Clarifying What We Mean When We Talk About Biomarkers: An NIH/FDA Joint Leadership Council Success

By: Melissa A. Robb, B.S.N., M.S. (RegSci), and Robert M. Califf, M.D.

What if there was a more uniform way to convey key technical terms to help advance scientific progress? Thanks to the Biomarkers, Endpoints, and other Tools (BEST) Resource, we’re one step closer to that goal.

Melissa Robb

Melissa A. Robb, B.S.N., M.S. (RegSci), FDA’s Associate Director for Regulatory Affairs, Office of Medical Policy, Center for Drug Evaluation and Research

Now available on the National Center for Biotechnology Information’s Bookshelf, the BEST Resource was developed through a collaboration of the Food and Drug Administration (FDA) and the National Institutes of Health (NIH). It includes a glossary of terms and definitions that will ensure the consistency and clarity needed to drive progress in biomedical research and clinical care.

Why is this textbook so important? In the spring of 2015, the FDA-NIH Joint Leadership Council identified a problem: Confusion about the definitions and inconsistent use of key terms–including biomarkers, surrogates, and clinical outcome assessments. This can deter progress in developing medical products and thereby potentially compromise efficiency in achieving public health benefits.

Accordingly, the council identified a high priority: harmonizing terms—or making sure that everyone is “speaking the same language”–that describe and categorize types of endpoints.

Members from multiple FDA Centers and NIH institutes formed a working group to focus on creating a glossary. This was the first step to a publicly available and open access textbook that could be continuously updated and expanded.

Robert Califf

Robert M. Califf, M.D., is FDA’s Deputy Commissioner for Medical Products and Tobacco

As the basis of their work, the group considered existing terminology and definitions. Those include FDA guidance documents and other literature, especially a seminal FDA-sponsored Institute of Medicine study.

The use of biomarkers has recently expanded widely to include fields such as mechanistic biomedical research, clinical trials, drug discovery, medical product development, clinical care, and regulatory science. Recognizing this broad influence and the accepted vernacular of these varied fields, the group sought to first reach consensus around biomarker taxonomy.

For example, there’s misunderstanding about the various types of biomarkers and the distinction between biomarkers and surrogate endpoints. One challenge was to settle upon definitions that were broad enough to be used by diverse communities, including biomedical scientists, translational researchers, clinical researchers, medical product developers, and clinicians, and also across diverse types of products.

Where possible, to provide more context and insight into important terms, examples are given alongside many definitions in the BEST Resource. NIH and FDA intend to use the definitions included in this glossary when communicating on topics related to its contents (e.g., biomarkers) to ensure a consistent use of the terms and therefore, a common understanding of the issues. FDA’s Biomarker Working Group, with representation from all of our Centers, contributed to developing these definitions.

Now we need your help. We need your feedback and comments on the glossary. You can provide them at the BEST (Biomarkers, EndpointS, and other Tools) Resource.

In the meantime, we’ll continue to work on adding context to terms related to regulatory science, clinical trials, and laboratory science.

Effective, unambiguous communication is essential for efficient translation of promising scientific discoveries into approved medical products. Once we are all speaking the same language, we can tackle other challenges to bring the promises of biomedical research and clinical care to fruition.

The FDA-NIH Biomarker Working Group members include: from FDA – Shashi Amur, Robert L. Becker, Robert Califf, Aloka G. Chakravarty, David S. Cho, Nina L. Hunter, Ilan Irony, Christopher Leptak, Kathryn M. O’Callaghan, Michael A. Pacanowski, Elektra J. Papadopoulos, Vasum Peiris, Melissa Robb, Hobart L. Rogers, Rachel E. Sherman, Robert J. Temple, Ann Marie Trentacosti, and Sue Jane Wang; and from the NIH – Holli Hamilton, Pamela McInnes, Lisa M. McShane, and Monica R. Shah.

Melissa A. Robb, B.S.N., M.S. (RegSci), is FDA’s Associate Director for Regulatory Affairs, Office of Medical Policy, Center for Drug Evaluation and Research

Robert M. Califf, M.D., is FDA’s Deputy Commissioner for Medical Products and Tobacco

Building a Case for Medical Device Interoperability: FDA’s Call to Action

By: Bakul Patel, M.S., M.B.A.

As Yoda might say: build a case for interoperability, we must. While we may not have yet realized the technological accomplishments of Yoda’s advanced world, today connectivity shows great promise for the future.

Bakul PatelFrom blood pressure to brain scans, today’s health care allows for the rapid transfer and use of information between and among different medical devices. This concept—called interoperability—is less about basic communication and more about the smart and safe interaction among medical devices and information systems.

Seamless interoperability among medical devices can improve patient care, reduce errors and adverse events, and lower costs. In fact, interoperability is one of the key factors for safety that can drive innovation in care delivery.

Think of a scenario in which devices collect a patient’s vitals during surgery. Then think about staff having to manually enter those vitals into a health care record because the format of the data generated by operating room devices isn’t compatible with the format necessary for the health care record, which by the way, only operates in one format. In this situation, the lack of interoperability can lead to errors during the manual entry process, and possible inefficiencies in patient care.

Now think about another scenario in which a patient is connected to a ventilator that can alert a caregiver—or automatically adjust its function—by monitoring an oximeter that measures blood’s oxygen saturation levels. In this situation, the interoperability between the ventilator and oximeter better coordinates their interaction and may reduce nuisance alarms, allowing clinicians to focus on true clinically significant alarms.

FDA has been collaborating with hospitals, health care providers, manufacturers, standards-development organizations, and other interested parties to promote medical device interoperability because it helps patients.

Some key activities in pursuit of this goal include the following:

In addition, we recently released draft guidance, Design Considerations and Pre-market Submission Recommendations for Interoperable Medical Devices, which outlines our ideas on design considerations for manufacturers developing interoperable devices. It contains our recommendations for information manufacturers should include in their pre-market submissions and ultimate product labeling. It also encourages manufacturers to make all necessary and relevant functional, performance, and interface characteristics openly available, enabling users to safely use medical devices with other devices or systems.

This draft guidance is intended to promote and facilitate development of safe and effective interoperable devices, thereby strengthening the much needed “case” for interoperable medical devices. We intend to work with stakeholders toward a future where interoperable devices increase care efficiency and reduce care costs, while keeping patient safety in the forefront.

We’re encouraging all stakeholders to share comments on this draft guidance with us.

We believe now is the time for all stakeholders—including medical device manufacturers, health care organizations, researchers, and information systems firms—to come together and continue to build this case to accelerate the development and availability of safe interoperable medical devices.

In Yoda’s words…may the force of interoperability be with us!

Bakul Patel, M.S., M.B.A., is associate director for digital health in FDA’s Center for Devices and Radiological Health

Using Social Media to Teach Consumers About Heart Health

By: Jonca Bull, M.D.

Jonca BullFebruary is American Heart Month. Heart disease remains a significant problem in the United States – it’s the leading cause of death, disproportionately affecting minorities. In particular, minorities have higher rates of hypertension, diabetes, and smoking, which are risk factors that can cause heart disease. This month, we’ll be working with the Centers for Disease Control and Prevention and the National Institutes of Health to help raise awareness.

Our social media platforms will be key to engaging the multicultural population. And they have a proven reach: 65% of Hispanics and 56% of African Americans use social media. In 2014, on average 40% of all cell phone owners used a social media site, with blacks and Hispanics leading the trend at 48% and 49%, respectively.

So, how will FDA’s Office of Minority Health use social media to reach key populations? Here are just a few things we have in store for February:

  • Sharing culturally relevant messages for Twitter and Facebook. We want to stimulate dialogue on two key areas: (1) knowing your risk factors and (2) using our resources to help manage them. This month, our outreach will provide information and resources on the following:
    • Heart Disease: Who does it affect and what are the risk factors?
    • Smoking: Smoking is a risk factor for developing heart disease. FDA has resources to help you quit.
    • Healthy Eating and Living: FDA has materials to help consumers make heart healthy decisions (e.g. how to read the food label), manage their risk factors through FDA-approved medications, and tips for preparing healthy meals.
  • Working with stakeholders to use social media as an engagement tool. We have developed a social media toolkit to guide stakeholders in communicating with their members. The toolkit will contain drafted social media messages, infographics, and links for consumers on heart disease and risk factor management. Email omh@fda.hhs.gov to receive the toolkit.
  • Hosting a bilingual Twitter chat with our partner, @SaludToday on Tuesday, Feb. 16th from 1 p.m. – 2 p.m., EST. We’ll chat about risk factors for heart disease and provide tips to lead a heart healthy lifestyle. We hope you can join us and provide your insights on this important topic.
  • Spearheading an #ILoveMyHeart social media campaign with our partners @SaludToday and @ABCardio1 asking you to show us how much you love your heart! Participants will upload pictures with the #ILoveMyHeart hashtag describing their heart healthy activities. Be sure to post your picture and tag @FDAOMH!

We know that social media is becoming a valuable health education tool to reach minorities. And, we will continue to use it to engage with our audience. Please follow us and share heart-healthy messages all month.

For more information about FDA’s OMH visit us at: www.fda.gov/minorityhealth

Follow us on Twitter @FDAOMH

Jonca Bull, M.D., is FDA’s Assistant Commissioner for Minority Health

Changing course: A new approach to opioid pain medication at FDA

By: Robert M. Califf, M.D.

As a doctor, I have a first-hand understanding of the important and legitimate need for powerful medication to help people deal with chronic or severe pain. If you have had a family member or loved one touched by a serious illness or injury, you understand it too. You know how tough it can be to see them try to endure pain that can’t be touched by anything you can get over the counter.

Dr. Robert Califf official photoBut as all of you know, more Americans now die every year from drug overdoses than they do in motor vehicle crashes. Opioids were involved in 28,648 deaths in 2014, according to the CDC.

The FDA is deeply concerned about this growing epidemic, and I am personally disturbed by the toll it has taken in communities across the country. It’s an issue I’ve been involved with for years as an academic, having overseen the NIH’s National Institute on Drug Abuse Clinical Trial Network, which was involved in some of the early medication assisted treatment studies.

After seeing the dependence and mortality numbers continue to rise and hearing from voices who care about this issue, I asked our folks to take a hard look at whether we’re doing everything we can to ensure that we’re appropriately taking into account the public health crisis that confronts us in the context of the role we play in ensuring the safety and efficacy of drugs.

The conclusion of that comprehensive assessment was that we can do more.

So we are announcing a change in course in how our agency approaches opioids – their approval, their labeling and their prescribing. We are going to fundamentally re-examine the risk-benefit paradigm for opioids and ensure that we consider their wider public health effects.

To that end, we have developed a comprehensive action plan to take concrete steps toward reducing the impact of opioid abuse on American families and communities.

There are four main pillars to the plan.

First, we’re going to be more transparent and open in the approval process for this category of drugs. Starting today, the FDA will convene an expert advisory committee before approving any new drug application for an opioid that is not in an abuse-deterrent formulation (ADF).

Additionally, we’re going to engage the Pediatric Advisory Committee to make recommendations on pediatric opioid labeling before any new labeling is approved.

Importantly, the advisory committee process is going to provide opportunity for public input, which is going to help us better understand and answer the concerns people have about these drugs.

We have also engaged the National Academies of Sciences, Engineering, and Medicine on how to take into account our evolving understanding of the risks of opioids, not only to the patient but also the risks of misuse by other persons who obtain them. The goal is to formally incorporate the broader public health impact of opioid abuse in approval decisions. And in March, we will seek advice from the Agency’s Science Board to reassess the risk-benefit approval framework for opioid use. The results of these efforts will be made public.

Second, we’re going to improve our communication with the medical community about these drugs. That starts with enhancing safety labeling. Our goal is to provide better information to doctors about the risks of these drugs and how to safely prescribe them. We’re developing changes to immediate release opioid labeling that will bring it more in line with the extended-release/long-acting labeling that occurred in 2013.

After reviewing the existing requirements and hearing recommendations from an advisory committee, we’re also going to update our Risk Evaluation and Mitigation Strategy (REMS) program requirements for opioids. We need to increase the number of prescribers who receive training on pain management and improve the safe prescribing of opioids to decrease inappropriate prescribing.

That effort will complement work being done at the Department level and at the CDC to help ensure that opioids are prescribed appropriately. We believe that this is a key component of ending this public health crisis. The more than 250 million prescriptions for these types of pain killers in 2012 – enough for every adult in the U.S. to have a bottle of pills – is clear evidence of the work ahead of us.

Third, we’re going to work to improve the information that’s available about opioid use. We’re going to require drugmakers to strengthen post-market analysis of these drugs. Today, that information, especially about long-term use, is lacking. We need more and better evidence on the risks of misuse and abuse associated with long-term opioid use and to better understand predictors of addiction, among other issues.

Finally, we’re going to focus efforts on approving drugs that have the potential to help mitigate the crisis. That means spurring the development of promising generics with abuse deterrent formulations. The FDA will issue draft guidance with its recommendations for the approval standards for generic abuse-deterrent formulations. We believe the availability of less costly generic products should accelerate prescribers’ update of abuse deterrent formulations.

And we’re going to work to improve access to naloxone, which is effective at treating overdoses. The FDA is reviewing options, including over-the-counter availability, to make naloxone more accessible. That work builds on FDA’s recent approval of intranasal naloxone.

What I’ve just described is a change in course – a framework for how FDA can better do its part to confront the opioids epidemic. In the coming weeks and months, we’re going to further develop these plans and continue to fill in the details for each initiative I’ve described.

But it’s time for us to act – to take the first steps toward changing how we do business and addressing this problem.

Robert M. Califf, M.D., is FDA’s Deputy Commissioner for Medical Products and Tobacco

Building a Modern Generic Drug Review Process

By: Stephen Ostroff, M.D.

Recent hearings on Capitol Hill highlighted an issue of growing importance for patients and for public health: access to quality, affordable medicines, in particular generic drugs. FDA’s generic drug program promotes access to quality affordable medicines by reviewing Abbreviated New Drug Applications (ANDAs), the pathway that allows generic drugs to come to market.

Acting FDA Commissioner, Stephen Ostroff, M.D.The generic drug sector has been enormously successful, growing from about 40 percent of drugs dispensed about 20 years ago to 88 percent today. And the cost savings have been enormous – approximately $1.68 trillion from 2005 to 2014 alone.

As my colleague Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER) at FDA, said in Congressional testimony, FDA is currently working to efficiently process and approve generic drug applications, at record or near-record levels, so when drug patents expire, less expensive generic options are available.

What’s helping FDA keep up that pace of approvals is the added resources that FDA and industry agreed to several years ago in the Generic Drug User Fee Amendments (GDUFA), part of the law passed by Congress known as the Food and Drug Administration Safety and Innovation Act of 2012. With this funding, we were able to hire and train over 1,000 new employees, develop an updated informatics platform to support our review program, and reorganize our generic drug office. Now, after several years of building a modern generic drug review process, FDA is on track to achieve the kind of success this legislation envisioned.

Today FDA is achieving – and in some instances surpassing – important GDUFA goals, including our approval of the ‘first generic” versions of an innovator drug.

generic drug chart

Generic Substitutions & Annual Savings

Although potential first generics constitute only a small percentage of our overall workload, they are very important for the market. Over the past three years, we have approved hundreds of first generics for over 200 new drug products. How? We made substantial program improvements. We solicited nationwide technical input from outside experts and organizations; issued a public-facing, transparent prioritization policy; formed a team to expedite the review of first generics; trained review staff; and enhanced our computer systems to streamline the process.

We’ve also eliminated our filing backlog of ANDAs. In August 2014, there were more than 1,100 applications that had not been reviewed for an initial filing decision. Today there is no backlog.

The cumulative result of our efforts is a huge increase in the productivity of the generics program. We ended 2015 at a new monthly high of 99 generic drug approvals and tentative approvals in December.

Finally, FDA is undertaking major changes in quality regulation so the public can be confident that we’re holding generic drugs to the same standards as brand drugs, no matter where in the world they are manufactured or tested.

All of us at FDA are extremely proud of what we’ve accomplished in implementing GDUFA. In the first two years of the program, we substantially enhanced our ANDA review program. Now we’re cranking it up. There will be up months and down months, but the overall trend will be one of continuing increases in output. More approved generics, if marketed, can further expand patient access to quality, affordable medicines.

We are currently engaged in discussions with industry and the public regarding the development of the second generation of GDUFA, which we call GDUFA II. GDUFA II is scheduled to begin in 2017. We welcome the opportunity which GDUFA II offers to build on our success, and make significant program improvements. Our goal is to bring safe, effective, high quality, affordable generics onto the market. This will benefit the health of every American.

Stephen Ostroff, M.D., is Acting Commissioner of Food and Drugs

Modernizing Pharmaceutical Manufacturing to Improve Drug Quality: Ensuring a Safe and Adequate Supply of Drugs

By: Michael Kopcha, Ph.D., R.Ph.

FDA is working with drug makers in a new way to help the industry adopt scientifically sound, novel technologies to produce quality medicines that are consistently safe and effective — with an eye toward avoiding drug shortages.

Michael KopchaWhen manufacturing problems arise in drug manufacturing facilities, drug shortages may follow. In fact, 65 percent of all drug shortages are caused by manufacturing and quality issues. This underscores the need for a safe and reliable drug supply chain.

In recent years, hundreds of drug shortages have been reported to FDA. We’ve done much to minimize their impact and prevent future drug shortages. For example, we’ve expedited the review of new applications for generic drugs when potential shortage issues arise with approved drugs.

Unfortunately, a significant number of these shortages have affected patients with serious conditions, including cancer, life-threatening infections, and severe malnutrition. These shortages can delay or prevent care to patients and can lead practitioners with no other option but to prescribe less effective therapies.

Other industries (such as electronics, chemicals, and automobile) have embraced the use of advanced manufacturing technologies and demonstrated improved quality, increased efficiency, and a reduced number of product failures. These lessons learned could be replicated. Working to modernize pharmaceutical manufacturing technology is key to our new approach to help the industry reduce and prevent drug quality and shortage problems.

By adopting similar technological advances as other industries, the pharmaceutical industry can create a more robust drug manufacturing process with fewer interruptions. This will minimize product failures and provide greater assurance that the product will consistently deliver the expected clinical performance.

FDA strives to support the modernization of pharmaceutical manufacturing by providing guidance to drug companies that are pursuing new technologies. One example is the recent approval of the first ever 3D printed pill which was for Spritam (levetiracetam), a medication to treat epilepsy. In this case, FDA worked closely with the manufacturer to make 3D printing technology a reality.

By adopting this novel technology, the drug maker is able to produce pills that can disintegrate more rapidly in a patient’s mouth, greatly aiding those who have trouble swallowing. This approval is a strong example to FDA’s efforts to put emerging technology to work for the health of Americans.

FDA is taking further measures to improve drug quality. To further help advancements in pharmaceutical manufacturing, FDA established the Emerging Technology Team (ETT). This specialized group—which includes representation from the Agency’s Office of Pharmaceutical Quality and the Office of Regulatory Affairs—works directly with industry to help identify and resolve scientific issues for new technologies. What makes this approach novel is that this dialogue can occur during early technology development prior to the submission of a drug application to the FDA. Such early engagement enables the FDA to proactively identify and address potential roadblocks and helps eliminate potential delay in the adoption of promising new technologies.

To clarify the mission and scope of the ETT, we’ve recently issued a draft guidance titled, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base. It provides recommendations to pharmaceutical companies on effective ways to work with the ETT. The document explains the ETT and provides specific recommendations to drug manufacturers for obtaining important early feedback from the FDA regarding their efforts to develop novel manufacturing technologies.

We’ve received much positive feedback and look forward to continuing productive interactions with industry. Expanding this program will not only help to prevent drug shortages, it will help reinvigorate our country’s pharmaceutical manufacturing sector while fulfilling a critical part of FDA’s mission: ensuring that safe and effective drugs are consistently available to the American public.

Michael Kopcha, Ph.D., R.Ph., is FDA’s Director, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research

2016: The Year of Diversity in Clinical Trials

By: Robert M. Califf, M.D.

Controlled clinical trials provide a critical base of evidence for evaluating whether a medical product is effective before the product is approved for marketing. One challenge that remains for FDA is ensuring that research participants are representative of the patients who will use the medical product.

Robert CaliffMoving from the result of a clinical trial to applying it in practice is complex. But it’s generally agreed that the composition of the population enrolled in a trial should help FDA reviewers, clinicians, or policy makers to have confidence that the trial results will apply to future practice.

Furthermore, a wide range of people should have the opportunity to participate in trials, both for access to new therapies and to have the chance to contribute to better treatment of everyone, an important altruistic goal for many Americans.

Historically, the elderly, women (in some therapeutic areas), and racial/ethnic minorities have been underrepresented in trials. A substantial body of literature has documented this under-representation in recent years, particularly for women in some cardiovascular trials and general inclusion of black/African-American and minority participants in clinical trials. In response to these concerns, Congress included Section 907 in the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, giving FDA direction to evaluate this issue and take action.

FDA has responded in multiple ways, including the creation of Drug Trials Snapshots that give the public readouts of the demographic profile of people participating in clinical trials for approved drugs. While progress has been made, we’ve learned from this program that we still have work to do. An evaluation of the Snapshots since the program began more than a year ago shows that some groups, especially ethnic and racial groups, aren’t always well represented in clinical trials.

These data are critical, because certain groups of patients may respond differently to therapies. For example, studies for a recently approved schizophrenia drug found that one side effect – the urge to move constantly – was seen more often in black/African-American patients. Two important classes of blood pressure drugs were found to work less well in black patients. And a drug for heart failure works very well in black patients but not in white patients. We also have seen labeling changes due to differences in dosing requirements between men and women, such as the recent labeling change with a sleep medication. These few examples show the importance of improving diversity in clinical trials, so medical products are safe and effective for everyone.

Increasing diversity in clinical trials is a priority for FDA. To that end, in 2016, the Agency is planning a variety of activities to push for greater inclusion, including more minority participation. For example:

  • FDA’s Office of Minority Health has developed a variety of tools to support clinical trial participation, including collaboration with the National Library of Medicine to help consumers and patients find clinical trials, educational materials on trials, as well as a multi-media campaign highlighting the importance of clinical trial participation. These materials are designed to urge those underrepresented in clinical trials to find out more information, and consider enrolling.
  • FDA’s Office of Women’s Health launched its Diverse Women in Clinical Trials initiative. Developed in collaboration with the National Institute of Health’s Office of Research on Women’s Health, this multipronged effort will raise awareness and share best practices about clinical research design, recruitment, and subpopulation analyses.
  • Our biostatisticians, trial design experts, and quantitative scientists will continue to work with the research community to develop methods to refine our approach to the conduct and analysis of trials to provide the best estimates of treatment effects for diverse populations.
  • We will continue our commitment to include patient advocacy groups to engage patients in clinical trial design, feedback and evaluation from a patient’s perspective. By engaging patients early in the trial design process, feasibility and participation may be improved.
  • Finally, our Office of External Affairs plans to publish a consumer update describing what it is like to participate in a clinical trial and encouraging the public to enroll in trials, if possible.

As mentioned above, these activities – and, indeed, the Snapshot program itself – were conceived as part of FDA’s response to Section 907 of FDASIA. This provision directed FDA to conduct an inventory of how well various population groups were being represented in clinical trials of FDA-regulated medical products and whether these data were publicly reported. Once that was done, FDA was directed to develop an action plan, which we published in August 2014. And we’ve been diligently working toward implementation and sustainability ever since.

As you heard from Barb Buch, M.D., Associate Director for Medicine at CBER, earlier this month, the public meeting at the end of next month will continue the dialogue with important stakeholders –like you – to continue this momentum.

And there’s more to come.

We want to make 2016 the year of more diversity in clinical trials. But we can’t do it alone. Stay tuned in the coming months for how we can work together to make this critical goal a reality.

Robert M. Califf, M.D., is FDA’s Deputy Commissioner for Medical Products and Tobacco

Making Progress in Protecting Consumers from Unsafe Supplements

By: Stephen Ostroff, M.D.

An estimated 200 million Americans take dietary supplements to maintain or improve their health. Protecting consumers from unsafe or contaminated dietary supplements is extremely important to FDA.

Acting FDA Commissioner, Stephen Ostroff, M.D.We’ve recently taken a number of important steps to prevent illnesses and deaths from unsafe supplements, and, while our current authority over supplements is arguably limited, we are doing what we can to strengthen our existing oversight. I’d like to give you a picture of the challenges, achievements and opportunities regarding the regulation of these products, beginning with the challenges.

One challenge is sheer volume. The dietary supplements industry is one of the fastest-growing in the world. When the Dietary Supplement Health and Education Act (DSHEA) was passed by Congress in 1994, annual sales of dietary supplements totaled about $5.8 billion. Since then, sales have risen six-fold to about $35 billion annually. Large volumes of supplements are also now sold on the Internet. The significant growth in the dietary supplements industry, and the various ways supplements reach consumers, outpace FDA’s resources to regulate this industry.

Moreover, tracing these products can be difficult because supply chains are often fragmented, with a single product sometimes passing through numerous suppliers, manufacturers and distributors of all kinds, sizes, and locations (including those overseas). Ultimately, when proper quality control and recordkeeping procedures are not followed across the supply chain, it can be difficult to guarantee what ingredients in what amounts are in the final product, and whether the ingredients are safe or even qualify as dietary supplements.

Under DSHEA, FDA does not have the authority to approve dietary supplements before they are marketed to consumers. However, we do have the authority to take enforcement actions after a product is on the market – only when we can establish that the dietary supplement is adulterated (e.g., unsafe); misbranded (e.g., misrepresentations are made on the product labeling); or cannot be marketed as a dietary supplement (e.g., an unapproved new drug). We monitor the marketplace through market surveys, undercover buys, label reviews, a review of reports of illness or deaths, and product testing. When necessary, we take actions to protect public health, including issuing public warnings, taking legal action, and working with the company to recall the product. But all this must be done based on evidence and within the bounds of our legal authority and limited resources.

Despite these constraints, our actions have produced important results over the past year. Here are just a few key accomplishments:

  • At the request of FDA, this month U.S. Marshals seized almost 90,000 bottles of dietary supplements labeled as containing kratom. Kratom has been indicated to have both narcotic and stimulant-like effects.
  • Use of pure powdered caffeine products has already resulted in the deaths of two teenagers. We took action to help prevent harm, including deaths, from the use of these products, by issuing warning letters to five distributors of these potentially dangerous products.
  • In 2015, FDA identified products containing BMPEA, DMBA and picamilon that are unlawfully marketed and issued a series of warning letters to 24 companies that marketed dietary supplements containing these ingredients. The companies that received the warning letters market products that are either misbranded for falsely declaring the ingredients as dietary ingredients or marketing products containing new dietary ingredients without the required pre-market notification.
  • We worked closely with our government partners, including the Department of Justice, the Federal Trade Commission and the U.S. Postal Inspection Service, on a year-long sweep to identify potentially unsafe products and/or products containing undeclared ingredients. In November 2015, that sweep culminated in civil injunctions and criminal actions against 117 manufacturers and/or distributors of dietary supplements and tainted products.
  • We issued more than 100 consumer alerts warning about products falsely marketed as dietary supplements that were found to contain active pharmaceutical ingredients.
  • We conducted more than 600 inspections of dietary supplement firms in the U.S. and other countries. We also worked with companies on voluntary compliance actions, such as removing illegal claims, destroying inventory and ceasing distribution.

I am excited about the opportunities that await us in this area, and the plans we’re making for the future. For example, within FDA, we have established the new Office of Dietary Supplement Programs and are working on increasing the visibility, capacity and staffing for that new office. This will include hiring permanent leadership to sharpen our focus on potential safety problems and to support regulatory actions.

We want to expand our use of criminal investigation and enforcement tools to address serious safety-related violations and cases of intentional fraud; and further build strategic investigatory and enforcement collaborations with the Federal Trade Commission, Department of Justice, and state governments, including state health departments and attorneys general.

Ultimately our top priority is to protect the consumers who want to improve, not damage, their health and have a right to expect that dietary supplements will be safe for them and their families.

Stephen Ostroff, M.D., is Acting Commissioner of the U.S. Food and Drug Administration

Advancing Women’s Health Research

By: Pamela E. Scott, Ph.D.

Career inspiration can come from many sources. My inspiration came from a broken ankle.

Pamela ScottIn the winter of 1999, I broke several bones and had three surgeries to repair my ankle. While working with my doctors on my treatment plan, I had to make some serious decisions about the proposed medical devices that would be used in my care.

I had more information at my fingertips than the average person. I was an FDA insider who had worked on medical devices. I had worked as a statistical reviewer, and I was in the process of completing my PhD in epidemiology and clinical trials methodology. But despite my background and access to information, I still had questions about how well the devices work for women like me.

My experience motivated me to make sure that women have the data and information they need to make informed choices about their medical care. When I returned to FDA, I dedicated my efforts to promoting women’s health research. Years later, I continue this work in my current role as Deputy Director and Director of Research and Development for the FDA Office of Women’s Health (OWH).

Throughout its history, FDA has conducted research to help inform its regulatory and policy decisions. OWH and FDA Centers have supported research that has developed new methods and tools that can help predict the safety and efficacy of FDA-regulated products, identify sex differences, and guide product labeling.

Since its establishment in 1994, the OWH Research and Development Program has played an integral role in promoting sound policies and regulations by supporting research projects, workshops, and training to help FDA answer regulatory questions related to women’s health. OWH has funded more than 300 research projects that have expanded our understanding of the science of women’s health.

New Women’s Health Research Roadmap

To build upon these projects, OWH recently released a Women’s Health Research Roadmap that outlines seven broad areas where new or enhanced regulatory science research would be beneficial to women’s health. Future OWH-funded research will seek to:

  1. Advance Safety and Efficacy
  2. Improve Clinical Study Design and Analyses
  3. Identify Novel Modeling and Simulation Approaches
  4. Advance Biomarker Science
  5. Expand Postmarket Data Sources and Analysis
  6. Improve Health Communications
  7. Identify Sex Differences related to Emerging Technologies.

OWH will work with FDA Centers to increase collaboration and communication on research endeavors related to women’s health. By promoting collaborative research in mission critical areas, the Roadmap will better position FDA to foster the advancement of innovative products that promote and protect the health of all Americans.

While I may never be able to run a marathon, my injury helped guide my career at FDA and my work to strengthen FDA’s commitment to advancing women’s health research. And with the new Roadmap, we are well positioned to continue the progress that has been made in women’s health.

Pamela E. Scott, Ph.D., is Deputy Director and Director of Research and Development, FDA Office of Women’s Health.

Progress and Collaboration on Clinical Trials

By: Barbara D. Buch, M.D.

There are few responsibilities at FDA more important than reviewing the design and outcomes of clinical trials. Understanding the science behind the trials — and the individuals included in them — helps us to ensure that the medical products we approve are safe and effective.

Dr. Barbara BuchLast year, FDA took important steps to support the inclusion of diverse populations in clinical trials. Following Congress’s directive in Section 907 of the Food and Drug Administration Safety and Innovation Act, FDA is looking more closely at the sex, age, and race/ethnicity data that are collected in clinical trials.

In August, FDA published an Action Plan designed to address three specific priorities: improving the quality and comprehensiveness of demographic subgroup data collection, reporting and analysis; identifying and eliminating barriers for increased participation in clinical trials; and improving the transparency of subgroup data.

We’ve come far in achieving this plan. As we begin 2016, I want to outline our progress in preparation for the next important milestone: a public meeting on this topic on February 29.

Priority 1 – Quality

  • FDA updated and/or finalized relevant guidance on demographic subgroup data, as illustrated by these two examples of FDA staff training and/or outreach to external stakeholders:
  • The Office of Minority Health (OMH) developed a plan that supports specific research projects and leads to better understanding of medical product clinical outcomes in racial/ethnic demographic subgroups.
  • The Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Center for Biologics Evaluation and Research (CBER) modified their clinical review templates:
    • CDER developed a review process that encourages reviewers to watch for inappropriate clinical trial exclusion and inclusion criteria; accompanying training emphasizes the need to include broad population diversity in clinical trials.
    • CDRH and CBER modified statistical reviewer templates to include analysis of demographic subgroup information.
  • CBER and CDER incorporated discussions on diverse inclusion and subgroup participation and analysis into pre-application submission meetings with industry.
  • FDA updated its MedWatch forms to standardize collection of demographic information on possible adverse events that occur after medical products are broadly available on the U.S. market.
  • And a few days ago, the Office of Women’s Health (OWH) posted their Research Roadmap and its strategic plan for women’s health research. OWH also funded two research projects:
    • Methods to improve data quality in demographic subgroups
    • Examination of sex-specific outcomes with cardiac resynchronization therapy.

Priority 2 – Participation

  • FDA is making demographic information from clinical trials more easily available to consumers through its easy-to-read online Drug Trials Snapshots webpage and a corresponding article for consumers.
  • The Office of Minority Health and the Institute of Medicine convened a Public Meeting to discuss minority health disparities and clinically meaningful differences.
  • FDA and The Johns Hopkins University co-sponsored a clinical trials workshop, Assessing Safety and Efficacy for a Diverse Population.

Priority 3 — Transparency

  • FDA established a Language Access Plan Working Group designed to implement communication strategies sensitive to the needs of under-represented subpopulations, focusing on language access and health literacy.
  • CBER launched a transparency pilot program to make demographic information available to physicians and the public for original Biologics License Applications.
  • CDRH modified templates for certain documents that are posted to the FDA website upon approval of certain medical devices to ensure that demographic information is consistently included.

We’ve certainly made progress, and will continue the forward momentum in the years to come. And we will need the continued investment of our stakeholders and partners.

We look forward to continuing this important and productive conversation with you next month at the public meeting.

Barbara D. Buch, M.D., is the Chair of the 907 Steering committee and the Associate Director for Medicine in FDA’s Center for Biologics Evaluation and Research