What IS Metabolomic Science?

By: Richard Beger, Ph.D.

My 10-year-old son and 12-year old daughter asked me the other day, “Dad, we know you work doing science research in metabolomics for FDA at NCTR (i.e. National Center for Toxicological Research). But… (hesitating)…We’re not sure what metabolomics is. Can you help us understand?”

Dr. Richard Beger

Wow! My two pre-teen geniuses (OK, some bias may exist here) posed a simple, but interesting, question. How can I best describe, in plain language, the benefits of metabolomics research, and the many positive ways that research can affect a person’s life?

Well kids, I began, metabolomics is an exciting and growing field. The research data we work with can be used to help identify and explain genetic disorders and disease states, the particular stage a disease may be in, like “onset” of Alzheimers. The research can also help identify and explain a person’s bad response to a drug and what other factors in their environment might be playing a role in that response. For example, if an adult drinks a beverage like alcohol or grapefruit juice before a medical intervention and those liquids affect his ability to metabolize a particular drug, then that information would be taken into account when considering their response to that drug.

Or, researchers might use metabolomics nutrition and plant studies to find new soil conditions that might make a tomato grow better, or they may try to understand which set of metabolites might help tomatoes taste better.

Metabolomics is also used to understand how disease occurs. The current set of clinical chemistry biological markers, such as glucose for diabetes or cholesterol for heart disease, may not always diagnose a disease early or detect bad responses humans can have to drugs. Researchers use metabolomics to look for new biomarkers or patterns that can identify a disease. Discovering these new indicators may lead to earlier detection and safer treatments for diseases like cancer or diabetes.

My children looked fascinated! So I continued….

We get many of our answers from metabolites – things like lipids, sugars, and amino acids. These are the small molecule byproducts of metabolism. The way a cell transfers energy or communicates to other cells is controlled by metabolites. By looking at metabolites and/or chemicals in urine, blood, and tissue, we are able to get a “physiological snapshot” of living cells and the organism in which they exist, like the human body.

And that is what metabolomics is – the study of the molecules involved in metabolism in a living organism, by evaluating tissues and body fluids such as blood and urine, for metabolite changes.

At this point, the time-honored, “Ewww, gross” comments began to flow. The mention of blood and urine in the same sentence seems to do that to adolescents. But I persevered.

Using metabolomics, we also try to understand how a person responds to a drug. There are potential metabolomic biomarkers that show whether a person is having a good or bad response to a drug. Genetics, gender, age, taking multiple drugs, taking drugs in combination or with dietary supplements, and other factors may change the pattern of small molecules in a person. Today’s technology allows FDA researchers to detect hundreds of small molecules in a short period of time. The ability to see how a person’s patterns of small molecules – their metabolites – change can help researchers develop a more personalized medicine approach to human health.

“Cool,” the kids said. Indeed. Metabolomic science IS cool! If YOU would like to learn more about this exciting field, the 8th Annual Meeting of The Metabolomics Society, Metabolomics 2012, will be held from June 25-28, 2012 in Washington, D.C. In addition to FDA, The National Institute of Standards and Technology (NIST), the National Institutes of Health (NIH), and The Metabolomics Society will host the event.

Dr. Richard Beger is Director, Biomarkers and Alternative Models Branch, Systems Biology Division at FDA’s National Center for Toxicological Research, in Jefferson, Arkansas.

The Commissioner’s Fellowship Program: Fostering Scientific Talent at FDA

By: Jesse L. Goodman, M.D., M.P.H.

As the May 25th application deadline for the Commissioner’s Fellowship Program rapidly  approaches, it’s time to acknowledge the tremendous contributions our Fellows and their FDA mentors have made in support of FDA’s Advancing Regulatory Science effort. I also want to highlight the opportunities the Fellowship Program offers health care professionals, scientists, and engineers who may not have considered FDA in planning their career path.

FDA launched the Fellowship Program in October 2008 to achieve three essential goals: to attract outstanding scientists who could tackle Center-selected and targeted research or regulatory issues, to train these scientists in regulatory science, and to help build our scientific staff. Since then, FDA has graduated 48 Fellows from the class of 2008 and 50 from the class of 2009. The class of 2010 will graduate this coming Sept. 25th.

This two-year program is open to scientists and medical professionals with doctoral level degrees, although we also welcome applicants with a bachelor’s in an engineering discipline.  Fellows pursue a rigorous regulatory science curriculum and conduct research that addresses a scientific or regulatory gap, under the mentorship of an FDA senior scientist.

Hundreds of applicants from leading labs, institutions, and industry apply to the program each year, attracted by the opportunity to participate in research on critical issues in product development, evaluation, and safety. They also come for the unique and comprehensive training and the chance to make a difference in our nation’s health. In addition to peer-reviewed publications, during their tenure Fellows complete regulatory reviews and work with FDA staff scientists to develop research tools, like new protocols, assays, screening methods, detection, and characterization methods. Many Fellows also work in a variety of scientific and policy areas, ranging from laboratory and population sciences to engineering.

Dr. Khaled Bouri, a former Fellow and current FDA staff member, had this to say about his experience:

As a research scientist, with a focus on the use of genomic technologies, I was struck by the lack of progress in medical product development, despite the enormous advances seen in scientific knowledge and medical technologies over the last decade.  I wanted to identify the reasons behind this gap and participate in building a bridge from bench to bedside. The Fellowship Program gave me a deep appreciation of the complexity of the medical product development process and provided me with the tools and knowledge to more effectively help FDA achieve its mission.

Former Fellow and current staff scientist in FDA’s Center for Drug Evaluation and Research, Dr. Dionna Green, adds:

I came to the program seeking experience in the drug development process from the unique perspective that only the FDA can offer.  As a clinician with training in pediatrics, I was interested in the regulatory and scientific considerations that are pertinent when developing drugs and biologics to treat diseases and conditions affecting neonates, infants, children, and adolescents.  In the Fellowship program, I participated in the extensive work underway at FDA to advance pediatric therapeutics.  The program gave me a comprehensive understanding of how all of the agency components work together toward the goal of promoting and protecting the public’s health.

The research performed by the Commissioner’s Fellows highlights the breadth of creativity fellows bring to their projects — from testing the potential toxicity of nanomaterials, to developing methods to evaluate process controls for fresh produce, to predicting side effects of drugs in genetically predisposed subpopulations, to advancing pediatric cardiovascular device development. It is just the kind of innovative work the program aims to foster. And, it is the infusion of new ideas and tools FDA needs as we work to transform regulatory science in the 21st century.

Many Fellows have stayed on at FDA, while others have sought careers in industry and academia. Those who do pursue careers outside the agency bring a deeper understanding of regulatory science to their organization or institution.

A highly skilled workforce capable of conducting cutting-edge research and addressing complex regulatory issues is core to FDA’s capacity to protect and promote the public health. FDA’s Critical Path, Advancing Regulatory Science and Global initiatives have all described the enormous challenges and opportunities the agency faces as it transforms its operational model to accommodate a globalized economy, new areas of science, and rapidly evolving technologies. Together with our own outstanding scientists, the Fellows tackle the challenges of emerging science and technology to enable innovation while at the same time ensuring the safety, effectiveness, and quality of the products FDA regulates.

Jesse L. Goodman, M.D., M.P.H., is FDA’s Chief Scientist and Deputy Commissioner for Science and Public Health

National Women’s Health Week: The Dangers of Using Tobacco Products

By: Lawrence R. Deyton, M.S.P.H., M.D.

The health of every American is of the utmost importance to the Food and Drug Administration, which regulates the manufacture, marketing, and distribution of tobacco products.  Our Center for Tobacco Products works to improve public health, with the goal of making sure that tobacco-related death and disease is part of America’s past, not its future. Lawrence R. Deyton, M.S.P.H., M.D.National Women’s Health Week, May 13-19, provides an opportunity for us to reach out and remind the women in our lives about the dangers of tobacco use and exposure to second-hand smoke — which claims the lives of nearly 200,000 women every year.

Never starting to use tobacco products and quitting tobacco use – for those who do use tobacco – is proven to lead to longer and healthier lives for everyone.

There is no question that tobacco use is dangerous to women. Just consider a few of the facts:

  • An estimated 173,940 women die every year due to cigarette smoking
  • An estimated 18,000 non-smoking women die every year from exposure to second-hand smoke
  • Smoking causes almost 80% of lung cancer deaths in women
  • Smoking causes cervical cancer and eight other cancers
  • Smoking causes infertility and poor pregnancy outcomes
  • Smoking causes low bone density and hip fractures in women

National Women’s Health Week is the perfect time for you — or one of the important women in your life — to break a dangerous addiction to tobacco, and for those who do not use tobacco, it is a time to be empowered to never start. Need help? Here are some great resources:

When we spend countless hours taking care of our families and friends, it’s far too easy to forget to look after our own health. This coming week, make an investment in yourself and the women who are close to you by committing to a life that’s free of tobacco-related disease and death.

Lawrence R. Deyton, M.S.P.H., M.D., is the Director of FDA’s Center for Tobacco Products

FDA’s Role in Promoting Women’s Health

By: Marsha Henderson, M.C.R.P.

For one week in May, the nation celebrates women’s health. I often find at these celebrations that no one mentions FDA. This is unfortunate, because throughout its 100-year history FDA has played a leading role in advancing women’s health. 

Marsha Henderson, M.C.R.P.In its early years, the Agency worked to ban harmful, addictive and poisonous tonics that were marketed as cure-alls for women. Later, FDA worked to help women avoid public health tragedies like the serious birth defects seen in many countries where pregnant women used thalidomide – a drug that was not approved in the U.S. thanks to Dr. Francis Kelsey, an FDA medical officer.

When I joined FDA in the 1990’s, the Agency was working hard to remove regulatory barriers that limited our understanding of how medicines and medical devices affect women. We changed the regulations. We partnered with NIH, academia, advocacy groups, and drug companies to support women’s health research. We also developed strategies to increase the number of women included in clinical trials for new medical products. These activities helped all of us learn more about the ways sex differences affect the safety and usefulness of FDA-regulated products.

During this time, I also helped launch the Take Time to Care Outreach Program. Through this program, FDA has been able to use creative partnerships and innovative outreach tools like telenovelas to connect millions of women with reliable information they can use to make better health decisions for themselves and their families.   

All of these efforts have helped to protect and promote the health of women – leading the way to improved policies and greater awareness about vital women’s health issues such as diabetes, mammography, and medication use during pregnancy.  We have made great strides; however, there is still much work to be done. FDA will continue to promote policies, research and educational initiatives that advance women’s health.

During this year’s National Women’s Health Week, I thank FDA employees and our external partners for their continued service to women’s health. I also encourage the nation’s health professionals and the women they serve to look to FDA for women’s health resources.  We are here for you. 

Marsha Henderson, M.C.R.P., is FDA’s Assistant Commissioner for Women’s Health

Talk With Your Kids About Tobacco

By: Margaret A. Hamburg, M.D.

The next time you’re out with your kids, take a moment to pause and look at the adult smokers you pass on the street.  Research shows that many of them took up the addictive habit when they were kids — and too young to truly understand the very real risks and dangers of tobacco use.

Margaret Hamburg, M.D.By law, a person has to be at least 18 years old to purchase tobacco products, yet more than 80 percent of adult smokers began before they were 18.  Each day in the United States more than 3,800 youth smoke their first cigarette.  It’s estimated that more than 1,000 youth become daily smokers each day.

As a mother and a doctor, I know that this is something that must change.  And, one of the best ways to help our kids grow into healthy, happy adults is to teach them about the dangers of smoking and tobacco use. And, just as you do with your family, you can play an important role in your community when it comes to getting the word out about the dangers of tobacco. FDA is working to ensure retailers are fully aware of regulations that help protect kids from the dangers of tobacco.  Everyone — from moms (and dads!) to retailers and community leaders — can help protect kids from tobacco.

We all know that our nation’s youth hold the key to our future.  This Mother’s Day, let’s make sure it’s a healthy one.

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

FDA’s Modern “Corps of Discovery” in China

By: Christopher Hickey, Ph.D.

I love history.  I especially love the story of Meriwether Lewis and William Clark who, in their famed venture to explore the newly-purchased Louisiana Territory at the direction of U.S. President Thomas Jefferson, fashioned a lean and mean team largely consisting of seasoned, highly qualified frontiersmen. While Lewis and Clark’s “Corps of Discovery” benefitted to some degree from maps that had been developed by previous explorers who had traversed similar terrain, there was a large swath of territory in the middle of their journey that was literally “off the map”—no non-native groups had ever set foot on those pieces of the North American continent.  And while brawny, rough-and-tumble, frontiersmen may have dominated the rolls of the Lewis and Clark expeditionary force, they would have all frozen or starved to death had it not been for the keen and savvy brilliance of Sacagawea, surely one of the unlikeliest heroines in American history.

Christopher Hickey, Ph.D.

The Honorable Margaret Hamburg, Commissioner, FDA and Dr. Christopher Hickey, Country Director, FDA China

I also love my job.  I run FDA’s China Office.  Nearly four years in, I still pinch myself most mornings to make sure I’m actually getting paid to lead this fascinating, unpredictable 21st century expedition to explore new public-health frontiers for my country.

Like Lewis and Clark, we in the FDA China Office have been fortunate enough to benefit from a surfeit of talented “frontiersmen” – and women! – who’ve volunteered for this pioneering venture.  They include inspectors and policy analysts who, in some cases, have served FDA for nearly four decades!  They’ve seen marked similarities between the challenges we face in China in 2012 and the challenges FDA faced in regulating domestic U.S.industry several decades ago.  Our “pioneers” include FDA food scientists and biochemists with deep, rich expertise who are now applying that knowledge to work in collaboration with Chinese authorities as they develop a regulatory system that will keep pace with increasing Chinese economic growth, and ever-expanding exports to U.S.markets. And our “FDA Corps of Discovery” includes legal, policy and health diplomacy professionals.  These professionals apply their knowledge of FDA standards and regulations, as well as their scientific and diplomatic expertise, to enhance the Agency’s knowledge base about China’s regulatory landscape. In addition, they track industry trends to inform U.S. regulatory decisions and actions, and strengthen collaboration on mutual regulatory challenges.

And we certainly find ourselves, like Lewis and Clark, “off the map,” at times.  How do you navigate a regulatory system that assigns responsibility to government agencies not by product category but by where the product currently sits in the system of production and distribution? How do you engage a regulatory counterpart that has export promotion as a primary mission?  How does FDA engage a regulatory system where the legacy of state-owned enterprises still looms large?  These are all “off-the-map” types of questions we’ve had to face.

And we have our Sacagaweas—unsung, unlikely public-health heroes.  While U.S.civil servants lead the way for our efforts in China, Chinese nationals play a key role to support our work—liaising with the Chinese Government, negotiating cross-cultural communications, and supporting our inspections throughout China.  FDA could not do its work in China—or in any of its overseas offices—without dedicated foreign service nationals.

“Those who cannot remember the past are condemned to repeat it,” Spanish philosopher George Santayana once opined.  In FDA’s China Office, we strive to remember the best of our past so that we can know how best to engage our emphatically globalized future.

Christopher Hickey, Ph.D., is FDA’s China Country Director


Six Month Check-Up: FDA’s Work on Drug Shortages

By Margaret Hamburg, M.D.

This week marks the six-month anniversary of President Obama signing an Executive Order to help FDA in our ongoing efforts to prevent and resolve prescription drug shortages. At FDA, we saw the Executive Order as an important step in bringing awareness to this critical public health issue and signaling the necessary tools and resources, such as early notification and additional staff, FDA must have to help address this problem. Following the Executive Order, we sent out letters to drug manufacturers asking them to voluntarily report to FDA if they saw the emerging potential for a drug shortage.

Margaret Hamburg, M.D.Six months later, I am both amazed and delighted to see the progress that’s been made. Early notification to FDA of potential disruptions in drug supply has made a huge difference in our efforts – and the numbers really tell the story. Since reaching out to industry, there has been a six-fold increase in early notifications from manufacturers. Also in that six month timeframe, we have been able to prevent 128 drug shortages, and we’re seeing fewer numbers of shortages occur – 42 new drugs in shortage reported in 2012, compared to 90 new shortages at this time last year. This data is a testament to how FDA exercises flexibility and discretion in much of our work on drug shortages and the importance of strong collaboration and constant communication with industry, health professionals, and patients.

January-October 2011 10 notifications per month and November 2011-April 2012 60 per monthBut these are simply statistics. Consider instead the impact of our work on patients, who need particular drugs to treat life-threatening diseases. For instance, supplies of methotrexate, a cancer drug used to treat childhood leukemia and osteosarcoma, are currently meeting all demand, and we do not expect any further supply issues. Also, to address the shortage of Doxil (liposomal doxorubicin), a drug used for ovarian cancer and other cancer regimens, FDA exercised enforcement discretion for the importation of Lipodox, another brand of liposomal doxorubicin, from India, meeting patient needs until Doxil is available again.

While many shortages of cancer drugs are resolving, we are still working hard to address others. Leucovorin injection, a cancer drug that is used along with methotrexate for children with a serious form of leukemia, has been in short supply for some time. We are working with the manufacturer, Teva Pharmaceuticals, to produce additional shipments in the coming weeks to help improve supplies. Mustargen (Mechlorethamine HCl) – another cancer drug used in multiple cancer regimens — has also been in shortage. FDA has worked with the manufacturer to resume production of Mustargen, and the company is planning to have product available again by August.

January 2010-October 2011 about 9, and November 2011-April 2012 about 21; 86 shortages prevented in late 2011 involved a single firmWe are equally concerned about other types of drugs in shortage. Anesthesia drugs, such as benzodiazepines and fentanyl injections, have recently been in short supply. Here again, early notification is helping. One manufacturer, Hospira, notified FDA of anticipated delays in supply of the critical anesthesia drug propofol. This advanced notice allowed FDA to work with the other manufacturer of propofol who was able to increase supplies to keep the product available for patients undergoing surgery.

Drug shortages remain a serious, complex problem, and the agency remains extremely concerned about all current and potential drug shortages, not just those that I mentioned. Our efforts require a multifaceted approach involving industry, regulators, payers, and others. And we’re working with Congress on bipartisan legislation to expand early notification of drug supply problems that could cause shortages. All of us have a responsibility to help ensure that patients have reasonable access to the drugs they need. Drug manufacturers in particular have a responsibility to manufacture quality drugs and to have a process to ensure supply continuity of critical drugs.

2005 about 60, 2006 about 55, 2007 about 85, 2008 about 110, 2009 about 160, 2010 about 180, 2011 about 445 and  about 105 prevented, 2012 about 130 and about  100 prevented; Data on Shortages prevented only available for 2011 and 2012.  Data for 2012 are projected.In a blog I wrote earlier this year, I reminded readers that “the critical issue of drug shortages isn’t about industry; it isn’t about government, or even about the drugs themselves. It is about getting people the treatments they trust, they need, and they rely on.” While that remains as true as ever, I would like to add a different kind of reminder. Today’s six-month check-up demonstrates what government and industry can accomplish when we work together. While there’s no simple solution, we are making progress. And we’ll remain vigilant – doing all we can and using every resource available – to make sure patients have access to the critical medicines they need, when they need them.

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

Enabling Innovation for Biological Product Safety

By: Leslie Kux, J.D.

Last year President Obama issued Executive Order (EO) 13563, “Improving Regulations and Regulatory Review.”  This EO directs Federal agencies to review existing regulations to determine whether a regulation is outmoded, ineffective, insufficient, or excessively burdensome.  One of FDA’s main goals as we implement this Executive Order is revising our regulations to promote innovation and advance the use of new technology.

Syringe plunged into vial I’m pleased to announce that, based on a retrospective review, we are finalizing a rule to modernize the agency’s regulations for sterility testing requirements for most biological products, for example, vaccines such as flu vaccines. These regulations have an important public health purpose – to make sure that products such as vaccines do not contain any organisms that could cause illness. During our review, FDA determined that the existing regulations were too narrow in light of new technology and new products. The final sterility rule supports state-of-the-art testing technologies that give accurate and reliable results, often quicker and with less effort than the methods required in the current regulations. The rule will not add any additional regulations to those already followed by the industry and will not place significant burdens on small companies that make these products. Manufacturers can keep their existing procedures for sterility testing or take advantage of modern methods as they become available, provided that the modern methods meet certain criteria.

These changes reflect FDA’s approach to ensuring both biological product safety and getting patients these products as rapidly as possible. The changes also exemplify FDA’s broad vision for advancing regulatory science and its potential to improve public health by developing new tools, standards, and approaches to assess the safety, efficacy, quality and performance of FDA-regulated products.

Leslie Kux, J.D., is Assistant Commissioner for Policy in FDA’s Office of the Commissioner