Mind the Gap: Strengthening relations with the European Medicines Agency to the benefit of public health

David Martin, M.D., M.P.H.

Cars driving on the left side of the road and exhortations to “mind the gap” when exiting the underground became a part of my daily routine when I joined the FDA Office of International Programs as the Acting FDA Liaison to the European Medicines Agency (EMA) in London. EMA is an important partner for the FDA: It coordinates a network of 4,500 European scientists and evaluates and supervises human and animal medicines for more than 500 million people in 31 countries.

Sabine Haubenreisser and David Martin

EMA’s Sabine Haubenreisser, MSc, Ph.D., and David Martin, M.D., M.P.H., who served as the Acting FDA Liaison to the European Medicines Agency from June through September 2014.

On my first day at the EMA, I learned that its Pharmacovigilance Risk Assessment Committee (PRAC) was debating a suspension of the European marketing authorization for a product approved in the United States by FDA. Moreover, PRAC was seeking urgent action within a week, which required quick response by FDA. Without it, suspension of a marketing authorization by Europe for an FDA-approved product could be confusing to patients, medical care providers, and industry in the U.S.

Consulting with management, review team members, and the international team from the FDA Center for Drug Evaluation and Research (CDER), I described the decision points to be addressed by the Europeans. The CDER team was already conducting a preliminary epidemiologic analysis of the possible relationship between the product and the adverse event in a large U.S. medical claims database. EMA had been already made aware of the ongoing CDER analysis, but needed formal detailed information to include in its benefit/risk assessment. PRAC had to be briefed on the broad outlines of the FDA evaluation within 48 hours, and needed access to FDA’s interim analysis within two weeks.

After a quickly arranged briefing under the auspices of an FDA-EMA confidentiality arrangement, CDER completed and shared the analysis in less than one week. At a follow-up meeting, FDA, EMA, and PRAC experts reviewed all data sources. The information indicated that the benefits of the product outweighed the low potential risk of adverse events. This information was included in the formal review by the PRAC, and a majority of PRAC members voted to maintain the product’s marketing authorization.

This episode showed  the importance of reciprocal FDA and EMA representation at each agency, which is currently carried out by EMA’s Sabine Haubenreisser, MSc, Ph.D. in FDA’s headquarters in White Oak and FDA’s Amy Egan, M.D. in London. Contacts between the liaisons and host agency leadership facilitate strategic dialogue that informs future policy making. And through close observation of the U.S. and European regulatory agencies in action, the FDA and EMA liaisons can help both sides find common ground when they are faced with regulatory decisions that could impact global public health.

David Martin, M.D., M.P.H., served as the Acting FDA Liaison to the European Medicines Agency from June through September 2014. He is the Director of the Division of Epidemiology within FDA’s Center for Biologics Evaluation and Research.

About EMA: European Medicines Agency

EU facts and figures: European Union

EMA/FDA confidentiality agreement: International Programs

Partnerships Are the Key to Keeping Foods Safe Worldwide

By: Michael R. Taylor

The success or failure of our efforts to keep foods safe all over the world rests on the strength of our global partnerships and the work we can do together to verify that food safety standards are being met. That’s why, today, after two days of meetings in Beijing with Chinese regulators, I am speaking at the China International Food Safety and Quality Conference and Expo in Shanghai about meeting the food safety challenges that all nations face.

Mike Taylor speaks in China

Deputy FDA Commissioner Michael R. Taylor giving the keynote address at the China International Food Safety and Quality Conference and Expo.

No matter where we live, we all want to feed our families with the confidence that the foods we are enjoying are safe to eat. Food safety is thus a goal that transcends international borders, and the food supply has never been so global. In the United States, 15 percent of our food supply is imported from other countries, including nearly 50 percent of fresh fruit and 20 percent of fresh vegetables. And last year, the U.S. exported a record $136 billion in foods, feed and beverages.

Congress recognized this when it enacted the FDA Food Safety Modernization Act (FSMA) and established a new regulatory paradigm for food safety, drawing on widely accepted international practices. The paradigm is simple. No matter where food comes from, we will achieve the best food safety results if we define—in workable, science-based standards—the approaches to managing food safety systems that we know are effective in preventing food safety problems AND if we achieve high rates of compliance with those standards.

Verification is key to the success of the FSMA paradigm and our global understanding of how to make food safe. It is also key to the consumer confidence that makes robust trade in food possible. Verification begins with what food producers do in their operations to verify, on an ongoing basis, that they are successfully implementing proper controls to prevent safety problems. But verification is also a public responsibility and a challenge that all nations face in our global food system.

FDA Staff at China Event

From left, Christopher Hickey, director of FDA’s China offices, Deputy Commissioner Michael Taylor and Roberta Wagner, co-chair of FDA’s FSMA Operations Team Steering Committee, visiting the China Food and Drug Administration.

Domestically, we will use inspections and other means, including sampling and testing, to verify that private food safety management systems are working effectively to prevent problems. This is a shift from our historic focus on enforcement of adulteration standards, although we will continue to act swiftly and forcefully when violations are putting consumers at risk.

In FDA’s oversight of imported foods, FSMA’s new Foreign Supplier Verification Programs (FSVP) will make importers accountable to FDA for documenting that their foreign suppliers have taken preventive measures to help ensure the safety of their food products. And we will inspect importers to verify that they are doing their job with regard to FSVP.

But we know that is not enough. Congress also mandated that we work more closely with foreign governments to verify that food safety standards are being met, so we are investing heavily in new forms of partnership with major trading partners with the goal of relying on each other’s verification activities as an element of the overall assurance system.

A prime example and model for collaboration is our joint initiative with Mexico to build a full operational partnership on produce safety, based on a strongly shared commitment to food safety as a public health goal. We are working directly with SENASICA and COFEPRIS – the agencies in Mexico that are responsible for produce safety – to expand the sharing of information, personnel and best practices, and to improve laboratory and other technical harmonization. Our goal is mutual reliance on each other’s oversight work. This initiative includes an important public-private partnership component.

Another model for building verification partnerships is our pursuit of what we call “systems recognition agreements” with countries whose overall food safety systems are comparable to ours. We have one with New Zealand and are working on agreements with Canada and Australia.

We also believe that being present in foreign countries is important to our own verification work and to building partnerships with foreign governments. That’s why we have increased our foreign inspections and have FDA offices in China, India, Europe, and Latin America. China, with its size and complexity, poses unique challenges as we seek to build food safety partnerships, so we are working to increase our China-based staff as a way to improve verification and foster mutual understanding and confidence.

The challenge of implementing the FSMA food safety paradigm on a global scale is huge, but I’m convinced from all the dialogue we’ve had around the world that we are on the right track. We have a long way to go, of course, but I have no doubt we’ll get there with the continued collaboration and commitment of our trading partners.

Michael R. Taylor is FDA’s Deputy Commissioner for Foods and Veterinary Medicine

Getting Potentially Life-Saving Drugs to High-Risk Breast Cancer Patients Faster

By: Tatiana Prowell, M.D. and Richard Pazdur, M.D.

Last month, researchers at an international oncology conference in Spain reported that pertuzumab, which was FDA-approved for treatment of HER2+ metastatic breast cancer in June 2012, improved survival by an average of nearly 16 months when added to standard treatment. This was yet another piece of good news, and one of unprecedented magnitude, for patients living with what was once the most dreaded type of breast cancer.

Tatiana Prowell and Richard Pazdur

Tatiana Prowell, M.D., Breast Cancer Scientific Lead, Division of Oncology Products 1,
Office of Hematology Oncology Products, and Richard Pazdur, M.D., Director of the Office of Hematology and Oncology Products, both of FDA’s Center for Drug Evaluation and Research

In the past, the next step would have been to wait for years while large clinical trials were conducted to determine if the drug also worked for earlier stages of breast cancer. This is beginning to change.

Although most women diagnosed with early breast cancer have surgery first to remove their tumor and then drug treatment to reduce risk of recurrence (as “adjuvant therapy”), it is also possible to give the same anti-cancer medicines before surgery (as “neoadjuvant therapy”) with equally beneficial results. Most breast cancers will shrink when drugs are given before surgery, and some will completely disappear by the time of surgery. This is called a pathological complete response, or pCR. Patients with a pCR at the time of surgery are at much lower risk of having their cancers “metastasize,” or spread, in the future.

To help speed drug approval for high-risk patients, in May of 2012, we proposed using pCR as a new endpoint that could support accelerated drug approval in high-risk early breast cancer. The basis for drug approval in early breast cancer to that point had generally been disease-free survival (how long patients survive without their cancer coming back) or overall survival. Such long-term outcomes remain tremendously important both to patients and regulators and will continue to be measured in clinical trials of every drug for early breast cancer. But relying exclusively on these outcomes for drug approval creates a gap of 5-10 years between approval for metastatic breast cancer and subsequent approval for use in patients with earlier stages of the disease.

Last month, we finalized FDA’s policy on use of pCR for accelerated approval in high-risk early breast cancer. Since we first proposed to rely on the endpoint for approval more than 2 years ago, we have learned a lot. FDA staff have spoken in conferences around the country, held webinars, and reviewed dozens of comments on the policy from academia, pharmaceutical companies, patients, and engaged citizens. We hosted an open public workshop that gathered breast cancer thought leaders, patient advocates, drug developers, and regulators, and produced consensus on use of pCR to support accelerated approval. To refine our understanding of pCR as a regulatory endpoint, FDA also led an international effort to pool data from more than 12,000 women enrolled in neoadjuvant trials.

So where are we in 2014? This pathway clearly has the potential to put the most promising drugs in the hands of the highest risk breast cancer patients years earlier than would ever have been possible previously, and in so doing, may increase their odds of cure.  Nonetheless, uncertainty remains about how well pCR rate can predict a drug’s ability to improve outcomes for patients with high-risk, early breast cancer, and what magnitude of increase in pCR rate is meaningful. For now, to make our decisions on accelerated approval in early breast cancer, we will rely on everything we know about a drug: the science behind how it works; how effective it is in other types of cancer or in more advanced stages of breast cancer; how well other drugs in the same class work; what side effects the drug causes, and how much it increases pCR rate compared to what can be accomplished with standard treatment.

Our first approval of a neoadjuvant drug for high-risk, early breast cancer occurred in September 2013. Pertuzumab was granted accelerated approval upon the basis of pCR rates and safety data from two neoadjuvant trials of the drug, as well as earlier efficacy and safety results from the metastatic breast cancer trial. At the time it granted accelerated approval, FDA required the sponsor to conduct a large adjuvant trial to confirm that pertuzumab does in fact reduce the risk of recurrence or death for women with earlier-stage tumors. The first results of that trial are expected in about 2 years.

There will always be uncertainty whenever we grant an accelerated approval for a neoadjuvant breast cancer drug, and this case is no exception. But, for the first time, women facing a new diagnosis of high-risk HER2+ breast cancer and their doctors will be able to decide whether the benefits and risks of pertuzumab make sense for them. There is still much to be done, but this is an important first step.

Tatiana Prowell, M.D., is Breast Cancer Scientific Lead, Division of Oncology Products 1, Office of Hematology Oncology Products, at FDA’s Center for Drug Evaluation and Research

Richard Pazdur, M.D., is Director of the Office of Hematology and Oncology Products at FDA’s Center for Drug Evaluation and Research

FDA as part of a coordinated global response on Ebola

By: Margaret A. Hamburg, M.D.

The tragic Ebola epidemic is an extraordinary global public health crisis, and FDA is taking extraordinary steps to be proactive and flexible in our response – whether it’s providing advice on medical product development, authorizing the emergency use of new diagnostic tools, quickly enabling access to investigational therapies, or working on the front lines in West Africa.

Margaret Hamburg, M.D.FDA has an Ebola Task Force with wide representation from across FDA to coordinate our many activities. We are actively working with federal colleagues, the medical and scientific community, industry, and international organizations and regulators to help expedite the development and availability of medical products – such as treatments, vaccines, diagnostic tests, and personal protective equipment – with the potential to help bring the epidemic under control as quickly as possible.

These efforts include providing scientific and regulatory advice to commercial developers and U.S. government agencies that support medical product development, including the National Institutes of Health (NIH), the Office of the Assistant Secretary for Preparedness and Response (ASPR), the Centers for Disease Control and Prevention (CDC), and the Department of Defense (DoD). The advice that FDA is providing is helping to accelerate product development programs.

Our medical product reviewers have been working tirelessly with sponsors to clarify regulatory requirements, provide input on manufacturing and pre-clinical and clinical trial designs, and expedite the regulatory review of data as it is received. FDA has been in contact with dozens of drug, vaccine, device, and diagnostic test developers, and we remain in contact with more than 20 sponsors that have possible products in pipeline.

We also have been collaborating with the World Health Organization and other international regulatory counterparts—including the European Medicines Agency, Health Canada, and others—to exchange information about investigational products for Ebola in support of international response efforts.

Investigational vaccines and treatments for Ebola are in the earliest stages of development and for most, there are only small amounts of some experimental products that have been manufactured for testing. For those in limited supply, there are efforts underway to increase their production so their safety and efficacy can be properly assessed in clinical trials.

As FDA continues to work to expedite medical product development, we strongly support the establishment of clinical trials, which is the most efficient way to show whether these new products actually work. In the meantime, we also will continue to enable access to investigational products when they are available and requested by clinicians, using expanded access mechanisms, also known as “compassionate use,” which allow access to such products outside of clinical trials when we assess that the expected benefits outweigh the potential risks for the patient.

In addition, 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, among other reasons, based on scientific evidence available, there is no adequate, approved, and available alternative. To date, FDA has authorized the use of five diagnostic tests during this Ebola epidemic: one was developed by DoD, two were developed by CDC, and this week FDA issued EUAs for two new, quicker Ebola tests made by BioFire Defense.

To further augment diagnostic capacity, we have contacted several commercial developers that we know are capable of developing rapid diagnostic tests and have encouraged them to work with us to quickly develop and make available such tests. Several entities have expressed interest and have initiated discussions with FDA.

We also are monitoring for fraudulent products and false product claims related to the Ebola virus and taking appropriate action to protect consumers. To date, we have issued warning letters to three companies marketing products that claim to prevent, treat or cure infection by the Ebola virus, among other conditions. Additionally, we are carefully monitoring the personal protective equipment (PPE) supply chain to help ensure this essential equipment continues to be available to protect health care workers.

And at least 12 FDA employees are being deployed to West Africa as part of the Public Health Service’s team to help with medical care. We are proud that they are answering the call.

As you can see, FDA has been fully engaged in response activities and is using its authorities to the fullest extent possible to continue its mission to protect and promote the public health, both domestically and abroad. Our staff is fully committed to responding in the most proactive, thoughtful, and flexible manner to the Ebola epidemic in West Africa.

I could not be more proud of the dedication and leadership that the FDA staff involved in this response has shown. I therefore want to take this opportunity to thank more than 250 staff, including those soon to be on the ground in West Africa, who have already contributed countless hours to this important effort, and who will continue to do so in the coming days and weeks as we address this very serious situation. I am hopeful that our work and the coordinated global response will soon lead to the end of this epidemic and help reduce the risk of additional cases in the U.S. and elsewhere.

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

The more we know about rare diseases, the more likely we are to find safe and effective treatments

By: Janet Woodcock, M.D.

Janet WoodcockYou may be inclined to think that rare diseases affect only a tiny fraction of the more than 320 million people in our country. That’s true about a single rare disease. But there are about 7,000 rare diseases. If you add them all together, there are about 30 million – or almost one in ten — people in the U.S. with some form of rare disease. Sadly, although great progress has been made in some areas, many of these people have no FDA approved drug to cure their condition, help them feel better, or even slow the disease’s progress.

That’s why I am pleased about FDA’s support for an exciting new tool researchers are using to study rare diseases. It’s a new database with information about the diseases’ “natural history.”

“Natural history” is the scientific term to describe how a disease would progress with no treatment. Since a disease can affect different people differently, scientists must study many cases of a disease to acquire a thorough understanding of its natural history. Well-conducted studies of natural history can yield vital information about:

  • Biomarkers, demographic, genetic, and environmental variables that correlate with the course and stages of the disease;
  • Identification of patient subpopulations with different characteristics and effects of the disease;
  • Patient perspectives on what aspects of disease are most important to treat; and,
  • How to quantify those aspects so that they can serve as useful outcome measures for clinical trials.

But when it comes to rare diseases, their natural histories frequently are not fully understood because there are simply not enough cases that have been observed and studied. This lack of knowledge limits researchers’ ability to study rare diseases and develop new treatments. Knowledge of natural history is essential for developing more efficient clinical trial designs. It also could help reduce the length and cost of drug development and, possibly, contribute toward greater predictability of clinical development programs.

Recently The National Organization for Rare Diseases (NORD), has teamed up with the patient advocacy group that represents people with the rare disease known as Von Hippel Lindau disease. This is a condition with many debilitating symptoms that also predisposes individuals to benign and malignant tumors. The Von Hippel Lindau Alliance and NORD have created an online tool that enables people with this rare disease to enter information about their experiences with the disease, such as the progression of symptoms, and to add to this information at intervals throughout their lives.

This tool is now helping researchers compile valuable data about the natural history of Von Hippel Lindau disease. The even better news is that this tool is universal.  If it can be used effectively to help researchers better understand Von Hippel Lindau disease, it can do the same for other rare diseases as well!

Importantly, this online tool was developed with direct input from patients, as well as patient organizations, researchers, FDA, and other international drug regulatory agencies.

The natural history tool has important features such as these:

  • It protects  the security and privacy of personal information, while making valuable information available to a researcher or drug developer interested in creating a new therapy for a rare disease;
  • It can be used by patients or health care professionals;
  • It helps make sure that text and online tools data are accurate.

FDA is committed to working with patient advocates and other organizations to support natural history studies for rare diseases.  We encourage the use of natural history data collection tools to describe natural history for many rare diseases. It is our deeply felt hope and wish that we can then take steps toward developing and approving new therapies for persons with rare diseases.

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

For more information about the NORD patient registry tool, visit their website: http://rarediseases.org/patient-orgs/registries

And please read: A Pivotal Moment for the Treatment of Rare Diseases — Address by Dr. Margaret A. Hamburg to the NORD Rare Diseases and Orphan Products Breakthrough Summit

FDA Invites Students to Sharpen their Research Skills

By: Nysia George, Ph.D., and Tom Powers

NCTR Intern Claire Boyle, a graduate student from Florida State University

NCTR Intern Claire Boyle, is a graduate student from Florida State University. Get this and other NCTR photos on Flickr.

Biology. Chemistry. Bioinformatics. Toxicology.

Practical, hands-on laboratory work is important for all college students who want to become scientists—but, for many of them, such experiences are out of reach.

That’s one of the reasons why every summer, our National Center for Toxicological Research (NCTR)—FDA’s internationally acclaimed toxicological research center in Jefferson, Arkansas—hosts a special internship program for science students interested in toxicology research.

The 2014 program was exceptionally successful for both the students and the Center.

Applications poured in from more than 200 students pursuing a variety of majors in universities from coast-to-coast. The competition was intense, and the 21 selected students came from schools in 13 states. But they were all alike in two fundamental ways: they were top students, and were eager to hone their scientific skills in real FDA laboratories.

NCTR Intern Luis Valencia, a senior from Texas A&M University

NCTR Intern Luis Valencia, is a senior from Texas A&M University. Get this and other NCTR photos on Flickr.

During their 10 weeks at NCTR, the students worked on projects varying from the development of bioinformatics and statistical methods for RNA sequencing data, to evaluating effects of silver nanoparticles in plastic food containers. They conducted in-vitro experiments; examined effects of nicotine treatment; gained lab experience in cell culture; and were trained in computational modeling or statistical programming.

Each student’s experience was unique and addressed the student’s interests.

The interns gave the program top grades. For example Claire Boyle, a graduate student from Florida State University, said about the lab work: “I like it a lot more than classes. There they tell you that you can do research once you get into the real world. I’ve never had an opportunity to do that before coming here [to NCTR], and that’s the aspect of the program I like best. It’s given me insight into what I want to do for the rest of my life!”

Luis Valencia, a senior from Texas A&M University, echoed similar praise. “This isn’t some pointless classroom assignment; this is the FDA. Something you discover [in this lab] could save a life.” He continued, “I’m having a great experience at NCTR. [My NCTR mentor] let me design my own experiment and helps me a lot. I’m already on my second trial and we’re getting good results.”

The internship program, which was partly funded by the FDA’s Office of Minority Health, is one of the many ways NCTR reaches far and wide to strengthen the scientific foundations of our agency. We engage with scientists within FDA and across other government agencies, industry, and academia to develop scientific information that is vital for sound regulatory policy. We cooperate with colleagues abroad to advance international standardization of regulatory science. And we’re mindful that all quest for knowledge starts with education.

If you are a science student interested in toxicology research, or if you know someone who is, it’s not too early to consider the NCTR’s 2015 internship program. To qualify for admission, a candidate must meet the GPA requirements and provide evidence of success in science courses. He or she will also need letters of recommendation and a personal statement describing his or her research interests.

If you believe you have what it takes, you could be among the select few chosen to join us in the summer of 2015. Applications are accepted throughout the month of February. We look forward to your application!

For more information about the program go to: Summer Student Research Program (NCTR)

For more information about the FDA Office of Minority Health go to: Minority Health

Nysia George, Ph.D., is the National Center for Toxicological Research’s Intern Program Coordinator.

Tom Powers is the National Center for Toxicological Research’s Communication Officer.

Two FDA drug approvals for idiopathic pulmonary fibrosis (IPF)

By: Badrul A. Chowdhury, M.D., Ph.D.

Badrul ChowdhuryPulmonary fibrosis is a disease in which tissue deep inside the lungs becomes thick, stiff, and scarred, decreasing the lungs’ ability to expand to take in air, and making it difficult to breathe. This is a progressive disease in which scarring and lack of elasticity in the lungs continues to increase until the patient can no longer breathe enough to sustain life.

Until recently, patients in the U.S. suffering from idiopathic pulmonary fibrosis (IPF), a form of pulmonary fibrosis in which the cause is unknown, had no drug treatment  approved by FDA for this debilitating, incurable, and terminal condition. However, this month, FDA approved Ofev (nintedanib) and Esbriet (pirfenidone), two important new therapies for the treatment of patients with IPF. Both drugs are “first-in-class” products that offer new hope for patients in the U.S. with IPF.

Researchers don’t understand exactly how Ofev and Esbriet work in the body against IPF, but the drugs seem to inhibit important pathways that help to prevent scarring. Neither drug is a cure. IPF may still progress after patients use these drugs. However, each drug has been shown to significantly slow the progression of the disease.

There is much work to be done, but this is a valuable start. In our continuing efforts to advance drug development for IPF, FDA recently hosted a Public Meeting on Idiopathic Pulmonary Fibrosis Patient-Focused Drug Development to obtain patients’ input on the impact of IPF on their daily life and their views on currently available therapies to treat the condition.

Many patients in the U.S. with IPF will now have effective treatments for their condition. We are addressing the input received from our public meeting on IPF and will continue to support the development and approval of new drugs, especially those that help patients with serious or life-threatening conditions for which no drug treatments are available.

Badrul A. Chowdhury, M.D., Ph.D., is Director, Division of Pulmonary, Allergy, and Rheumatology Products in FDA’s Center for Drug Evaluation and Research

FDA Working to Keep Patients Well Informed

By: Steve L. Morin R.N., B.S.N.

Steve Morin_2823My job in the Food and Drug Administration’s Office of Health and Constituent Affairs (OHCA) is to serve our nation’s patients in two ways: by listening to their concerns regarding FDA’s policy and decision-making and advocating for them in our agency;  and by informing many patients and patient organizations about FDA’s mission and its work to advance the development, evaluation and approval of new therapeutic products.

This dialogue was formalized and greatly expanded in 2012 when, after a series of listening sessions with many patient advocacy organizations, OHCA created the Patient Network.

Specifically designed for patients, caregivers, patient advocates and disease-specific patient advocacy organizations and the communities that advocate on their behalf, this program serves two goals. It facilitates patient engagement with FDA policy and decision makers, and it educates its audience about the process that brings new medications – both prescription and over-the-counter ­– and medical devices from a concept to the marketplace.

Our Patient Network covers a range of FDA-specific topics and conducts numerous activities that are of interest to patients and patient advocates. One of these activities were webinars with information about upcoming public meetings hosted by FDA.

For example on March 31, 2014, OHCA was pleased to host the first-of-its-kind “LiveChat” with the diabetes community. This online discussion gave patients an opportunity to interact with FDA experts and to better understand a recently released draft guidance dealing with the studies and criteria that FDA recommends be used when submitting premarket notifications (510(k)s) for blood glucose meters.

On September 10, 2014, our Third Annual Patient Network Meeting titled “Under the Microscope: Pediatric Product Development” brought together more than 100 patients, patient advocates, representatives of academia and industry, and FDA leaders. The participants discussed pediatric product development and the ways patient advocates can participate in it.

And on September 17, 2014, our Patient Network webpages were upgraded. The “For Patients” section on FDA’s website is presented in a clear manner with easy-to-use formats. Also, a “For Patients” button is located on our homepage.

We have continued to pursue our goals of informing the public and engaging with patients by building upon the patient-centered webpages and enhancing activities that express our desire to be helpful and transparent. This is our philosophy that has helped the Patient Network evolve to what you see today.

As the Patient Network program continues to grow, I hope to expand it to have more interactive webinars like the “LiveChat” that address specific concerns  of the patient communities. Also, we will continue to make it possible for patients to learn from FDA experts who approve medical products.

The FDA realizes that listening to the “patient voice” and conducting our dialogue is important, and it continues to develop its model for patient involvement through the Patient-Focused Drug Development Meetings and other OHCA sponsored meetings and webinars. We hope patients and those who care for them will join us in that effort, and make it still more helpful in protecting and promoting the public health.

Steve L. Morin, R.N., B.S.N., is a Commander of the United States Public Health Service and the Manager of the Patient Network in FDA’s Office of Health and Constituent Affairs

FDA’s giant NMR magnet puts more imaging power into our regulatory science

By: Carolyn A. Wilson, Ph.D.

Carolyn A. WilsonThe word spin might make you think of someone trying to influence your opinion. But in physics, spin refers to an intrinsic property of certain subatomic particles that make some nuclei act like small magnets. That kind of spin is key to a powerful laboratory technique scientists use to study complex, carbon-based biological products at the atomic and molecular level.

This technique, called nuclear magnetic resonance (NMR), uses a strong, external magnetic field and radio waves to trigger the release of electromagnetic energy from atoms with nuclei that have spin. Computers convert these data into contour plots that resemble topographic land maps. Scientists use these data to determine the locations of atoms in relation to each other in molecules. This enables them to create three-dimensional models they can hold in their hands and study, or 3D images they can rotate on a computer screen.

Scientists in FDA’s Center for Biologics Evaluation and Research (CBER) are using NMR to study two types of molecules relevant to the vaccines against bacterial and viral disease that we regulate: polysaccharides (long chains of sugar molecules), which occur in either the cell wall or the capsule surrounding some disease-causing bacteria, and shorter chains of sugars called oligosaccharides. Oligosaccharides are found in viruses and are also part of bacterial vaccines.

DSC_1820

Scientists at FDA discuss construction of the facility that will house the new NMR. From left to right: Hugo F. Azurmendi (CBER), Kang Chen (CDER), Darón I. Freedberg (CBER) & Marcos D. Battistel (CBER). Get this and other FDA photos on Flickr.

The microbes need these molecules to cause disease, so CBER scientists are using NMR to study how the structure of such polysaccharides and oligosaccharides triggers production of antibodies against the microbes that carry these molecules. The methods developed by CBER scientists will allow evaluation of licensed and investigational polysaccharide vaccines by using NMR to determine if those vaccines were developed in a manner consistent with these insights into how the structure of these molecules triggers antibody production. In addition, the outcomes of these studies might provide information that manufacturers could use to design novel polysaccharide vaccines that are safe and effective.

Insights into the structures of polysaccharides that play critical roles in generating protective immune responses would be especially useful in confronting dangerous pathogens for which there are no vaccines. Two such pathogens, the bacteria Neisseria meningitidis B and Escherichia coli K1, cause meningitis (a potentially fatal inflammation of the brain and spinal cord). The capsules surrounding these bacteria contain a polysaccharide called polysialic acid. This molecule is unusual because it doesn’t trigger antibody production when injected by itself into adult humans, but people infected with bacteria that have polysialic acid in their cell walls or capsules do produce antibodies against it. One logical explanation for this difference is that “free” polysialic acid has a somewhat different structure than polysialic acid on bacterial cell walls. But, using NMR, CBER scientists found that polysialic had the same structure whether free or as part of the pathogen. Figuring out why only bound polysialic acid triggers antibody production might help researchers develop much needed vaccines for these bacteria. Soon they will have a new NMR facility at the White Oak campus that could help them solve that puzzle.

NMR "Stick" Model; NMR studies at CBER are providing insights into the atomic and molecular ins and outs of polysialic acid, a molecule found on the surface of bacteria, including some that cause meningitis. This work is aimed at helping researchers develop safe and effective vaccines against such bacteria that are based polysialic acid. Using the NMR data from their studies, the CBER scientists created two models of polysialic acid, a “stick” model and a “solid spheres” model, shown in the two short animated videos (above and below).

NMR “Stick” and “Solid Spheres” Models: NMR studies at CBER are providing insights into the atomic and molecular ins and outs of polysialic acid, a molecule found on the surface of bacteria, including some that cause meningitis. This work is aimed at helping researchers develop safe and effective vaccines against such bacteria that are based polysialic acid. Using the NMR data from their studies, the CBER scientists created two models of polysialic acid, a “stick” model (above) and a “solid spheres” model (below), shown in these two short animations.

4SiA-rotation-dots

NMR “Solid Spheres” Model

The NMR spectrometer in the new facility will have a magnet that is much stronger than those previously used at FDA. The stronger the magnet, the more precise the data generated by NMR and the more precise the models that can be developed from this data.

To put this into perspective, the clinical application of NMR, called magnetic resonance imaging (MRI), uses magnets with strengths of 1.5 to 3 units of magnetic power called Tesla. The strength of NMR magnets at CBER is now about 16.4 Tesla (700 megahertz). The new NMR facility at White Oak will have a strength of 19.9 Tesla (850 megahertz)—about 6 times that of hospital MRI machines. In fact, the magnet is so powerful that the machine is isolated in a special room with walls thick enough to block its magnetic field from pulling unsecured metallic objects toward it. In the photograph you can see the NMR team visiting the facility as it is being prepared for the arrival of the machine.

CBER will share the new NMR spectrometer with the Center for Drug Evaluation and Research (CDER), which will use it to do extremely sensitive assessments of the purity of heparin and of the structures and properties of protein therapeutics.

This powerful magnetic molecular “microscope” is one way that FDA incorporates new technology into its regulatory science work to protect and promote the nation’s health.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

Regulatory Science Collaborations Support Emergency Preparedness

By: Jean Hu-Primmer, M.S.

Scientists love a challenge. And coordinating government agencies, healthcare providers, and numerous additional partners to protect public health in emergency situations is definitely a challenge.

Jean Hu-Primmer

Jean Hu-Primmer, Director of Regulatory Science Programs in FDA’s Office of Counterterrorism and Emerging Threats.

FDA’s Medical Countermeasures Initiative (MCMi) is working with federal agencies (through the Public Health Emergency Medical Countermeasures Enterprise), product developers, healthcare professionals, and researchers, among other partners, to help translate cutting-edge science and technology into safe, effective medical countermeasures. Through these collaborations, MCMi supports research to help develop solutions to complex regulatory science challenges.

Data are critical to help FDA evaluate the safety and effectiveness of medical countermeasures—products that can save lives—during public health emergencies. But collecting data in the midst of an emergency is exceptionally challenging. Working with the Biomedical Advanced Research and Development Authority (BARDA), FDA is teaming with critical care physicians nationwide to help address these challenges.

Under a contract awarded last month, FDA and BARDA will work with the U.S. Critical Illness and Injury Trials Group (USCIITG) to gather important information about medical countermeasures used during public health emergencies. Physicians will help address challenges with collecting and sharing data rapidly in emergencies, including streamlining electronic case reporting for clinical trials and rapidly disseminating key findings to FDA and other stakeholders to support clinical decision-making.

During this four-year project, USCIITG will also develop and pre-position a simple influenza treatment protocol in 10 hospitals throughout the U.S. during the 2015-2016 influenza season. The project will help doctors more easily use an investigational treatment protocol for patients with severe influenza, and test the data collection and reporting system during peak times. The goal is to help streamline the process during future influenza seasons and emergencies.

When it is not ethical or feasible to test the effectiveness of products in humans—such as countermeasures for potential bioterror agents—products may be approved under the Animal Rule. When products are approved under the Animal Rule, FDA requires additional studies, called phase 4 clinical trials, to confirm safety and effectiveness. In addition to the MCMi work, BARDA is funding USCIITG to investigate conducting phase 4 clinical studies during public health emergencies. USCIITG partners will train on these protocols, have them reviewed through their Institutional Review Boards (a requirement for all human studies), and create plans for enactment. USCIITG will then conduct an annual exercise to test these plans, a unique approach to broader science preparedness.

MCMi has also recently awarded regulatory science contracts to support other aspects of emergency preparedness, including two projects to investigate decontamination and reuse of respirators in public health emergencies (awarded to Battelle and Applied Research Associates, Inc.), and an award to support appropriate public use of medical countermeasures through effective emergency communication.

Our work involves big challenges. Through regulatory science, and through new and expanding collaborations, we continue to address these challenges to better prepare our nation to use medical countermeasures in emergencies.

Want to help? We’re currently accepting submissions for additional research to support medical countermeasure preparedness. If you have an idea for a new medical countermeasure regulatory science collaboration, we’d love to hear from you.

You can also visit BARDA’s MCM Procurements and Grants page for more information.

Jean Hu-Primmer, M.S., is Director of Regulatory Science Programs in FDA’s Office of Counterterrorism and Emerging Threats.