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

A Curriculum for Medical Device Progress

By: Francis Kalush, Ph.D.

Horace, the greatest Roman poet of antiquity, spoke of the need to “seek for truth in the groves of Academe” — and in the last four years, my colleagues in FDA’s Center for Devices and Radiological Health (CDRH) and I took his advice. In scores of meetings and two large workshops, we consulted with hundreds of academics about a novel idea: a university-level program to address an important public health need by stimulating the development of new medical devices.

Francis KalushIn 2011, CDRH embarked on an Innovation Initiative to help accelerate and reduce the cost of the development and regulatory evaluation of safe and innovative medical devices. Through that and other programs, we learned that the delivery of new therapies to patients can be accelerated if medical device innovators — including entrepreneurs and university students and faculty — understand FDA’s regulatory processes. We then established the Medical Device Technology Innovation Partnership, and tasked it with developing an educational program that would explain FDA’s standards and procedures for evaluating and approving or clearing medical devices.

This learning tool grew from collaborations with Stanford University, University of Virginia, Howard University, The Johns Hopkins University, University of Maryland at College Park and at Baltimore, and University of Pennsylvania.

The program, called the National Medical Device Curriculum, will provide students at academic institutions and science and technology innovators with the core information about the regulatory pathway to market. This includes an understanding of the expertise needed to design, test and clinically evaluate devices; identify the root causes of adverse events and device malfunctions; develop designs for devices with repetitive functions; and, navigate FDA’s regulatory process.

The mode of the curriculum is a series of fictional case studies based on real-world medical device scenarios. The four learning tools developed so far cover the following subjects: the regulatory pathways for medical devices; safety assurance and risk management planning; and the regulatory pathways for novel devices and for devices that are substantially equivalent to already marketed predicate devices.

Each of these fictionalized case studies includes a student module and an instructor’s guide with ideas for exercises and discussion in class. The curriculum was tested at several universities and received high praise. For example:

  • William E. Bentley, from the University of Maryland James Clark School of Engineering found that the case studies “are of tremendous pedagogical value, and we are definitely incorporating them into our curriculum.”
  • ŸArthur L. Rosenthal, Ph.D., a professor at Boston University’s College of Engineering, used the case studies to teach advanced biomedical product design and development and reported that “the students found the material engaging as well as providing essential context for their projects.”
  • ŸYouseph Yasdi, Ph.D., MBA, executive director at The Johns Hopkins Center for Bioengineering Innovation and Design, found that the cases are “a good fit” for his program to train engineers to better understand regulatory issues.

More case studies are being planned to help train the next generation of entrepreneurs and keep the U.S. a leader in medical device innovation. Regulatory training is particularly important in the development of medical devices, as the industry is heavily populated by small companies that may not have the expertise to navigate FDA’s requirements.

The National Medical Device Curriculum is a step forward in our Agency’s efforts to encourage and facilitate the development of new medical products — drugs, biological products and medical devices — that has been made possible by the great scientific breakthroughs in the last two decades, such as the mapping of the human genome and the invention of nanotechnology. Those of us who worked on this novel curriculum hope it will encourage and advance the development of new devices for patients and help protect and promote the public health.

Francis Kalush, Ph.D., is a senior science advisor at FDA’s Center for Devices and Radiological Health

OpenFDA Provides Ready Access to Recall Data

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

Every year, hundreds of human and animal foods, drugs, and medical devices are recalled from the market by manufacturers. These products may be labeled incorrectly or might pose health or safety issues. Most recalls are voluntary; in some cases they may be ordered by the U.S. Food and Drug Administration. Recalls are reported to the FDA, and compiled into its Recall Enterprise System, or RES. Every week, the FDA releases an enforcement report that catalogues these recalls. And now, for the first time, there is an Application Programming Interface (API) that offers developers and researchers direct access to all of the drug, device, and food enforcement reports, dating back to 2004.

Taha Kass-HoutThe recalls in this dataset provide an illuminating window into both the safety of individual products and the safety of the marketplace at large. Recent reports have included such recalls as certain food products (for not containing the vitamins listed on the label), a soba noodle salad (for containing unlisted soy ingredients), and a pain reliever  (for not following laboratory testing requirements).

At present, FDA provides various ways to access the recalls data, including an RSS feed, a Flickr stream, and a search interface. This new API supplements these sources as the first, and one-call, access to the entire enforcements archive. The hope is that this API will be useful to developers and researchers interested in FDA enforcement actions. Developers can now call into the API to add recalls data to mobile apps or consumer websites. And researchers could use the API to study individual manufacturers, product categories, or specific foods or drugs.

The recalls database is the second dataset to be released on openFDA. Since openFDA debuted on June 2, 2014, the website has generated considerable interest. In the past five weeks, the site has had 34,000 sessions (two-thirds are new sessions) from 26,000 unique visitors worldwide that generated 80,000 page views.

The adverse events API has been accessed by 18,000 Internet connected devices, with nearly 2.4 million API calls since the launch.  At least one new website, http://www.researchae.com, has been created to allow any user to submit queries on the adverse events data, and several other companies are integrating the data into their products and services. It is also being accessed by researchers inside and outside FDA and by journalists as well.

More APIs will follow in the weeks ahead. OpenFDA is taking an agile (development in small chunks of iterations) approach in the creation and release of these APIs, with the objective of getting feedback from developers and researchers (as well as from industry and the public) at the GitHub and StackExchange forums that serve our project. We plan to incorporate some of the feedback into future iterations of the API. Accordingly, as we learn more about how the public might seek to use this data — and as a result of our agile and user-centered methodologies — the API structure may change in quite a bit in the coming months. It’s also important to note that this API, like all others on openFDA, are in beta and are not ready for clinical use. However, their contribution to FDA’s public health mission already now grows every day.

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

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

Protecting the Global Drug Supply: FDASIA Title VII

By: Howard Sklamberg, J.D.

Since July 9, 2012, when President Obama signed the Food and Drug Administration Safety and Innovation Act (FDASIA), a group of my colleagues and I have had an urgent mission: implement Title VII of the statute. This section gave FDA new authority to better protect the global drug supply chain, which is a critically important public health task in an increasingly global marketplace.

Howard SklambergTitle VII will advance FDA’s transformation into a global public health agency, primarily by enabling it to better oversee the safety and integrity of drug ingredients and finished drugs in the supply chain. Thanks to this law, FDA can become better informed about supply chain risks.  This information allows FDA to target its resources to higher risk facilities, which makes us both more efficient and more effective in further ensuring the quality and safety of drug ingredients and finished drugs.  The law also provides us with important new enforcement tools and facilitates our cooperation with trusted foreign regulators, which is essential in a global marketplace.

FDA is working diligently to implement these authorities to better protect and promote the health of all Americans. In the past two years, FDA has made many parts of Title VII a reality. These successful accomplishments include:

  • proposed and a final rule to extend the agency’s administrative detention authority to include drugs, (Section 709, issued 5/29/2014). The rule prevents potentially adulterated or misbranded drugs from entering U.S. commerce while FDA decides whether to take such legal action as seizing the drug. Administrative detention is a particularly useful tool when there is a high likelihood that the drug will be moved before we can apply another enforcement tool. It aligns with FDA’s administrative detention authority for food and medical devices.
  • a draft guidance defining what the agency considers to be actions that delay, deny, or limit an inspection. (Section 707, issued 7/9/2013) In crafting this guidance, FDA surveyed its field force to come up with the types of behaviors that were observed by investigators, based on real-life situations. This authority has already been used to warn firms of possible enforcement action in instances when FDA was not allowed to inspect.
  • a public meeting was held to discuss how the agency might implement certain parts of FDASIA to protect the drug supply chain. (Sections 713/714, held July 12, 2013).  FDA is dedicated to providing transparency and ongoing opportunities for stakeholder input and participation as it works to implement Title VII.
  • a draft guidance specifying the unique facility identifier (UFI) system for drug establishment registration. (Sections 701/702, issued 9/5/2013)
    This data standard will improve our ability to identify drug establishments, both here and abroad, that make products for the U.S. market.
  • the first annual report as required under section 705, outlining the number of domestic and foreign establishments registered and inspected in fiscal year 2013 and the percentage of the FDA budget used to fund such inspections. (Section 705, issued 1/31/2014. This report provides a high level overview of FDA inspection resources.
  • a proposed rule regarding administrative destruction of imported drugs refused admission into the U.S. (Section 708, issued 5/6/2014)
    This authority will allow destruction of unsafe drugs valued at less than $2,500, rather than the current process that requires the return of these illegal products to the country of origin, which increases the risk that further attempts could be made to send them back into the U.S.

Working together with stakeholders, FDA will continue its strategic implementation of FDASIA Title VII by prioritizing its efforts based on the maximum benefit to the public health.

You can look up the current status of any FDASIA deliverable and sign up to receive Title VII updates using FDASIA-TRACK.

Howard Sklamberg, J.D., is FDA’s Deputy Commissioner for Global Regulatory Operations and Policy

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

Keeping You Informed: An Update on FDA’s Judicious Use Strategy for Antimicrobial Drugs in Food-Producing Animals

By: David G. White, Ph.D.

Today, “antibiotic resistance” is a widely recognized concern. With the rise of bacteria that are resistant to many, and in some cases, all standard treatments, scientists and medical professionals are not alone in focusing on this problem. The general public is increasingly aware of the ongoing research and how antibiotic resistance can affect their immediate communities.

David WhiteAntibiotic or antimicrobial resistance is an extremely complex and challenging phenomenon that is driven by many factors. For example, bacteria can spontaneously mutate to become resistant to antimicrobials, even ones they’ve never previously been exposed to. Overuse in both humans and animals is another complicating factor. Although progress has been made in curbing inappropriate drug uses in human and veterinary medicine, more work is clearly needed.

In December 2013, FDA started the clock on major changes regarding the use of antimicrobials in food producing animals by asking the animal pharmaceutical industry to relabel certain antimicrobials used in feed in two ways: by removing those indications approved for “growth production/feed efficiency,” and by requiring veterinary oversight and involvement in order to obtain these products when they are needed to assure animal health.

We’re now six months into a three-year transition period for these actions to take place, and we’re happy to report that we’ve secured the voluntary engagement of all 26 affected animal health companies. Out of the 283 drug products, 31 have been withdrawn from the market completely, and partial label changes have been completed for two other products.

Today we released our first biannual progress report on this strategy. FDA has committed to keeping the public updated on the implementation of these changes, and we intend to release progress reports every six months. These reports will highlight changes made by drug companies to their products over the previous six months, and provide a summary of changes that are in progress.

FDA will continue to update its chart of affected applications in real time as companies make label changes.

Developing strategies for reducing antimicrobial resistance is critical for protecting both human and animal health. We are still in the early stages of implementing this part of our overall effort to slow the development of antimicrobial resistance. We’ve been working with drug companies to move this strategy forward, and we are in continual discussions with both the animal health and animal production industries to help identify the most efficient ways to make these changes to their products.

While these changes are significant steps forward, the strategy is still in its early stages. The changes are just one part of FDA’s overall strategy for monitoring and reducing antimicrobial resistance. We see these progress reports as a way to evaluate the impact of our measures on how medically important antimicrobials are used in food producing animals, but we also know there’s more work to do. Additional actions may be warranted in the future, and FDA will be continually assessing their impact to determine appropriate next steps.

As we move forward, FDA is working with federal partners, veterinary groups, and consumer advocates to develop additional ways to measure success in slowing the development of antibiotic resistance and preserving the effectiveness of existing antimicrobial drugs. As with any strategy, there will be additional challenges, but FDA remains committed to addressing them and sharing what we learn along the way.

David G. White, Ph.D., is the chief science officer and research director in FDA’s Office of Foods and Veterinary Medicine

Empowering Consumers through Accurate Genomic Tests

By: Jeffrey Shuren, M.D., J.D.
We’ve come to recognize that almost every disease has a genetic component, and many consumers now are eager to know more about their genetic profiles. They need only send a sample of their DNA collected from their saliva or from a cheek swab to a company, and in exchange they’ll get back information about their genetic risk for development of future disease.

Jeffrey ShurenFDA understands and supports people’s interest in having access to their genetic information and believes such information can help them make more informed choices about their health – so long as that genetic information is accurate – that the results are correct, meaningful and written in a way that consumers can understand. FDA reviews genetic tests for medical conditions, whether they are intended to be ordered by a healthcare practitioner or directly by the consumer, to assure that consumers receive accurate test results.

Telling someone they are at high risk for a life-threatening cancer when they are not—or that they are at low risk for diabetes when they actually are at high risk for this chronic disease does not empower consumers. Consumers are not empowered by tests that tell them they need higher or lower doses of widely-used drugs, when the opposite is true. Moreover, some genetic tests have questionable value. Their impact on patient health is not known, and there are no guidelines for consumers or healthcare practitioners on how to interpret these test results, in part because the risk of getting a disease depends on a number of other factors such as age, sex, ethnicity, or environment and because genetic tests may only assess a limited number of genetic variations that only account for a small part of the risk.

Concerns about the need to demonstrate accuracy were at the heart of our five-year effort to work with the firm 23andMe that resulted last year in the company ceasing marketing its disease risk and drug dosing tests until it could demonstrate their accuracy.

These concerns were hardly theoretical ones. In 2010, at the behest of Congress, investigators from the U.S. Government Accountability Office purchased direct-to-consumer (DTC) genetic tests from four different companies—including 23andMe—and submitted two samples of their DNA to each company to receive risk predictions for 15 common diseases. The results varied across the four companies. One investigator was told that he was at below-average, average, and above-average risk for prostate cancer and hypertension. In some cases, the risk predictions conflicted with an investigator’s actual medical condition.

FDA is not standing in the way of 23andMe selling tests intended to help consumers trace their ancestry, identify relatives and tell them why they like or don’t like the taste of cilantro. Yes, that information can be fun. But Alzheimer’s disease, cancer and heart disease are serious matters. Our concern remains that genetic tests for diseases, just like other tests for medical conditions, such as hemoglobin A1C for diabetes (glucose control) should be accurate. Armed with that accurate information, consumers can take appropriate steps to take charge of their health.

Accurate information empowers. Consumers deserve no less.

Jeffrey Shuren, M.D., J.D., is Director of FDA’s Center for Devices and Radiological Health

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