FDA’s Mini-Sentinel exceeds 100 million lives (and counting)… A major milestone in developing a nationwide rapid-response electronic medical product safety surveillance program

By: CDR Melissa Robb

Having secure access to the electronic healthcare data of patients is an essential 21st Century tool for detecting potential safety problems with medical products once they are in common use.

This is because studies conducted prior to approval may not be able to detect rare problems or problems that might emerge following long-term use of a product.

Congress recognized this need for additional information in the FDA Amendments Act (FDAAA) of 2007 when it authorized FDA to develop a nationwide rapid-response electronic surveillance system for monitoring the safety of FDA-regulated medical products such as drugs, vaccines, other biologics, and medical devices.  FDA calls this the Sentinel System.

Now FDA is proud to report that it has met and EXCEEDED the legislation’s goal of achieving secure access to data from 100 million patients by July 1, 2012. In fact, FDA met that goal in December, 2011, and currently has secure access to data concerning approximately 126 million patients nationwide derived from 17 different data partners.

To better understand how the Sentinel System will work, FDA has been conducting a pilot program, dubbed “Mini-Sentinel,” that incorporates access to these 100 million-plus records. So far FDA has used Mini-Sentinel to conduct more than 120 data requests to gather safety information on various medical products.

As an example of the promise of this system, consider FDA’s recent use of the Mini-Sentinel pilot to help inform our ongoing safety analysis of the blood pressure drug olmesartan. FDA had received reports through our Adverse Event Reporting System (AERS) suggesting that olmesartan was associated with more cases of celiac disease than other “sartan” drugs in its class (losartan, irbesartan, telmisartan, valsartan). Celiac disease is a potentially dangerous condition in which the small intestine is damaged and the patient cannot absorb nutrients. FDA, through Mini-Sentinel, submitted a query request to the data partners for specific information on the number of patients with celiac disease who had taken these drugs.  The resulting data report allowed FDA to determine that celiac disease did not occur significantly more often with patients who had taken olmesartan than with those who had taken other “sartan” drugs.

While the Sentinel System holds much promise, it is intended to supplement, not replace, FDA’s existing safety surveillance tools, including AERS, which relies on individual reports filed by manufacturers, health care providers and patients. When weighing risk against benefit of a medical product, FDA compiles information from a variety of sources before making a regulatory decision.

FDA is committed to maintaining the highest world-wide standards of safety surveillance capabilities. The Sentinel System  is our next step forward towards that goal.  Stay tuned. As always, we’ll keep you informed on progress.

CDR Melissa Robb is FDA’s Associate Director for Regulatory Affairs, Office of Medical Policy Initiatives

User Fees: Ensuring a Stronger and Better FDA

By: Margaret Hamburg, M.D.

FDA receives thousands of applications for potentially promising medical products every year. Reviewing these often scientifically-complex submissions is the responsibility of a large team of doctors, chemists, bioengineers, statisticians and other experts who must determine whether a proposed new product is safe and effective for patients, and do so within a certain time period.

Margaret Hamburg, M.D.It takes steady and reliable funding to maintain and support a staff of trained reviewers capable of accomplishing this vital task. We’re gratified that Congress agrees, as demonstrated by today’s passage of the Food and Drug Administration Safety and Innovation Act in the US Senate by a vote of 92-4. Since the House of Representatives passed the bill last week by a voice vote, the bill now heads to the President’s desk, where it is expected to be signed into law. This legislation, when enacted, will authorize the FDA to collect user fees from industry to fund the review of innovator drugs, medical devices, generic drugs and biosimilar biologics.

Such overwhelming support for FDA user fees is a testament to the important role FDA plays in America’s healthcare continuum. FDA’s medical product decisions sit at the intersection of public health, innovation, and commerce and touch the lives of nearly every American every day.

Today’s positive vote also reflects the success of FDA’s commitment to transparency and collaboration in developing user fee proposals that all sides could support. FDA negotiators spent months in discussions with industry and consulted closely with patients, consumers and health care providers before arriving at proposals for each of the four programs.

Driving these discussions is the recognition that user fees have been a big success, reversing what was once a lag in the time needed for drug approvals. Since the prescription drug user fee legislation (PDUFA) was enacted in 1992, time to market for priority drugs has decreased from an average of 2 years to 1.1 years recently. This has provided patients faster access to over 1,500 new drugs and biologics, including treatments for cancer, infectious diseases, neurological and psychiatric disorders and cardiovascular diseases.

Under PDUFA V, fees paid by industry will support continued timely review of new prescription drugs, increase the use of standardized electronic data in product submissions, enhance communications with companies during drug development and implement a structured benefit-risk framework in drug review.  PDUFA V also puts more focus on regulatory science, which seeks to create new tools, standards and approaches for use in assessing the safety, effectiveness, quality and performance of products. Among other things, user fees will advance the development of drugs for rare diseases and encourage the development of biomarkers.

Patient groups in particular are heralding PDUFA V as a turning point because it acknowledges that patients who live with a disease have a direct stake in the outcomes of the drug review process and are in a unique position to contribute to the entire drug development enterprise, including FDA review and decision-making. Thus, PDUFA V will support the advancement of the use of patient-reported outcomes and other tools to assess clinical trial endpoints that can improve quality and reduce risks in drug development. It will also engage patients to obtain their perspective about disease severity and unmet medical needs in a therapeutic area. FDA will use this perspective to inform the context in which the agency weighs drug benefits and risks.

The legislation also reauthorizes the user fee program for medical devices for the third time. Under MDUFA III, user fees will nearly double, rising from 20 percent of the total of FDA’s review activity to 35 percent. The agreement facilitates more timely access to safe and effective devices with the shared goal of reducing average total time to decisions and achieving greater transparency, consistency, predictability and productivity. With the additional funding, the FDA will be able to hire over 200 full-time equivalent workers by fiscal year 2017.

Two other user fee programs in the legislation are new. User fees for generic drugs or GDUFA will address our current generic drug review backlog caused by the increase in generic drug applications, their growing complexity, and the number of generic drug facilities now located overseas where inspections are more challenging. The added money from user fees will reduce this backlog and eventually ensure that FDA is able to inspect overseas facilities as often as it does domestic facilities.

The second new user fee program, BsUFA, would collect fees for products under development shown to be “biosimilar to” or “interchangeable with” an innovator FDA-licensed biological product. The funds would support early meetings with companies.

The legislation also contains dozens of other provisions related to FDA.
Three provisions are worth highlighting: they provide FDA with new tools to better combat drug shortages, ensure the safety and security of the drug supply chain and encourage drug innovation.

It’s been a long, yet productive process since FDA first began meeting with industry and other public stakeholders on the reauthorization of user fees nearly two years ago. What has emerged, I believe, will truly result in a stronger and better FDA for everybody.

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

The Next Generation of Food Safety Innovators

By: Marianna Naum, Ph.D

How many of us played with LEGOs as children? I’d wager that a fair number of Americans across generations are familiar with those little colored blocks with their characteristic nubby surfaces. But you’d be forgiven if your first thought was to build a castle or a helicopter, and not a food safety robot.

FDA Commissioner Margaret A. Hamburg, M.D., along with FDA judges Marianna Naum and Keith Lampel

FDA Commissioner Margaret Hamburg, M.D., along with FDA judges Marianna Naum and Keith Lampel

Wait—LEGOs and food safety? That’s right. The 2011 FIRST LEGO League (FLL) Food Factor Challenge invited more than 18,000 teams of 9-to-14-year-olds to use LEGOs to build a machine to solve food safety problems. Commissioner Hamburg was on hand to give a congratulatory “high five” to the winners, and I was honored to be a judge in this year’s competition.

To be successful, the teams had to educate themselves very quickly on many different aspects of food safety in order to complete the first part of the challenge: identifying a specific food safety problem. Then each team had to come up with an inventive solution that was feasible, original, cost-effective, and commercially viable; a tall order even for experienced researchers who have spent many years studying food safety. Local competitions narrowed down the contestants from 18,000 to 270 teams. That is when FDA judges got involved.

I had first heard about the Food Factor Challenge from my nephew, Tom, who was a member of the ‘Robot Zombies’ in Milwaukee, WI. Unfortunately, the Robot Zombies’ proposal did not make the final cut for the contest, but the team’s enthusiasm echoes loudly to this day. I encountered that same energy in ‘Next Gen’ – a local Maryland team that invited me to speak to them about food safety and the challenges we face in food microbiology. I knew that if the other participants possessed the same zeal and enthusiasm as the ‘Robot Zombies’ and ‘Next Gen,’ we’d get to see some really innovative and resourceful proposals.

I was not disappointed. My expectation for creative, out-of-the box thinking was met when I reviewed 67 of the proposals and chose my top three. The proposals were amazingly well thought out, and I was impressed by the amount of work team members had completed to test the feasibility, efficiency or commercial viability of their innovative solution. It was tough having to eliminate teams, and my colleagues and I held what seemed like endless scientific debates over which teams to advance. Apparently we were not the only ones who had a hard time deciding! The panel of judges who selected this year’s winning team – different experts from those who screened the entries — also had a hard time.  How do I know?  This year’s competition resulted in not one, but two winning teams. The ‘S.I.S. Robotic Revolution’ won for designing a smart sticker – placed on the outside of a refrigerated food container – which changes color when food is not stored at proper temperatures. The second team to win, ‘Moderately Confused,’ developed the Erasable Barcode, which has temperature sensitive ink that prevents it from being scanned when meat is stored at improper temperatures.

Increasing consumer awareness of food safety is one of the keys to preventing foodborne illness. The Food Factor Challenge accomplished so much more. It encouraged participants to learn about food safety; fostered creativity by challenging teams to come up with imaginative solutions to existing food safety problems; and inspired thousands – many of whom may become our future food scientists.

Marianna Naum is a Policy Analyst, Division of Education and Communication, Office of Food Defense, Communication and Emergency Response, in FDA’s Center for Food Safety and Applied Nutrition.


BLOOD SUBSTITUTES: Working to Fulfill a Dream

By: Abdu I. Alayash, Ph.D., D.Sc.

The first recorded human blood transfusion occurred in Europe during the 17th Century. Those early attempts were usually fatal, since scientists had not yet discovered blood types; nor did they have available the transfusion technologies and techniques we now take for granted.

Today, FDA’s Center for Biologics Evaluation and Research (CBER) is responsible for ensuring that blood and blood products used for transfusions in the United States are safe and effective. But sometimes blood is simply not available in certain extreme situations, such as accidents or battlefield trauma, or in certain cases of blood incompatibility.

For the last 30 years, scientists in industry and academic institutions have been trying to develop a portable blood substitute that:

  • functions as an oxygen carrier in life-threatening situations;
  • is stable enough to be stored for prolonged periods in different conditions;
  • and, can be used to treat individuals of any blood type.

Abdu I. Alayash, Ph.D., D.Sc.To date, product developers have been unable to succeed in developing a blood substitute that is safe enough for FDA to approve its use in humans. That’s because the key element in making an effective blood substitute – hemoglobin – is also at the center of the problem.

Hemoglobin, a protein in red blood cells, is the molecule available to carry oxygen in the human body. Hemoglobin contains the common element iron, which makes it possible for hemoglobin to capture and hold oxygen when red blood cells circulate through the lungs. When the iron in hemoglobin releases oxygen in the tissues, it becomes more prone to a chemical reaction called “oxidation.” Oxidation prevents further binding of oxygen to the iron and the resultant effect on hemoglobin can lead to cellular damage. (We call the result of this reaction “rusting” when it happens to an iron object.) Fortunately, red blood cells contain an enzyme system that prevents oxidation. As a result, oxygen can reversibly bind to the iron on hemoglobin in red blood cells.

But this enzyme system is not available when hemoglobin is removed from red blood cells and becomes “free hemoglobin,” which is used to carry oxygen in the blood substitute products evaluated so far, known as hemoglobin-based oxygen carriers (HBOCs). Iron oxidation is not reversed resulting in the destruction of hemoglobin itself as well as other molecules in the body’s surrounding tissues.

In addition HBOCs have also been associated with severe medical complications, such as high blood pressure, heart attacks and strokes. FDA scientists and others are trying to solve this problem so that safe and effective hemoglobin-based oxygen carriers can finally be brought to market.

Since its inception in 1989, scientists in CBER’s hemoglobin research program have studied the complex chemical reactions of free hemoglobin, in test tubes, cell cultures and animal models. CBER has also studied ways to control those chemical reactions in an effort to help develop a safe form of free hemoglobin for use in a blood substitute. Among our major contributions to the field is a detailed confirmation of free hemoglobin’s chemical toxicity in kidneys, the brain, and in several animal models of transfusion.

Figure of hemoglobin prepared by Todd L. Mollan, CBER.
Figure of hemoglobin prepared by Todd L. Mollan, CBER.

In addition, we have experimented with molecules available in nature in an attempt to block free hemoglobin’s destructive chemical reactions within the body. One such molecule is haptoglobin, a naturally-occurring protein in the blood that prevents the damaging reactions of hemoglobin when it is present outside red cells. Our work suggests that it might be possible to control or reverse the toxic effects of free hemoglobin by transfusing patients with haptoglobin at the same time they are transfused with a hemoglobin-based oxygen carrier. We also showed that Vitamin C (ascorbic acid), a natural anti-oxidant, might also have this protective effect.

FDA is continuing this research to support the development of safe blood substitute products that provide new options for saving lives in the operating room and on the battlefield. Our research to facilitate development of safe and effective blood substitute products provides yet another example of FDA’s ability to carry out sophisticated biomedical research and our commitment to medical product innovation.

Abdu I. Alayash, Ph.D., D.Sc., is Chief of Laboratory of Biochemistry and Vascular Biology, OBRR, at FDA’s Center for Biologics Evaluation and Research.

Youth and Tobacco Town Hall: Involving Young People in Preventing the Use of Tobacco

By: Jenny Haliski, M.A.

This morning, FDA’s Center for Tobacco Products Director Lawrence Deyton, M.D., M.S.P.H., is participating in a Youth and Tobacco Town Hall Meeting in Seattle, Washington. He’ll be joining U.S. Surgeon General Regina M. Benjamin, M.D., M.B.A., other public health leaders, and youth from across the Pacific Northwest to discuss FDA’s action agenda for tobacco product regulation.

VADM Regina M. Benjamin, MD, MBA, Surgeon General, USPHS greeting (from left to right) Dr. Lawrence Deyton, director of the FDA Center for Tobacco Products; Howard Frumkin, DrPH, MPH, MD, AB, Dean of the University of Washington School of Public Health, Seattle, Washington, and moderator of the panel on Tobacco Free Campuses; and Kate Cole, MPH, coordinator of the Tobacco Studies Program at the University of Washington, Seattle, Washington, and moderator and panel chair for the conversation with the Surgeon General, “Young People’s Thoughts on Reducing Tobacco Use.”

View photos from the event on FDA’s Flickr
View archived webcast of the Youth and Tobacco Town Hall Meeting

Tobacco use is the leading cause of preventable death in the U.S., responsible for more than 443,000 deaths each year. Nearly all tobacco use begins during youth and young adulthood. The day-long event brings together tobacco prevention leaders, policy makers, advocates and—most importantly—young people from around the region.  Participants will be sharing tools and best practices in tobacco use prevention, discussing existing efforts, and devising new strategies to help youth resist pressures to start using tobacco.

This town hall is part of the broader effort on the part of the Federal Department of Health and Human Services to prevent children from starting to use tobacco and to help current tobacco users quit. The goals for the town hall meeting are to:

  • Help spread the word about the Surgeon General’s Report, Preventing Tobacco Use among Youth and Young Adults;
  • Learn about new initiatives at the FDA to reduce the public health burden of tobacco products;
  • Increase the already-considerable regional energy around efforts to prevent tobacco initiation and reduce tobacco use among young people; and
  • Provide an opportunity for advocates and experts working in this field to share experiences, solutions, and ideas for further reducing tobacco initiation and use among young people.

Watch the live webcast and follow along on Twitter!

  • Beginning at 12 p.m. EDT on June 14, join the live webcast of two plenary sessions with Dr. Deyton and other public health officials, and a conversation between the Surgeon General and youth.
  • Follow @FDAtobacco on Twitter and participate using the hashtag #PNWtobacco

Find out more about the event and view the agenda. Help spread the word!

Jenny Haliski, M.A., is a Press Officer in the Office of the Commissioner, Office of Public Affairs, who works with the Center for Tobacco Products.

FDA Inaugurates Annual Patient Network Meeting

By: Richard M. Klein

FDA has a long history of working with patients and patient advocates, beginning with the AIDS crisis of the 1980s. Our interactions with patient groups have evolved since then, and the agency now works with patients representing a broad spectrum of diseases and conditions.

FDA’s Office of Special Health Issues (OSHI) is the agency’s primary interface with patients and the patient advocacy community. OSHI educates patient advocates about medical product regulations and looks at ways to more effectively involve patients in regulatory decisions that affect them. We also assist patients with a broad range of patient issues related to approved and investigational medical products, including information about clinical trials and where to find studies, and about when access to investigational products outside of trials might be appropriate. Our office is expanding its efforts to communicate with patients by creating The Patient Network, a comprehensive new program designed to maximize our ability to outreach to patient groups.

The first component of the network is the twice monthly newsletter, Patient Network News launched in 2011. It provides FDA-related information on a variety of topics, including new product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings, proposed regulatory guidances and opportunity to comment, and other information of interest to patients and patient advocates.

Secondly, additional information will be available at a mouseclick when FDA unveils a new patient-centered web site later this year.

And a few weeks ago we inaugurated a third component of our new patient programming, an annual Patient Network Meeting. Held on May, 18, 2012, the first meeting focused on discussions of benefit-risk decision-making. FDA Working with Patients to Explore Benefit/Risk: Opportunities and Challenges, included an overview of the regulatory process for developing and bringing medical products to market and other aspects of FDA regulation and included ample time for audience participation and interaction during the day.

We believe it’s critical that we bring patients into the process of determining the best way to incorporate their level of risk tolerance when considering the potential benefits of medical products. It is also important to find ways to better characterize and communicate potential risks associated with particular medical products so that patients can better assess the balance against their medical needs, and make more informed decisions about their medical options.  

Our inaugural Patient Network Meeting is the beginning of a new, fruitful dialog with patient communities, collecting valuable thoughts and suggestions. When patients can work together with us addressing the wide range of conditions and diseases they deal with on a daily basis, everyone benefits.

Richard M. Klein, is Director of the Patient Liaison Program in FDA’s Office of Special Health Issues.

FDA Science and Research Working to Uncover the Immunology of Severe Drug Reactions

By:  Michael A. Norcross, M.D.

I vividly remember one of the first patients I saw as a medical student. She looked like a burn victim, but she had not been exposed to extreme heat. This patient had recently started a new anti-epilepsy medication, and within a few weeks had developed a skin rash over her entire body. The rash looked liked poison ivy, but instead of healing, it progressed to severe blisters and skin peeling – events typical of a severe burn. The patient was treated with standard care for a burn victim, but it wasn’t until the new medication was stopped and much intensive care was provided that the patient’s symptoms subsided and she survived. Sadly, many other patients with similar symptoms are not as lucky.

Michael A. Norcross, M.D.This patient experienced a condition called Stevens-Johnson syndrome (SJS), which can be caused by some anti-epilepsy and anti-gout medications as well as other drugs. With some drugs, the liver is the target of destruction and can become so damaged that a transplant is required to sustain life. We now know that these severe drug reactions that lead to SJS affect both the skin and the liver and, more critically, the immune system. In fact, patients who are susceptible to adverse effects of some drugs share common variations in immune system genes called Human Leukocyte Antigens (HLAs). 

Over the last few years as a Principal Investigator at FDA, I have focused my research efforts on HLAs. Our recent work has been studying the HIV/AIDS drug Ziagen (abacavir), which has well known side effects in a high percentage of patients with an “at-risk” HLA genetic variant called HLA-B*5701. Key to the success of this project was developing a collaborative team to study the complicated problem. I recruited scientists both from within the FDA, the National Institutes of Health, and the University of Oklahoma. 

Our team developed new techniques to measure effects of abacavir on HLA-B*5701, and found that the drug clearly changed the normal function of this HLA type. These changes can cause the immune system to “see” some of the body’s own proteins as foreign, which then triggers a series of steps resulting in the immune system mounting an attack on the body’s own tissues and organs. We call this type of reaction an “autoimmune” response and it is related to the types of immune responses seen in other autoimmune diseases such as lupus and rheumatoid arthritis.

I believe that our work unraveling how and why certain drugs cause severe reactions will give us new tools to analyze the safety of drugs that could cause severe allergic reactions. Our recent results may also provide biopharmaceutical companies and other research organizations new methods to identify drug candidates early in the development process that could cause severe adverse reactions. This work may also serve as a model for future research to predict drug reactions in different populations of at-risk patients. This “personalized medicine” approach refines the drug development and review processes and can lead to safer drug therapies.

Adverse drug reactions are a major obstacle to development and approval of new drugs and, in some cases, are responsible for withdrawal of drugs from the market. Continued research on the biochemical and immunological mechanisms involved in severe adverse drug reactions will be important, not only for treatment of drug reactions but, more critically, to identify individuals at greater risk in order to prevent an adverse event from occurring. Using this research as a foundation, we can continue to work to make autoimmune drug responses like the severe skin reaction I saw in medical school a thing of the past.

Michael A. Norcross, M.D. is a Principal Investigator in the Division of Therapeutic Proteins in the Office of Biotechnology Products in FDA’s Center for Drug Evaluation and Research

FDA’s Medical Countermeasures initiative – Protecting Public Health

By:  Luciana Borio, M.D.

FDA plays a pivotal role in thinking about the unthinkable: preparing for a chemical, biological, radiological or nuclear event that could result in mass casualties.

But the 2001 anthrax attacks in the United States, the 2009 influenza pandemic, and last year’s nuclear accidents in Japan demonstrate the critical need to plan for the unthinkable.

Luciana Borio, M.D.Food, medical products, and the blood supply are all essential elements when such events occur. As the regulatory agency responsible for their oversight, that means FDA is central to a successful response to these deliberate or unintentional threats.

Coordinating FDA’s efforts to think about the unthinkable is the Office of Counterterrorism and Emerging Threats (OCET).

The office provides strategic leadership and coordination, working closely with other offices within FDA, Federal and State partners, like the Centers for Disease Control and Prevention and the National Institutes of Health, as well as academia, and industry to make sure we can respond quickly and appropriately to counter and minimize the effects of these types of public health emergencies.

Part of preparing for the unthinkable is the development of medical countermeasures—the vaccines, therapeutic drugs, diagnostic tests, and other medical equipment and supplies.

In 2010, FDA launched its Medical Countermeasures initiative (MCMi), to make sure that such products are available. OCET is working closely with the medical product centers to enhance the product review processes by identifying and helping to resolve the scientific, legal, regulatory, and policy gaps that may be slowing development of medical countermeasures; working to modernize the regulatory and policy framework to support preparedness and response; and advancing regulatory science for MCM development and evaluation.

FDA’s drug, device, and biologics programs are fostering the development of MCMs in several high-priority areas and encouraging the use of advanced manufacturing technologies. Examples of key areas of focus include:

  • diagnostics and therapies to treat the multiple manifestations of acute radiation syndrome;
  • the special needs of pediatric patients and pregnant women;
  • next-generation diagnostic tests; and
  • care for American soldiers exposed to trauma or CBRN threats.

We are also working to speed MCM deployment and facilitate pre-event planning and positioning of MCMs at the local level.   

At FDA, science underpins virtually every regulatory decision we make. Through our MCMi regulatory science program, FDA is helping build the innovative scientific tools we need, tools like new testing models and other techniques to address the challenge of determining whether a new countermeasure is effective in treating an outbreak of anthrax, the effects of radiation exposure, or plague. Clearly these products can’t be tested on humans, so new models must be developed to accurately reflect human response.

And we’re making good progress. Just recently, an FDA Advisory Committee meeting considered data and voted unanimously on the significance of studies using animal models in evaluating the effectiveness of fluoroquinolones for treating humans with pneumonic plague. 

Next week we will be showcasing our many, scientific collaborations at a two-day public seminar, the MCMi Regulatory Science Symposium. By clicking on the Program Agenda, you can get a quick picture of the broad number of topics we’re working on.

I also invite you to visit FDA’s MCMi Web page to read further about this important part of our mission to promote and protect public health.

Dr. Luciana Borio is Assistant Commissioner for Counterterrorism Policy and
Director, Office of Counterterrorism and Emerging Threats