FDA’s Take on the Executive Order and National Strategy to Combat Antibiotic-Resistant Bacteria

By: Margaret A. Hamburg, M.D.

Few issues in public health today are as critical and time urgent as combating the growing threat of antibiotic resistance. We are delighted to stand with the White House in the development and response to the President’s Executive Order and the National Combating Antibiotic-Resistant Bacteria (CARB) Strategy. Fighting antibiotic resistance is both a public health and national security priority. FDA has played a key role in the development of this important effort, and we already have made strides on many fronts to make sure that we have effective antibiotics for the future.

Margaret Hamburg, M.D.Antibiotics are precious medicines that have saved millions of lives by treating infections caused by bacteria. But their misuse, and overuse, has serious health consequences and has contributed to antibiotic resistance—in which these drugs become less effective, or ineffective, against harmful bacteria.

The consequences of antibiotic resistance must not be underestimated. With each passing day, concern mounts that more patients will have few or no therapeutic options because of resistance to available therapies. In fact, the Centers for Disease Control and Prevention (CDC) estimates that each year at least 2 million illnesses and 23,000 deaths in the United States are caused by antibiotic-resistant bacteria.

It is a high priority for FDA to work with our partners to find solutions for this serious public health problem.

To address the need for effective antibiotics, FDA is working hard to ensure development of new strategies. These include vaccines to help prevent infection with bacteria in the first place; devices to aid in the accurate diagnosis of the cause of infection and of resistant infections; and new drugs to treat patients with serious infections for whom we have few, or no, treatment options because of resistance to currently available antibiotics.

We have been engaging with outside groups to advance the science of clinical trials. For instance, we have worked with the Clinical Trials Transformation Initiative on increasing the efficiency of clinical trials; with the Engelberg Center for Health Care Reform at the Brookings Institution to address overarching issues in antibiotic development, such as the major technical and financial barriers; and with the Biomarkers Consortium of the Foundation for the National Institutes of Health (NIH) on endpoints for studying antibiotics in clinical trials. In fact, we recently joined NIH to hold a workshop to examine the technical challenges related to antibacterial product development and to discuss innovative regulatory and clinical trial approaches for bringing new products to market. (The final agenda and presentations are available online.)

FDA also has been actively implementing the Generating Antibiotics Incentives Now (GAIN) Act, a provision within the Food and Drug Administration Safety and Innovation Act (FDASIA) to promote the development of antibacterial and antifungal drugs. To date, FDA has granted 57 Qualified Infectious Disease Product (QIDP) designations under GAIN to 39 different unique molecules. Antibiotics that have a QIDP designation receive, upon request, priority review, typically shaving four months off review times, and fast track designation, which results in early consultation, including on clinical trial design, between FDA and antibiotic sponsors. QIDPs also can receive an additional five years of marketing exclusivity in addition to existing exclusivity periods at the time of approval. We’re pleased that already three QIDP designated antibacterial drugs have been approved in the past few months: Dalbavancin in May 2014, Tedizolid Phosphate in June 2014 and Oritavancin in August 2014.

Furthermore, FDA promotes the appropriate and responsible use of antibiotics in clinical medicine. Antibiotic labels contain information for health care professionals and patients on appropriate use. And we work to improve the integrity of the global supply chain for pharmaceutical products to minimize the chance of a patient receiving a substandard drug, which in some instances could promote antimicrobial resistance.

In addition, FDA has developed—and is working to implement—two strategies to ensure the judicious use of medically important antimicrobial drugs in food-producing animals. This is a vital step to better protect antibiotic effectiveness for both human and animal populations. Accordingly, we asked the manufacturers of these antibiotics used in food-producing animals to remove all growth promotion indications. Once their labels have been changed, the products can no longer be used legally for growth promotion purposes, or without veterinary oversight. We have now secured the commitment of all 26 affected animal health companies, and 31 products have been withdrawn from the market. Two other companies have implemented label changes and we will be working with the other companies to make sure that they do so as well. The second track will ensure that all remaining therapeutic uses of the affected medically important antibiotics in food-producing animals will take place under the supervision of a veterinarian. The agency continues to work under a three-year transition period, and we remain encouraged by the process.

A successful strategy to combat antibiotic-resistant bacteria will require effort and input from all involved groups, including from health care professionals and patients themselves. For our part, FDA continues to work with government partners, product developers and the scientific community as well as other critical stakeholders to address the unique and complex regulatory, scientific and policy challenges associated with this public health issue. The Executive Order and CARB strategy announced today will clearly boost our and the nation’s efforts to meet these challenges more effectively.

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

20 Years of Improving Women’s Health: 1994 – 2014

By: Margaret A. Hamburg, M.D.

Margaret Hamburg, M.D.As we celebrate the 20th anniversary of the FDA’s Office of Women’s Health, I would like to highlight some of the work we’ve done to help improve women’s health, both looking across FDA and within the office. Whether it is approving new treatments for chronic conditions like heart disease, conducting research or helping to protect pregnant women from foodborne illnesses, the work we do at FDA makes a difference throughout a woman’s life.

Consider our product approvals. In 1996, for example, our agency approved a product for use in Pap smears that revolutionized the detection of cervical cancer; ten years later we approved the first vaccine for the prevention of this cancer. We have also approved advances in breast imaging, including 3D breast tomosynthesis and automated screening ultrasound.

We have encouraged innovation in lupus treatment and approved the first new lupus drug in 50 years. And we approved the latest generation of cardiac synchronization therapy devices which our own FDA scientists have shown particularly benefit women with heart failure.

FDA has also supported research to help us better understand how medical products affect women. Since 1994, the Office of Women’s Health research program has provided $30 million to support over 290 research projects, workshops, and trainings on a wide range of topics including cancer, HIV and osteoporosis. More than 25 percent of these research dollars have been directed at cardiovascular disease, the number one killer of women, with studies examining such issues as QT interval prolongation (a disorder of the heart’s electrical activity), how breast cancer drugs can affect the heart, and sex differences in various cardiac interventional therapies. FDA’s medical product centers have also sponsored women’s health research and initiatives such as the Health of Women Program that promote a better understanding of sex differences.

The results have been impressive: OWH’s research alone has been published in over 170 articles in peer-reviewed journals and has made impact on the regulatory decision-making process, including guidance documents, label changes, and standards development. Indeed, FDA’s guidance to industry is an important way that the agency has been helping to address important issues in women’s health.

Over the years, FDA guidance has encouraged greater inclusion of women in clinical trials and the evaluation of sex differences. Our own analysis last year found that women make up about half of the representation in these studies, but the numbers are lower for medical devices. So we have more to do and recently issued guidance to medical device developers to address this concern.

We have also made great strides in our communication and outreach to women during the past two decades. OWH’s Take Time to Care Program has built partnerships with other government agencies, retailers, and national organizations that provide millions of women with FDA safety information. Over the years, we have launched other educational initiatives like the Food Safety for Moms-to-Be and expanded the women’s health resources available via our “For Women” website and social media to make sure that women have tools to help them make informed decisions about the use of FDA-regulated products.

I am pleased at how much we have done to promote and protect women’s health since 1994. At the center of much of this change has been the consistent, driving force of the Office of Women’s Health and its determined leader, Marsha Henderson. I encourage you to check out OWH’s 20th Anniversary brochure to learn more about the progress that has been made. And I hope that you will collaborate with us on the work that still needs to be done.

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

FDA Works to Mitigate the West Africa Ebola Outbreak

By: Luciana Borio, M.D.

Luciana Borio, M.D.The world is witnessing the devastating effects of the Ebola virus outbreak in West Africa, the worst Ebola outbreak in recorded history. To date, more than two thousand people in Guinea, Liberia, Nigeria and Sierra Leone have become infected, and more than twelve hundred have died. The stories of so many lives lost, and those of so many others fighting for their lives, are heartbreaking and tragic. We at the Food and Drug Administration are dedicated to helping end this outbreak as quickly as possible. And we are working hard to accelerate the development and production of treatments and vaccines to help prevent future outbreaks like this.

The primary approaches to contain the current outbreak remain standard public health measures. However, this outbreak presents complex challenges, in part because there are no FDA-approved treatments or vaccines for the Ebola virus. FDA has an important role during situations like this.

For example, we are working closely with U.S. government agencies that support medical product development – including the National Institutes of Health, the Biomedical Advanced Research and Development Authority, and the U.S. Department of Defense (DoD) – to speed the development and production of medical products that could help mitigate outbreaks like this. And we are working interactively with medical product sponsors to clarify regulatory and data requirements in order to move investigational products forward in development as quickly as possible. We also are in close contact with the World Health Organization and several of our international regulatory counterparts to exchange information about these investigational products for Ebola treatment, and to exchange information about how FDA works to facilitate development of and access to these products.

The experimental vaccines and treatments in development are in the earliest investigational stages and have not been fully tested for safety or efficacy. Only small amounts of some experimental products have been manufactured for testing, which means few courses, if any, are available for companies to make available for compassionate use in response to this outbreak. We are working closely with our U.S. government colleagues to have experimental treatments and vaccines available for clinical evaluation in the next few months. We are hopeful that, in the future, we will have medical products approved and manufactured for wide-scale use to address the Ebola outbreak. However, these products are not at that stage yet.

In the meantime, FDA is doing all we can to alleviate the situation. FDA has one of the world’s most flexible regulatory frameworks, which includes mechanisms to enable access to available investigational medical products when, based on certain criteria such as the balance between expected risk and benefit to the patient, it would be appropriate to use such products.

For example, under certain circumstances, clinicians may request the use of an Emergency Investigational New Drug (EIND) application under the FDA’s Expanded Access program to access investigational products outside of clinical trials for their patients. And under the FDA’s Emergency Use Authorization (EUA) authority, we can allow the use of an unapproved medical product – or an unapproved use of an approved medical product – for a larger population during emergencies, when there are no adequate, approved and available alternatives.

This month, we authorized the use of an Ebola diagnostic test, developed by DoD, under an EUA to detect the Ebola virus in DoD-designated laboratories. This test can help facilitate an effective response to the ongoing outbreak in West Africa by helping to rapidly identify patients infected with Ebola virus and facilitate appropriate containment measures and clinical care.

It is an unfortunate fact that, during outbreaks like this, fraudulent products that claim to prevent, treat or cure a disease rapidly appear on the market. FDA has learned of several fraudulent products that claim to prevent or treat this Ebola virus infection, including so-called natural remedies. Consumers who have seen these fraudulent products or false claims should report them to us. For our part, we will remain vigilant for fraudulent products and false product claims related to the Ebola virus, and will take enforcement actions as warranted to protect public health.

FDA stands ready to work with companies and healthcare providers to speed product development and to facilitate access to investigational products to treat patients when appropriate. We are fully committed to helping end this outbreak as quickly as possible and to sustaining our efforts to help prevent such outbreaks in the future.

Luciana Borio, M.D., is the Assistant Commissioner for Counterterrorism Policy and Acting Deputy Chief Scientist.

Clinical Trials: Enhancing Data Quality, Encouraging Participation and Improving Transparency

By: Margaret A. Hamburg, M.D.

Today FDA is announcing important steps that the agency plans to take to enhance the collection and availability of clinical trial data on demographic subgroups – patient populations divided by sex, race/ethnicity or age.

Margaret Hamburg, M.D.Section 907 of the 2012 FDA Safety and Innovation Act directed us to take a closer look at the extent to which clinical trial participation and the inclusion of safety and effectiveness data by demographic subgroups is included in medical product applications, report our findings, and then, within one year, produce an action plan with recommendations for improvements.

Our report, issued on August 20, 2013, found that the agency’s statutes, regulations, and policies generally give product sponsors a solid framework for providing data in their applications on the inclusion and analysis of demographic subgroups. Overall, sponsors are describing the demographic profiles of their clinical trial participants, and the majority of applications submitted to FDA include demographic subset analyses. We also found that FDA shares this information with the public in a variety of ways. Now, one year later, we’re releasing the FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, which we developed after extensive interaction with stakeholders.

The action plan includes 27 action items that are designed to meet three overarching priorities – improving the completeness and quality of demographic subgroup data collection, reporting and analysis (quality); identifying barriers to subgroup enrollment in clinical trials and employing strategies to encourage greater participation (participation); and, making demographic subgroup data more available and transparent (transparency).

In addition to the action plan, we’re publishing a final guidance entitled, “Evaluation of Sex-Specific Data in Medical Device Clinical Studies.” It was written in response to the fact that certain medical devices may yield different responses in women than men, and yet women are under-represented in some medical device studies. This has led to less information for women regarding the risks and benefits of using these devices.

The guidance includes recommended methods for clinical study design and conduct to increase enrollment of men and women, if needed, and ways to analyze data for sex differences. FDA has held a series of public workshops to raise awareness about common strategies for enhancing recruitment and retention of women in medical device clinical trials. Fully integrating this final guidance into the templates used by FDA’s reviewers of medical devices, and providing a webinar for industry on how to use the guidance, comprise one of the 27 items in our action plan.

I hope you’ll find that the action plan is responsive and pragmatic and, most importantly, when fully implemented, it will improve medical care and public health. Many of the steps it outlines will have a broad impact on the work of FDA’s medical product centers and will require great thought and planning as they are implemented, depending on current evidence and available resources. The action items range from relatively short-term goals that can be achieved in a year, to others that will take 1-3 years, to a small number that will require a longer period, 3-5 years, to achieve.

Although the plan certainly places significant responsibilities on FDA’s medical product centers and other FDA offices, it also engages our partners inside and outside of government to share the responsibility for this important mission. For example, industry is being asked to help develop and share best practices for encouraging broad clinical trial participation, and the National Institutes of Health will be participating in several research projects with FDA.

We know that richer information is collected when different subgroups are enrolled in pivotal studies for medical products. This kind of enrollment in turn gives us greater assurance in the safety and effectiveness of the medical products used by a diverse population.

To set the plan in motion quickly, FDA is setting up a steering committee that will oversee implementation, come up with metrics for measuring progress and be responsible for planning a public meeting to be held within 18 months after release of the plan. FDA has already set up a website where the public will be able to track the agency’s implementation progress. That website will be updated on a regular basis.

Also, we’re reopening our Section 907 public docket to solicit comments for the action plan. I encourage everyone to review the document and consider how you might be able to partner with FDA and others in encouraging necessary and appropriate demographic subgroup diversity and representation.

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

Providing Easy Public Access to Prescription Drug, Over-the-Counter Drug, and Biological Product Labeling

By: Taha A. Kass-Hout, M.D., M.S.

Every prescription drug (including biological drug products) approved by FDA for human use comes with FDA-approved labeling. The labeling contains information necessary to inform healthcare providers about the safe and effective use of the drug for its approved use(s). Once a prescription drug is approved, the labeling may be updated as new information becomes available, including, for example, new approved uses, new dosing recommendations, and new safety information. Thus, the approved labeling is a “living document” that changes over time to reflect increased knowledge about the safety and effectiveness of the drug.

Taha Kass-HoutIn some cases, the approved labeling for a prescription drug can be extensive, consisting of 20,000 words or more. This amount of information, while important to guide safe and effective use of the drug, can present formidable challenges. For example, it can be a daunting task to study more than one labeling to better understand a class of drugs, or to compare drugs, and to keep up with their regular changes. Although they have been publicly available for many years on FDA’s website, now this labeling is available on openFDA through an Application Programming Interface (API), which provides a way for software to interact directly with the data.

For several years, the labeling has been posted publicly in Structured Product Labeling (SPL) format at http://labels.fda.gov/. The SPL format enhances the ability to electronically access, search, and sort information in the labeling. The SPL files are also available at the National Library of Medicine’s DailyMed site and can be downloaded. We’ve created an API for the data to supplement (not replace) these resources, and to provide easy and timely access to changes or updates to the labeling.

The openFDA drug product label API provides access to the data for nearly 60,000 prescription and over-the-counter (OTC) drug labeling. The prescription labeling includes sections such as the “Indications and Usage” and “Adverse Reactions” sections and the OTC labeling includes “Purpose” and “Uses” headings and so forth.

This API can be used, for instance, to identify those medications that have a Boxed Warning, that have lactose as an inactive ingredient, that have a known interaction with grapefruit juice (or other fruit juices and where the labeling states “the concomitant use of DRUG-X with grapefruit juice is not recommended”), and to answer other queries.

This API is just one more example of how openFDA is helping make publicly available data more accessible and useful. Since the first API for adverse events was posted on June 2, 2014, there have been more than 2.6 million API accesses with approximately 20,000 internet devices connected to the adverse events API alone, and more than 30,000 unique visitors to the site.

It’s very important to note that the labeling for prescription drugs is proposed by the applicant, reviewed by FDA, and approved by FDA. The labeling for OTC medications is also either approved by FDA or must conform to applicable regulations that govern the content and format of OTC drug labeling that are not pre-approved by FDA.

As a research and development project, openFDA is a work in progress (Beta phase), and we are eager to learn from the developer and research communities what possible uses these data might have. We are also interested in hearing from the community about other publicly available FDA datasets for which an API might prove useful.

We are actively involved in the openFDA communities on GitHub and StackExchange, and encourage people interested in the project to participate in those communities. In addition to providing access to datasets, openFDA encourages innovative use of the agency’s publicly available data by highlighting potential data applications, and providing a place for community interaction with one another and with FDA domain experts.

Over time, we hope that openFDA can become an important resource where developers, researchers, and the public at large will learn about the medications and other FDA-regulated products that protect and promote the health of Americans.

Taha A. Kass-Hout, M.D., M.S., is FDA’s Chief Health Informatics Officer and Director of FDA’s Office of Informatics and Technology Innovation

FDA’s JumpStart program: Supporting drug innovation

By: Lilliam Rosario, Ph.D.

When it comes to public health, the U.S. Department of Health and Human Services (HHS) recognizes that innovation drives success.

Lilliam RosarioAs part of the HHS Innovates program, HHS Secretary Sylvia Mathews Burwell and Deputy Secretary Bill Corr acknowledge excellence in the field with the Secretary’s Pick Award, an honor that identifies and celebrates internal innovation by HHS employees.

I’m proud that this year, the winner of one of three Secretary’s Pick Awards was the Food and Drug Administration’s Office of Computational Science (OCS), part of the Office of Translational Sciences (OTS) in the agency’s Center for Drug Evaluation and Research (CDER). OCS received the award for its work in developing CDER’s JumpStart program, an innovative initiative dedicated to enhancing the efficiency of CDER’s new drug development and review process.

The JumpStart program provides CDER’s new drug review teams with clinical trial data analyses early in the review process when they assess quality, data composition, exploratory analyses, and tools for the analyses. It gives the reviewers a “jump start” on their review providing the information on the quality of the submission as well as analyses to support an effective and efficient evaluation of the medical product submission. You can learn more about JumpStart here. 

Our congratulations to the two other Secretary’s Pick Award recipients, the “Breast Cancer Startup Challenge,” led by the National Cancer Institute, and “Whole Genome Sequencing: Future of Food Safety,” led by the Centers for Disease Control and Prevention. It is a great honor to be recognized side by side with these two innovative programs!

We are proud of the team effort involved in making the JumpStart program a success, and look forward to continued efforts and innovative actions that will help bring safe, effective, and high quality new drug therapies to the American public as efficiently as possible.

For more information on HHS Innovates, visit HHS Innovates Celebrates 7th Round of Innovations!

Lilliam Rosario, Ph.D., is Director, Office of Computational Science, Office of Translational Sciences, at FDA’s Center for Drug Evaluation and Research

Achieving our Mission through Enhanced IT Service Delivery

By: Walter S. Harris, M.B.A, P.M.P.

At its core, FDA is an information- and process-driven organization. Day-in and day-out, FDA’s experts make thousands of weighty and complex decisions by evaluating, and allowing access to, life-sustaining, life-enhancing and life-saving products. This is done using a vast amount of sophisticated and reliable data. And it is done while continuously engaging with consumers, patient representatives, industry, academia and other government agencies.

Walter HarrisSince the establishment of the Office of Information Management and Technology (OIMT) seven months ago, we have fundamentally changed how we support the Agency’s mission — primarily, to increase transparency, and better align functions and resources to achieve more efficient and improved customer support and services. To further these objectives, we have taken the following steps to help transform our service to our internal and external stakeholders.

  • Reorganized the Office of Information Management into a more stable structure that is focused on our customers and the delivery of services. This new IT structure includes robust leadership, increased scientific capability and closer attention to IT’s business and customer needs, including a new IT audit and compliance program.
  • Hired the first Chief Health Informatics Officer (CHIO), Taha Kass-Hout, MD, M.S., to promote and develop innovative enterprise solutions and identify opportunities for transparency and availability of FDA’s public health data to our consumers while ensuring accountability and privacy. With the launch of openFDA, we have demonstrated our ability to respond quickly and accurately to emerging scientific, technological and economic trends.
  • Requested that the CIO Council, FDA’s IT governance board with representation across all of its Centers, focus on opportunities to consolidate IT solutions into capabilities that benefit the agency, eliminating duplication of efforts and creating possibilities for reinvestment.
  • Creating an IT service cost-allocation model that will include a service catalog and identification of cost drivers for IT services.
  • Restructuring our IT portfolio to a service based portfolio model that is in alignment with our cost allocation model.

OIMT, together with IT leaders in the Centers, will transform our IT operation to minimize redundancies, streamline IT, and enhance customer service while lowering IT costs to the agency. We continue to seek opportunities to  identify and tackle issues, improve communications across functional lines, and more fully capitalize on the expertise of our talented staff.

These are exciting endeavors and I am proud of the efforts IT leaders across the FDA have taken to focus on customer service. With a renewed emphasis on service delivery to enable mission outcomes, we are better able to use resources in a manner that will achieve greater efficiency, improve support across the FDA, and provide results that benefit the public health.

Walter S. Harris, M.B.A, P.M.P., is FDA’s Deputy Commissioner for Operations

FDA’s multi-pronged approach helps meet the challenge of bringing new and innovative antibiotics to patients who need them

By: Edward M. Cox, MD, MPH

With a growing number of infections becoming increasingly resistant to our current arsenal of antibiotics, developing new antibiotics to treat serious or life-threatening infections has become a key priority.

Edward Cox interview

There are significant scientific and economic challenges inherent to the development of new antibiotics. From a scientific standpoint, many patients with bacterial infections are often very sick and need to begin antibiotic therapy immediately, without further complications that enrollment in a clinical trial might involve. Moreover, it can be difficult to conduct a clinical trial involving very sick patients.

From an economic standpoint, antibiotics may be perceived as less potentially profitable for a company because they are generally taken only for a short period of time and often only for one course of treatment, by any given patient. Compare this to the long, dependable income stream from a diabetes medicine or a blood pressure medicine that a patient takes indefinitely, often for the rest of their life. These economic realities, which are rooted in the biology of acute bacterial infections, can make it challenging for a company to justify large expenditures for the development of drugs in this area, as a recent report by Eastern Research Group (ERG) affirms.

Provisions in a law passed a little over two years ago, commonly known as the GAIN Act, or the Generating Antibiotics Incentives Now Act, is helping to stimulate the development of new antibiotics. Under GAIN, certain antibacterial or antifungal drugs intended to treat serious or life-threatening infections can be designated “Qualified Infectious Disease Products” (QIDPs). As part of its QIDP designation, a drug receives priority review and can also receive fast track designation at the sponsor’s request. At the time of approval, a product with QIDP designation may be eligible for an additional five years of marketing exclusivity, exclusive marketing rights without competing with a generic drug product. To date FDA has granted 52 QIDP designations to 35 different unique molecules. We are already beginning to approve new antibacterial drugs with this beneficial QIDP designation.

FDA is working hard to streamline requirements for clinical trials for studying new antibacterial drugs and the provisions of the GAIN act are being actively implemented, but more is needed. There are still significant economic and scientific challenges in the development of new antibacterial drugs that need to be addressed. Additional financial incentives as well as new approaches for studying antibacterial drugs such as common clinical trial protocols could provide other important means to stimulate antibacterial drug development. We also need cutting-edge science to stimulate the development of new and innovative antibacterial drugs. To help drive this effort, FDA has assembled our Antibacterial Drug Development Task Force, a group of expert scientists and clinicians from within FDA, to consider opportunities to promote antibacterial drug development.

To advance this field, our Task Force is working with many leaders including those drawn from academia, regulated industry, professional societies, patient advocacy groups and government agencies. For example, FDA has contributed to the efforts of the Biomarkers Consortium of the Foundation for the National Institutes of Health to develop new endpoints for studying antibacterial drugs. FDA also works closely with the Clinical Trials Transformation Initiative (CTTI), a key group of dedicated scientists focused on advancing clinical trials for more efficient drug development. As a result, FDA and CTTI have helped convene a variety of important scientific meetings and activities on vital topics related to efficient clinical trial designs for testing new antibiotics. Our Task Force has also helped FDA team up with colleagues at the Brookings Institution’s Engelberg Center for Health Care Reform to help galvanize the scientific community’s efforts in new antibiotic drug development. August, 2012 began the first Brookings Council for Antibacterial Drug Development (BCADD) meeting, with meetings that occur approximately twice a year.

FDA and our Task Force members have also been busy on our own.  In February of 2013 we held a public meeting focused on creating an alternative approval pathway for certain drugs, such as antibacterial drugs, that are intended to address unmet medical need. We have also asked the public for their thoughts; in March of 2013, we issued a Federal Register Notice seeking input from the public on a wide range of topics related to antibacterial drug development. FDA has generated a number of guidance documents for industry, in draft and final form, that describe FDA’s scientific thinking with regard to developing new antibacterial drugs.

As part of our Task Force’s collaborative efforts, FDA is working closely with The National Institutes of Health (NIH) to further advance the development of new antibacterial drugs. Together, we are hosting a two-day Public Workshop to identify strategies for promoting clinical trials for antibacterial drugs and encouraging partnerships to accelerate their development. The ERG report will be presented at the workshop and other specific issues will be discussed including:

  • Priorities and strategic approaches to conducting clinical trials for antibacterial drugs
  • Regulatory pathways—including streamlined development programs for antibacterial drugs for patients with limited or no treatment options
  • Clinical trial design issues such as the development of common clinical protocols; using common control groups; statistical analysis issues; sharing data across trials (and data standards); appropriate clinical trial endpoints; and lessons learned from other therapeutic areas
  • The role of public-private partnerships in advancing the scientific and clinical trials enterprises

The work of the FDA Task Force as well as the GAIN Act have provided good first steps toward strengthening the antibacterial drug pipeline, but as the findings from the ERG report indicate, the forecast for antibacterial drug development likely will include a less than robust pipeline. Thus, additional attention on both financial incentives, new approaches for studying antibacterial drugs such as common protocols, as well as streamlined development pathways, likely will be needed to improve the climate.

Edward M. Cox, MD, MPH, is Director, Office of Antimicrobial Products, in FDA’s Center for Drug Evaluation and Research

Dr. Frances Kelsey, Who Protected Americans from Thalidomide, Turns 100

By: John Swann, Ph.D.

Today marks the 100th birthday of one of America’s most celebrated public servants. Frances Oldham Kelsey, Ph.D., M.D., was born in Cobble Hill, Vancouver Island, British Columbia, and earned her Ph.D. in pharmacology and her M.D. at the University of Chicago. She was on the faculty of the University of South Dakota and practicing medicine when, in 1960, she accepted the offer to become a medical officer at FDA.

John SwannA month after assuming her position she was assigned the review of a new drug application for thalidomide, a sedative that had been used by expectant mothers and many others in dozens of countries since the late 1950s. U.S. law at the time required a firm to provide evidence of a drug’s safety as a requirement for sale. Despite the global popularity of this drug, and despite a constant and increasing pressure from the firm to approve the application, Dr. Kelsey refused to do that without adequate evidence that the drug was safe, a decision that was supported by her colleagues and superiors.

By late 1961 scientists discovered that thalidomide was responsible for crippling birth defects in thousands of babies in many parts of the world. Thanks to Dr. Kelsey’s “exceptional judgment in evaluating a new drug” — as her firm stand was described in the President’s Award for Distinguished Federal Civilian Service she received from President John Kennedy — the U.S. was mostly spared the tragedies. But the close encounter with a public health catastrophe convinced Congress and the White House to resuscitate proposals to revitalize the regulation of pharmaceuticals. The result was the 1962 enactment of the Kefauver-Harris Drug Amendments that mandated “substantial evidence” of a drug’s effectiveness as developed by “experts qualified by scientific training,” in addition to evidence of a drug’s safety, and provided for greater oversight of drug investigations. These and other requirements in the new law established a global standard for the evaluation of drugs.

Frances Kelsey

Dr. Kelsey today, pausing between crossword puzzles.

After 1962, Dr. Kelsey oversaw the evaluation of investigational drugs and, later, of oncologic drugs and radioisotopes. Concerns in the agency with problematical clinical investigations continued in the early 1960s, such that FDA created the Division of Scientific Investigations in 1967 and placed Dr. Kelsey in charge. She remained in this position until 1995. The division engaged in inspections of clinical investigators, animal studies, and institutional review boards involved in drug trials. Thus, Dr. Kelsey helped ensure the reliability of data vital to FDA’s evaluation of therapeutic products over a span of four decades.

Frances Kelsey, the recipient of the highest honor that can be bestowed on a federal civil servant, officially retired from FDA in 2005, but her commitment to the integrity of science in service to the public health continues to inspire those in the FDA and beyond.

To learn more about the life and work of Dr. Kelsey, see her “Autobiographical Reflections.”

More about thalidomide and the 1962 Kefauver-Harris Drug Amendments that came out of this crisis can be seen at http://www.fda.gov/Drugs/NewsEvents/ucm320924.htm.

John Swann, Ph.D., is an Historian at FDA

A reminder of the promise and limitations of abuse-deterrent properties

By: Douglas C. Throckmorton

The ongoing growing amount of drug abuse in our nation, particularly with prescription pain relievers known as opioids, has prompted a lot of talk about the potential of opioids with “abuse-deterrent” properties to help combat this public health problem. But care must be taken in putting  too much promise into abuse-deterrent technology at this time because the science is still relatively new and evolving.

Douglas C. Throckmorton, M.D.While the FDA strongly supports the development of products with effective abuse-deterrent properties and believes they can make a real difference, abuse-deterrent properties do not make an opioid impossible to abuse, and do not prevent overdose and death – they only makes certain kinds of abuse more difficult or less rewarding.

Current abuse-deterrent technologies tend to focus on making the drug either harder to crush, which makes them harder to snort or inject; harder to extract, which means the opioid cannot be easily separated from the other ingredients in the drug for purposes of abuse; more difficult to abuse orally, which is the most common form of opioid abuse; or  less attractive for abuse (e.g., the drug may contain an ingredient that counteracts the action of the opioid, making the drug less “likeable” or even unpleasant).

This week, FDA approved a new prescription opioid tablet called Targiniq ER, which contains a combination of the opioid pain medicine oxycodone and a drug called naloxone, an opioid antagonist. Naloxone can block the euphoric effects of opioid medicines and is used most often to treat an overdose. The science behind this particular abuse-deterrent formulation works like this: If the Targiniq ER tablet is taken as directed (i.e., swallowed according to its approved use), the naloxone will not interfere with the oxycodone. If, however, the tablets are crushed into a powder and snorted or injected, the naloxone inside the tablet will be absorbed and block the desired effect from the oxycodone.

Targiniq ER joins OxyContin (oxycodone) as the second drug FDA has approved with labeling describing the product’s abuse-deterrent properties consistent with FDA’s 2013 draft guidance for industry Abuse-Deterrent Opioids –Evaluation and Labeling which states that for claims to be made, they must be based on robust, compelling, and accurate data and analysis, and the description of the abuse-deterrent properties or potential to reduce abuse must be clearly and fairly communicated.

OxyContin gets its abuse-deterrent properties differently than Targiniq, by including ingredients that make the tablet hard to crush or dissolve. Efforts to pulverize the tablets into a powder result in a chemical reaction that makes the crushed tablet into a gooey gel that makes it more difficult to be inhaled or injected the way drug abusers would like.  While Targiniq and OxyContin use different abuse-deterrent technologies, they serve the same purpose: they are expected to help deter the often lethal practice of snorting or injecting prescription drugs.

In the context of this important and evolving area of science, FDA is very encouraged to see another drug with proven abuse-deterrent properties come to the market. We do need to remember that “abuse-deterrent” is not the same as “abuse-proof” and even abuse-deterrent formulations can be abused and people who take them can overdose and die.  For example, someone who wants to “get high” from prescription opioids can still swallow more than the prescribed amount, and this simple but common form of abuse can result in overdose and death.

Currently available products with abuse-deterrent properties are an important step in the right direction, but there is much more work to be done. The technologies involved in abuse deterrence and methods for evaluating whether those technologies actually deter abuse are rapidly evolving. To address this rapid change, FDA is working with many drug makers to advance the science of abuse deterrence and to help them navigate the regulatory path to market as quickly as possible. While FDA strongly supports a transition to opioids with abuse-deterrent properties, we do not believe it is feasible or in the interest of public health at this time to require all opioid products to have such properties.

To help support the safe use of all opioid products, FDA is working in many other ways to help prescribers and patients make the best possible choices about how to use these powerful drugs. Our goal is to find the balance between appropriate access to opioids for patients with pain and the need to reduce the tragedies of their abuse and misuse.

Douglas Throckmorton, M.D., is Deputy Center Director for Regulatory Programs in FDA’s Center for Drug Evaluation and Research