FDA Works to Mitigate the West Africa Ebola Outbreak

By: Luciana Borio, M.D.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Stem cell therapy: FDA regulatory science aims to facilitate development of safe and effective regenerative medicine products

By: Steve Bauer, Ph.D.

One of FDA’s primary missions is to make sure that the products we approve are safe and effective. There is tremendous interest in the development of regenerative medicine, including numerous proposed products that rely on stem cells. Stem cells have the ability to generate more stem cells or to turn into more mature cell types such as nerve- or bone-producing cells. These properties make stem cells potentially well suited for use in regenerative medicine. They might be used in repairing heart, nerve, and brain damage or in treating diabetes and other diseases by repairing or replacing cells and tissues.

Steve Bauer

Steve Bauer, Ph.D., chief of the Cellular and Tissues Therapy Branch, Division of Cellular and Gene Therapies, in the Office of Cellular, Tissue and Gene Therapy at CBER.

Because stem cells can change based on their surroundings, whether during growth outside of the body or following injection into the body, ensuring the safety of effective regenerative medicine products can be challenging. One type of adult stem cell, the multipotent marrow stromal cell (MSC) — more popularly called the mesenchymal stem cell — is the subject of a great deal of research in regenerative medicine. These cells can divide repeatedly, making additional cells, and under the right conditions can be turned into a variety of more specialized and mature types of cells. Depending upon the culture conditions, these more specialized cells have the potential to produce cartilage, bone, and fat, and help with control of inflammation and immunity.

MSCs can be obtained from bone marrow and adipose tissue (fat) and can be grown outside of the body to produce the large numbers needed for many proposed clinical trials. Donated MSCs can also suppress the immune system in individuals who receive them, preventing their rejection and allowing cells from one donor to potentially treat many different people, unlike most other cells or tissues.

But there are still scientific questions to answer about MSCs. A particularly important set of questions is how the manufacturing of these cells outside of the body could affect their potential healing properties and their safety. FDA scientists believe that answering these questions will improve the way MSCs are characterized and thereby facilitate the development of products made from MSCs. For this reason, the FDA’s Center for Biologics Evaluation and Research assembled seven of its laboratories into a consortium to develop tests and techniques that will help answer these types of questions as these products move through the development process.

Using bone-marrow-derived MSCs from eight different human donors, the consortium has published scientific articles on the following topics:

  • Evaluation of the ability of human MSCs to suppress activation of certain types of mouse immune cells in order to reduce variation in MSC immune suppression assays that use T-cells from human donors who might have many different T-cells. The mouse cells come from a genetically modified strain in which all of the mouse immune T-cells are identical.
  • Creation of a large database of MSC proteins (a total of 7753) that enabled us to demonstrate the large variability among proteins from different MSC samples. This database will enhance our understanding of MSC biology and help define the variability among various MSC samples.
  • Identification of 84 proteins (14 identified for the first time) on the surface of MSCs that may be useful for tracking these cells as they grow, divide, and differentiate to produce specific tissues.
  • Development of techniques that enable scientists to quantify the ability of MSCs to multiply and to differentiate into specific cell types.
  • Identification of specific genes that distinguish aging MSCs grown in cell culture, which could facilitate development of tests that evaluate the quality of MSCs before they are used to treat patients.

These contributions are part of the overall effort of FDA to bring safe and effective stem cell-based therapies to the many patients who could potentially benefit from this type of regenerative medicine.

Steve Bauer, Ph.D., is the chief of the Cellular and Tissues Therapy Branch, Division of Cellular and Gene Therapies, in the Office of Cellular, Tissue and Gene Therapy at FDA’s Center for Biologics Evaluation and Research.

Achieving our Mission through Enhanced IT Service Delivery

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

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

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

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

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

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

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

Achieving an AIDS Free Generation – Highlights from the PEPFAR Annual Meeting in Durban, South Africa

By: Katherine Bond, Sc. D. and Jude Nwokike, MSc, MPH

The U.S. Global AIDS Coordinator, Ambassador Deborah Birx, recently described the President’s Emergency Plan for AIDS Relief (PEPFAR) as “one of the greatest expressions of American compassion, ingenuity, and shared humanity in our nation’s rich history.”

Kate Bond and Jude Nwokike

Katherine C. Bond, Director of FDA’s Office of Strategy, Partnerships and Analytics, Office of International Programs and Jude Nwokike, FDA’s PEPFAR Liaison, Office of Strategy and Partnerships, Office of International Programs.

We recently attended the PEPFAR 2014 Annual Meeting in Durban, South Africa. Since its inception in 2003, PEPFAR, the U.S. Government’s initiative to help save the lives of those living with HIV/AIDS around the world, is supporting 6.7 million people on anti-retroviral treatment (ART) and has resulted in one million babies born HIV-free. In FY 2013 alone, PEPFAR supported 12.8 million pregnant women for HIV testing and counseling and as of September 30, 2013 will have supported voluntary medical male circumcisions for 4.2 million men in east and southern Africa.

The focus of this year’s conference was on delivering a sustainable AIDS Free Generation. We were privileged to represent FDA at the meeting, along with other Health and Human Services operating divisions –including the Centers for Disease Control, the National Institutes of Health, the Health Resources and Services Administration, and the Substance Abuse and Mental Health Services Administration.

FDA has played a critical role in the PEPFAR program. As of March 2014, the Agency had approved or tentatively approved 170 antiretroviral drugs for use by PEPFAR, including 80 fixed dose combinations (FDCs), 24 of which are triple FDCs. Triple FDCs are significant because they have simplified ART from up to 20 pills a day to one pill daily — improving adherence to treatment, reducing the risk of developing resistance, and simplifying the supply chain.

We saw the direct impact of the program during a visit to the KwaMashu Community Health Centre, north of Durban in South Africa’s KwaZulu-Natal Province. Formerly a sugar plantation, the area saw a mass resettlement of poor people in the early 1960’s. It was often the site of political violence during the Apartheid era, and is now characterized by inadequate housing, poor infrastructure, high unemployment and crime, and among the highest rates of HIV in the world.

In 2012, the prevalence of HIV in antenatal women in KwaZulu-Natal Province was 37.4%. With the support of PEPFAR, in 2014 over 12,000 adults and nearly 800 children are receiving anti-retroviral therapy at KwaMashu, extending life expectancy, and giving hope for a better future. This hope was especially apparent in two girls, ages 12 and 14, each living with HIV/AIDS, who spoke eloquently to us about being cared for by grandmothers and a dedicated cadre of area doctors, nurses, pharmacists and community workers.  One girl dreams of becoming a medical researcher and the other aspires to be a lawyer.

At the conference we learned that thirteen low- and middle-income countries (LMICs) are at the tipping point of overcoming the HIV/AIDS epidemic, with the number of those starting therapy exceeding the number of newly infected. This makes the goal of an AIDS Free Generation plausible. PEPFAR is supporting HIV/AIDS response in more than 100 LMICs. Also, promising comprehensive prevention strategies present great opportunities to stem the epidemic’s tide. But, even with PEPFAR’s numerous achievements, challenges still exist. In 2012 alone, there were 1.6 million deaths, 2.3 million new infections, and 260,000 babies born infected with HIV.

Scaling up treatment and effective preventive interventions, and sustaining support and access to care are critical to achieving an AIDS Free Generation.  Essential to sustainability is ensuring product availability, quality, and safety of medical products used in the PEPFAR program.  Several PEPFAR country representatives described challenges in supply chains attributable to weak regulatory infrastructure (for example, limited sources for Tenofovir-containing FDCs used as first line regimen); lack of capacity of PEPFAR country regulators to assure quality of rapid diagnostic kits; seizure of products at border posts because products are not registered or approved in a country; few national standards for diagnostics and medical devices; and limited capacity of local regulators for regulating medical devices. Representatives of several countries called for strong pharmacovigilance and post marketing surveillance.

Despite these challenges, there are promising developments that are likely to bring benefits to regulators in PEPFAR countries, and ultimately, the PEPFAR program’s beneficiaries. In May 2014, African nations voiced unified support for a World Health Assembly resolution on strengthening regulatory systems; reductions in time to register medicines has been reported by the African Medicines Registration Harmonization Initiative; and the WHO global surveillance and monitoring system for substandard, falsified and counterfeit medical products is receiving reports from, and issuing drug alerts based on vigilant reporting by, African regulators.

We held a special session on strengthening regulatory systems with our colleagues from a number of PEPFAR countries and identified several possible areas for future collaboration. Strengthening regulatory systems will be a key component in defining a sustainable path forward.

Katherine C. Bond is Director of FDA’s Office of Strategy, Partnerships and Analytics, Office of International Programs

Jude Nwokike is FDA’s PEPFAR Liaison, Office of Strategy and Partnerships, Office of International Programs

For more information please visit:

PEPFAR BLUEPRINT: Creating an AIDS-free Generation

Approved and Tentatively Approved Antiretrovirals in Association with the President’s Emergency Plan

Developing new tools to support regulatory use of “Next Gen Sequencing” data

By: Carolyn A. Wilson, Ph.D.

When you’re thirsty, you don’t want to take a drink from a fire hose. And when scientists are looking for data they don’t want to be knocked over with a flood of information that overwhelms their ability to analyze and make sense of it.

Carolyn WilsonThat’s especially true of data generated by some types of both human and non-human genome research called Next Generation Sequencing (NGS). This technology produces sets of data that are so large and complex that they overwhelm the ability of most computer systems to store, search, and analyze it, or transfer it to other computer systems.

The human genome comprises about 3 billion building blocks called nucleic acids; much medical research involves analyzing this huge storehouse of data by a process called sequencing—determining the order in which the nucleic acids occur, either in the entire genome or a specific part of it. The goal is often to find changes in the sequence that might be mutations that cause specific disease. Such information could be the basis of diagnostic tests, new treatments, or ways to track the quality of certain products, such as vaccines made from viruses.

NGS is a complicated technique, but basically it involves cutting the genome into millions of small pieces so you can use sophisticated chemical tricks and technologies to ignore the “junk” you don’t need, and then make up to hundreds of copies of each of the pieces you want to study. This enables additional techniques to identify changes in the sequence of nucleic acids that might be mutations. NSG enables scientists to fast-track this process by analyzing millions of pieces of the genome at the same time. For comparison, the famous human genome sequencing and analysis program that took 13 years to complete and cost $3 billion could now be completed in days for a few thousand dollars.

Man with HIVE Computer

The Center for Biologics Evaluation and Research (CBER) supported the development of High-Performance Integrated Virtual Environment (HIVE) technology, a private, cloud-based environment that comprises both a storage library of data and a powerful computing capacity being used to support Next Generation Sequencing of genomes.

In order to prepare FDA to review and understand the interpretation and significance of data in regulatory submissions that include NGS, the Center for Biologics Evaluation and Research (CBER) supported the development of a powerful, data-hungry computer technology called High-Performance Integrated Virtual Environment (HIVE), which can consume, digest, analyze, manage, and share all this data. HIVE is a private cloud-based environment that comprises both a storage library of data and a powerful computing capacity. One specific algorithm (set of instructions for handling data) of HIVE that enables CBER scientists to manage the NGS fire hose is called HIVE-hexagon aligner. CBER scientists have used HIVE-hexagon in a variety of ways; for example, it helped scientists in the Office of Vaccines Research and Review study the genetic stability of influenza A viruses used to make vaccines. The scientists showed that this powerful tool might be very useful for determining if influenza viruses being grown for use in vaccines were accumulating mutations that could either reduce their effectiveness in preventing infections, or even worse, cause infections.

There’s another exciting potential to HIVE-hexagon research: the more scientists can learn about variations in genes that alter the way they work—or make them stop working–the more they can help doctors modify patient care to reflect those very personal differences. These differences can affect health, disease, and how individuals respond to treatments, such as chemotherapy and influenza vaccines. Such knowledge will contribute to advances in personalized medicine.

Team members at work in FDA's HIVE server room.

CBER scientists showed that HIVE might help scientists determine if influenza viruses being grown for use in vaccines were accumulating mutations that could either reduce their effectiveness in preventing infections or cause infections. Genome studies supported by HIVE will also contribute to advances in personalized medicine.

Because CBER’s HIVE installation has been so successful we are now collaborating with FDA’s Center for Devices and Radiological Health (CDRH) to provide a second installation with greater capacity and computer power that takes advantage of the high-performance computing capacity there. When ready and approved by FDA for use, we will use this powerful, CBER-managed, inter-center resource to handle regulatory submissions.

HIVE-hexagon and its innovative NGS algorithms are just one major step CBER has taken recently as it continues its pioneering work in regulatory research to ensure that products for consumers are safe and effective. I’ll tell you about other exciting breakthroughs in my next update on CBER research.

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

For more HIVE photos go to Flickr

FDASIA at Year Two

By Margaret A. Hamburg, M.D.

Margaret Hamburg, M.D.Anniversaries are a time for stock-taking and today, on the second anniversary of the Food and Drug Administration Safety and Innovation Act or FDASIA, I’m pleased to report on the progress we’ve made implementing this multi-faceted law.

To date, we have completed nearly all of the deliverables we had scheduled for the first two years after FDASIA became law. And many of the new authorities under FDASIA are already having a positive impact on health. It’s difficult to cover all of our FDASIA work, but here are some highlights:

Preventing Drug Shortages: Drug shortages, which can have serious and immediate effects on patients and health care professionals, reached an all-time high in 2011, the year before FDASIA was enacted. In response to a Presidential Executive Order in December of that year, FDA issued an interim final rule to amend and broaden FDA regulations requiring certain manufacturers to give early notification of production interruptions that could cause drug shortages. FDASIA further broadened this requirement by requiring that other prescription drug manufacturers provide notification and also gave FDA additional authorities. In October 2013 FDA proposed a rule to implement these authorities and issued a strategic plan for addressing drug shortages. So far, with the help of early notifications, FDA was able to prevent 282 shortages in 2012 and 170 shortages in 2013. The number of drug shortages that did occur has also declined.

Promoting Innovation: FDASIA includes many provisions designed to encourage innovation. We have held meetings on the use of meta-analyses in drug applications; put in place a plan for implementing a benefit-risk framework for drug reviews, and issued a variety of guidance documents covering such topics as drug studies in children, abuse-deterrent drug development, antibacterial drug development and expedited review and development programs for serious diseases.

This latter guidance provided information that sponsors needed to know about our new Breakthrough Therapy designation that was part of FDASIA. This option exists for new drugs intended to treat a serious or life-threatening disease that, preliminary clinical evidence suggests, could provide a substantial improvement over available therapies. As of June 23, we had granted 52 requests for this designation, and of those, approved four new drugs and two new indications for previously approved drugs.

As part of our implementation of the FDASIA-related provisions related to medical devices, we proposed a strategy and recommendations for a risk-based health information technology (health IT) framework that would promote product innovation while maintaining appropriate patient protections and avoiding regulatory duplication; issued a proposed rule for implementing FDASIA’s streamlined new procedures for reclassifying a device; and published a final rule on a medical device unique identification or UDI with implementation in accordance with the timetable set in the law. UDIs will help the FDA identify product problems more quickly, better target recalls and improve patient safety. The riskiest medical devices will start bearing their UDI by September 24th.

Establishing and Strengthening User Fee Programs: An important element of FDASIA was reauthorizing user fees for prescription drugs and medical devices and creating new user fee programs for generic drugs and biosimilar biological drugs. User fees on some types of applications offer an important source of funding to support and maintain key activities, including FDA’s staff of experts who review the thousands of product submissions we receive every year. Since FDASIA took effect, review times for medical devices have been declining.  Our prescription drug user fee program is meeting or exceeding almost all of our performance goals agreed to with industry. We have acted on 54 percent of the generic drug applications, or amendments and supplements to generic drug applications which were pending in our inventory as of October 1, 2012. This helps ensure that consumers can have access to more low-cost drugs. And we have been able to provide advice concerning most of the 93 submissions from companies who are developing biosimilar biological drugs under a pathway that could also ultimately lower costs for consumers.

Enhancing Patient Engagement: A hallmark of FDASIA was a series of provisions intended to tap the patient perspective. Our Patient-Focused Drug Development Program allows us to more systematically obtain the patient’s perspective on a disease and its impact on the patients’ daily lives, the types of treatment benefit that matter most to patients, and the adequacy of the available therapies for the disease. In accordance with FDASIA, we have held patient meetings on eight diseases and have plans for meetings on 12 more. We have learned a great deal from patients in terms of their views of the symptoms of their condition, their feelings about how it affects their life, and their thoughts on ideal treatments and on participation in clinical trials to aid future drug development.  A FDA Voice blog post on patient reports captures these patient perspectives and much more.

Finally, Title VII of FDASIA provided FDA with numerous new authorities to protect the drug supply chain. We thought now was a good time to provide the public with a more detailed description of our work on Title VII, so we asked Howard Sklamberg, Deputy Commissioner for Global Regulatory Operations and Policy, to write a separate blog on that topic.

FDA laid out a three-year plan for implementing FDASIA and we’re on our way to achieving our stated goals. To help the public follow our progress, we set up a dedicated webpage—the FDASIA-Track. It provides useful links to each action and is updated on a regular basis.

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

A Blueprint for Helping Children with Rare Diseases

Editor’s Note: This blog has been updated to provide additional information about our use of expedited programs to speed rare disease medical product development.

By Jill Hartzler Warner, J.D.

Jill WarnerThe U.S. Congress and the Food and Drug Administration have long focused on bringing new therapies to patients with rare diseases, including children.

Two years ago this week, Congress made another contribution to this effort by enacting the Food and Drug Administration Safety and Innovation Act (FDASIA). The law directs our agency to take two actions to further the development of new therapies for children affected by rare diseases: (1) to hold a meeting with stakeholders and discuss ways to encourage and accelerate the development of new therapies for pediatric rare diseases, and (2) issue a report that includes a strategic plan for achieving this goal.

There are unique challenges when developing drugs, biological products and medical devices for the pediatric population. Not only is there the potential for children to respond differently to products as they grow but there are also additional ethical concerns for this patient population.

But these challenges are further compounded when developing therapies for pediatric rare diseases. For example, rare disease product development, by definition, means there is only a small potential group of patients available to participate in clinical studies that can help determine whether a product is safe and effective.

In our FDASIA meeting in January, we heard a variety of suggestions on clinical trial design and data collection from hundreds of the participating stakeholders from academia; clinical and treating communities; patient and advocacy groups; industry and governmental agencies.

These discussions helped inform our Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases, which we posted on our website today. It outlines how we plan to meet the following four objectives:

Enhance foundational and translational science. Our strategy is to fill essential information gaps through such measures as fostering the conduct of natural history studies for pediatric rare diseases and by identifying unmet pediatric needs in medical device development. We also plan to issue guidance for sponsors on common issues in rare disease drug development and to refine and expand the use of computational modeling for medical devices.

Strengthen communication, collaboration, and partnering. Robust cooperation within FDA, among agencies, governments and private entities is necessary to enable the exchange of information on the issues of developing treatments for pediatric rare diseases. Single entities by themselves usually don’t have sufficient resources or expertise to overcome the product development challenges posed by pediatric rare diseases.

Advance the use of regulatory science to aid clinical trial design and performance.  Regulatory science helps develop new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products. Of note, we plan to facilitate better understanding of biomarkers and clinical outcome assessments that are useful for the development of treatments for pediatric rare diseases. We also plan to further develop the expedited approval pathway for medical devices intended to treat unmet medical needs; and use FDA’s web-based resources to update and expand awareness of issues involving the development of medical products for pediatric rare diseases.

Enhance FDA’s review process. Our strategies include fostering efforts to learn patients’ and caregivers’ perspectives and incorporating this information into medical product development. We also plan to further develop and implement a structured approach to benefit-risk assessment in the drug review process and establish a patient engagement panel as part of the medical device advisory committee process.

The report notes our use of expedited programs to speed rare disease medical product development. For example, the accelerated approval program allows for approval of products to treat serious and life-threatening diseases based on an effect on a surrogate marker, such as blood test, urine marker, or an intermediate clinical endpoint, that is believed to be reasonably likely to predict clinical benefit to the patient. Under accelerated approval, further studies are required after approval to confirm that the drug provides a clinical benefit to the patient.

More than 80 new products have been approved under the accelerated approval program, and many of these have been for rare diseases. But it’s important to note that in some cases FDA exercises regulatory flexibility to approve drugs under the traditional approval pathway, rather than under the accelerated approval program. In fact, most of the recent new drug approvals for rare diseases have been approved under the traditional approval pathway because FDA has determined that the drug provides a clinical benefit to the patient. Such approvals make new drugs available to patients, and also mean that companies are not required to do confirmatory trials after approval.

FDA is committed to continuing its use of expedited programs and regulatory flexibility to speed development and approval of safe and effective drugs for all patients with rare diseases, and the strategies outlined in this plan will help us achieve a major goal of FDASIA and for our agency, which is to speed the development of therapies for children with rare diseases.

 

Jill Hartzler Warner, J.D., is FDA’s Associate Commissioner for Special Medical Programs

Finding the Cause of Thrombosis in Some Immunoglobulin Treatments

By: Mikhail Ovanesov, Ph.D.

The Food and Drug Administration’s Office of Blood Research and Review (OBRR) has a broad mission to ensure the safety and efficacy of products it regulates. It also does mission-related research, some of which can be described as problem-solving.

Mikhail OvanesovOne of the problems on which OBRR focused recently was a serious adverse effect linked to some treatments with immune globulin intravenous (IGIV), a product that contains pooled immunoglobulin (antibody) extracted from the plasma of thousands of donors. Licensed IGIV uses include the treatment of immune deficiencies and autoimmune disorders.

These immunoglobulin treatments are generally safe, although they can cause mild to moderate adverse effects during and after infusion, such as headache, malaise and nausea. Less common but potentially fatal complications are the formation of blood clots.  These thrombotic events (TEs), as they are known, can block large arteries or veins, causing heart attack, stroke, deep venous thrombosis and pulmonary embolism. That’s why, since October 2003, FDA has recommended precautionary labeling for IGIV products that includes the risk of thrombotic events. But while the new labeling helped raise awareness of this risk, the causes of TE remained unclear. In fact, since many patients receiving IGIV are already considered at risk for thrombosis, the causes were often attributed to the patient’s medical condition. The fact that TEs only rarely occurred in clusters linked to a single lot of IGIV from a particular manufacturer also made it difficult to pin down a specific cause for these adverse effects.

That all changed in May 2010 when TEs — stroke and myocardial infarction in several patients — linked to two lots from one manufacturer prompted the company to put a hold on the release of these lots. My laboratory responded by launching a series of tests to find out what caused the TEs. We studied the ability of four different lots of IGIV to generate the blood protein thrombin, which triggers clotting. Specifically, we compared two lots which caused stroke or myocardial infarction in several patients with those that did not. Our work showed that the lots linked to TEs induced faster and higher generation of thrombin. We then confirmed these results by recording blood clot formation under a specially designed video microscope. The lots associated with TEs again demonstrated higher rates of clotting. Additional tests confirmed that the thrombin generation test reliably identifies lots that are potentially thrombogenic.

In early August 2010, OBRR shared its data with the company, which confirmed the results and established product evaluation methods using similar coagulation assays. After the company voluntarily withdrew 31 IGIV lots from the United States market, there were many more international reports of TEs. By the end of September, all product lots were voluntarily removed from the U.S. market.

But we still didn’t know what was triggering the rapid rise in thrombin. So we continued our studies and identified a blood protein called coagulation factor XIa as an impurity in IGIV products causing thrombosis. This enabled us to develop a Factor XIa assay that could determine if an IGIV lot contained this thrombogenic impurity. We then tested other lots of licensed and investigational IGIV products, which prompted testing and manufacturing changes by industry to improve the safety of several other products.

OBRR has since then been working with the World Health Organization and other laboratories to ensure that tests for factor XIa done anywhere in the world will work the same way and give reliable results.

This work has also contributed to the ongoing development in CBER of a new lot release assay for immunoglobulin products.

These important contributions by OBRR illustrate the leading role the FDA plays in ensuring the safety and efficacy of the products it regulates. As FDA Commissioner Margaret Hamburg, M.D., put it when discussing the role of the agency: “The bottom line is that if FDA does not do its job, there is no backstop. Ours is a unique role, and it is critical that we do it well.”

Mikhail Ovanesov, Ph.D., is a visiting scientist in the Laboratory of Hematology in the Office of Blood Research and Review at CBER

FDA and Health Professionals, Safeguarding the Public’s Health

By: Anna M. Fine, Pharm.D.

At our recent third annual Health Professional Organizations Conference, some of FDA’s most senior leaders exchanged views and discussed issues of mutual interest with senior representatives from key health professional organizations.

Anna FineHeld on FDA’s White Oak campus in Silver Spring, Md., and organized by the FDA’s Office of Health & Constituent Affairs (OHCA), the event was attended by 30 professional organizations representing physicians, nurses, physician assistants, dentists, optometrists, nurse practitioners, pharmacists, and others.

An open and ongoing dialogue between these professionals and FDA is a vital part of addressing many important public health issues. In her opening remarks, FDA Commissioner Margaret Hamburg offered a few examples, such as health professionals’ contributions to the FDA’s MedWatch and Adverse Event Reporting programs and their work in interpreting and addressing medical products’ safety signals. A drug’s safety profile is continually evaluated after FDA approval, and health professionals are encouraged to report suspected adverse events to FDA which allows FDA to conduct comprehensive safety evaluations. Dr. Hamburg also emphasized the importance of health professionals’ engagement in regulatory science research, which provides essential support for the agency’s decisions and ability to bring innovative products to market.

Mitch Zeller, the Director of FDA’s Center for Tobacco Products, speaking at the third annual Health Professional Organizations Conference, on May 14, 2014

Mitch Zeller, Director of FDA’s Center for Tobacco Products, speaking at the agency’s third annual Health Professional Organizations Conference. See more photos of this event on Flickr.

Key FDA leaders who gave presentations throughout the day included Mitch Zeller, the Director of FDA’s Center for Tobacco Products; Dr. Stephen Ostroff, Acting Chief FDA Scientist; and Dr. Peter Lurie, Acting Associate Commissioner of FDA’s Office of Planning and Policy.

In addition, senior scientists from FDA’s centers for drugs, medical devices and food discussed FDA’s priorities and answered questions from the audience. The robust dialogue between the panel members and our stakeholders covered many public health issues including youth and tobacco and FDA’s proposed changes to the food label.

Feedback from the audience highlights the need for such a conference.

“It’s great to have this dialogue with FDA officials. It demonstrates that they respect our organizations and want our feedback,” said one stakeholder representative.

“I love coming to these annual meetings, not only to meet FDA personnel but to talk with colleagues in other professions. This is a one-of-a-kind forum,” said another.

As a pharmacist and team leader within OHCA, I can attest to the fact that my FDA colleagues and I benefited as well. We learned a lot about our stakeholders’ concerns and established new connections with health professional organizations—contacts that we plan to follow-up on to explore new opportunities for mutual cooperation and collaboration in the interest of the public health.

Anna M. Fine, Pharm.D., is Director of the Health Professional Liaison Program in FDA’s Office of Health and Constituent Affairs.