Mission Possible: Moving the Needle Forward to Advance Health Equity

By: CAPT Richardae Araojo

Every April our country observes National Minority Health Month to spotlight what we’re doing to eliminate health disparities among minority populations. A health disparity is a particular type of health difference that is closely linked with social and economic disadvantage, discrimination, or exclusion. We strive for what we call health equity―the attainment of the highest level of health for all people―by enlisting a range of approaches to remove the social and economic obstacles to health faced by racial and ethnic groups.

CAPT AraojoAs the Director of FDA’s Office of Minority Health (OMH), I lead cross-agency efforts with my team to protect, promote, and advance the public health of our country’s most vulnerable and underrepresented populations. OMH does this in many ways. For example, we:

  • Conduct and fund research on diseases that disproportionately affect minorities, like HIV/AIDS, diabetes, and heart disease.
  • Work to diversify the public health workforce by training principal investigators and pharmacists from diverse backgrounds, such as African Americans, Hispanics, American Indians/Alaska Natives, and Asian Americans and other Pacific Islanders, who can relate to research volunteers and patients from underserved communities. Research shows that people want their health professionals to look like them, so a workforce that reflects the demographics of the community it serves is vital.
  • Help minorities make better informed health decisions by creating culturally and linguistically tailored health education materials for use across different social media platforms.
  • Engage with minority-serving institutions of higher learning to protect and improve the health of the populations they serve.
  • Serve as a voice for those in need by encouraging all our constituents to participate in the work that we do. One example is the inaugural FDA Rural Health Symposium, a cross-Agency effort among OMH, the Office of Health and Constituent Affairs, and the Center for Tobacco Products, with participation from other FDA product centers. The symposium offered stakeholders from rural and tribal communities a forum to discuss how we can work together to address rural health challenges that range from the opioid crisis and tobacco use among youth to the need for telemedicine.

In the spirit of this year’s theme for National Minority Health Month, Partnering for Health Equity, I’d like to share a couple of other ways we’ve been partnering with private- and public-sector organizations to further equity on all fronts.

Getting culturally sensitive messages out to minority communities

My office conducts robust communications and outreach activities to share research and information on FDA-regulated products and to promote public health. For instance, Asian Americans, African Americans, and Latinos have lower immunization rates for adult vaccinations like herpes zoster, whooping cough, hepatitis B, and influenza. To better understand these disparities, OMH is supporting a study to assess the impact of advertising and promotional labeling as it relates to vaccine health disparities. OMH has message-tested FDA’s communications with consumer panels, among others, and we’re using the information from this research to shape FDA’s health education materials and outreach to minority communities.

Ensuring minority representation in clinical trials

Ensuring minority representation in clinical trials is crucial to improving minority health because we need to understand how different racial and ethnic groups respond to medical products before they are approved for use in the broad population. To that end, FDA developed guidance for industry and FDA staff. This guidance provides recommendations on using a standardized approach for collecting and reporting race and ethnicity data used to support marketing applications for FDA-regulated medical products.

OMH also works collaboratively with organizations whose mission includes encouraging more minorities to participate in clinical trials. We’ve partnered with the Veteran Health Administration’s Office of Health Equity to launch two videos featuring veterans talking about why diverse representation is so important. These veterans will also appear in the first installment of our new podcast series on health equity and disparities to share their experiences as participants in clinical trials.

Another important partnership involves our newly formed memorandum of understanding (MOU) with Yale University. Under this MOU, we’ll be working to advance scientific collaborations, outreach, and educational initiatives. Especially exciting is the cultural ambassador’s program, which will engage community members to get more involved in clinical research.

In sum, to create a world where health equity is a reality for all we must involve all stakeholders in new ways of thinking and working. And that requires the kind of teamwork, partnerships, and collaboration across disciplines, experiences, and sectors that I’ve shared with you here.

Visit www.fda.gov/minorityhealth for more information on FDA’s Office of Minority Health, and follow us on Twitter @FDAOMH for updates.

CAPT Richardae Araojo is FDA’s Associate Commissioner for Minority Health

New CDER Report Highlights Ongoing Drug Safety Initiatives and Priorities

By: Janet Woodcock, M.D.

At FDA’s Center for Drug Evaluation and Research (CDER), drug safety is among our highest priorities. Before we approve a drug, we make every effort to ensure its benefits outweigh its risks. After approval, we keep a careful watch for new safety issues that can arise once new therapies are prescribed for a broad population of patients.

Janet WoodcockIt’s a complex and ever-changing responsibility. As drug therapies become increasingly advanced, so too must our methods to prevent and/or manage risks related to their use. These risks come in many forms – including adverse events (side effects), problems arising from inappropriate or incorrect use, manufacturing issues related to sophisticated new production techniques, criminal tampering or counterfeiting, and the devastating effects of addiction, like that of the opioid epidemic. And, as innovative study methods provide new information, new safety issues can emerge for drugs that have been on the market and widely used for decades. For these reasons, we focus our efforts both on newly approved drug therapies and those already on the market.

Our annual report, Drug Safety Priorities 2017, provides updates on our ongoing initiatives, discusses new work, and highlights last year’s safety-related milestones and achievements.

Protecting the American public from risks associated with medications requires teamwork from many scientific and medical specialists at FDA working together to inform decisive regulatory action. Key efforts include the Safe Use Initiative to reduce preventable harm from medications; the FDA Adverse Event Reporting System (FAERS), which collects vast amounts of data about side effects and medication errors from medical products reported by patients, health care professionals, and manufacturers; and the Sentinel System, our state-of-the-art electronic drug safety surveillance system. We also collaborate with health care professionals, academia, researchers, and other health and science agencies in studying the effects of medications before and after approval to help ensure that the benefits of these therapies outweigh their risks.

Our report describes many ways CDER worked in 2017 to enhance drug safety for the American public. These include:

  • Safety surveillance and oversight of marketed drug products: In 2017, CDER’s Office of Surveillance and Epidemiology (OSE) conducted 7,446 safety reviews. Of those, 2,860 were initiated as a result of ongoing OSE surveillance.
  • The importance of real-world evidence to help advance drug safety science: Although randomized clinical trials (RCTs) are the gold standard for medical and scientific evidence needed to support FDA drug product approval decisions, they are often conducted in specialized and controlled research settings and are time-consuming and costly. And at the end of a drug development program, RCTs can leave critical questions unanswered, particularly about the effects or impacts of a drug after it gets into the “real world,” and is used by hundreds of thousands of people over an extended period. CDER safety scientists are using powerful new scientific computing and data storage technologies to enhance our capabilities of gaining valuable information from “real world evidence.”
  • New tools and new approaches for fighting our Nation’s opioid crisis: Our report emphasizes that in 2016, an estimated 11.5 million people misused prescription opioids — and that each day of that year, an estimated 116 people died from an opioid-related overdose. FDA actions taken in 2017 in response to the opioid epidemic align with our current four key priorities in this area: 1) decreasing exposure and preventing new addiction, 2) safely treating those with opioid addiction, 3) developing safe and effective novel alternative therapies to opioids, and, 4) improving enforcement of safety measures and assessing benefit-risk ratios.
  • Safety oversight for generic drugs: The report explains how we evaluate generic drugs to ensure they meet quality standards and deliver the necessary amount of active ingredient, and how we monitor generic drug use in the marketplace to flag early safety concerns. CDER’s Clinical Safety Surveillance Staff (CSSS) is addressing post-marketing safety concerns related to complex generic drug-device combination products. In 2017 a generic drug had two intravenous (IV) bag ports (rather than a single IV bag port used by the brand name drug). This difference raised concerns for potential confusion, risk of incompatibility issues, and potential adverse events in patients. The CSSS’s collaboration activities led to the development of a new process for managing review of similar IV bags with different port configurations.
  • Efforts to reduce preventable harm from medications: More than a million Americans are injured or killed each year due to preventable medication errors. FDA’s Safe Use Initiative works to reduce preventable medication-related errors, such as medicines dispensed in error, medicines taken for too long or not long enough, or medicines inappropriately mixed with other medicines or with foods that can increase risks of side effects. Among many other efforts, our work through the Safe Use Initiative in 2017 included making recommendations to enhance the safety of fluoroquinolone antibiotics, identifying “high-risk” prescribers (those who write prescriptions for high doses or co-prescribe with medications which increase the risk of adverse events) and educating them about safer prescribing practices, and identifying which diabetic patients may be at high risk of hypoglycemia (low blood sugar).
  • Compounded drugs – continuing regulatory and oversight efforts: FDA has taken many steps to strengthen safety measures for compounded medications since the 2012 outbreak of fungal meningitis associated with contaminated compounded drugs. Among other actions, the agency conducted 140 inspections, sent 55 warning letters, and issued 40 recalls related to compounding.
  • Diverse strategies, tools, and services for communicating drug safety: Effectively communicating what we do is an essential component of our work to protect the public. In 2017, we responded to 57,094 inquiries from the public (39,883 by phone, 16,269 by e-mail, and 942 via written letters), each an opportunity to help a patient ensure they are safely using their medication. Our Drug Safety Podcasts reached an estimated 350,000 listeners each week. These and many other communication efforts, such as our Drug Safety Communications that alert consumers and health care professionals about new or potential safety issues, serve to keep the public informed of important drug safety concerns that may impact them.

The report also details a variety of ways we keep pace with the rapid evolution of technology. For instance, we are evaluating the use of technologies, such as machine learning methods and other advanced computation techniques, to help our analytics systems contribute to more predictive safety and risk data. We are also exploring ways to leverage mobile apps, social media, and electronic prescribing data while ensuring patient privacy. As we pursue a wide-ranging safety agenda, CDER Drug Safety Priorities 2017 offers a deeper dive into FDA’s drug safety research, surveillance, and regulatory activities. We hope this report serves to demonstrate CDER’s ongoing commitment to protect the American public.

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

Ironed Out

By: Vanessa Burrows, Ph.D.

During the early part of the 20th century, the growing scientific knowledge that certain diseases were caused by vitamin and mineral deficiencies sparked public interest in products that touted these substances. But the public had little understanding of this emerging health care field and, as a result, was often easy prey for unscrupulous marketers who used phony claims that their products had therapeutic value.

Vanessa BurrowsOne such charlatan was a man named E. Virgil Neal, whose past schemes included palm-reading and hypnotism performed under the name Xenophon LaMotte Sage; a mail-order health and self-improvement program, which earned him a conviction for mail fraud; and a French cosmetics company that marketed false hair regenerators and bust enhancers.

Operating at the dawn of the modern advertising age, Neal employed a sophisticated and misleading marketing campaign to sell Nuxated Iron pills, which included iron and nux vomica, a derivative of the strychnine tree, which is highly toxic to humans and other animals. Beginning in 1917, Neal’s advertisements used celebrity endorsements that touted the product’s invigorating and strength-building qualities, promising to alleviate “that tired feeling.” However, the pills contained so little iron that their health impact was questionable, and so much strychnine that, in at least one case, they caused the fatal poisoning of a young boy.

Neal’s fraudulence was exposed by the American Medical Association and journalists in the early 1920s, but FDA was unable to prosecute him because the misbranding provisions of the 1906 Pure Food and Drugs Act did not outlaw misleading promotional material of the type that Neal distributed. Neal’s product actually contained some iron, albeit negligible amounts, and only made therapeutic claims in promotional materials. It wasn’t until 1944, after the passage of the 1938 Federal Food, Drug, and Cosmetic Act, when FDA was able to take action against the product on new types of misbranding grounds, which forbid, among other things, misrepresenting the quantity of ingredients contained in the product.

Today, FDA continues to play a critical role in protecting consumers from fraudulent, adulterated, and misbranded products like Nuxated Iron.

We hope you enjoy your visit to the History Vault.

Vanessa Burrows, Ph.D., is an FDA Historian

In Forum and On Farms, FDA and Partners Work to Harvest Agreement on Water Issues

By: Samir Assar, Ph.D.

A two-day summit on the topic of agricultural water, followed by farm tours organized by FDA’s Produce Safety Network (PSN), illustrate FDA’s collaborative approach to implementing provisions of the FDA Food Safety Modernization Act (FSMA).

The Produce Safety Rule under FSMA includes standards for the microbial quality and testing of agricultural water that comes in direct contact with the harvestable portion of produce. In response to stakeholder concerns that these standards may be too complex to understand and implement, FDA is exploring ways to simplify them while still protecting public health.

That exploration recently took shape in two different ways. My team and I attended an agricultural water summit on February 27 and 28 with hundreds of participants in Covington, Kentucky, and 28 satellite locations across the country to discuss ways to simplify the agricultural water standards. And after the summit, a handful of FDA produce safety experts embarked on a different kind of fact-finding mission – an educational tour of two South Florida farms covered by new FDA regulations.

Both the summit and the farm tours included representatives from government agencies, academia, and the produce industry, along with farmers who must implement the produce rule provisions. Many of the participants know each other and have been working together to leverage strengths and trade knowledge as they cross territory that’s new for all of us.

There was a consensus at the summit that it’s time to agree on next steps. Some want the water standards to be redone; others want to stay with the standards as written but with a lot more interpretive guidance on how to meet them. There were frank discussions during breakout sessions about the challenges presented by the current requirements, specific on-farm hazards of concern and how they translate into food safety risks, and alternate water management strategies that could be used to control these hazards. Outcomes from these group discussions will help inform the decisions that FDA makes on these important issues.

I spoke at the summit about our need for more information about on-farm conditions and water systems. Ongoing dialogue with stakeholders will be crucial as we move forward.

We received feedback that additional clarity on how we arrived at the current agricultural water requirements in the final rule would be helpful, as would be increased communications on the research FDA is funding, particularly for projects involving cooperative monitoring programs. There was also a push for FDA to establish partnerships with other federal agencies that have water quality databases and tools that might be used to alleviate some compliance challenges. Throughout this process, we have been engaging with people who have technical expertise on a variety of relevant issues (for example, produce safety, water microbiology, and water systems). During the summit, we were able to establish connections with more technical experts, and we plan to continue engaging with all of these experts as we consider ways to simplify the standards.

Farm photo

Canals bring water from Lake Okeechobee to the Duda fields, where it reaches the crops through seep irrigation.

These conversations continued as my colleagues in FDA’s Division of Produce Safety joined their counterparts in the public and private sectors on the two Palm Beach County farms on March 1 and 2. In addition to the produce team and colleagues from the agency, those on the tours included representatives of the Florida Fruit and Vegetable Association, the University of Florida/Institute of Food and Agricultural Science Extension, and state partners from the Florida Department of Agriculture and Consumer Services and the Florida Department of Health.

FDA has been putting these educational farm tours together for about a year, having done 117 in 2017 alone. Trevor Gilbert, the PSN representative whose region includes Florida, organized tours of the J&J Family of Farms and the Duda Farm Fresh Foods Facility, both of which began as family farms and grew to become national suppliers of produce. Both use a kind of irrigation unique to Florida’s high water table called the seepage method. The growing fields are intersected by canals that supply the water that is pulled up through a below-surface bed of sand to reach the crop roots. And both farms have staff specifically dedicated to food safety.

At J&J, the visitors were taken through fields of peppers and squash, the latter being cleaned and packed right in the field—in equipment invented on this farm—because of the crop’s sturdiness. The peppers are cleaned and packed in an off-farm facility. As the J&J food safety staff outlined the steps taken there to prevent the contamination of their crops, the main concern expressed about FSMA is a desire that the standards provide enough flexibility to allow room for innovative methods to ensure adequate supplies of water.

Farm photo

Perry Yance, Duda’s Farm Manager, talks to visitors from FDA about the farm’s use of water resources.

The next day, the team traveled to the Duda Farms, which started as a celery farm in 1926 and has staff members who have worked there for decades. Duda’s fields are fed by water that flows down from Lake Okeechobee, its fields laced with canals and pumps to control the water levels. The visitors were taken through fields of celery and radishes, marked by the occasional alligator sunning itself on the edge of a canal. As at J&J, some of the crops—celery in this case—are packed in the field using equipment invented by these farmers. The sentiment expressed here by the food safety team was one that I heard from others at the water summit: It’s time to reach agreement on the water standards and move forward.

Both farms follow food safety standards that preceded FSMA, ones shaped by audits required by retailers. The need to harmonize the requirements of such audits with FSMA is another challenge that has surfaced in discussions with the produce industry.

One of the calls for action that came out of the agricultural water summit was a need for more transparency and communications. That call will be answered in multiple ways, including building new connections through more of these educational farm tours. And the PSN’s team members are based all over the country to provide information and technical assistance.

FDA will continue working with dedicated teams of produce experts to find the right path forward, one that, where possible, makes the standards easier to understand and follow while still producing safe fruits and vegetables for consumers across America and throughout the world.

Samir Assar, Ph.D., is the Director of FDA’s Division of Produce Safety

We’re Committed to Guarding Against the Intentional Adulteration of Food and Implementing the New Rule Efficiently

By: Scott Gottlieb, M.D.

The U.S. food supply is among the safest in the world. But to keep it safe we must recognize that our foods are vulnerable – not just from unintended contamination, but from those who would seek to deliberately do us harm.

Dr. Scott GottliebEnsuring that we’re prepared to minimize the risk of an intentional attack on our food supply is a goal that we share with the food industry and consumers.

The FDA Food Safety Modernization Act (FSMA) charges FDA with addressing the burden of foodborne illness by requiring that producers, importers and distributors of food take systematic steps to prevent contamination. Congress passed FSMA with a view of the unique risks posed by a global food supply. Six of FDA’s seven “foundational rules” for FSMA focus on the safe production, storage, and transport of human and animal food by addressing conventional food safety hazards

But a different reality shapes the seventh rule on Intentional Adulteration. This provision seeks to prevent acts of terrorism meant to harm and kill many people.

Food facilities covered by this rule (both domestic and foreign facilities that export to the United States) are required to implement — for the first time — a food defense plan that identifies vulnerabilities and ways to reduce the risk of intentional adulteration.

Congress directed FDA to focus its efforts to prevent intentional adulteration on the highest risks to the food supply. That’s why the Intentional Adulteration Rule primarily covers large food companies whose products reach many people.

Extensive analysis shows that some of the most significant risks are posed by an attack perpetrated by someone who has legitimate access to a facility, perhaps under the guise of an employee. This is why the new rule asks facilities to focus their efforts on processing activities that — if deliberately attacked by a rogue insider — could potentially result in widespread contamination of products.

FDA is committed to making the implementation of the Intentional Adulteration rule as practical and flexible as possible for the food industry. Even though the initial compliance date for the largest businesses is July 2019, more than a year away, I’m taking steps right now to fully understand stakeholder concerns and challenges, and address them.

As part of this fact-finding process, I recently visited the Nestlé Dreyer’s Grand Ice Cream facility in Laurel, Maryland. My FDA colleagues and I were taken on a tour of the facility, from the receiving dock to the production line to the packaging equipment. It was very helpful for me to see, first hand, the processes and practices that Nestlé has in place that could be used to guard against deliberate contamination.

Addressing Misconceptions

Having this kind of direct interaction with stakeholders is important. This is new regulatory territory for both FDA and industry. We need to make sure we implement these new requirements in a way that achieves its public health goal, without creating unnecessary burdens or costs on industry. From my interactions, I’ve come to believe that there may be misconceptions about how we’re expecting the food industry to implement this rule.

I want to use this opportunity to provide more transparency on our work.

Food facilities covered by the rule will be able to choose from a wide range of options to identify and reduce their vulnerabilities. They have the flexibility to tailor individual options that are cost-effective and make sense for each particular facility.

We recognize that many companies have already made significant efforts to reduce their vulnerability in response to terrorism concerns since the attacks of 9/11. These are important steps. And we believe these existing efforts can help food facilities meet many of the intentional adulteration rule requirements.

Existing measures may be in place for reasons related to business, food safety, and food defense. Many current steps companies take can become important parts of a food defense plan to meet the Intentional Adulteration requirements. However, we also know that there are some areas where additional measures will be needed.

We want to make sure these new measures can be implemented in a way that’s the least burdensome while achieving its intended, food protection purpose.

We agree with food companies that the “inherent characteristics” of food production equipment and processes should be considered when conducting a vulnerability assessment. At Nestlé, for example, vats of chocolate with hatches at the ground level can’t be opened without creating a flood of chocolate, which certainly wouldn’t escape notice. Our rules are meant to be practical. In this case, the inherent characteristics of chocolate vats make the ground-level hatches a low area of vulnerability. This means that mitigation steps may not be needed at this point of access.

During discussions with stakeholders, we’ve also heard that some people believe that plants might be required to construct vast enclosures for their equipment, invest in advanced computer systems, or reengineer whole processing lines.

That’s not the case. We want expectations to be clear to industry stakeholders.

We’ve also heard that some companies believe they’ll have to hire more workers for the sole purpose of observing other workers. We don’t believe that’s going to be the case.

Moreover, we’ve also heard concerns that implementing some food defense measures required under the rule may create conditions that negatively impact worker safety, food safety and food quality. During our extensive work with industry to develop the proposed rule, we’ve identified a variety of strategies that are very practical to implement and don’t impact food production or safety of any kind.

I want to be very clear about this point. Facilities will be given enough flexibility in selecting options for mitigation strategies that there should be no conflicts between food defense and food safety. We’ll work with any company that has those concerns.

And make no mistake, food safety is — and will remain — our first priority. In implementing the requirements of the intentional adulteration rule; we don’t want facilities to take any steps taken that could jeopardize food or worker safety.

I’ve also heard concerns expressed about the potential paperwork requirements associated with the rule and costs associated with monitoring the food defense protective measures required in the rule. We’ll provide examples of how to minimize paperwork and templates for recordkeeping so that costs are kept to a minimum.

We also expect that many of the options for monitoring can be incorporated into an employee’s existing responsibilities. And the frequency of monitoring for some strategies can also be kept to a minimum while still assuring the measures are working, thereby reducing costs.

Upcoming Guidance

Part of the feedback that we received during the Nestlé tour was the need for FDA to provide a guidance document to provide clarity on how firms can more easily meet the new requirements. That’s something we’re working on right now. We plan to publish this new guidance document well in advance of the initial compliance date in 2019.

We’ll soon be publishing the first chapters of this three-part draft guidance to focus on important questions that I’ve heard. Our hope is that this guidance will help manufacturers focus on those measures that have a meaningful impact on protecting food from intentional adulteration. We plan to publish the remaining two parts of the guidance this summer. The entire draft guidance will be available for public comment.

The first two installments of the guidance focus on the greatest concerns expressed by the food industry and the requirements that drive costs.

The first installment includes a simple, cost-effective way to identify the most vulnerable parts of the production process. It details numerous ways to guard against deliberate contamination, including some existing and cost-effective measures, as well as additional ways to monitor the operation to make sure that protections are working.

The second installment includes guidance on an additional, detailed, and flexible method to identify a facility’s most vulnerable points.

Finally, the third installment focuses on corrective actions, verifying that the system is working, how to reanalyze the plan and its parts, and record keeping.

Protecting Against an Inside Attacker

Importantly, the guidance will also address measures facilities can take to address the risk of an inside attacker. The rule identifies that the greatest risk comes from an inside attacker rather than from an outsider. The new measures require that the assessment of vulnerabilities must consider the potential threat from within a facility.

While the possibility of an inside attacker is hopefully not likely at a particular facility, we’re not talking about a theoretical danger. The threat landscape for intentional adulteration continues to grow regarding an inside attack even since the rule was finalized in 2016.

To take one vivid example: There was a recent report of a foiled terror plot in the United Kingdom that involved an employee at a food manufacturing plant who had been investigating ways to poison supermarket-ready foods.

FDA has worked on food defense assessments for more than a decade in collaboration with food manufacturers, universities, and government partners — including the intelligence and law enforcement communities. Our interactions with intelligence and law enforcement communities have repeatedly indicated that an inside attacker presents the greatest potential danger.

Some existing, protective measures in food facilities, such as perimeter fencing and general visitor protocols, are focused on thwarting an outside threat. These measures are also important. But they don’t address the full scope of risks, including an inside attacker, that must be considered when identifying a facility’s most vulnerable points.

The guidance document will provide examples of how to protect against an inside attacker using a range of measures that can be adapted to best meet individual facility needs. In many cases, food facilities will be able to leverage their existing protections.

Next Steps

Industry has also asked about the availability of training on these new requirements, both for food facilities and regulators. We’re working on both fronts to create training and technical assistance for food facilities that’s consistent with other FSMA-related training. And we’ll be training both federal and state regulators as well.

I was grateful to meet and learn from the professionals at Nestlé. I’m impressed by their commitment to food safety and food defense. I know that their efforts, and their commitment, reflect the ethic that’s in place at a lot of leading food companies.

We’ll continue to work through the issues raised by food manufacturers covered by the Intentional Adulteration rule. We need to make sure we implement these requirements in a way that’s cost-effective and efficient. Safeguards that are too costly to put into place, or are too hard for firms to adhere to, don’t work. They don’t meet their purpose.

I look forward to continuing to engage personally in this dialogue. Keeping food safe from contamination during production, storage and transport remains a primary focus of the FSMA rules. And food defense is an important component of achieving that goal.

While intentional adulteration is unlikely, a successful attack could have devastating public health consequences. FDA and the food industry are committed to the overarching goal of protecting consumers from these and other risks. I look forward to partnering with industry to ensure that appropriate measures are in place to give us all confidence that the food supply is as safe as possible from hazards of all kinds.

Scott Gottlieb, M.D., is the Commissioner of the U.S. Food and Drug Administration

FDA Blood Supply and Demand Simulation Model Could Help Nation Prepare for Emergencies

By: Arianna Simonetti, Ph.D., and Richard Forshee, Ph.D.

Keeping the nation’s blood supply and demand system working efficiently can be a matter of life and death. That often means moving blood to meet critical needs when an area of the country experiences shortages. In fact, ensuring that blood gets to where it is needed, when it is needed, during emergencies is an important part of national security preparedness, and part of FDA’s mission.

Arianna Simonetti

Arianna Simonetti, Ph.D., is a Mathematical Statistician at FDA’s Office of Surveillance & Biometrics, Division of Biostatistics in the Center for Devices and Radiological Health

That’s why FDA developed a blood supply model that estimates the amount of blood available in the system during both routine conditions and emergencies. This model is designed to help public health officials effectively plan strategies that will minimize any disruption of the blood supply should blood collection efforts be reduced as a result of an emergency. The model has the advantage of being easily customized to explore various “what-if” scenarios, so it could assist in the development of sound regulatory policy and strategic planning for emergency preparedness and medical responses requiring blood transfusions.

The model estimates how much blood is available during two types of emergencies—a pandemic influenza outbreak and a mass casualty event caused by the detonation of an improvised nuclear device. Either scenario could threaten the blood supply in two ways—by reducing the number of people available to donate or by increasing the amount of blood needed to respond to such an emergency.

Richard Forshee

Richard Forshee, Ph.D., is Associate Director for Research at FDA’s Office of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research

To our knowledge, this model is the first attempt to estimate how much blood would be available for the U.S. blood system during potential national emergencies.

One of the challenges in dealing with an emergency is that red blood cells (RBCs) have a relatively short shelf life. The model allows us to calculate the supply—and the potential for shortages—based on how long RBCs have been in storage.

An earlier model designed by our group provided overall national daily estimates of the number of RBC units available in the demand system. Our new, inter-regional model divides the U.S. blood supply into four regions: East, West, South, and Midwest. This gives us a more fine-tuned look at the blood supply system’s response to emergencies by tracking the collection and transfer of blood across the different regions. It can also give us a snapshot of the blood supply at any time and in any region. This suggests that the model could help in planning for emergencies that trigger higher demands of blood in potentially affected regions.


Blood Availability: A Model of Supply and Demand

The amount of blood that is collected and used in different regions of the country varies. The FDA model of the U.S. blood supply enables public health officials to estimate the availability of blood in each region at any given time. This helps minimize disruption and avoid shortages in the blood supply.The amount of blood that is collected and used in different regions of the country varies. The FDA model of the U.S. blood supply enables public health officials to estimate the availability of blood in each region at any given time. This helps minimize disruption and avoid shortages in the blood supply.In the South, as shown in the example above, the amount of blood donated in a region may be less than the amount needed for transfusions in that region. This potential shortage in donations can be mitigated by blood transfers from other regions, as indicated by the arrows. The FDA model accounts for blood transfers among regions based on data provided by America’s Blood Centers, which collects about 55% of the U.S. blood supply.In the South, as shown in the example above, the amount of blood donated in a region may be less than the amount needed for transfusions in that region. This potential shortage in donations can be mitigated by blood transfers from other regions, as indicated by the arrows. The FDA model accounts for blood transfers among regions based on data provided by America’s Blood Centers, which collects about 55% of the U.S. blood supply.

To build a model that reflected actual blood collection and use in the four regions as closely as possible, we went to real-world sources of data. For example, we used the daily report on the national blood supply produced by America’s Blood Centers to determine how much blood was available in each region. To track blood use in each region, we calculated regional daily RBC units transfused from the 2007-2012 Center for Medicare and Medicaid Center for Medicare and Medicaid Services database. We also used national estimates of blood collections and use from the 2011 National Blood Collection and Utilization Survey. Using this information, the model estimates the average number of RBC units available each day for each region.

To create our scenario for a pandemic, we used data on the outbreak of Pandemic A(H1N1) influenza from the Centers for Disease Control and Prevention and the weekly flu-like activity levels reported by the states.

Guided by a previously-developed computer model simulating the effect of a pandemic on blood donations and blood supplies in Germany, we ran a simulation on how the pandemic could affect the inter-regional supplies of blood in the U.S. One important finding was that the new model estimated that 541,000 RBC units were lost overall and that the South region had the highest percentage of blood lost (15.5%), while the East region had the lowest lost (13.8%), compared to the levels at the beginning of the pandemic.

For our simulation of the demand for RBC units needed following a mass casualty event caused by an improvised nuclear device, we used data on the expected casualties from each type of injury from a previous study. Our own inter-regional simulation let us predict the effect of such an event on the U.S. blood supply. For example, we saw that if the event occurred in the East region, given the current data available, this area of the country rapidly recovered to its original level of blood supply due to increased blood transfers from other regions.

The FDA model showed that, based on current levels of blood collection, use, and other factors, the U.S. blood supply and demand system is flexible and reliable enough to respond to these events.

But our simulation model is just an attempt to replicate the workings of the U.S. blood supply and demand system under various circumstances. Our conclusions could change if patterns of blood donation and use change. However, our experience with this model thus far shows that, as we add more accurate and current data and, make it available to planners, it could help the nation prepare for disruptions of blood collection and demand.

Arianna Simonetti, Ph.D., is a Mathematical Statistician at FDA’s Office of Surveillance & Biometrics, Division of Biostatistics in the Center for Devices and Radiological Health

Richard Forshee, Ph.D., is Associate Director for Research at FDA’s Office of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research

FDA is Using Innovative Methods to Prevent Illegal Products with Hidden Drug Ingredients from Entering the United States

By: Scott Gottlieb, M.D., Melinda K. Plaisier, M.S.W., and Michael Kopcha, Ph.D., R.Ph.

One of the Food and Drug Administration’s important public health functions is to closely monitor the FDA-regulated products arriving at the nation’s international mail facilities (IMFs) every day to prevent unsafe, counterfeit, and unapproved products from entering the country. This sometimes includes interdiction of illicit products, in support of the U.S. Customs and Border Protection (CBP).

Dr. Scott Gottlieb

Scott Gottlieb, M.D., Commissioner of the U.S. Food and Drug Administration

Given the volume of mail, the increasing sophistication of bad actors, and the amount of time it takes to inspect just one package, this is an increasingly challenging task. FDA is taking new steps to increase the scope and effectiveness of this mission. One tool that FDA has deployed is advanced screening technologies that can allow FDA inspectors to screen packages containing suspected drug products more efficiently and reliably.

According to a January 2018 report by the U.S. Senate Permanent Subcommittee on Investigations, in just three years from 2013 to 2015, the number of packages processed by the nation’s nine IMFs nearly doubled. Today, these combined facilities receive more than 275 million packages a year. Most of the mail arrives without advanced or specific identifying information. As a consequence, we have no way of knowing exactly how many packages contain FDA-regulated products.

What we do know is that every year thousands of packages are found to contain FDA-regulated products and a surprising percentage of those products are illegal. These products come in all different shapes and forms – some with sophisticated packaging and others in nondescript plastic bags.

They include unapproved products; counterfeit or substandard drugs; and purported dietary supplements being sold for weight loss, sexual enhancement, bodybuilding or pain relief. Many products promoted as dietary supplements contain potentially dangerous undeclared drug ingredients. Any package initially suspected of containing controlled substances is immediately referred to the U.S. Drug Enforcement Administration. Still, FDA is seeing an increase in the number of packages containing opioids including tramadol, codeine and morphine, making FDA’s investigators the last line of defense for drugs that may not be easily identified as narcotics.

Melinda Plaisier

Melinda K. Plaisier, M.S.W., FDA’s Associate Commissioner for Regulatory Affairs

Last year, FDA increased the number of investigators it has in the IMFs from 8 to 22 full time employees; taking the number of packages FDA is able to open and screen from 10,000 a year to 40,000. These are packages that our partners at CBP have flagged for additional screening in order to intercept and detail what are believed to be nefarious products prior to refusal of admission and possible destruction.

To do so, based on current laws, FDA must first establish that the products are drugs based on their intended use, then determine if the drug is subject to refusal of admission. This requires documenting the contents, which can be a labor-intensive process. Some of the packages may contain loose pills without any packaging or contain hundreds of small internal packages. Screening a single package can take about 20 minutes, while packages that contain multiple products or large quantities can take much longer. This limits the number of packages that FDA is able to inspect. CBP will only pull for inspection the number of packages that FDA is able to complete in a given day. CBP and FDA target the highest risk packages for physical inspection. This is where good intelligence work is key. But packages that can’t undergo a physical inspection will typically be sent on to their recipient. The more that FDA can improve the efficiency of its process, its authorities, and the tools that it uses to evaluate products; the more higher-risk packages that the agency is able to subject to vetting.

Although the agency’s professional staff works hard to examine and document suspicious contents, FDA investigators are only able to inspect a fraction of the incoming international mail packages. It’s estimated that FDA is able to physically inspect less than 0.06 percent of the packages that are presumed to contain drug products that are shipped through the IMFs. Recognizing these hurdles, we’re doing all we can by increasing our existing resources, working more efficiently and identifying innovative ways to extend our efforts.

In addition to tripling the size of our staff, we’ve invested in, and would like to enhance, our screening equipment at the IMF locations and laboratory equipment for the forensic confirmations needed – all of which serves to increase efficiency and strengthen our ability to more quickly identify and assess suspect products entering through IMFs. FDA’s current analytical process requires sending samples to an FDA laboratory for analysis. It can take days or weeks to get results and during that time products would have to be held within the IMF’s limited space, restricting the number of products that can be tested by FDA.

Michael Kopcha

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

One of the most promising technical developments is the successful use of various portable screening devices that will allow us to rapidly test for unsafe ingredients at the IMFs with similar reliability and accuracy as the current laboratory methods. FDA recently concluded a successful six-month pilot at two IMFs, testing whether we might be able to increase the number of packages we screen by making use of a portable screening device called an ion mobility spectrometer. This is the same technology used by airport security to swipe your luggage for explosives and by prisons to screen visitors for illegal narcotics. The device works by comparing the chemical signature of the unknown substance against the chemical signatures of known compounds in a process that takes less than 30 seconds.

For the pilot, the device was loaded with a custom-built library of pharmaceutical compounds to test whether products marketed for weight loss and sexual enhancement contained undeclared drug compounds such as sibutramine, phenolphthalein and sildenafil. These compounds have significant safety concerns and are often counterfeited; and are commonly found within packages coming into the IMFs. When criminals secretly spike products with these compounds, consumers do not know that they are at higher risk of harm from the products.

An astonishing 65 percent of the samples we screened tested positive for the presence of undeclared pharmaceutical ingredients, results that were confirmed in a FDA laboratory. Based on these results, we’re able to demonstrate that the device was reliable, efficient, and produced valid results. As a result of this pilot, we’ve decided to expand the use of this new technology and add devices at two additional IMFs. Our aim is to refine our use of this device, and eventually install it in all nine of our IMF facilities so that our staff can more quickly determine whether products contain undeclared drug ingredients.

This is a significant milestone.

The scanner’s methods are flexible enough to be used to detect the presence of an active ingredient in a drug product or to identify active ingredients in counterfeit drug products, simply by adding new pharmaceutical libraries developed by FDA laboratories. This will allow the agency to more quickly identify and respond to emerging issues. Already we’re actively working on developing an opioid screening method for the device. We hope to initiate a pilot study using this method very soon.

As we advance the science behind rapid, deployable, screening methods, we aim to shift the paradigm of how FDA screens products; increasing the effectiveness of our oversight. It’s an example of the creative measures we’re taking to keep harmful products out of the U.S. marketplace.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Melinda K. Plaisier, M.S.W., is FDA’s Associate Commissioner for Regulatory Affairs

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Read more: U.S. Food and Drug Administration and the International Mail Facilities

Visit FDA’s Flickr photo album: FDA and the International Mail Facilities

FDA’s New Pilot Program Aims for More Transparency about New Drug Approvals

By: Janet Woodcock, M.D.

When FDA approves a new drug, it has been found safe and effective when used under the conditions described in the label. Although this concept seems simple, the execution can be complex. Many factors are involved in weighing the benefits a drug can provide against the risks associated with its use. To that end, after we approve a new drug, we also want to make sure the scientific community and the public can understand why we approved it. This can help inform future drug development and, in turn, may facilitate the approval of additional safe and effective medicines.

Janet Woodcock, M.D.One way we explain the “why” behind a drug approval is by sharing information from the clinical trials that supported the approval decision. This information is usually discussed in FDA review documents authored by our physicians and other scientists. But often there is no complete description of the important efficacy trials, including the trial protocols, descriptions of any modifications made during the trial itself, and an explanation of all of the results. That’s why we launched the Clinical Data Summary Pilot in January. During the pilot, we will post key portions of the Clinical Study Reports (CSRs) – documents that sponsors create for FDA on each of their clinical studies. These portions would contain complete summaries of the study results, the protocol and protocol amendments, and the statistical plan. FDA plans to release these portions of the CSRs for the pivotal studies that supported the approval. The reports will be redacted by FDA to exclude confidential commercial information, trade secrets, and personal privacy information. FDA will not release patient-level data. Our goal is to share more directly complete summaries of the clinical trial information we have evaluated to determine whether a drug is safe and effective.

Currently FDA posts its review documents on line – material we call drug approval action packages. While the action packages include a significant amount of information pulled in from the sponsor’s application, that information is frequently separated into different sections and does not provide a complete summary of the results of any given study. This makes it difficult for academic researchers, regulators in other agencies, and other stakeholders to gain an in-depth understanding of the studies supporting approval. By providing the CSRs we hope to:

  • Enhance the accuracy of information used in scientific publications;
  • Increase stakeholders’ understanding of the basis for FDA’s approval decisions; and,
  • Inform physicians and other healthcare providers about the detailed results that regulatory decisions were based on.

The pilot will post the CSRs from up to 9 approved new drug applications of participating sponsors. We hope that reviewing the CSRs will help the scientific community better understand the information FDA used to evaluate an application and make an approval decision. At the end of the pilot we plan to seek comment from the public through a Federal Register notice to hear first-hand how the information was accessed and used. We hope to hear from a wide variety of stakeholders!

Our first pilot participant is Janssen Biotech for the approval of Erleada (apalutamide), the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer, as well the first to use the clinical trial result, or endpoint, of metastasis-free survival. Today we posted the CSR of the pivotal study with the regular action package. It’s a novel drug and we believe the CSR information, together with the FDA review, label, and other supporting documents, will facilitate a deeper understanding of how we reached our approval decision.

As an added benefit, our pilot program can help with global alignment, as our counterparts at the European Medicines Agency are similarly working to make information about their approvals more accessible and easier to understand.

The Clinical Summary Pilot is one of many efforts underway that require FDA working with industry to advance science. Now that it’s launched, we look forward to collaborating with sponsors who have an active or forthcoming NDA at FDA and who wish to participate in the pilot. For more information, visit the Center for Drug Evaluation and Research’s new pilot program page on our website.

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

Predicting Stem Cell Activity to Ensure Safe and Effective Therapies

By: Steven R. Bauer, Ph.D.

We can admire an individualist for being independent and self-directed. But these traits can be disruptive and troublesome when they’re shared by cells called mesenchymal stem cells (MSCs). When these cells (also called human multipotent stromal cells, or MSCs) are being prepared for use as therapies to treat human diseases or medical conditions, what’s important is predictability.

Steve Bauer

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

MSCs are called ‘multipotent’ because they can produce more than one type of specialized cell of the body, but not all types. For example, they will respond to various types of substances called growth factors by differentiating − or specializing − into cartilage, bone, or fat. MSCs may also help the body control inflammation by suppressing immune cell functions. These processes, immunosuppression and differentiation, justify MSC use in regenerative medicine clinical trials investigating their use to protect, restore, or repair tissues in the body.

But there’s a catch. As of January 2018, no MSC-based clinical trials have resulted in FDA-approved treatments. One significant challenge is ensuring that the MSCs will work together to perform the same desired function when they are administered to patients. So FDA scientists have been developing ways to predict whether specific populations of MSCs intended for use as a therapy are made up of individualists or sufficient numbers of team players. It turns out that MSCs are very responsive to their environment. In a lab-based manufacturing process, MSCs are exposed to an environment very different from the body — one that could change the way they respond to growth factors and one that could result in MSC preparations with lots of unexpected – and undesirable – individualism. Additionally, this might change the way the cells behave after they are put into a patient. For example, they might not suppress inflammation very well, might form tissue where it isn’t wanted, might form the wrong tissue, and even form tumors.

Recognizing these potential issues, FDA’s MSC Consortium is trying to develop methods that would predict with more certainty how manufactured or isolated MSCs will behave in patients.

My own laboratory has been developing ways to predict the behavior of MSCs that have been stimulated by growth factors. Our study has involved identifying changes in the size and shape (or morphology) of stimulated MSCs that may predict their future behavior. We call this approach functionally-relevant morphological profiling. It’s made possible by powerful imaging technologies that make it practical for us to routinely monitor and analyze the changes in the size and shape of many thousands of cells in a matter of hours.

Stem Cell lab photo

Human multipotent stromal cells undergo morphological changes after being stimulated by growth factors. FDA scientists have demonstrated that these changes can predict the ability of the cells to develop specialized properties that might support their use in regenerative medicine clinical trials.

Why are sizes and shapes so important to predicting MSC activity?

Think of it this way: you can tell the difference between basketball players and baseball players by looking at their uniforms. And you know what kind of behavior you can anticipate when they’re playing their respective games. Likewise, morphological profiling can help scientists predict whether stimulated MSCs are going to differentiate into specific cells that do specific tasks.

We’ve used this approach to follow MSCs that were stimulated to undergo a process called mineralization, the laying down of minerals that support bone growth. Previously, we had to wait for over a month to see if stimulated MSCs would mineralize. But, by using our profiling method, we can predict with over 90 percent certainty on day three whether the stimulated cells would mineralize by day 35.

In another study, we measured more than 90 morphological features — including their sizes and shapes, and the shapes of internal structures — of stimulated MSCs. Based on our knowledge of the changes in the size and shapes of MSCs that go on to develop immunosuppressive activity, we could predict which MSCs would suppress a certain type of immune cell (T cell). Immunosuppression makes these stimulated MSCs potentially effective treatments for inflammatory diseases, such as Crohn’s disease (chronic inflammation of the intestine), and multiple sclerosis (loss of nerve cell signaling).

In short, this type of profiling allows us to measure the extent to which there are similarities or differences in these cell preparations and to compare our findings with the profile of specific cell types associated with the biological functions we are seeking. That may help us predict whether the cells will perform the function we want if they are administered to patients.

MSC-based therapies are not available yet. But the ability to predict specific functions of different preparations of MSCs in the lab may be a big step toward getting safe and effective FDA-approved treatments to patients. We think our work is widely applicable to a variety of potential stem-cell based products, and it will help us determine if new techniques for stimulating MSCs to differentiate will produce safe and effective therapies.

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

The FDA Grand Rounds on March 8 features Steven Bauer discussing his research.

Brain Implant for Some Blind People Shows Benefits of FDA’s Breakthrough Device Program

By:  Malvina Eydelman, M.D.

FDA’s Breakthrough Devices Program is beginning to show important results for patients since it was established in late 2016 under the 21st Century Cures Act to help patients gain timely access to breakthrough technologies.

Malvina Eydelman

Consider Second Sight Medical Products Inc.’s Orion Cortical Visual Prosthesis System, which recently qualified for the FDA’s voluntary Breakthrough program.

Eligible technologies must provide more effective treatment or diagnosis for life-threatening or irreversibly debilitating diseases. In addition, there must be no approved or cleared treatment, or the device must offer significant advantages over existing approved or cleared alternatives.

The Orion is a brain implant for patients with blindness caused by damage to the optic nerve. With the designation, Second Sight qualified for interactive and timely communication with FDA, even before the Sylmar, Calif., company embarked on a clinical trial to study the device in patients. These early interactions resulted in the development of a flexible study design, review team support, and senior management engagement, all of which may allow a sponsor to evaluate complex, innovative technologies more efficiently.

And, when the development and evaluation of a technology or device is more efficient, beneficial medical devices may be able to reach the patients who need them sooner, even though they may be more complex or challenging to study because they are breakthrough products.

For Second Sight, early interaction meant that specialists across disciplines such as ophthalmology and neurology, representing the sponsor and FDA, could pose questions and solve problems. Oftentimes, early interaction can be especially helpful in solving any potential stumbling blocks – for instance, how best to go about measuring the benefits or risks of devices.

diagram of eye nerves

In normal vision, the optic nerve connects the eye to the brain. The optic nerve carries the electrical impulses (signals) formed by the retina (specialized nerve tissue at the back of the eye) to the visual cortex.

In normal vision, the optic nerve connects the eye to the brain. The optic nerve carries the electrical impulses (signals) formed by the retina (specialized nerve tissue at the back of the eye) to the visual cortex. The brain processes these impulses into the images that we perceive when we “see.”

There was no standard way to evaluate the benefits or risks of a device like the Second Sight Orion, which mimics the perception of light through a miniature video camera worn by a patient that transmits signals to an implant in their visual cortex.

Thanks to the breakthrough program, which builds on the FDA’s Expedited Access Pathway program, FDA was able to work closely with the company on a novel way to measure benefit and risk, clearing the way for the company to proceed with a small clinical trial, a necessary step before the company could seek approval for their device.

The Second Sight trial, approved by FDA’s Center for Devices and Radiological Health (CDRH), involves five patients at two sites, Baylor College of Medicine and the University of California in Los Angeles. The first patient received the implant on Jan. 30, 2018.

The Orion isn’t the only device to take advantage of the Breakthrough program. Since the Cures Act was passed, CDRH has received 94 requests for breakthrough status for devices treating a variety of conditions and granted 54, with patients as the ultimate beneficiaries.

In FDA’s Breakthrough Device Program, the interaction among specialists across disciplines representing the sponsor and FDA, could lead to devices that have the potential to change patients’ lives, without compromising safety or effectiveness.

In short, it shows FDA at its best, committed to patient access and willing to balance benefits and risks in a scientifically robust manner led by compassion and respect for the perspective of patients.

Malvina Eydelman, M.D., is the Director of the Division of Ophthalmic, and Ear, Nose, and Throat Devices, Office of Device Evaluation, at FDA’s Center for Devices and Radiological Health