Dr. Frances Kelsey, Who Protected Americans from Thalidomide, Turns 100

By: John Swann, Ph.D.

Today marks the 100th birthday of one of America’s most celebrated public servants. Frances Oldham Kelsey, Ph.D., M.D., was born in Cobble Hill, Vancouver Island, British Columbia, and earned her Ph.D. in pharmacology and her M.D. at the University of Chicago. She was on the faculty of the University of South Dakota and practicing medicine when, in 1960, she accepted the offer to become a medical officer at FDA.

John SwannA month after assuming her position she was assigned the review of a new drug application for thalidomide, a sedative that had been used by expectant mothers and many others in dozens of countries since the late 1950s. U.S. law at the time required a firm to provide evidence of a drug’s safety as a requirement for sale. Despite the global popularity of this drug, and despite a constant and increasing pressure from the firm to approve the application, Dr. Kelsey refused to do that without adequate evidence that the drug was safe, a decision that was supported by her colleagues and superiors.

By late 1961 scientists discovered that thalidomide was responsible for crippling birth defects in thousands of babies in many parts of the world. Thanks to Dr. Kelsey’s “exceptional judgment in evaluating a new drug” — as her firm stand was described in the President’s Award for Distinguished Federal Civilian Service she received from President John Kennedy — the U.S. was mostly spared the tragedies. But the close encounter with a public health catastrophe convinced Congress and the White House to resuscitate proposals to revitalize the regulation of pharmaceuticals. The result was the 1962 enactment of the Kefauver-Harris Drug Amendments that mandated “substantial evidence” of a drug’s effectiveness as developed by “experts qualified by scientific training,” in addition to evidence of a drug’s safety, and provided for greater oversight of drug investigations. These and other requirements in the new law established a global standard for the evaluation of drugs.

Frances Kelsey

Dr. Kelsey today, pausing between crossword puzzles.

After 1962, Dr. Kelsey oversaw the evaluation of investigational drugs and, later, of oncologic drugs and radioisotopes. Concerns in the agency with problematical clinical investigations continued in the early 1960s, such that FDA created the Division of Scientific Investigations in 1967 and placed Dr. Kelsey in charge. She remained in this position until 1995. The division engaged in inspections of clinical investigators, animal studies, and institutional review boards involved in drug trials. Thus, Dr. Kelsey helped ensure the reliability of data vital to FDA’s evaluation of therapeutic products over a span of four decades.

Frances Kelsey, the recipient of the highest honor that can be bestowed on a federal civil servant, officially retired from FDA in 2005, but her commitment to the integrity of science in service to the public health continues to inspire those in the FDA and beyond.

To learn more about the life and work of Dr. Kelsey, see her “Autobiographical Reflections.”

More about thalidomide and the 1962 Kefauver-Harris Drug Amendments that came out of this crisis can be seen at http://www.fda.gov/Drugs/NewsEvents/ucm320924.htm.

John Swann, Ph.D., is an Historian at FDA

A reminder of the promise and limitations of abuse-deterrent properties

By: Douglas C. Throckmorton

The ongoing growing amount of drug abuse in our nation, particularly with prescription pain relievers known as opioids, has prompted a lot of talk about the potential of opioids with “abuse-deterrent” properties to help combat this public health problem. But care must be taken in putting  too much promise into abuse-deterrent technology at this time because the science is still relatively new and evolving.

Douglas C. Throckmorton, M.D.While the FDA strongly supports the development of products with effective abuse-deterrent properties and believes they can make a real difference, abuse-deterrent properties do not make an opioid impossible to abuse, and do not prevent overdose and death – they only makes certain kinds of abuse more difficult or less rewarding.

Current abuse-deterrent technologies tend to focus on making the drug either harder to crush, which makes them harder to snort or inject; harder to extract, which means the opioid cannot be easily separated from the other ingredients in the drug for purposes of abuse; more difficult to abuse orally, which is the most common form of opioid abuse; or  less attractive for abuse (e.g., the drug may contain an ingredient that counteracts the action of the opioid, making the drug less “likeable” or even unpleasant).

This week, FDA approved a new prescription opioid tablet called Targiniq ER, which contains a combination of the opioid pain medicine oxycodone and a drug called naloxone, an opioid antagonist. Naloxone can block the euphoric effects of opioid medicines and is used most often to treat an overdose. The science behind this particular abuse-deterrent formulation works like this: If the Targiniq ER tablet is taken as directed (i.e., swallowed according to its approved use), the naloxone will not interfere with the oxycodone. If, however, the tablets are crushed into a powder and snorted or injected, the naloxone inside the tablet will be absorbed and block the desired effect from the oxycodone.

Targiniq ER joins OxyContin (oxycodone) as the second drug FDA has approved with labeling describing the product’s abuse-deterrent properties consistent with FDA’s 2013 draft guidance for industry Abuse-Deterrent Opioids –Evaluation and Labeling which states that for claims to be made, they must be based on robust, compelling, and accurate data and analysis, and the description of the abuse-deterrent properties or potential to reduce abuse must be clearly and fairly communicated.

OxyContin gets its abuse-deterrent properties differently than Targiniq, by including ingredients that make the tablet hard to crush or dissolve. Efforts to pulverize the tablets into a powder result in a chemical reaction that makes the crushed tablet into a gooey gel that makes it more difficult to be inhaled or injected the way drug abusers would like.  While Targiniq and OxyContin use different abuse-deterrent technologies, they serve the same purpose: they are expected to help deter the often lethal practice of snorting or injecting prescription drugs.

In the context of this important and evolving area of science, FDA is very encouraged to see another drug with proven abuse-deterrent properties come to the market. We do need to remember that “abuse-deterrent” is not the same as “abuse-proof” and even abuse-deterrent formulations can be abused and people who take them can overdose and die.  For example, someone who wants to “get high” from prescription opioids can still swallow more than the prescribed amount, and this simple but common form of abuse can result in overdose and death.

Currently available products with abuse-deterrent properties are an important step in the right direction, but there is much more work to be done. The technologies involved in abuse deterrence and methods for evaluating whether those technologies actually deter abuse are rapidly evolving. To address this rapid change, FDA is working with many drug makers to advance the science of abuse deterrence and to help them navigate the regulatory path to market as quickly as possible. While FDA strongly supports a transition to opioids with abuse-deterrent properties, we do not believe it is feasible or in the interest of public health at this time to require all opioid products to have such properties.

To help support the safe use of all opioid products, FDA is working in many other ways to help prescribers and patients make the best possible choices about how to use these powerful drugs. Our goal is to find the balance between appropriate access to opioids for patients with pain and the need to reduce the tragedies of their abuse and misuse.

Douglas Throckmorton, M.D., is Deputy Center Director for Regulatory Programs in FDA’s Center for Drug Evaluation and Research

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

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

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

Using electronic health records to help advance drug development and safety monitoring

By: Janet Woodcock, M.D.

Not long ago, electronic health records (EHRs) were an idea solely for the future. Today, they’re a reality. Paper records are becoming part of the past. These days, when patients go to their physician’s offices, they are much more likely to have their care documented electronically. EHRs give health care professionals more data to provide patients higher levels of quality care and safety.

Janet WoodcockNow that EHRs are more widely used, they collectively represent huge amounts of important data about the medical products and prescription drugs patients are using. Significant amounts of information in patient EHRs may be used in clinical research, with appropriate protection of patient privacy, to aid the development of new and more effective medical therapies or to provide information on using existing treatments more effectively and safely. These data, combined with other sources of electronic healthcare data such as information from healthcare claims, are being used to better understand the performance of medical products.

A key challenge for the research community is to effectively harness the data contained in EHRs. There are many kinds of EHRs and many ways to collect and store electronic data. To readily understand and combine information from different sources, we need to further standardize the data and the way it is exchanged. This work will allow computer systems to better “talk” to each other and, ultimately will lead to better treatment decisions as clinicians will have a more complete picture of their patients’ medical histories, including visits with other providers. 21st Century data sharing also will expand opportunities for researchers to ask questions that may improve our understanding of how and when drugs should be used. EHRs are only part of the puzzle, though. Defining standards for capturing data from clinical trials, and using standard terms for items such as “adverse events” or “treatments” will allow researchers to combine data from different clinical studies to learn more.

At FDA, we’re working to help realize the potential of electronic healthcare data to better protect and promote public health. FDA’s pilot program for the agency’s Sentinel System, dubbed Mini-Sentinel, uses electronic healthcare data, principally claims data but also including data from EHRs, to monitor the safety of FDA-regulated medical products.

Here’s a quick snapshot of how Mini-Sentinel works: 18 large health care organizations across the country serve as data partners for Mini-Sentinel. When FDA safety scientists have a safety question they can submit “queries” to the Mini-Sentinel data partners about the drugs being used by the patients cared for by their organization. Each partner organization maintains its own secure and privacy-protected data, in some but not all cases including EHR as well as claims data, but with the use of a common data model, the necessary information from all of the different systems can be analyzed in the same way. This capability enables Mini-Sentinel to provide answers to FDA questions about drug safety. The Mini-Sentinel system can survey more than 350 million person years of observation, 4 billion pharmaceutical dispensings, and 4.1 billion patient encounters. Thanks to the ability to access data from various sources, the Mini-Sentinel system can use the information from potentially more than 150 million covered lives in our nation’s health care system to help answer important drug safety questions.

FDA is actively engaged with standards-setting organizations to develop solutions that aid researchers, medical product developers and healthcare professionals in their efforts to increase our collective knowledge and tools in medicine. We collaborate with, and support others in our health care system and in the research community who are working on efforts to harness the power of electronic healthcare data. We applaud those endeavors and encourage others to join these efforts.

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

FDA Leverages Big Data Via Cloud Computing

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

Last year, I worked with a group of colleagues throughout the Food and Drug Administration (FDA) on a project that is critical for the agency’s future: the modernization of our information technology platforms to prepare for the influx of “Big Data”—the enormous data sets we receive daily from manufacturers, health care providers, regulatory bodies, scientists and others.

Taha Kass-HoutThese data sets are not only larger than ever before, they are also arriving more frequently than ever and varying enormously in format, and quality.

This year alone, we expect to receive somewhere between 1.5 and 2 million submissions through our eSubmission Gateway – and some submissions can now be as large as a Terabyte (one trillion bytes) in size. This is the very definition of a big data.

But, at FDA, we view it as an opportunity and a challenge. To meet both, we are building an innovative technology environment that can handle vast amounts of data and provide powerful tools to identify and extract the information we need to collect, store and analyze.

A key example is our recent leveraging of cloud computing.

“Cloud computing” is, basically, computing on demand. Think of how you use water, or electricity, at the same time as do your neighbors and millions of others. You pay only for what you use, and service is always guaranteed. You don’t need to wait till your neighbor is done to use the washer or dryer because there is only enough electrical capacity to handle one person at a time.

The same is true of cloud computing, which stores data on the Internet, rather than on the hard drive or drives of computers. In essence, it gives us the ongoing, simultaneous capacity to collect, control and analyze enormous data sets.

For example, FDA, partnering with state and local health organizations, identifies thousands of foodborne pathogen contaminants every year. We sequence, store and analyze this data to understand, locate, and contain life-threatening outbreaks. Again, cloud computing aids us in this effort.

Finally, FDA has some of the world’s most valuable data stores about human health and medicine. Through OpenFDA, our newest IT program, we are making some of these existing publicly available data sets more easily accessible to the public and to our regulatory stakeholders in a structured, computer readable format that will make it possible for technology specialists, such as mobile application creators, web developers, data visualization artists and researchers to quickly search, query, or pull massive amounts of public information instantaneously and directly from FDA datasets on an as needed basis. OpenFDA is beginning with an initial pilot program involving the millions of reports of drug adverse events and medication errors that have been submitted to the FDA from 2004 to 2013 and will later be expanded to include the agency’s databases on product recalls and product labeling.

OpenFDA promotes data sharing, data access, and transparency in our regulatory and safety processes, and spurs innovative ideas for mining the data and promoting the public health.

Big data is important to the way we carry out regulatory science, which is the science of developing new tools and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products. Through innovative methods such as cloud computing, we are taking advantage of this flood tide of new information to continue to protect and promote the public health.

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.