphan Products

By: Gayatri R. Rao, M.D., J.D.

2014 was a strong year for rare disease product development at FDA. It was also a year of significant firsts.

Dr. Gayatri RaoIn recognition of Rare Disease Day, February 28th, we want to reflect on the progress we have made thus far as we renew our commitment to rare disease patients. A rare disease is generally defined as a disease which affects fewer than 200,000 Americans a year. At FDA, the commitment to increase access to diagnostics and treatments to change the day-to-day reality of those living with rare diseases began over 30 years ago with the passage of the Orphan Drug Act.That commitment has steadily increased since then.

In 2014, we received our highest number to date of new requests for orphan drug designation. We received over 440 requests while just 7 years ago, we received less than half of that. We designated and approved more orphan drugs in 2014 than we had in previous years – nearly 300 drugs were designated and 48 were approved, including both novel and repurposed drugs. In 2014, 41% of all novel new drugs approved by the Center for Drug Evaluation and Research were for the treatment of rare diseases. Many of these orphan drug approvals were new and innovative, including Sylvant, to treat Castleman’s disease, which results in excessive lymph node growth, and Impavido, to treat forms of the tropical disease, leishmaniasis.

2014 was also a year of firsts for rare disease product development:

There were firsts in device development. For example, the Center for Biologics Evaluation and Research approved its first device through the Humanitarian Device Exemption (HDE) pathway. This device, CliniMACS CD34 Reagent System, helps to mitigate potentially serious immune reactions associated with stem cell transplantation in patients with acute myeloid leukemia.

FDA produced in 2014 its first agency-wide blueprint to accelerate the development of therapies for pediatric rare diseases – a report and strategic plan outlining how to address issues for developing products for this population.

2014 saw the issuance of the first rare pediatric disease priority review voucher for the treatment of mucopolysaccharidosis type IVA (Morquio A syndrome), a rare lysosomal storage disease which affects about 1000 patients in the United States and can lead to debilitating and life-threatening abnormalities of bones, joints and the heart.

In recognition of Rare Disease Day 2015, the international rare disease community is coming together to pay tribute to the millions of individuals impacted by rare diseases all over the world. Through the solidarity and commitment of many stakeholders – patients and families, healthcare professionals, researchers, companies, and policy makers – the awareness of the daily challenges that are unique to each rare disease and the efforts to create solutions has risen exponentially in the past several decades. As members of the rare disease community, we are proud of our collective accomplishments but remain acutely aware of how much more there is still to be done. Given how 2015 is already shaping up, we expect that by working together, we will continue to make great strides in developing much needed products for the millions of patients living with rare diseases.

Gayatri R. Rao, M.D., J.D., is FDA’s Director for The Office of Orphan Products Development

Shedding some light on FDA’s review of sunscreen ingredients and the Sunscreen Innovation Act

By: Theresa M. Michele, M.D.

With recent record snowfalls in many parts of the country, the use of sunscreens may not have been on many people’s minds. But here at FDA, sunscreens have been a front-and-center issue.

Theresa Michele, M.D.On November 26, 2014, Congress enacted the Sunscreen Innovation Act (SIA) that provides a new process for the review of safety and effectiveness of nonprescription sunscreen active ingredients. Among other things, the SIA creates timelines for FDA review.

Before the law was enacted we followed the regulatory process known as the Time and Extent Applications process, or TEA process for sunscreen active ingredients. This regulatory process provides, among other things, a mechanism for sponsors to request that FDA evaluate active ingredients that are used in over-the-counter (OTC) drug products, particularly those marketed in other countries. The TEA process can be summarized in two basic steps. Step 1 is FDA’s determination of eligibility, made upon a showing that the ingredient has been marketed over-the-counter in one or more countries for a material time and extent. Step 2 is FDA’s evaluation of the data to determine whether the ingredient is generally recognized as safe and effective (GRASE) for its intended use in an OTC drug product as described in the relevant regulation. If, after review of the data, FDA ultimately finds the ingredient to be GRASE for its intended OTC use, the ingredient may enter the U.S. marketplace. There were eight TEAs for sunscreen ingredients submitted to FDA before the SIA went into effect.

On January 7, we met the first requirement of the SIA. In doing so, we announced our tentative determinations that six of these ingredients are not GRASE for use in sunscreens because we need more data from the manufacturers to help establish the safety and effectiveness of these products.

Today, we completed another requirement by taking initial action on the last two pending ingredients, ecamsule and enzacamene. We tentatively determined, as we had with the other six ingredients, that we need more data to decide if these ingredients are, in fact, GRASE for use in OTC sunscreen products. Information about the SIA and our recent actions under the law are available on our new web page for this topic.

At this time there is not enough generally available data to determine whether any of the ingredients under review meet FDA’s safety and effectiveness standards.

We know our careful actions to seek more information may be disappointing to some who would like to see additional sunscreen products on the market immediately, but I’d like to take this opportunity to clarify some misconceptions about the SIA and the process for making sunscreen ingredients available for use in OTC products marketed without individual premarket review in the U.S.:

  • The law does not change FDA’s standard for general recognition of safety and effectiveness. The SIA requires strict deadlines for FDA to take action on these ingredients, but it does not relax the FDA’s scientific standards for evaluating the ingredient’s safety and effectiveness, or our need for adequate data on which to base such determinations.
  • The law does not provide FDA with additional resources. Recognizing the public health importance of sunscreen use, the FDA is proceeding as quickly as practicable to meet the requirements of the legislation. To assist in this process and to reduce the negative impact on other work, FDA is requesting funds for implementation of the SIA as part of the President’s fiscal year (FY) 2016 budget.
  • The SIA does not guarantee that products with additional sunscreen ingredients will be on the market in a specified timeframe. Because additional data are needed for each of the eight sunscreen ingredients, timelines for FDA actions are triggered by industry’s submission of required data.
  • There is apparent confusion as to why ingredients that have been on the market for years in other countries cannot be used in the U.S. without further review by FDA. While information on marketing history in other countries is helpful, what we can learn from it is limited. For example, such information doesn’t tell us anything about the long-term effects from use of the ingredient or how much is absorbed. Because of the widespread daily use of sunscreen products by a broad population, including babies and pregnant women, FDA has proposed data requirements that will allow us to determine that sunscreen ingredients are generally recognized as safe and effective. These data requirements were unanimously supported by a panel of scientific experts at a recent public Advisory Committee meeting on sunscreens.

We cannot achieve success in bringing additional sunscreens to market on our own. FDA is committed to doing our best to meet the new statutory deadlines, and we will be transparent in our process and progress. Successful implementation of the SIA will require a cooperative effort with industry and other stakeholders. We look forward to continuing this important work.

Theresa M. Michele, M.D., is the Director of the Division of Nonprescription Drug Products in FDA’s Center for Drug Evaluation and Research’s Office of New Drugs

Recent Progress on Demographic Information and Clinical Trials

By: Barbara D. Buch, M.D.

At FDA, one of our foremost responsibilities is to evaluate and if medical products meets the appropriate standard, to approve or clear drugs, biological products and medical devices. We know that these products are safer and more effective for everyone when they are tested in clinical trials that include diverse populations.

Dr. Barbara BuchThe design and analysis of clinical trials has evolved significantly over the last three decades.  FDA now has a variety of statutory, regulatory, and policy-related tools at its disposal that provide a framework for guiding medical product sponsors and FDA review teams in the collection, subset analyses, and communication of these data.

Collecting and analyzing information in clinical trials about sex, age, and race/ethnicity, makes it possible for individuals or groups considering a treatment option to look at the information and ask, “Was there anyone like me in the clinical studies? And if so, how did they do?”

Section 907 of the Food and Drug Administration Safety and Innovation Act (FDASIA) directed FDA to look at these questions on a broader scale: to investigate how well demographic subgroups (sex, age, race and ethnicity) are included in clinical trials; whether they are analyzed for safety and effectiveness by these subgroups; and to improve on making the resulting information available to the public. After systematically reviewing 72 medical product applications, FDA published a report, in August 2013, which concluded that FDA has been doing a good job, but we acknowledged we could do better.  In August of last year we came up with a plan to improve our performance. The Action Plan includes 27 action items focused on three priorities:

  • Quality: to improve the completeness and quality of demographic subgroup data collection, reporting and analysis;
  • Participation: to identify barriers to subgroup enrollment in clinical trials and employ strategies to encourage greater participation;
  • Transparency: to improve the public availability of demographic subgroup data.

Since the release of the report, FDA has formed an agency-wide steering committee, which I chair. FDA has made significant progress.

So far, FDA:

  • Has launched the Drug Snapshots web page that extracts Demographic Subgroup Data for FDA approved products. The information in a drug trials snapshot is taken from the data submitted in a new drug application or a biologic license application. It includes information on study participants, how the study was designed, the results of the efficacy and safety studies and the differences in side effects and in benefits among sex, race and age groups.
  • Is leveraging IT platforms already in place to support electronic submissions that enhance FDA’s systems for collecting, analyzing, and communicating standardized data collection categories by age, racial and ethnic groups in submitted applications. This will facilitate harmonized data collection and analysis of subgroup outcome trends, and diverse clinical information in diverse populations over the total product life cycle in a standard way. These systems are also developed to facilitate industry’s data input and allow for better tracking of these data.
  • Has added education/training for reviewers about demographic inclusion, analysis, and communication of clinical data. We have also developed plans to incorporate details of demographic subgroup analyses in review templates.
  • Has proposed changes (to the MedWatch adverse event reporting forms to enhance the clarity and utility of the demographic information FDA is able to collect in the post-market setting. These include collecting data about race/ethnicity and age.
  • Has launched a study with health care professionals to improve usability and understanding of medical device labeling, including instructions for use.
  • Is working with industry to try to establish best practices and ways to help ensure appropriate use of enrollment criteria in clinical trial protocols.
  • Has established a joint working group with the National Institutes of Health (NIH) to create a framework for collaborating and exchanging information on inclusion policies, practices and challenges.
  • Is participating with NIH in a session at the Society for Clinical Trials annual meeting in May 2015, on approaches to clinical trial study design and analyses that maximize sex-specific data reporting.

We are proud of our progress to date – but we can always do more. That is why in early 2016, FDA will host a public meeting to gain insight and feedback. Watch this space for details, as well as new developments in our quest to integrate more fully the demographics of patient populations into our review of medical products.

Barbara D. Buch, M.D., is the Chair of the 907 Steering committee and the Associate Director for Medicine in FDA’s Center for Biologics Evaluation and Research

 

The Meaning of Wearing Red

By: Margaret A. Hamburg, M.D.

Last night I had the pleasure of attending the annual Woman’s Day Red Dress awards ceremony in New York City. The event is one of the highlights of American Heart Month, and it was created by that magazine to educate Americans about, and help fight, heart disease, which has become the number one killer of women. Many are surprised to learn that while breast cancer is the cause of death of one in every 31 American women, one of every three women dies of heart disease. So I found it particularly meaningful, both as a doctor and a woman, to be honored for FDA’s work to improve women’s cardiovascular health.

Commissioner Hamburg at Event

FDA Commissioner Margaret A. Hamburg, M.D., at the Woman’s Day Red Dress awards ceremony in New York City

One of our efforts toward this end that was cited by the magazine was the proposal to update the Nutrition Facts Label. The proposed updates would more prominently highlight calorie and serving size information, inform consumers about “added sugars,” update the daily values for nutrients, and ensure that the serving size requirements reflect the amounts of food people actually consume. They would encourage consumers to use the label to take note of foods high in sodium, saturated fat, and trans fat, which can increase the risk of coronary heart disease.

We also published final rules on restaurant menu and vending machine labeling. Calorie information is the key component of these requirements, and obesity is associated with a range of heart disease related problems. The new rules also require that other nutrition information, such as sodium, is provided upon the consumer’s request. High sodium intake can increase blood pressure, a major risk factor for heart disease. As with the nutrition facts label, these menu labeling requirements will give consumers nutrition information they need to be able to make healthy food choices for themselves and their families.

Another part of FDA that matters for cardiovascular health is our Center for Tobacco Products. Though its work is designed to protect the health of all Americans, it has special significance for women who, sadly, are catching up to men in the prevalence of tobacco-related diseases.

In the last 50 years, a woman’s risk of dying from smoking has more than tripled, and is now equal to that for men – not what we desire when we talk about equality. The more than 20 million women in the U.S. who smoke cigarettes are at risk not just for heart attacks, lung cancer, and strokes, but also emphysema and other serious chronic illnesses such as diabetes.

Our actions on smoking and nutrition have been complemented by the work of the Office of Women’s Health. Its outreach initiatives have helped provide women with tips and resources they can use to make better heart health decisions for themselves and their families. This Office has also supported research on treatment of heart disease in women.

FDA’s responsibilities also include reviewing, approving, and helping advance new and innovative medical products to diagnose, treat and prevent heart disease, including life-saving medical devices such as artificial hearts, stents, and heart valves, essential tests like echocardiograms, and important drugs for hypertension, lowering cholesterol and treating other aspects of cardiovascular disease.

Over the years, FDA’s support of women’s health has grown thanks to scientific advances, changes in society, and improvements in the agency itself. We will continue to promote these goals, not just in the area of cardiovascular health, but in women’s health more generally.

Of course, we can’t do it alone. And that’s why I sincerely welcome such events as the National Wear Red Day and Woman’s Day’s Red Dress awards. They help focus our nation’s attention and energy on the fight against women’s heart disease to which we, at FDA, are fully committed.

Margaret A. Hamburg, M.D., is the Commissioner of Food and Drugs

A Year of Significant Progress in Public Health

By: Margaret A. Hamburg, M.D.

Margaret Hamburg, M.D.A new year offers both an opportunity to look forward and an opportunity to reflect on the achievements of the previous year. And, in 2014, FDA’s accomplishments were substantial, touching on many of the agency’s broad responsibilities to protect and promote the public health.

Whether our achievements involved medical product safety and innovation, food safety and nutrition, tobacco control, or other areas of our important work, all were accomplished thanks in large part to our ability to respond to evolving needs and opportunities including the embrace of new approvals, technologies and cutting-edge science.

Consider these highlights:

Drug Approvals: This past calendar year, FDA approved 51 novel drugs and biologics (41 by CDER and 10 by CBER), the most in almost 20 years. Among CDER’s 2014 approvals are treatments for cancer, hepatitis C and type-2 diabetes, as well as the most new drugs for “orphan” diseases since Congress enacted the Orphan Drug Act over 30 years ago. Seventeen of these new approvals are “first in class” therapies, which represent new approaches in the treatment of disease. In addition, CBER approved many important biological products in 2014, including a number of groundbreaking vaccines for meningitis B, the flu, and certain types of Human Papillomavirus, the latter of which is expected to prevent approximately 90 percent of the cervical, vulvar, vaginal and anal cancers caused by HPV.

These developments are a testament not just to our expanding understanding of human biology, the biology of disease and the molecular mechanisms that drive the disease process, but also to FDA’s innovative approaches to help expedite development and review of medical products that target unmet medical needs, while adhering to the established standards for safety and efficacy. These include enhanced guidance to shape the research and development agenda, early input on clinical study needs and design, expedited review programs, targeted regulatory advice and other tools and incentives that spur investment and innovation in new medical products to address unmet medical needs.

Opioids: This past year FDA took several actions to address the abuse of opioid drugs. First, we approved abuse deterrent labeling for three opioid products that are designed to deter prescription drug abuse. These drugs used different technologies to combat the abuse problem in different ways, such as by making the product resistant to crushing or dissolving or using “aversive technology” to discourage users from taking more than the approved dosage of the drug. To help encourage the development of more drugs in abuse-deterrent forms, we are also working to provide additional advice to manufacturers. Although abuse-deterrent opioid drugs are not a silver bullet to prevent opioid abuse, we believe that our work in this area will give physicians effective new treatment options with less risk of abuse.

FDA also worked to improve the treatment of patients who overdose on opioids. We approved a new dosage form of naloxone, with an autoinjector to enable a caregiver to administer the drug in the emergency treatment of opioid overdose (as it rapidly reverses the effects of an overdose). While we continue to support development in this area, this approval offers a new valuable tool to help prevent the tragedy of opioid drug overdose.

Antibiotic Resistance: We made important strides in confronting the growing resistance of some bacteria to antimicrobial drugs. Our efforts, which are a critical part of the recently unveiled National Strategy on Combating Antibiotic Resistant Bacteria, offer a multi-pronged approach that recognizes that to effectively address this challenge means simultaneously addressing the many different causes for increasing antibiotic resistance. One important response has been efforts to expand the pipeline of new medical products, including therapeutics to treat and cure infection, diagnostics to aid in the identification of the cause of infection and of resistant infections, and vaccines to help prevent infection with bacteria in the first place.

These efforts are already having an impact. In 2014, FDA approved four novel systemic antibiotics. In contrast, only five new antibiotics had been approved in the previous ten year period.

In addition to working on the human medical product side, we also developed and, over the next two years will be implementing, an important complementary strategy to eliminate the use of medically important antibiotics for growth promotion in food-producing animals. This strategy, once fully implemented, also will bring the remaining uses of such drugs to treat, control or prevent disease in these animals under the oversight of veterinarians. All 26 animal health companies who produce those drugs have committed to participate, and 31 products already have been withdrawn from the market.

Pharmacy Compounding: We continued to respond effectively to the 2012 outbreak of fungal meningitis that was linked to contaminated compounded drugs. This included conducting more than 90 inspections of compounding facilities across the nation in the past year. As a result, numerous firms that engaged in poor sterile practices stopped making sterile drugs, and many firms recalled drugs that have been made under substandard conditions. Where appropriate, we have worked with the Department of Justice to pursue enforcement action against some of these facilities.

We also have continued to implement the compounding provisions of the Drug Quality and Security Act (DQSA), and to develop and implement policies to address compounding by state-licensed pharmacies and the new category of registered outsourcing facilities.

Food Safety: Over the past year, the Agency has made great strides in implementing the landmark FDA Food Safety Modernization Act (FSMA). Through our proposed rules for preventive controls requirements for both human and animal food, standards for produce safety, foreign supplier verification programs, third party auditor accreditation, focused mitigation strategies to prevent intentional adulteration of food aimed at causing large-scale public health harm, and requirements for sanitary transportation practices to ensure the safe transport of food, we are working to ensure the safety of American consumers related to the foods they eat.

Nutrition: Good health depends not just on food safety, but also on what we choose to eat. FDA plays an important role in promoting good nutrition and healthy food choices by helping consumers understand the importance and benefits of good nutrition – and of being able to make informed choices about what we eat.

New rules in 2014 to finalize requiring calorie information on restaurant menus and vending machines give our citizens information they need to make healthy food choices and hopefully help reduce the epidemic of obesity in the United States. We also proposed changes to the familiar “Nutrition Facts” label on packaged foods which, when finalized, will give our citizens updated nutrition information, reflecting the most current nutrition science, to help them make healthy choices when purchasing packaged foods.

Tobacco Control: There are few areas that have as profound an impact on public health as tobacco products, which is why, five years ago, Congress gave FDA the responsibility to oversee the manufacture, marketing, distribution, and sale of tobacco products.

Over the past year, we worked with state authorities to conduct more than 124,000 inspections of retailers to enforce the ban on the sale of tobacco products to children. We unveiled the first of its kind national public education campaign—The Real Cost—to reduce youth smoking. And we took the first steps towards extending the agency’s tobacco product authority over additional products such as electronic cigarettes (e-cigarettes), cigars, pipe tobacco, nicotine gels, waterpipe (hookah) tobacco, and dissolvables not already subject to such authority through our proposed “Deeming Rule.” In addition, as part of ongoing work on product review decisions, eleven tobacco products that were allowed to enter the market during a provisional period established by the Tobacco Control Act were found “not substantially equivalent” to a predicate tobacco product. As a result of this finding, these products can no longer be sold or distributed in interstate commerce or imported into the United States.

Ebola: The tragic Ebola epidemic in West Africa demonstrates that we do not have the luxury of closing our eyes – or our borders – to the public health problems that exist in the rest of the world. I’m proud that FDA has played an important role in the response to this disease, working closely with colleagues in our government as well as the scientific community, industry and a range of other organizations and nations. We have helped facilitate the development, testing, manufacture, and availability of investigational products for use in diagnosing, treating and preventing Ebola, and worked with sponsors and health care providers to facilitate access to these products as clinical circumstances warrant. In August 2014, FDA designated the drug Z-Mapp as an orphan drug for Ebola, with the hope that this would incentivize further development and study.

And I’m very pleased to report that FDA is represented on the ground in West Africa by dedicated officers of the Commissioned Corps of the Public Health Service who continue to staff and operate the Monrovia Medical Unit in Liberia that was built to treat the health workers who became ill responding to the outbreak. Like everything FDA does, both at home and abroad, our actions on Ebola represent our agency’s continuing commitment to health and safety, and the use of science to advance these important goals.

I am extremely proud of our accomplishments in 2014, and I am confident that FDA will have a successful 2015, as we continue our work to protect and promote the public health.

Margaret A. Hamburg, M.D., is Commissioner of the Food and Drug Administration

A big step to help the patients most in need

By: Peter Lurie, M.D., M.P.H.

Today, I had the pleasure of announcing an important measure intended to help streamline expanded access to investigational drugs. We heard concerns from patients and physicians that the process for gaining access to investigational drugs was too difficult, and pulled together a team to find a way to make that process simpler. Today, we’re introducing a much simpler draft form for comment that, when finalized, should accelerate patient access to investigational drugs. We know what an important tool this will be for physicians who treat those patients with serious or immediately life-threatening diseases or conditions for which there are no comparable alternative treatments.

Dr. Peter LurieThe new draft document, entitled “Individual Patient Expanded Access Applications: Form FDA 3926,” includes a simplified application form that, when finalized, will be used for requesting the medications, and is designed to greatly simplify and accelerate the process by which a physician can request that FDA permit the use of an experimental — so-called “investigational” — drug or biological product while it’s still being tested to establish its safety and effectiveness.

The draft guidance and draft form continue a policy that started in the early years of the AIDS epidemic when FDA authorized, in certain cases, “compassionate use” of unapproved investigational drugs. In 2009, FDA made these rules broader and clearer. However, concerns persisted that the existing application form was too complex: it called for 26 separate types of information and seven attachments. In fact, it was originally designed for manufacturers seeking to begin human testing, not for physicians seeking use by single patients.

FDA authorizes the vast majority of expanded access requests, typically within days or even hours. However, FDA is committed to streamlining its processes wherever possible. The agency therefore tasked a special working group with designing a form more suitable for use by a physician not necessarily familiar with the IND process. The revised process, when finalized, will not change the agency’s rigorous requirement that all medical products on the market be studied in clinical trials in order to be FDA-approved as safe and effective. As before, expanded access to an investigational medication may be available when there is no other product that can diagnose, monitor, or treat the patient’s disease or condition, and the patient is not and cannot be enrolled in a clinical study testing it.

But we know why patients want access to these drugs and we know how busy their treating physicians can be. So we streamlined the new draft form to be shorter and simpler for physicians to fill out. The new draft form, when finalized, will require only eight elements of information and a single attachment. We estimate that physicians will be able to complete the finalized version of the form in just 45 minutes, as compared to the 100 hours listed on the previous form.

Additionally, to further assist the physician seeking access to an experimental therapy, we have redesigned our website to make it easier to navigate and to explain the new proposed process in detail.

For years, FDA has maintained a staff dedicated to assisting physicians and patients to navigate our system. These efforts will continue. The new draft guidance and draft form are the latest examples of FDA’s determined effort to minimize unnecessary red tape, increase efficiency and better serve patients in need.

Peter Lurie M.D., M.P.H. is associate FDA commissioner for public health strategy and analysis.

FDA’s FY 2016 Budget Request

By: Margaret A. Hamburg, M.D.

Margaret Hamburg, M.D.FDA oversees products that represent more than 20 cents of every dollar that American consumers spend. Today, FDA presented its FY 2016 budget to Congress.This sensible budget request will help ensure that FDA can continue to fulfill its vast responsibilities to protect the public health, safety, and quality of life of the American public.

I want to share the cover letter that I wrote to Congress outlining some of our specific proposals.

 

Letter from the Commissioner

I am pleased to present the FY 2016 Food and Drug Administration (FDA) Budget.

FDA fulfills its important mission to promote and protect health in an increasingly complex and globalized world in many ways.  The scope of our work includes assuring that foods are safe, wholesome, sanitary and properly labeled; ensuring that human and veterinary drugs, vaccines and other biological products, and medical devices intended for human use are safe and effective; and regulating tobacco products.  We also play a lead role in protecting the public from electronic product radiation and assuring that cosmetics and dietary supplements are safe and properly labeled.  Finally, we have devoted – and will continue to devote – substantial resources to advancing the public health by helping to speed product innovations.

FDA’s responsibilities continue to expand as we work to fulfill the mandates of groundbreaking legislation passed in recent years, including the Family Smoking Prevention and Tobacco Control Act of 2009, the Patient Protection and Affordable Care Act of 2010, the Food Safety Modernization Act (FSMA) of 2011, the FDA Safety and Innovation Act (FDASIA) of 2012, and the Drug Quality and Security Act of 2013.  Further, with so many FDA-regulated products manufactured in whole or in part outside of our borders, FDA is keenly focused on the complexities of regulating in a global marketplace.

In FY 2014, we took important steps to finalize a key set of proposed food safety rules; worked to improve the safety of compounded pharmaceutical products by conducting more than 90 inspections and implementing compounding legislation through proposed regulations, guidances, and other actions; published the “deeming rule” to extend FDA’s tobacco authority; and collaborated with federal, international, and industry partners to expedite the development and availability of medical products.  In addition, FDA has worked intensively to respond to the Ebola epidemic in West Africa by facilitating the development and availability of investigational diagnostics, therapeutics, and vaccines with the potential to help combat the epidemic.

FDA continues to seek new ways to obtain the most public health value for the federal dollar as we implement expanded authorities.  The products that FDA regulates are essential to public health, safety, and quality of life and represent over 20 cents of every consumer dollar spent on products in the United States.  Yet, in terms of our FDA budget, each American taxpayer contributes approximately $8 per year for the vast array of protections and services provided by FDA.

In FY 2016, we are requesting essential and timely resources to address critical food and medical product safety issues.  Mindful of the fiscal environment, we have identified targeted reductions where possible and identified long-term needs for additional user fees to balance budget authority growth.  FDA is requesting a total of $4.9 billion to support our various mandates to protect the American people.  This includes a $148 million budget authority increase to focus on the following:

  • delivering a farm-to-table system of prevention, including improved oversight of imported foods, through effectively implementing the final rules required by FSMA;
  • combating the growing threat of antibiotic resistance – in which drugs become less effective, or ineffective, against harmful bacteria;
  • promoting the development and appropriate use of reliable molecular and genetic diagnostics – precision medicine tools – to “personalize” the diagnosis, treatment, and prevention of disease;
  • implementing key FDASIA requirements to improve medical product review and inspections;
  • addressing the safety of compounded drugs;
  • continuing implementation of new requirements for review of sunscreen ingredients under the Sunscreen Innovation Act; and
  • supporting modern facilities to provide the laboratories and office space needed to meet FDA’s expanded legislative mandates.

As a science-based regulatory agency with a public health mission, FDA plays a unique and essential role in promoting and protecting public health and safety.  We are committed to meeting the needs and expectations of the American people.

Margaret A. Hamburg, M.D.

Commissioner of Food and Drugs

FDA Considering How to Tailor its Oversight for Next Generation Sequencing

By: Margaret A. Hamburg, M.D.

FDA is weighing the appropriate regulatory approach to advances in technology that allow physicians to obtain information on large segments of a patient’s genetic makeup very quickly.

Margaret Hamburg, M.D.This technology is known as next generation sequencing, where a single test potentially can be employed to identify thousands—even millions—of genetic variants carried by a single individual. The results of such tests could be used to diagnose or predict a person’s risk of developing many different conditions or diseases and potentially help physicians and patients determine what course of treatment should be used to treat specific individuals.

Reliable and accurate NGS technologies promise to accelerate “personalized” or “precision” medicine, the tailoring of medical treatment to the individual characteristics of each patient. But they also pose some novel issues for FDA in carrying out our mission of protecting and promoting public health.

Most diagnostic tests follow a one test—one disease paradigm that readily fits FDA’s current device review approaches for evaluating a test’s analytical and clinical performance. Next generation sequencing produces a massive amount of data that may be better handled using a new approach.

Last year we took steps to adapt our oversight approach to this new technology with the marketing authorization of the first NGS sequencing instrument, Illumina’s MiSeqDx Instrument and its two tests for cystic fibrosis (CF) mutations. We applied practical regulation to these products: we looked at how accurately the instrument sequenced a representative set of genetic variants across the genome rather than requiring data on every possible variant. Doing so avoided years of data gathering and unnecessary delay in the public’s access to the benefits of this technology while still assuring its accuracy and reliability.

Similar flexibility was employed in assessing the two CF tests. FDA allowed Illumina to leverage a well-curated, shared database of CF mutations to demonstrate the clinical value of its tests, rather than requiring them to independently generate data to support each mutation’s association with the disease.

In the future, next generation sequencing tests may be available to rapidly address new medical knowledge that can be applied in treating patients. Medical knowledge itself can be strengthened through creating databases of research and clinical information tied to particular genetic variants. FDA intends to develop a practical and nimble approach that will allow medical advances to be implemented as soon as possible, using its regulatory flexibility and the power of the information placed into high-quality databases.

This week President Obama unveiled his Precision Medicine Initiative. As part of that effort, FDA has been reviewing the current regulatory landscape involving next generation sequencing as the technology moves rapidly from research to clinical practice. To get the dialogue started, FDA published a preliminary discussion paper in late December that posed a series of questions about how to best assure that tests are not only accurate and reliable, but are available for patients as soon as possible. Public comment is essential, so FDA has opened a public docket and will be holding a public meeting on NGS technology on February 20.

NGS technology is clearly integral to the future of personalized medicine. Whatever approach FDA ultimately adopts must be selected with care to ensure continued innovation in the advancement of medical care and public health for this still evolving technology.

Margaret A. Hamburg, M.D., is Commissioner of the Food and Drug Administration

CDER Approved Many Innovative Drugs in 2014

By: John Jenkins, M.D.

Each year, FDA’s Center for Drug Evaluation and Research (CDER) will typically approve more than 100 new medications. A portion of those are novel new drugs, medications that have not previously been approved by FDA and are often among the most innovative products serving previously unmet medical needs or otherwise significantly helping to advance patient care and public health.

John JenkinsThis year, the news media has been concentrating on the number of novel new drugs – either new molecular entities or new therapeutic biologics – approved by CDER in 2014. And that’s understandable because we approved 41 novel drugs this year, the most in nearly 20 years. But instead of looking at the approval tally, we prefer to focus on the significant benefits that many of these drugs bring to patients and the steps that CDER took to get these products to market in a timely manner while maintaining FDA’s standards for safety, effectiveness, and quality.

Many of the 41 new drugs have the potential to add significant clinical value to the care of thousands of patients with serious or life-threatening diseases. They include eight new drugs for treating patients with various types of cancer, four new drugs to treat type-2 diabetes, four new antibiotics to treat serious infections, and two new products to treat patients with hepatitis C.

Moreover, consider these facts:

  • Seventeen (41%) of the 41 novel new drugs were approved to treat rare diseases that affect 200,000 or fewer Americans. This is the highest yearly total of such drugs ever — surpassing the previous high of 13 from 2012. These approvals are particularly significant because patients with rare diseases often have few or no drugs available to treat their conditions.
  • Seventeen (41%) of the 41 novel new drugs are identified by CDER as “First-in-Class,” one indicator of a drug’s degree of innovation. The total for First-In-Class approvals in 2014 approaches the highest yearly total of 20 reported in 2012.

To expedite the development and review of these products, CDER used a number of regulatory programs, including Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval.

  • Fast Track and Breakthrough Therapy designations are designed to speed the development of promising new drugs intended to treat serious conditions with unmet medical needs. Almost half – 19 or 46% of the 41 novel new drugs approved in 2014 — were designated as Fast Track, Breakthrough, or both.
  • Twenty-five (61%) of the 41 novel new drugs were designated for Priority Review. These are drugs in which CDER sees potential for providing a significant advance in medical care, and sets their review target to within six instead of the standard 10 months.
  • Six (20%) of the 41 novel new drugs were approved under FDA’s Accelerated Approval program, which allows early approval of a drug for a serious or life-threatening illness that offers a benefit over current treatments. Accelerated Approval is based on a “surrogate endpoint” or an intermediate clinical endpoint that is thought to be “reasonably likely to predict clinical benefit.” Additional clinical trials are required after approval to confirm the predicted clinical benefit. A surrogate endpoint is a marker of drug effect (e.g., an effect on a lab value or tumor size) that does not directly represent an improvement in how a patient feels or functions, but is expected to predict such a benefit.

Here are a few other ways we assess our contributions to last year’s approvals:

  • Under the Prescription Drug User Fee Act (PDUFA), sponsors pay fees when they submit a product application. This money is used to provide FDA with additional resources to meet performance goals, such as a goal date for completing its review of the application. In 2014, CDER acted on or before the PDUFA goal date for 40 (98%) of the 41 novel new drugs approved.
  • CDER approved more than three-quarters — 32 (78%) — of the 41 novel new drugs on the “first cycle” of review, meaning without requests for additional information that would delay approval and lead to another cycle of review.
  • Nearly two-thirds of the novel new drugs – 26 (63%) — were approved in the U.S. before approval in another country.

It’s been another strong year for approval of novel new drugs for patients in need. We are proud of our role in helping to safely and efficiently bring important new medications to the American public.

Our Novel New Drug Summary for 2014 provides more details. A current list of CDER’s 2014 novel new drug approvals is available on our Web site.

John Jenkins, M.D., is Director of the Office of New Drugs in FDA’s Center for Drug Evaluation and Research

Another important step in FDA’s journey towards enhanced safety through full-scale “active surveillance”

By: Janet Woodcock, M.D.

They say the longest journey begins with a single step. In 2008, FDA launched the Sentinel Initiative and thus began a long journey toward the challenging goal of developing a full-scale medical product safety monitoring program using an important scientific technique called “active surveillance,” which complements our FDA Adverse Event Reporting System (FAERS). FAERS is already well developed and uses the equally important technique of “passive surveillance.” Today, I’d like to recognize our progress along the way.

Janet WoodcockAfter a successful five-year pilot program, which began in 2009, FDA’s Mini-Sentinel program is now transitioning, as planned, to the full-scale Sentinel System. I’d like to share with you the success of our Mini-Sentinel pilot program and some of FDA’s visions for our new leg of the journey toward full-scale “active surveillance” under the new Sentinel System.

First, a quick discussion of the importance of “active surveillance”: Over many years, FDA’s program that we now call FAERS has been our main tool for assessing the safety of medical products. This system relies on patients, medical professionals, and product manufacturers to report to us potential safety issues of the products FDA regulates.

FAERS is an invaluable asset, and we’re not seeking to replace it. However, the Sentinel System offers us the exciting possibility of not waiting for safety information to come to us in the form of reports, but rather it enables us to go out and get that information, adding greatly to our safety monitoring capability. This is active surveillance.

Over the past five years, the Mini-Sentinel pilot program has established secure access to the electronic healthcare data of more than 178 million patients across the country, enabling researchers to evaluate a great deal of valuable safety information. While protecting the identity of individual patients we can get valuable information from Mini-Sentinel that helps us better understand potential safety issues, and share with you information on how to use medicines safely. We have used Mini-Sentinel to explore many safety issues, helping FDA enhance our safety surveillance capabilities, and giving us valuable input in decision-making on drugs and vaccines.

We’re now well on our way to developing a nationwide rapid-response electronic active surveillance system, Sentinel System, for monitoring the safety of FDA-regulated drugs and other medical products.

So where does our journey take us from here?

  • FDA will build on the successes of the Mini-Sentinel Pilot. We have a variety of safety assessments ongoing under Mini-Sentinel that will continue and we will seek to expand our reach and capabilities with the Sentinel System;
  • Mini-Sentinel gave us an important start, but it is essential to continue to develop and refine existing scientific methods to evaluate the data we access through the Sentinel System;
  • We see Sentinel as a potentially valuable national resource for other safety researchers, besides those at FDA. Looking even further ahead, our hope is that, working with other scientific groups, we will be able to create a National Data Infrastructure that would enable other users (e.g., other governmental agencies, researchers from academia or industry) to access the Sentinel infrastructure for multiple purposes (e.g., medical product research, quality improvement);
  • Not only will such access directly serve the public health, it will also help sustain these programs because stakeholders will have an incentive to provide support (financial and otherwise) for its maintenance and growth.

From the outset, the goals of the Sentinel Initiative have been large and of ground-breaking scale. We knew it would be years in the making, but Mini-Sentinel’s successful completion marks important progress. We look forward to continuing and expanding our active surveillance capabilities as we now transition to the full-scale Sentinel program.

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