FDA Budget Matters: Infrastructure to Support Robust Generic Drug Competition

By: Scott Gottlieb, M.D.

The FDA launched its Drug Competition Action Plan more than a year ago, with the aim of advancing policies that would promote robust generic drug entry as a way to foster competition and lower drug prices. Access to drugs is a matter of public health. And among the best ways to help consumers get broader access to medicines is through policies that help ensure branded drugs are subject to timely generic competition.

Dr. Scott GottliebOur work is far from finished. But the policies we’ve advanced are already showing benefits toward these goals. The benefits we’ve seen reinforce the fact that policy can be used as a vehicle to advance these purposes.

New resources have also helped advance our work. Owing in large measure to the FDA’s implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA), which funded critical enhancements to FDA’s generic drugs program, our staff eliminated the backlog of generic drug applications. In 2017, we also approved the largest number of generic drugs in the FDA’s history.

As part of GDUFA, as well as through our own new efforts, the FDA also has put policies in place to promote generic drug development in areas where there’s inadequate competition. This includes a focus on developing new guidance aimed at promoting development of generic versions of complex drugs. These are drugs that are often harder to copy. By advancing clear, objective, science-based guidance for developing generic copies of complex drugs, we hope to foster more competition.

And the FDA also has improved the efficiency and predictability of the generic drug review process to help promote more robust generic drug competition. For example, we’re prioritizing the review of generic drug applications for which there are no blocking patents or exclusivities. The aim is to promote competition so that there are at least four approved applications for each product (including the brand drug). Our data shows that there are significant price decreases once there are at least three generic drugs on the market. Our new policy will help ensure that there is robust competition across the market that will drive down drug costs to consumers.

In addition, we’re taking other new steps to curtail various forms of “gaming” by brand companies, where some sponsors sometimes adopt tactics that seek to delay entry of generic competition.

But we know that we need to do even more to promote access and competition. And so we’ve put forward a broader plan, as part of the President’s Budget, to achieve these aims.

Toward these goals, the President’s fiscal year 2019 Budget Request included $37.6 million to fund two initiatives that will help modernize aspects of our generic drug review process.

The first initiative will create a new review platform — the Knowledge-aided Assessment & Structured Application (KASA) platform — to modernize generic drug review from a text-based to a data-based assessment. The KASA will enable a structured review that will make the application review process more efficient, and allow deficiencies to be spotted earlier. This will allow the FDA to provide earlier feedback to generic drug makers that will, in turn, help to reduce multiple cycles of application review, one of our key aims and a primary focus of our overall efforts to speed market access to new generic medicines. Going through multiple review cycles is one of the primary reasons why the approval of generic drug applications is sometimes delayed many years. The new KASA system will help sponsors submit high-quality and more complete applications on the first submission. It will decrease the risk that applications will be refused for receipt and reduce the number of review cycles that applications undergo.

We anticipate that the new platform will allow more generic applications to be approved after the first cycle. This will promote timely generic entry and increase overall competition.

The new platform will also enable more efficient and robust knowledge management across different aspects of the FDA’s review process, helping reviewers capture and manage all of the information about products allowing for more seamless and effective product surveillance based upon quality and risk. This system will benefit both the agency and generic drug sponsors by increasing overall speed and efficiency of the pre- and post-market processes.

Having a structured template that completely replaces the current largely narrative-based review will allow for more consistent and predictable entry and analysis of data. Current assessments require manual review of the entire application. KASA will enable automated analysis of some portions of the application, which will save time, and ensure consistency.

The second initiative is aimed at promoting the more widespread use of existing generic drugs by looking for ways to keep generic drug labeling up-to-date with the latest information about each medicine’s risks and benefits. Generic drugs are generally required to have the same labeling as the brand drug they reference. And the burden to update the labeling with new safety and effectiveness information is typically born by the brand company.

However, when brand reference drug companies voluntarily withdraw their marketing applications, they also stop updating their labeling. When this happens, the FDA loses a key mechanism that the agency relies on as a way to update generic labeling. This can stymie the ability to modernize generic labels. In turn, when labels become out-of-date, providers may not have complete information about the full range of benefits and risks of the product. This can serve to diminish the use of these lower cost alternatives.

Consistent with our current authorities, which allow for certain types of labeling changes to continue to be made for generic drugs after the brand drug is withdrawn, this budget request will provide the funding to allow the FDA to assume more responsibility to help bring these drug labels up to date. We intend to launch this initiative initially for oncology products.

Our goal is to help ensure that doctors and patients have up-to-date information for these products. This will better inform clinical decisions regarding these medicines, and help promote more widespread use of low-cost, generic alternatives. By ensuring generic product labels are up to date, we’ll promote wider and more clinically optimal use of these drugs, which can save patients money.

We appreciate that the appropriations committees of both chambers of Congress supported this budget request in their appropriations bills. Congress has long recognized the need for — and importance of – investments in our generic drug program and efforts to promote generic drug use. The benefits of these initiatives are significant to the FDA’s modernization and efficiency. They’ll help advance a robust generic drug market that drives product competition and lowers drug prices.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Report Spotlights Achievements of FDA-Mexico Produce Safety Partnership

En Español

By: Stephen M. Ostroff, M.D.

The United States and Mexico are major trading partners in fresh produce. Each year, billions of dollars of fruits and vegetables move across the border. These include Mexican tomatoes, avocados, chilies, berries, cucumbers, lemons, and limes that reach U.S. consumers, as well as American apples, pears, grapes, onions, strawberries, potatoes, peaches and other produce that are sent to Mexico.

Stephen Ostroff, M.D.Both our countries benefit when we can help to ensure that these valuable commodities are safe for consumers on both sides of our borders. For that reason, the FDA-Mexico Produce Safety Partnership (PSP) was formed in July 2014, forging a stronger relationship between the FDA and Mexico’s National Agro-Alimentary Health, Safety, and Quality Service (SENASICA) and its Federal Commission for the Protection from Sanitary Risk (COFEPRIS).

We are pleased to share that our partnership is making real progress toward our goal of reducing the risk of foodborne illness associated with our produce trade. A new report, titled U.S. FDA-Mexico Produce Safety Partnership: A Dynamic Partnership in Action, provides some specific examples of this progress.

For example, the partnership recently worked to address the contamination of papayas grown in Mexico. In the fall of 2017, the FDA, SENASICA and COFEPRIS worked together to respond to four outbreaks of salmonellosis tied to Mexican-grown papayas. The Mexican agencies conducted inspections and sampled various farms and packing houses in several Mexican states, and shared their findings with the FDA. We were able to leverage their work and resources, along with the findings of our own outbreak investigation, to place four farms on import alert, thus providing information to the FDA inspectors who detained those products without having to physically examine them. SENASICA likewise implemented a regulatory response. In October 2017, Mexico strengthened its food safety oversight of papayas, which are subject to the Produce Safety Rule under the FDA Food Safety Modernization Act if they will be imported or offered for import in the U.S.

Chart - Mexico Exports of Fresh Produce to USAIn another example, in 2015, Listeria monocytogenes was detected in kiwi and apples grown in the U.S. and exported to Mexico. The exchange of information under the PSP, including the sharing of bacterial isolates and testing by both FDA and SENASICA laboratories, helped prevent more contaminated produce from entering Mexico. It also established a protocol for the future exchange of bacterial strains to improve detection and understanding of contamination.

These are just two of several instances in which the partnership has led to coordinated preventive activities in addition to enforcement activities that help to reduce the risk of foodborne illnesses and enable both countries to respond more rapidly to a potential or actual outbreak, better protecting both American and Mexican consumers.

Chart - U.S. Exports of Fresh Produce to MexicoBut the partnership has also provided benefits beyond individual outbreaks. Both countries have also been working collaboratively through working groups on institutionalizing approaches that reinforce preventive practices and rapid response to outbreaks. The groups have focused on information sharing, education and outreach, training, laboratory methods and processes, and how to respond effectively to outbreaks.

Looking to the future, the report outlines our five-year plan to increase engagement and the exchange of knowledge with key public and private partners. Through the partnership, we plan to also work on identifying common approaches for auditors and inspectors to better execute compliance and enforcement activities, and will create a strategy to conduct joint inspections and sampling. This will help both countries maximize their resources for the benefit of consumers on both sides of the border.

This is a long-term partnership. While there are differences in our systems, technologies, and environments, the U.S. and Mexico both want consumers to be confident in the safety of their food. By working together, we can achieve that goal.

Stephen M. Ostroff, M.D., is FDA’s Deputy Commissioner for Foods and Veterinary Medicine.

FDA’s New Efforts to Advance Biotechnology Innovation

By: Scott Gottlieb, M.D., and Anna Abram

Scientific advances in biotechnology, such as genome editing and synthetic biology, hold enormous potential to improve human and animal health, animal welfare, and food security. And researchers and companies based in the United States helped pioneer these technologies. They position the U.S. as a global leader of this rapidly growing and highly promising field.

Dr. Scott Gottlieb

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

To advance this progress, it’s key that the FDA adopt a regulatory approach to these technologies that’s as innovative and nimble as the opportunities that we’re tasked with evaluating.

FDA is committed to helping ensure the safety of biotechnology products, while also facilitating innovation by applying a risk-based regulatory approach that provides developers with regulatory clarity and predictability and maintains public confidence in our regulatory system.

And we’re taking some new steps to advance these goals. We know that products enabled by new techniques of biotechnology have the potential to significantly enhance public health.

For instance, these new methods can be used to alter animals to minimize or prevent their ability to spread human disease. Genome editing in animals and plants also can be used to produce human drugs, devices, or biologics, including tissues or organs for xenotransplantation. Scientists are also exploring editing the genomes of animals with the goal of improving the health and welfare of food producing animals and public health, for example by reducing their susceptibility to diseases like novel influenzas and resistance to zoonotic or foreign animal diseases.

Similar and equally beneficial applications of genome editing are currently being explored in food crops. These include our ability to develop disease-resistant plants and plants with increased resistance to environmental stress. Such advances can have many advantages to consumers, including better yields, more product variety, and healthier nutrient profiles.

Anna Abram

Anna Abram, FDA’s Deputy Commissioner for Policy, Planning, Legislation, and Analysis

We believe the FDA is uniquely positioned — with the expertise, experience, credibility and trusted scientific framework — to advance innovation and support the development of products with immense potential for public benefit. And we’re fully committed to these goals.

The breadth of FDA’s statutory authorities and regulatory framework allows us to comprehensively review the potential impacts of products on both human and animal health. For example, for genetically engineered animals, FDA evaluates not only the safety of food or drug products derived from that animal, but also the effect of the genetic alteration on the health of the animal. FDA has decades of experience successfully evaluating products of complex technologies, such as recombinant DNA-derived plant foods, medicines made with nanotechnology, and cellular and gene therapy products.

Moreover, because of the wide spectrum of products that we regulate, and the in-depth scientific and policy engagement that the agency has with innovators and counterpart regulatory agencies around the world, FDA can help facilitate the progression of research and development. For example, we’re focused on the timely transition of technologies from animal research models to products intended for use in humans. As our knowledge of genome editing applications increases over different product areas, we expect to build on those even greater synergies and increase our understanding to help with assessments of risks to human and animal health.

FDA will continue to apply a risk-based framework grounded in sound science to evaluate products of plant and animal biotechnology, and our framework will continue to evolve as science advances and experience with these technologies grows. We also look forward to working with stakeholders to help understand current scientific information and describe challenges and gaps in regulatory science that are important for our regulatory decision-making. We’re also going to take new steps to help developers understand their responsibility to ensure product safety and we’ll identify ways to help reduce unnecessary regulatory burden and undue barriers to bring potential beneficial products to commercialization while ensuring their safety.

Protecting and promoting public health is our mission and we’re taking steps to help ensure the safety (and as applicable, effectiveness) of products that can benefit patients and consumers, while supporting innovation and sustaining public confidence.

To help advance these goals, in early May, FDA formed a new Biotech Working Group. This Working Group is comprised of representatives from multiple FDA centers and offices. In the coming months, we’ll release an Action Plan that lays out the steps we intend to take to ensure that we have a flexible regulatory framework for evaluating the safety of products that also supports plant and animal biotechnology innovation.

Our actions will focus on three key areas:

First, advancing and protecting public and animal health by promoting innovation through an efficient and predictable science- and risk-based regulatory framework; second, strengthening public outreach and communication through strong, effective and transparent engagement with stakeholders; and third, increasing engagement with domestic and international partners through coordinated and collaborative actions to support regulatory alignment and efficiency.

The Working Group’s efforts are well underway and we’ll be providing more details soon.

Finally, we’ll continue the work we began to modernize the regulatory system for biotechnology, including the effort in 2015 with USDA and EPA to ensure preparedness of federal regulatory agencies for future products of biotechnology; as well as the implementation of the 2018 recommendations of the Interagency Task Force on Agriculture and Rural Prosperity. We’ll also continue to build on our Formal Agreement with the USDA, which commits the FDA and USDA to better align and enhance our efforts to develop regulatory approaches to biotechnology.

We’re committed to all of these goals, and we look forward to working with the Interagency Task Force and sharing more of our important work with our stakeholders going forward.

FDA is taking concrete and proactive steps to help ensure the safety of plant and animal biotechnology products, while promoting innovation and enhancing public and market confidence in FDA’s regulation of these products at home and abroad. We recognize the tremendous opportunities offered by this new technology. We’re committed to developing a framework that allows these innovations to safely advance, to fulfill the potential envisioned by those who are pioneering these approaches, and to inspire public confidence in these methods.

The advance of these technologies holds significant public health promise. Unlocking their full potential and competitiveness depends on the trust we build now and in the years to come.

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

Anna Abram is FDA’s Deputy Commissioner for Policy, Planning, Legislation, and Analysis

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

FDA Proposes Process Modernization to Support New Drug Development

By: Janet Woodcock, M.D.

The staff of the FDA’s Center for Drug Evaluation and Research (CDER) always tries to utilize cutting-edge science and up-to-date process management, befitting our stature as the global “gold standard” in drug regulation. Maintaining that standard requires us to keep up with evolving technology and the latest scientific, medical and regulatory advances. Current factors impacting drug development include the genomic revolution, the rise of targeted therapy, the availability of digital health data, the focus on patient involvement, complex drug-device combinations, globalization of drug development and harmonization of international standards. To be successful drug regulators, we reach well beyond the borders of the FDA. We collaborate with a wide variety of medical and scientific organizations such as those in biomedical research, the pharmaceutical industry, academia, global organizations and other regulatory agencies. Importantly, these collaborations also extend to patients and their caregivers and advocacy groups. All these interactions are critical to successful drug regulation.

Janet Woodcock

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

I have recently proposed changes to CDER’s new drug regulatory program. These changes are intended to free up resources so that our scientists and physicians have more time to focus on drug development, particularly for unmet medical needs, and on the multiple collaborations needed to make sure candidate drugs are developed and assessed properly, with appropriate input from external scientists, expert physicians and patient communities. The proposals include regulatory and review process changes, as well as organizational restructuring. We also intend to strengthen the support structures, including personnel and Information Technology (IT), that underpin the regulatory process.

As always, our goals are to expand access to safe and effective new drug therapies, conduct efficient and comprehensive safety surveillance, and ensure that accurate information about those drugs is available.

Here are some highlights of our proposal:

  • Recruiting the best and brightest individuals from many disciplines – Scientific leadership is vital for our ongoing success. After hiring talented scientists, we need to develop long-term career paths for them so they can become our next generation of seasoned leaders. Our recruitment efforts, strengthened by hiring incentives and other provisions in a new law called the 21st Century Cures Act, will help provide the staffing necessary for continued success in supporting the development and approval of innovative new therapies that meet previously unmet medical needs.
  • Enhancing our focus on multidisciplinary teams – Setting standards for approval and assessing innovative new drugs requires large and well-coordinated teams of highly trained professionals with many different types of expertise. CDER’s Office of New Drugs (OND) has a staff of more than 1,000 individuals who work together in many ways. New drug development and approval also requires coordination across many offices within CDER, including the Office of Translational Sciences (OTS), the Office of Surveillance and Epidemiology (OSE) and the Office of Pharmaceutical Quality (OPQ). A central component of our proposed changes involves stronger integration of our talented staff so they can better work together – within and across offices, a concept we refer to as “integrated assessment.” Previously, CDER reviewers would seek consults from specialists in other scientific disciplines (as issues were identified in the course of review). For greater collaboration, a cross-disciplinary team will be assigned to work on a new drug application at the outset.
  • Prioritizing operational excellence – Staff throughout CDER face a staggering pace of work, much of which involves attention to detailed administrative procedures. Our proposal would centralize project management functions within OND. CDER currently has 19 separate review divisions that regulate drugs. Over time, many divisions have developed procedures specific to their areas of review. We are proposing a single and consistent process: One organization with one process. Our aim is to enable our scientific and clinical experts to focus on what they know best – science and medicine – and our regulatory experts to manage the many processes we conduct.
  • Improving knowledge management – The information we process in our work is vast and diverse. Knowledge management is essential to control the data we receive from outside sources as well as what we generate from within the FDA. We plan to enhance our IT capabilities and access to information to better enable the storage and management of the collected experience of our scientific review staff. Accurate historic information from many past drug reviews is essential to informing current and future reviews – and to assure consistent regulatory decision-making. We want to make it easy for staff to find and use scientific and regulatory data, information and precedents. We’re also proposing changes that will increase the number of offices that oversee our review divisions from five to nine – and we’re envisioning 30 review divisions within those offices – up from our current 19. In addition to enabling greater efficiency, these envisioned changes will help us to better understand the diseases intended to be treated by the drugs we evaluate for approval – another way we aim to enhance our knowledge management.
  • Emphasizing the importance of safety across a drug’s lifecycle – Safety remains a key component of our new plans. We will work to establish a unified post-market safety surveillance framework to monitor the benefits and risks of drugs across their lifecycles, both before and after approval.
  •  Incorporating the patient voice – Patients are the FDA’s most important stakeholder and our vision includes incorporating the patient voice in modern patient-focused drug development. In fact, all the elements in our proposal have a common thread: they ultimately serve to improve health for patients.

Last year, CDER approved 46 novel drugs, 100% of which were reviewed on time – fulfilling our commitments under the Prescription Drug User Fee Act (PDUFA). Our system is effective, but we can always improve. Our new plan is designed to help us generate efficiencies so we can build stronger external collaboration capabilities and enhanced support for the scientific, clinical and technological innovation necessary for new drug therapies.

This proposal to modernize our new drug review processes will help us maintain and advance our global leadership, and better support our deeply committed staff. Both science and technology are changing at a blistering pace, and we need to keep up. Patients depend on the FDA to do what is necessary to provide access to safe and effective drug therapies. They take FDA-approved drugs because they trust us. While we have many steps to go before we can realize these changes, we feel confident that they will reinforce that trust and align us for ongoing success.

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

Statement from FDA Commissioner Scott Gottlieb, M.D., on proposed modernization of FDA’s drug review office

 

 

FDA Update on Traceback Related to the E. coli O157:H7 Outbreak Linked to Romaine Lettuce

By: Scott Gottlieb, M.D., and Stephen Ostroff, M.D.

The FDA continues to investigate the outbreak of E. coli O157:H7 infections associated with romaine lettuce from the Yuma growing region. Any contaminated product from the Yuma growing region has already worked its way through the food supply and is no longer available for consumption. So any immediate risk is gone. However, the FDA is committed to investigating the source of the outbreak and working with industry to help prevent similar events in the future.

Dr. Scott Gottlieb

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

This is a serious and tragic outbreak. And we’re devoting considerable effort to identifying the primary source. We’ve made progress in recent weeks toward this goal. This outbreak of E. coli O157:H7 illnesses is the largest in the United States in more than 10 years. As of today, it has affected 172 persons in 32 states, and it is anticipated the numbers will be updated on Friday. Tragically, 45 percent of these ill people have been hospitalized, and one has died. And 20 of these people have developed hemolytic uremic syndrome (HUS), one of the most serious complications that can occur with E. coli O157:H7 infection.

These statistics reflect the severity of this particular foodborne illness. The kidney damage that’s associated with HUS can require temporary dialysis and the kidneys may never fully recover. For these reasons, anytime outbreaks caused by this pathogen occur, we need to find the root cause of the contamination and determine what went wrong. We need to relay these findings to industry so that measures can be put in place to prevent it from happening again.

The FDA’s investigators are actively searching for answers as to the source of this outbreak, and what steps can be taken to prevent it from recurring in future growing seasons. In the current outbreak, illness has generally been linked to the consumption of chopped romaine lettuce. The lettuce was generally consumed at restaurants or purchased at markets. In one cluster of illnesses at an Alaska correctional facility, the prison received and served whole head romaine lettuce rather than chopped and bagged romaine.

The FDA and our state partners have been involved in extensive traceback efforts of the romaine lettuce that was likely consumed by those who became ill. Traceback involves working backwards from the point of consumption or purchase of the product through the supply chain. It often includes investigating the multiple steps along the way. These steps can include suppliers, distributors and processors where the lettuce was chopped and bagged, and then back to the farm or farms that could have grown the lettuce that ended up in those bags. It’s a labor-intensive task. It requires collecting and evaluating thousands of records; and trying to accurately reproduce how the contaminated lettuce moved through the food supply chain to grocery stores, restaurants and other locations where it was sold or served to the consumers who became ill.

Stephen Ostroff, M.D.

Stephen Ostroff, M.D., FDA’s Deputy Commissioner for Foods and Veterinary Medicine

Our traceback efforts are designed to find points of convergence from several well identified clusters of illness with a common point of exposure, such as a restaurant or grocery store. This means that as we draw lines for each cluster from one point in the supply chain to another point, we look for places where the lines will intersect and lead back to a common location. This can then help clarify where the contamination may have taken place.

We usually do this for clusters of ill individuals that occurred in different parts of the country; since lettuce in one part of the country may not follow the same pathway as lettuce in another part of the country. When that point of convergence is identified, efforts can then focus on how the contamination occurred at that location.

We’ve conducted traceback activities for many of the illnesses identified in this outbreak. We’ve used this information to create a traceback diagram that we’re releasing today. The diagram does not include tracebacks for all 172 cases. Rather, it focuses on settings where there were several well-documented clusters of cases. As additional traceback information is received, we anticipate the diagram will be updated.

As can be seen in the diagram, in the current outbreak, and based on the information we have to date, there are still no obvious points of convergence along the supply chain. There is only one straight line back to a single farm. And that particular instance involves the whole head lettuce served in the Alaska correctional facility, since it was not processed and was not mixed with lettuce from multiple farms, as seen in other parts of the traceback.

In these other tracebacks in the diagram, there are different suppliers, distributors and/or processors. These pathways lead back to different farms, sometimes many farms, where possibly contaminated lettuce could have been harvested during the timeframe of interest. The only point of commonality in our traceback efforts to date is that all of the farms are located in the Yuma growing region. This region is where a large portion of the romaine lettuce supply in the United States comes from during the winter months.

What does this traceback diagram tell us?

It says that there isn’t a simple or obvious explanation for how this outbreak occurred within the supply chain. If the explanation was as simple as a single farm, or a single processor or distributor, we would have already figured that out. The traceback diagram does show us that the contamination with E. coli O157:H7 was unlikely to have happened near the end of the supply chain (such as at a distributor) because there are no common distributors among the places that received and sold or served contaminated lettuce. The contamination likely happened at, or close to, the Yuma growing area.

Our task now is to investigate what happened. We are actively evaluating a number of theories about how romaine lettuce grown on multiple farms in the same growing region could have become contaminated around the same time. It’s possible that contamination occurred on multiple farms at once, through some sort of environmental contamination (e.g., irrigation water, air/dust, water used for pesticide application, animal encroachment). Another possibility is that it happened just after the lettuce left the farm. We are examining all possibilities and as we investigate we learn more about a potential common source we will communicate this information with growers and consumers. But the source and mode of contamination may remain difficult to identify.

Our efforts are complicated by the fact that romaine lettuce is a perishable commodity with a short shelf life of a couple of weeks. None of the lettuce that likely made people sick was available for testing because of the time between the incubation period of E. coli O157:H7 (the time between exposure to the lettuce and the onset of illness) and the time it takes to seek health care and collect specimens from ill people, test those specimens, report the illnesses to public health officials, fingerprint the pathogen to make sure it is part of the outbreak, and interview the ill people to identify where and when they were exposed.  By that time, the lettuce they ate which could have made them ill is long gone.

Similarly, the lettuce growing and harvesting season in the Yuma growing region was essentially over by the time the outbreak was recognized in April, and harvesting has since ceased. That is why we, and our colleagues at the Centers for Disease Control and Prevention, have said that there’s no longer any romaine lettuce from the Yuma growing region available for purchase or consumption.

Romaine lettuce production in this area is now idle until later in the year. This makes it difficult to find places where the E. coli O157:H7 organism that caused the outbreak may have been hiding.

We have no evidence that romaine lettuce from other growing regions have been a part of this outbreak.

The FDA is looking at all possibilities for how the contamination may have caused such a large outbreak. This work will continue. In these efforts, we’re collaborating with outside experts who may have insights, ideas, or suggestions. This includes working with farmers, technical experts, the lettuce processing industry, state partners, and others. It also includes on-site assessments. Through such assessments we may be able to find a possible explanation so that steps can be taken to prevent this problem from recurring.

We’re committed to these efforts, and finding the root cause of this outbreak.

Romaine lettuce is one of the most popular types of lettuce in this country. We want American consumers to be confident in the quality and safety of the lettuce they consume. In addition to working to identify the source and mode of contamination, we will also continue working after the outbreak to evaluate what happened and how lessons learned can be used to provide feedback to industry on best practices and areas to work on. These include better tools to more efficiently and swiftly traceback commodities like lettuce through the supply chain, and better ways to standardize record keeping. We also want to explore the use of additional tools on product packaging that could improve traceability. For example, could QR codes be used to provide additional information that could help consumers more easily identify which lettuce should be avoided and which lettuce is ok to eat?

We’re also working with the leafy greens industry and technical experts to explore methods to grow and process lettuce in ways that further reduce the risk of outbreaks. We live in an era of unprecedented innovation and technology, and we want to bring more of that innovation and technology to bear to help solve this problem and ensure consumer confidence in healthy fruits and vegetables.

Food safety is one of the highest priorities at the FDA. This outbreak is a clear illustration of why that’s the case. It shows the terrible consequences when something goes wrong.

This outbreak marks the importance of moving forward with the Food Safety Modernization Act’s Produce Safety Rule. That rule is designed to implement practical measures to prevent contamination of fruits and vegetables at the farm. This rule is being implemented in close collaboration with our state partners and with our federal partners at the U.S. Department of Agriculture.

State partners will do the vast majority of routine inspections under the Produce Safety Rule. They are often the most familiar with their farming communities and growing and harvest practices. These inspections are slated to begin next year. We’re currently in the process of finalizing the guidance and training farmers throughout the country and those who ship produce to the U.S. on the rule’s requirements.

We believe that the measures outlined by the Produce Safety Rule, when fully implemented, will reduce the chance of an outbreak similar to the one we just experienced. That’s our goal, and our commitment, to the American public.

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

Stephen Ostroff, M.D., is FDA’s Deputy Commissioner for Foods and Veterinary Medicine

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

The FDA Issues Draft Guidance About the Absorption of Active Ingredients Being Considered for Inclusion in Over-the-Counter Drug Products Applied to the Skin and Marketed without Approved Applications

By: Theresa M. Michele, M.D.

All drugs have some risk — even over-the-counter (OTC) drugs available without a prescription — and the FDA is always taking steps to help ensure their safety. When you take a pill, you generally expect that some of the active ingredient gets into your body, but what about when you apply a topical product to the skin? How much of the product gets absorbed through the skin and enters the bloodstream, and is it safe? At the FDA, we’ve been working to better understand the absorption and safety profile of topical OTC products such as sunscreens and topical antiseptics. We are particularly interested in learning how these products affect vulnerable populations such as children, the elderly, and pregnant and breastfeeding women.

Theresa Michele, M.D.Until recently, there was little data available to demonstrate the extent to which topical OTC drugs are absorbed into the bloodstream after application, and whether there are any long-term consequences of this. In fact, many topical OTC products were first marketed when these products were thought not to be absorbed through the skin and when there were no effective methods available to measure absorption. Now, better measurement tools are available, and research indicates that topical drugs can indeed be absorbed into the body through the skin.

Consequently, the FDA has been generally encouraging manufacturers to collect data on the potential risks of a topical drug when used according to the maximum limits of the product’s instructions, what we call Maximal Usage Trials or MUsT studies. Most recently we included MUsT studies among the list of safety and efficacy studies recommended for sunscreen active ingredients being evaluated under a new marketing pathway established by the Sunscreen Innovation Act in a final guidance for industry in November 2016. Now we are issuing draft guidance that, when finalized, will provide recommendations to industry on how to design and conduct MUsT studies for topical active ingredients that are under consideration for inclusion in an OTC monograph.

The draft guidance includes discussions about how to study the topical active ingredient’s effects on specific subgroups of vulnerable patients like children and the elderly. The studies require a relatively small sample of patients for a short period of time and should not be overly burdensome. In fact, this draft guidance reflects the same safety and efficacy standards that have applied to all drug products marketed under the OTC Monograph System for more than 40 years.

Absorption studies have contributed significantly to the FDA’s knowledge of the safety of topical prescription products. Applying a similar level of safety research to active ingredients being considered for inclusion in an OTC monograph to that which currently exists for prescription products can help the FDA determine whether these ingredients should be included in OTC products marketed without approved applications.

Theresa M. Michele, M.D., is the Director of the Division of Nonprescription Drug Products, Office of New Drugs, at the FDA’s Center for Drug Evaluation and Research

Addressing Needs of Patients While Stemming the Tide of the Opioid Crisis

By: Scott Gottlieb, M.D.

The biggest public health crisis facing FDA is opioid addiction. Not a day goes by in my role at FDA without hearing stories of the emotional, physical, and financial toll this epidemic is taking on Americans.

Dr. Scott GottliebFDA is committed to making every possible effort to stem the tide of this crisis. A little over a year ago, I announced a redoubling of that commitment through the formation of the Opioid Policy Steering Committee (OPSC). This group, comprised of the agency’s most senior leaders, was tasked with developing new approaches to impacting this crisis. One overarching goal of the committee was to develop new policy solutions to reduce overall exposure to opioids, prevent new addictions, and support the development and use of better FDA-approved medications to treat those with opioid use disorder.

Part of this effort resulted in two important actions led by the OPSC. In September 2017, FDA solicited public input on how the agency’s authorities could be used to address the crisis. A meeting in 2018 was held to solicit specific input on how FDA’s actions could assist more appropriate prescribing.

These actions generated a wide range of feedback, and they included the important voices of the patients. The feedback we received affirmed for us that as we address this crisis, we wouldn’t lose sight of the needs of Americans living with chronic pain or coping with pain at the end of life.

We’ve heard the concerns expressed by these individuals about having continued access to necessary pain medication, the fear of being stigmatized as an addict, challenges in finding health care professionals willing to work with or even prescribe opioids, and sadly, for some patients, increased thoughts of or actual suicide because crushing pain was resulting in a loss of quality of life.

We’re focused on striking the right balance between reducing the rate of new addiction while providing appropriate access to those who need these medicines. In some medical circumstances, opioids are the only drugs that work for some patients. This might include patients with metastatic cancer or severe adhesive arachnoiditis. Today, to address these goals and challenges, we announced an upcoming meeting focused solely on the needs of those suffering from chronic pain.

This public meeting is an opportunity for FDA to hear directly from patients, including adult and pediatric patients. We want to hear their perspectives on the impacts of chronic pain, their views on treatment approaches for chronic pain, and the challenges or barriers they face accessing treatments. 

As FDA learns more about the types of chronic pain that are managed with analgesic medications such as opioids, acetaminophen, NSAIDs, antidepressants, other medications, and non-pharmacologic interventions or therapies, we gain valuable insight into strategies FDA can adopt to help strike the right balance between policies that allow appropriate prescribing for those in true need of these medicines and preventing unnecessary exposure to opioids that can increase the rate of new addiction.

For example, one idea FDA is considering is the development of a strategy for encouraging medical professional societies to develop evidence-based guidelines on appropriate prescribing for different acute medical indications, how to assess the scientific support for these guidelines and impact on prescribing behavior, and considering the possibility of incorporating new prescribing information in opioid analgesic labeling. We believe such guidelines could encourage the use of an appropriate dose and duration of an opioid for some common procedures and promote more rational prescribing, including that patients are not being under prescribed and patients in pain who need opioid analgesics are not caught in the cross hairs. In short, having sound, evidence-based information to inform prescribing can help ensure that patients aren’t over prescribed these drugs; while at the same time also making sure that patients with appropriate needs for short and, in some cases, longer-term use of these medicines are not denied access to necessary treatments. We will take the first steps toward developing this framework in the coming months, with the goal of providing standards that could inform the development of evidence based guidelines.

We’re also going to be creating a new series of guidance documents focused on laying out an efficient, modern pathway for development of drugs targeted to the treatment of various types of pain. These will be up-to-date policies that focus on the treatment of specific areas of pain. This will allow us to tailor our requirements to the indications for which pain treatments are being developed. The aim will be to modernize FDA’s current guidance on analgesic drugs, to promote more new drug innovation.

As we address the opioid crisis with new approaches, and take more vigorous steps to confront addiction, we can’t lose sight of patients who have appropriate needs for these medicines. This meeting is one of many steps we’re taking to make sure we protect the needs of patients with chronic and acute pain even as we take new actions to reduce overall prescribing and dispensing of opioid medicines.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Emerging issues of misuse and abuse of OTC loperamide challenge FDA to address a new turn in the opioid addiction crisis, while maintaining access for patients

By: Scott Gottlieb, M.D.

The opioid epidemic has reached tragic proportions. Yet it continues to take many new, and troubling turns. If there’s one lesson we’ve learned from this crisis, it has been the ability of the mounting abuse and misuse to evade our interventions. This history challenges us to deal more quickly and aggressively when new aspects of the addiction crisis emerge. For example, we’re seeing a crisis that began largely with the misuse of prescription opioids evolve into an epidemic that’s increasingly being driven by an influx of street drugs like illicit fentanyl and heroin. We must be alert to these new patterns of abuse and misuse of different drugs.

Dr. Scott GottliebOne such concern relates to the inappropriate use of loperamide – an FDA-approved drug to help control symptoms of diarrhea, including travelers’ diarrhea. Loperamide is sold under its over-the-counter (OTC) brand name Imodium A-D, as store brands and as a prescription drug. Loperamide is an opioid agonist, and it’s safe and effective at its approved doses. The drug acts locally, inside the gut, to treat the symptoms of diarrhea.

But when loperamide is abused and taken at extremely high doses, some of it can cross the gut lining, giving users an opioid like “high.” We’re aware that those suffering from opioid addiction see loperamide as a potential alternative to manage opioid withdrawal symptoms or to achieve euphoric effects. But at these very high doses, it’s also dangerous. We’ve received reports of serious heart problems and deaths, particularly among people who intentionally misuse or abuse high doses. Sometimes people are using as much as 100 times the recommended dose.

As with other new patterns of abuse and misuse related to the opioid crisis, the FDA acted with urgency to address the issues related to loperamide. We’ve issued a Drug Safety Communication and worked with sponsors to revise both prescription and OTC drug labeling to warn about serious heart problems associated with high doses of loperamide. We’re also encouraging changes to packaging of the OTC products to help deter abuse, such as the use of blister packs. And we’ve reached out to online sellers of these products to inform them of the public health risks and ask for their attention to the issue and their commitment to stop selling large quantities of the product.

At the same time, we’re very mindful of balancing benefit and risk and the needs of patients in our mission to promote and protect public health. We recognize that there are important and legitimate uses of loperamide, including for patients suffering from chronic diarrhea in adults associated with inflammatory bowel disease (IBD), including Crohn’s disease. We need to take the additional steps I outlined to address the abuse and misuse of loperamide. But preserving appropriate access to this treatment for patients who need it is something we take seriously. So we’re seeking input from the patient community on how best to strike this careful balance. In order to ensure that we don’t create access issues for such patients, we’re proceeding in a step-wise, deliberative fashion to ensure that the actions we take in relation to OTC loperamide use are reasonable and scientifically sound, and that these actions are necessary to achieve safe use of the drug and to address the issues of abuse and misuse.

It’s also the case that loperamide is available by prescription for patients who require maintenance therapy for chronic disease and are under the care of a health care provider.  We’ve also heard concerns that the changes to packaging could drive up the price. Affordability of medicines is one of my key concerns. We’re carefully evaluating the impact that our actions could have on the cost of this medicine. Based on our analysis to date, we don’t expect that the steps we’re taking will have much, if any, impact on cost, given that loperamide is available as a generic drug and manufactured by a range of competitors.

OTC loperamide is currently approved in packages of 8 to 200 tablets, which are often sold in multipacks of more than 1,000 tablets at a time. This is more than a three-year supply if the drug is taken according to the product label. Evidence suggests that reasonable packaging limitations and unit-of-dose packaging may reduce medication overdose and death.

Therefore, as we announced in January, the FDA has sent letters to the OTC brand manufacturers requesting that they implement packaging changes. We’re currently evaluating the maximal package size appropriate for OTC use, and plan to take into account data manufacturers provide on consumer use and needs; current OTC labeling and indications; the dose-response relationship of loperamide to cardiac events and known adverse event data; and importantly, the feedback of patients who rely on this medicine.

The agency is discussing implementation timeframes to ensure that manufacturers can continue to meet consumer need while package reconfiguration is taking place.

I also recently wrote to online distributors asking them to take two voluntary steps to help reduce the risks of loperamide abuse and misuse. First, I asked them not to sell bundled amounts of loperamide that contain more than one package of the drug. And second, I asked them to ensure that consumers can easily access and read the product labeling and warnings for drugs sold on shelves or on websites before purchase.

We appreciate the responsiveness from both the manufacturing and retail industry. Several companies are already committing to implement these packaging changes or purchasing safeguards. For example, Walmart has already taken a number of concrete steps to address the FDA’s request. These include ensuring that all loperamide products sold by Walmart/Sam’s Club have the product labeling clearly visible on the website; limiting purchase of 200 count tablet products in stores or online to a single bottle; and, moving the sale of bundled products at Sam’s Club behind the pharmacy counter and limiting sale to a single package. Walmart is also working to remove all loperamide “marketplace products” (i.e. products sold on their website by a third-party vendor) from their website. These vendors appear to be the primary source of bundled products and products that do not display product labeling on the Walmart site.

Amazon also has already taken some steps to address our recommendations and eBay has stated publicly that they also intend to follow our recommendations. We continue to work with other retailers to encourage them to take steps to help prevent abuse and misuse of loperamide.

All of us must do our part to address the public health challenges posed by the opioid addiction crisis.

The FDA will continue to assess the loperamide safety issue, and monitor adverse events, scientific literature, and data submitted by the public. We want to ensure that the steps we’re taking improve the safety of loperamide without limiting OTC access for consumers using the product according to labeling. The FDA’s actions to address drug misuse and abuse must be informed by an understanding of the complex social environment in which changing patterns of drug consumption occur. The agency is committed to addressing emerging issues of abuse and misuse while taking steps to safeguard the needs of patients who depend on these medicines.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Spring Unified Agenda: FDA’s Anticipated Upcoming Regulatory Work

By: Scott Gottlieb, M.D.

Today, the federal government published the Spring 2018 “Unified Agenda of Federal Regulatory and Deregulatory Actions” (Unified Agenda), which provides federal agencies with the opportunity to update the American public on our government’s regulatory priorities.

Dr. Scott GottliebFor its part, the U.S. Food and Drug Administration (FDA) continues to make swift progress on our regulatory agenda, which reflects the key strategic priorities of the FDA and the Administration. Our regulatory agenda reflects our adherence to science based decision making and our commitment to our mission to protect and promote public health.

I provided a detailed overview of many of our proposed regulations for 2018 around the release of the Unified Agenda last fall – most of which we continue to take forward. I’d like to take this opportunity to highlight for you some of FDA’s new contributions to the Spring Unified Agenda.

Addressing the Nicotine Addiction Crisis

Smoking remains the leading cause of preventable death and disease. And too many young people are still being initiated on tobacco products, and becoming addicted to nicotine.

We’ve taken steps to address the morbidity and mortality associated with tobacco through the comprehensive plan that we announced last summer. We’re considering regulating the nicotine levels in combustible cigarettes, to render cigarettes minimally or non-addictive.

At the same time, we’re continuing to advance our framework for how we’ll regulate both novel nicotine delivery products, such as e-cigarettes, and traditional tobacco products. One goal of our efforts is to encourage innovation of less harmful products. We will ensure that all tobacco products, whatever their nicotine content or delivery mechanism, are put through an appropriate series of regulatory gates to maximize any public health benefits and minimize harms.

To that end, we will be proposing a new regulation to establish product standards for electronic nicotine delivery systems or ENDS. The proposed standard will, among other things, address the levels of toxicants and impurities found in nicotine, propylene glycol, and vegetable glycerin e-liquid, as these toxicants and impurities can cause death or other adverse health effects.

As part of our comprehensive plan, we’re also working hard to prevent access to products we believe are adulterated or misbranded. We recently joined with the Federal Trade Commission to issue 13 joint warning letters to companies that misleadingly labeled or advertised nicotine-containing e-liquids as kid-friendly food products (juice boxes, candies, and cookies).

As part of our comprehensive approach, we’ll also be proposing new regulations to establish requirements for the administrative detention of tobacco products encountered during an inspection that an officer or employee believes to be adulterated or misbranded. These steps will allow us to more effectively block the distribution and use of products that are ultimately found to be violative, including products that are misbranded because their labeling or advertising causes them to resemble kid-friendly foods.

Modernizing and Harmonizing Standards

As part of our efforts to continue to ensure efficiency of existing regulations, we will be taking another step to modernize medical device regulation, by proposing a new regulation to replace certain aspects of existing Quality System regulations with specifications of an international consensus standard for medical device manufactures (ISO). This rule, if finalized, will harmonize domestic and international requirements and modernize the regulation to make it more efficient for manufacturers of medical devices seeking to sell their products globally, while also continuing to ensure they adhere to high, internationally-accepted quality systems.

Enhancing Clinical Trial Processes

The Spring Unified Agenda also will propose rules to support the clinical trial process, for instance regarding the requirements for cooperative research. We’re proposing a new rule that would, in most cases, allow any institution located in the U.S. that is participating in a multisite cooperative research to be able to rely on approval from a single institutional review board.

We also will be issuing a proposed rule to update the agency’s investigational new drug application regulations to define and clarify the roles and responsibilities of the various persons engaged in clinical investigations to enhance protection of the rights, safety, and welfare of subjects and better ensure the integrity of clinical trials.

In addition to the new proposed regulations I’m highlighting here, FDA will continue to pursue a multitude of other important rules across the Agency, such as taking forward our compounding policy priorities and advancing food and drug safety initiatives. Moreover, we continue to remove outdated rules or reconsider proposed rules in light of our evolving policy priorities. I want to note, however, that some previously identified regulations that weren’t included in this Unified Agenda may still remain FDA priorities. Just because you don’t see them here, doesn’t mean that we don’t intend to continue advancing some prior policy proposals.

While we continue to have a robust regulatory agenda for the coming year, regulation is only one way in which we can foster our mission and improve public health. We’ll continue to tackle many additional priority areas through guidance documents and other policy efforts. These areas will include efforts to reduce the cost of drugs by encouraging competition – including in biosimilars; spurring innovation across medical products; battling obesity through our various nutrition initiatives; and, continuing to attack the opioid addiction crisis facing our country.

I look forward to keeping you updated as we progress toward these goals.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

The FDA is Asking for More Information on Application Forms — Here’s Why That’s Good for Innovation and Improving Health

By: Christopher Leptak, M.D., Ph.D.

To be most effective, electronic health records (EHRs) use a systematized and standardized nomenclature for the hundreds of thousands of clinical terms that characterize patient care. This helps to ensure consistency from EHR to EHR and allows these records to be usable from healthcare entity to health care entity, a concept known as interoperability. This nomenclature, used by both industry and the federal government, is called SNOMED CT.

Christopher LeptakRecognizing the value of such a comprehensive and standard clinical healthcare terminology, the FDA is also embracing the use of SNOMED CT to characterize disease names for its drug development pipeline and for FDA-approved products. The forms drug developers submit in their product applications now request use of this nomenclature. Forms for Investigational New Drugs (INDs) (FDA Form 1571) and New Drug Applications (NDAs), Biologic License Applications (BLAs) and Abbreviated New Drug Applications (ANDAs) (FDA Form 356h) have been revised to request additional supplemental systematized information using the SNOMED CT nomenclature to state for what disease or diseases the drug in the application is indicated.

Here’s why the new nomenclature is good for innovation and improved health: By clearly identifying the intended uses or indications for a potential new drug, SNOMED CT enabled metrics will better inform review activities and aid in consistency in the FDA advice for applications with similar indications. Newly systematized indication information will allow the FDA to better identify areas of unmet medical need for future drug development. This information will also help inform policy development, and with it, allow FDA to become more proactive about developing guidances and gathering public feedback. Additionally, using SNOMED CT will make it possible for the FDA to link its internal data with other data sources coded to SNOMED CT (e.g., EHRs).

To help industry understand what to do, we just released an online tutorial for industry explaining the newly revised forms in detail.

We look forward to working closely with industry to make sure applicants understand the revised forms and how to fill them out. We encourage industry to watch the tutorial, learn the coding system, and partner with the FDA on improving public health.

Christopher Leptak, M.D., Ph.D., is Director, Office of New Drug’s Regulatory Science Program in the FDA’s Center for Drug Evaluation and Research.