FDA Advances Efficient Approaches to Designing and Conducting Cancer Clinical Trials

By: Richard Pazdur, M.D.

Over the past decade, advances in understanding of cancer biology have led to the development of targeted treatments that are more effective than the chemotherapies of the past century. These therapies are demonstrating response rates large in magnitude or response durations prolonged in early trials, or both. Patient demand to enter these trials has increased, and so have calls to expedite the drug development and approval processes, all while maintaining high standards for safety and efficacy. We never lose sight of our dedication to patients faced with a life-threatening disease and to making progress in the fight against cancer.

Dr. Richard PazdurThe FDA works with industry, researchers, and other stakeholders developing innovative cancer therapies. We must ensure clear understanding of our latest thinking on how clinical trials can be efficiently and effectively designed to demonstrate a cancer therapy’s safety and efficacy.

Last week, the FDA published a draft guidance to help advance effective and innovative clinical trial designs early in drug development to help bring new cancer therapies to patients as quickly as possible. Below is a quick summary of this guidance:

Draft Guidance for Industry – Use of Expansion Cohorts in First-In-Human Clinical Trials to Expedite Development of Cancer Drugs and Biologics

Traditionally, clinical trials have been conducted in phases with one or two main objectives per study. For example, phase 1 studies help determine safety and the dose range for exploration in future trials, while phase 2 studies provide preliminary evidence of safety and activity in a single setting. This latest guidance, Use of Expansion Cohorts in First-In-Human Clinical Trials to Expedite Development of Cancer Drugs and Biologics, provides advice on designing and conducting adaptive trial designs in which pharmaceutical companies and researchers can assess many different aspects of a drug in development in a single clinical trial while enrolling the minimum number of study participants necessary to obtain this information. Trials with multiple expansion cohorts can be inherently more efficient and expedite early drug development. They can allow for addressing multiple questions in a single trial that is amended as new objectives are identified, avoiding the time lag and additional resources experienced with the opening of new clinical trials.

The principal advantage of expansion cohort trials is efficiency in drug development, with the goal of making highly effective drugs widely available to the public as quickly as possible. Well-designed and well-conducted clinical trials help ensure patient safety while also obtaining quality data that may support drug approval. This new draft guidance describes our proactive steps to help industry design clinical trials for today’s highly complex cancer therapies—and to conduct these trials in cost-effective and timely ways.

Maintaining Progress

From 1990 through 2014, the overall cancer death rate in the United States fell by 25 percent. In 2014, the number of people living beyond a cancer diagnosis reached 14.5 million, and by 2024, is expected to climb to approximately 19 million. In 2017, the FDA approved 16 new cancer drugs and biologics, including the first two in an exciting new category called CAR-T cell therapy. We also approved 30 new indications (uses) for existing cancer drugs and biologics, and the first two biosimilars indicated to treat cancers. Additionally, we recently approved the first cancer treatment based on a genetic feature of a cancer rather than the location of the body where the tumor originated.

The new draft guidance is intended to help the drug development community continue this progress against cancer. We want your input to make sure that the final guidance is comprehensive and forward looking and adapts to rapidly changing research developments and technologies. Our regulatory work needs to remain as advanced as the many new cancer therapies currently working their way through development. We encourage stakeholders to comment and look forward to your valuable feedback.

Richard Pazdur, M.D., is Director, FDA Oncology Center of Excellence

Advancing Tobacco Regulation to Protect Children and Families: Updates and New Initiatives from the FDA on the Anniversary of the Tobacco Control Act and FDA’s Comprehensive Plan for Nicotine

By: Scott Gottlieb, M.D., and Mitch Zeller, J.D.

This summer marks nine years since the Family Smoking Prevention and Tobacco Control Act (TCA) was signed into law, and one year since we announced the FDA’s Comprehensive Plan for Tobacco and Nicotine Regulation. This comprehensive plan places nicotine, and the issue of addiction, at the center of the agency’s tobacco regulation efforts. The multi-year roadmap provides a framework for regulating nicotine and tobacco and is designed to reframe the conversation around nicotine and harm reduction.

A principal reason people continue to smoke cigarettes — despite the dangers — is nicotine. Our plan recognizes that nicotine isn’t directly responsible for the morbidity and mortality from tobacco, but creates and sustains addiction to cigarettes. It’s the delivery mechanism for nicotine that’s more directly linked to the product’s dangers. That’s why our plan focuses on minimizing addiction to the most harmful products while encouraging innovation in those products that could provide adult smokers access to nicotine without the harmful consequences of combustion and cigarettes.

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

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

Over the past year, we’ve taken important steps toward fully implementing this plan as part of our overarching goal: a world where cigarettes can no longer create or sustain addiction, and where adults who still seek nicotine could get it from potentially less harmful sources. In implementing this comprehensive plan, we’ve already issued three important advance notices of proposed rulemaking (ANPRMs) that have the potential to reframe the tobacco landscape. These ANPRMs focus on:

  • The potential development of a product standard to lower nicotine in cigarettes to minimally or non-addictive levels – which could make it harder for future generations to become addicted in the first place and could allow more currently addicted smokers to quit more easily or switch to potentially less harmful products. Given their combination of toxicity, addictiveness, prevalence and effect on non-users, it’s clear that to maximize the possible public health benefits of our regulatory tools granted to us under the Tobacco Control Act, we must focus our efforts on the death and disease caused by addiction to combustible cigarettes. We believe this pivotal public health step has the potential to dramatically reduce smoking rates and save millions of lives;
  • The role that flavors – including menthol – play in initiation, use and cessation of tobacco products. Input on these issues will assist in the consideration of the most impactful regulatory options the FDA could pursue to achieve the greatest public health benefit. We’re proceeding in a science-based fashion, building a strong administrative record by securing more information about the potential positives and negatives of flavors in both youth initiation and in getting adult smokers to quit or transition to potentially less harmful products; and,
  • The patterns of use and resulting public health impacts from what are often referred to as “premium” cigars to inform the agency’s regulatory policies.

The public comment periods for all three ANPRMs, which were extended by 30 additional days to allow more time for submissions, have now closed. We are beginning the process of reviewing those comments.

Mitch Zeller, J.D., Director of FDA's Center for Tobacco Products

Mitchell Zeller, J.D., Director of FDA’s Center for Tobacco Products

At the same time, the FDA is also pursuing additional new policies as part of our comprehensive plan as well as our ongoing commitment to improve the efficiency and effectiveness of our tobacco regulatory programs.

Part of these efforts are aimed at making the pathway for developing nicotine replacement therapy (NRT) products more efficient to promote the development of novel NRT products. The agency’s efforts to re-evaluate and modernize its approach to the development and regulation of NRT products is aimed at opening up new pathways for the development of improved products, regulated as new drugs, that demonstrate that they are safe and effective for the purpose of helping smokers quit.

Many of our new efforts, as part of our comprehensive plan, are aimed at using our existing authorities under the TCA to minimize addiction to the most harmful products, principally cigarettes, while encouraging innovation in new products that may offer adults less harmful forms of nicotine delivery.

A key part of achieving these goals is issuing foundational rules and guidances to help industry better understand what is needed to submit product applications. At the same time, we are pursuing new efforts to improve the transparency and efficiency of the premarket review process.

These important foundational steps are a key element of our efforts to advance the pre-market review of tobacco products. This review is one of the most important responsibilities we have. It’s how we can assess new products and their potential impact on the public health. This is our opportunity to determine how a product may positively or negatively affect both non-users and current users. So, it’s crucial that we continually improve in this area and have a transparent and efficient process.

To address these goals, we’re committing to a number of steps, some new, to respond to stakeholders and to make the regulatory process more efficient, predictable, and transparent for industry, while also advancing the agency’s public health mission. Establishing a rigorous, predictable, science-based framework for the premarket review of tobacco products is a key element of our program.

Among the steps that we are pursuing to better achieve these goals:

  • Proposing foundational rules: We all need to be on the same page regarding the basic “rules of the road,” especially when it comes to what’s expected in premarket applications. We’re working to propose new rules to help industry on topics including Substantial Equivalence, Premarket Tobacco Applications, Modified Risk Tobacco Product Applications, and Tobacco Product Manufacturing Practices. We will begin publishing these foundational proposed rules in the coming months. They will lay out a transparent, modern, and science-based framework for manufacturing practices and the development of tobacco product applications that meet the legal requirements.
  • Holding a public meeting on premarket review: Within the next few months, the FDA will hold a public meeting on the premarket application and review process. The goal of the meeting is to solicit comments on our processes and provide a dedicated venue for specific suggestions on how to further improve them. Potential topics for discussion include: how to achieve greater efficiencies in review, while continuing to protect public health; how to review products that are rendered “new” due to changes made to comply with a product standard; and, how to facilitate greater company consultation with the FDA prior to submitting applications.
  • Exploring opportunities for premarket review efficiencies through rulemaking and guidance and new administrative steps to modernize and improve the review process: The FDA is taking additional steps to pursue the shared interest with industry of increased flexibility and efficiencies within the application review process. If carefully developed, rulemaking and guidance efforts in this area could help ensure that our public health standards for premarket review are met while mutually benefiting both the industry and the FDA. For example, an opportunity may exist to allow for faster and cheaper development of products that will benefit public health. In the months ahead, the FDA intends to explore what improvements can be made along these lines within our existing legal authorities. We also plan to advance a comprehensive suite of improvements to the review process, as part of a Regulatory Modernization, to make our program more efficient, transparent, predictable, and efficient. We will unveil these programmatic reforms in advance of our upcoming public meeting.

These programmatic and process improvements are aimed at solidifying the FDA’s regulatory pathways and improving its predictability and transparency. As the FDA advances its regulatory approach to these important public health considerations, it’s critical that we keep in mind a bedrock principle: No kids should be using any tobacco or nicotine-containing products, including e-cigarettes.

Protecting our nation’s youth from the dangers of tobacco products is among the most important responsibilities of the FDA. That is why we recently launched our Youth Tobacco Prevention Plan.

We look at the marketplace for tobacco products today and see increasing concern from parents, educators, and health professionals about the alarming youth use of tobacco products like JUUL and other e-cigarettes. Our mission at the FDA is to protect the public’s health, and we want to assure the public we’re using all of our tools and authorities to quickly tackle this public health threat. We will not allow our efforts to give manufacturers time to file premarket applications with FDA — that are informed by the foundational rules and guidance that we’re now advancing — to become a back door for allowing products with high levels of nicotine to cause a new generation of kids to get addicted to nicotine and hooked on tobacco products.

Our Youth Tobacco Prevention Plan reflects our commitment to address these risks. Congress gave us many powerful authorities, including enforcement, product standards, premarket review, sales and promotion restrictions, and public education. We’ll use every tool available to protect our nation’s kids.

We’ve already announced several vigorous enforcement actions and education efforts aimed at addressing youth use of nicotine, and e-cigarettes in particular. More such actions are imminent. Among the steps we’ve already taken are: sending warning letters to companies for selling e-liquids resembling juice boxes, candies and cookies; sending warning letters to retailers for selling JUUL e-cigarettes to underage youth; working with eBay to remove Internet listings for JUUL, and with other e-cigarette manufacturers to help the FDA better understand the youth appeal of these products; and, creating the  first e-cigarette public education ad, with a full-scale advertising campaign to begin this fall.

These are important first steps. But we still need to do more to address use of tobacco products by kids. That’s why we’re working to quickly advance the following three new initiatives:

  • Expediting action on flavors: The issue of flavors, including flavored e-cigarettes and e-liquids, is at the forefront of any discussion of youth use. However, some flavored tobacco products may also play a role in helping some adults quit smoking cigarettes. Now that the comment period has closed, we intend to expedite the review and analysis of the comments so that we can leverage the information into policy as quickly as possible, should the science support further action.
  • Developing an e-cigarette product standard: The FDA has also begun exploring a product standard for e-cigarettes to help address existing concerns. As part of the standard, the agency will consider, among other things, levels of toxicants and impurities in propylene glycol, glycerin, and nicotine in e-liquids. While the process for establishing a product standard takes time, we recognize the urgency in setting some minimum, common sense standards, and will work to address this on an accelerated timeline.
  • Exploring ways to accelerate enforcement: We’re also looking at ways that the FDA can act even more efficiently when we become aware of violations affecting youth use of e-cigarettes, such as illegal product marketing to youth. We need to be faster and more agile when we identify new risks. We’ve also become aware of reports that some companies may be marketing new products that were introduced after the FDA’s compliance period and have not gone through premarket review. These products are being marketed both in violation of the law and outside of the FDA’s announced compliance policies. We take these reports very seriously. Companies should know that the FDA is watching and we will take swift action wherever appropriate. We are evaluating new ways to strengthen our partnership with sister agencies, including the Federal Trade Commission. We will also announce a robust series of additional enforcement actions in the coming months.

We have made great strides since we first unveiled our Comprehensive Plan for Tobacco and Nicotine Regulation last year. The components of this program we have outlined are intended to work as an integrated package of reform. We will pursue all of these policies simultaneously. Each is interconnected. Each element supports the others. We intend to achieve all of the elements.

We remain on track to meet our ambitious goals. But there is still much work to be done.

The staff at the FDA’s Center for Tobacco Products is working hard to use our available tools to protect Americans from the harms of being addicted to tobacco products. And today, we’re committing to redoubling our efforts. Too many kids are still starting to use tobacco products and getting addicted. And, too many adults are still struggling to quit or to switch to less harmful options. To reduce the disease and death caused by tobacco use, the FDA will do everything within our power to help all ages.

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

Mitch Zeller, J.D., is Director of the FDA’s Center for Tobacco Products

 Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Follow the FDA Center for Tobacco Products on Twitter  https://twitter.com/FDATobacco

 

FDA Announces Two Initiatives to Modernize Drug Quality Programs

By: Janet Woodcock, M.D., and Michael Kopcha, Ph.D., R.Ph.

Patients expect and deserve high-quality drugs – this means consistently safe and effective medicines, free of defects and contamination. To satisfy these important expectations, the FDA strives to make sure that FDA-approved drugs are manufactured to meet quality standards to ensure that every dose is safe, effective, and capable of providing its intended benefit.

Janet Woodcock

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

Quality metrics are used in a variety of industries to monitor the quality control systems and processes that ensure standards are met, and to identify opportunities for manufacturing improvements. For the pharmaceutical industry, the use of quality metrics offers potential benefits to patients, manufacturers, and the FDA – including the potential to better combat drug shortages.

With these benefits in mind, the FDA has announced two new voluntary programs – the Quality Metrics Feedback Program and the Quality Metrics Site Visit Program – in response to stakeholder requests for continued dialogue on quality metrics, and to provide methods for industry to engage and inform the FDA’s use of them in the future. The programs will also help drug manufacturers to gain a better understanding of how quality metrics are a common feature of quality culture, and support improvements in product and process quality.

Feedback from early adopters and manufacturers who implemented quality metrics programs to address manufacturing problems, as well as independent academic research supported by the FDA, indicates that a manufacturer’s overall quality program benefits from the use of quality metrics. Quality metrics, such as data on the rate at which manufactured lots have been rejected for failing to meet established standards, can help manufacturers monitor quality control systems and drive continuous improvement efforts. For the FDA, data on quality metrics can help us better assess risk when scheduling inspections. This has the potential of decreasing the frequency of surveillance inspections for lower-risk establishments and narrowing the focus of on-site inspections conducted.

Michael Kopcha

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

The proximal cause of many drug shortages are quality issues such as substandard manufacturing facilities or processes. Quality metrics can be useful in identifying situations in which a drug supply disruption may occur, which can help mitigate potential future drug shortages. This will help to reassure patients that quality medicines will be available when they need them.

  • The Quality Metrics Feedback Program solicits information from drug manufacturers and sponsors that have implemented and are currently using quality metrics programs. The FDA is encouraging applicants eligible for Type C meetings as well as abbreviated new drug application (ANDA) holders to submit meeting requests to the FDA to discuss quality metrics for specific products. As part of the feedback effort, the FDA is also beginning a pilot study to gain feedback from other types of establishments where these types of meetings are not applicable, such as active pharmaceutical ingredient suppliers, over-the-counter monograph product establishments, and contract manufacturing organizations (CMOs).
  • The purpose of the Quality Metrics Site Visit Program is to provide on-site, firsthand learning opportunities to the FDA staff involved in the development of the FDA Quality Metrics Program. The Site Visit Program also is intended to provide stakeholders with the opportunity to explain the advantages and challenges they’ve experienced when implementing and managing their quality metrics programs.

The FDA’s new initiatives continue to enhance the focus of the conversation between the FDA and drug manufacturers to better understand – and make use of – quality metrics programs. We are confident these efforts will improve both the efficiency and the effectiveness of drug manufacturing, helping to assure a reliable and high-quality drug supply.

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

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

Protecting and Promoting Public Health: Advancing the FDA’s Medical Countermeasures Mission

By Anna Abram

The U.S. Food and Drug Administration’s wide-ranging public health responsibilities include the vital role we play on the frontlines of national security by facilitating the development and availability of safe and effective medical countermeasures. These are the vaccines, diagnostics and therapeutics that are needed to protect our nation from chemical, biological, and radiological and nuclear threats, whether naturally occurring, accidental, or deliberate. As in so many areas of public health, our work here is critical, and we are ever-cognizant of its urgency.

One of the many areas in which the agency is continuing to take steps to facilitate the development of medical countermeasures to protect Americans is with respect to the threat of smallpox. The World Health Assembly declared naturally occurring smallpox eradicated worldwide in 1980, following an unprecedented global immunization campaign. However, small amounts of the variola virus – the virus that causes smallpox – still exist for research purposes in two labs; one of these labs is in the U.S. and the other in Russia. Despite the eradication of naturally occurring smallpox disease, there are longstanding concerns that the variola virus could be used as a weapon. Since routine vaccination was discontinued in the 1970s, many people would be at high risk of getting very ill or dying if exposed to this highly contagious virus.

Medical Countermeasures Against Smallpox

The development of medical countermeasures for smallpox presents complex and unique challenges. It is not possible to conduct clinical trials involving patients with naturally occurring smallpox and exposing humans to the variola virus would be ethically unthinkable. To address this challenge – which also applies to many of the high-priority threat agents for which medical countermeasure are being developed – the FDA in 2002 established the Animal Rule, which allows efficacy data to be obtained solely from studies in animals when studies in humans are not ethical or feasible, provided the results can be reasonably extrapolated to expected human use and plans can be made for follow-up study when appropriate. (The FDA finalized guidance on product development under the Animal Rule in 2015).

Anna Abram

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

However, the variola virus poses additional issues for drug developers. Unlike other products studied under the Animal Rule, studies of smallpox countermeasures require not just a surrogate host but also a surrogate pathogen. Most pathogens are capable of infecting multiple host species and therefore can be studied in other, nonhuman, species. But the variola virus only infects humans, which means that variola virus animal models are unlikely to convincingly resemble the human disease. To help delineate a path forward, the FDA issued a draft guidance “Smallpox (Variola) Infection: Developing Drugs for Treatment and Prevention” in 2007 and brought these important issues to an FDA public workshop in 2009 and an FDA advisory committee meeting in 2011. The revised draft guidance issued last week incorporates this input, providing developers with additional clarity on the regulatory path for products intended to treat smallpox. It recommends that efficacy be demonstrated based on studies in two animal models infected with related viruses – such as a monkey model using monkeypox and a rabbit model using rabbitpox. This guidance underscores how the FDA is continually working to identify and apply efficient solutions based on the most up-to date science in its regulation of safe and effective medical products.

The ultimate testament to the success of these efforts is the approval on July 13 of TPOXX (teconvirimat), the first drug with an indication for the treatment of smallpox and the 14th medical countermeasure approved under the Animal Rule. In conjunction with this product approval, the sponsor was awarded the first Material Threat Medical Countermeasure Priority Review Voucher, established by the 21st Century Cures Act, to incentivize the development of certain medical countermeasures against some of the most serious threat agents.

The FDA’s Other Recent Work on Medical Countermeasures

Smallpox isn’t the only area of medical countermeasure work ongoing at the FDA. On July 10, we approved an autoinjector which provides a one-time dose of the antidote atropine to block the effects of a nerve agent or certain insecticide poisonings (organophosphorus and/or carbamate).

We also recently issued an Emergency Use Authorization (EUA) to the Department of Defense (DoD), permitting the emergency use of a specific freeze-dried plasma product manufactured to treat U.S. military personnel with severe or life-threatening hemorrhage or coagulopathy (a condition that affects the blood’s ability to clot) due to traumatic injuries sustained in the conduct of military operations in situations when plasma is not available or when its use is not practical. The use of plasma in combat settings is severely limited by logistical and operational challenges, such as the need for refrigeration and, in the case of frozen plasma, a long thawing period. In January 2018, the FDA and DoD announced a joint program to prioritize the efficient development of safe and effective medical products intended to save the lives of American military personnel.  We are working closely with our DoD colleagues in these important priority areas, including the goal of having a licensed freeze-dried plasma product as soon as possible.

These are just some of the ways in which the FDA has been hard at work to advance our medical countermeasure mission. But there is more work to do and the agency is committed to doing it. We are constantly reminded that chemical, biological, radiological, and nuclear threats – whether deliberate, naturally occurring or accidental – can, and often do, emerge with little to no warning. Emerging threats are often not deterred by geographical boundaries in our modern times. The recent Ebola outbreak in the Democratic Republic of Congo is a reminder of the need to remain ever vigilant in our work to advance medical countermeasures as part of protecting and promoting public health.

We are committed to doing all that we can to continue to facilitate the development and availability of medical countermeasures. The FDA’s Medical Countermeasures Initiative (MCMi), established in 2010, is focused on providing clear regulatory pathways for medical countermeasures, advancing regulatory science to support regulatory decision-making, and articulating important regulatory policies and mechanisms to facilitate the timely development and availability of medical countermeasures. These actions are translating into tangible results. Since 2012, the FDA has approved, licensed or cleared more than 120 medical countermeasures (including supplemental changes to already approved applications and modifications to diagnostic devices) for a diverse array of threats including anthrax, smallpox, botulinum toxin, plague, and pandemic influenza.

Under the MCMi, the FDA is taking key actions to address many of the challenges associated with countermeasure development. For example, we still do not have adequate animal models to support the development of medical countermeasures against many potential biothreats nor do we have sufficient biomarkers to assist in supporting the extrapolation of data generated in animal models to humans. Without such tools, it can be difficult to generate the data necessary to support regulatory decision-making.

Given the urgency inherent in our medical countermeasure work, addressing these regulatory science gaps remains a high priority for the agency. To help address these challenges, the FDA has established a broad and robust portfolio of cutting-edge research under the MCMi Regulatory Science Program and is working with our private sector and government partners, including DoD, to help facilitate the translation of discoveries in science and technology into safe and effective medical countermeasures. Congress has also provided vital support and our recent actions in this space underscore how we are fully leveraging the authorities Congress has given us, including measures enacted as part of the Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 and the 21st Century Cures Act.

The FDA remains deeply committed to working closely with its partners to achieve our mission of protecting and promoting the public health, both at home and abroad, by doing our part to facilitate the timely development of safe and effective medical countermeasures to protect our nation.

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

FDA Budget Matters: Investing in Advanced Domestic Manufacturing

By: Scott Gottlieb, M.D.

There’s new technology that can improve drug quality, address shortages of medicines, lower drug costs, and bring pharmaceutical manufacturing back to the United States. At the FDA, we’re focused on propelling these innovations, collectively referred to as advanced manufacturing.

Dr. Scott GottliebAdvanced manufacturing, which includes various technologies, such as continuous manufacturing and 3D printing, holds great promise for improving the American market for drugs and biologicals.

Consider continuous manufacturing. These methods integrate traditional step-wise manufacturing processes into a single system that’s based on modern process monitoring and controls. This enables a steady output of finished drug products even as raw materials are continuously added to the closed system. The closed and continuous nature of these manufacturing systems means that the process is easier to control. These systems also require smaller footprints to operate.

And they’re far more efficient than standard manufacturing processes.

3D printing is another approach to advanced manufacturing. These methods are capable of manufacturing pre-determined 3D geometric structures of solid drug products in various shapes, strengths and distributions of active and inactive ingredients. This approach provides a unique opportunity to produce medicines that are tailored for individual needs of patients.

But harnessing the potential of these innovations requires deliberate private and public investments and new policy development. We need to define how these new technologies will be regulated for their reliability and safety. And provide clear guidance on how they can be adopted by sponsors.

The FDA is taking many steps to help realize the potential of advanced manufacturing. We’ve been issuing guidance on emerging technologies and approving continuous manufacturing for several New Drug Applications. However, to drive an earnest and more efficient conversion to these often-superior platforms, it’s going to take a broader effort on the part of the Agency.

The bottom line is this: Drug makers won’t switch to these systems until we create a clear path toward their adoption, and provide more regulatory certainty that changing over to a new manufacturing system won’t be an obstacle to either new or generic drug approvals. The FDA recognizes that it’ll require additional investment in policies and programs that’ll provide regulatory clarity to enable these new methods to be more quickly and widely adopted. To achieve these goals, the President’s fiscal year 2019 budget dedicates $58 million to accelerate the development of the regulatory and scientific architecture needed to progress this technology.

diagrams of continuous and batch manufacturingMany of the technologies currently used in traditional “batch” drug manufacturing – where the ultimate finished product is made after many stops and starts in a series of steps – are decades old. This shouldn’t come as a complete surprise. Drug development is a risky endeavor. After drug makers have navigated the years of risk involved in discovering and developing a new medicine, the last thing they want to do is inject a whole bunch of uncertainty at the last step toward approval – the adoption of the manufacturing process. So most drug makers have continued to use tried and true methods, even if these conventional processes have shortcomings.

However, this customary calculus is changing.

These continuous manufacturing systems are more ideally suited to new trends in drug development, such as personalized medicine and regenerative medicine products. Drugs that target small patient populations will require much greater manufacturing flexibility. The small scale of continuous manufacturing equipment works well for these endeavors. Close and continuous manufacturing systems can provide cost-effective drug product for early stage clinical development and yet can easily ramp up production for commercialization.

While development trends and market forces have made the commercial impetus for private capital investment in these technologies clear, meaningful adoption will not occur without supporting regulatory science and a collaborative regulatory environment. To drive adoption, the FDA will need to establish clear principles for how these new platforms will be evaluated and approved. We need to invest in the regulatory science to develop policies to support these innovations. That includes, for example, the development of analytical tools for monitoring these continuous systems. While much of this scientific work will be done outside the agency (typically through public and private partnerships) the basic regulatory principles need to be defined by the FDA.

The FDA has recognized and embraced the potential for this technology for years. We established an Emerging Technology Team in 2014 that works collaboratively with companies for both new and currently marketed drugs to support the use of advanced manufacturing.

The FDA’s Center for Biologics Evaluation and Research is building on that effort. We’re advancing the application of continuous manufacturing and other cutting-edge technologies. These manufacturing approaches may be ideally suited to new biological platforms like cell and gene therapies, as well as vaccines. In some cases, these manufacturing approaches may be the key enabling technology for the safe and effective development of these new biological platforms.

Take gene therapy as one example. Many gene therapies are being developed for very small populations ranging from tens to hundreds of patients. It can be costly and slow to build traditional manufacturing platforms to support such small yields, or to switch from a small, research grade manufacturing platform to one capable of supporting bigger trials, or commercial launch. And when it comes to products like gene therapies, a lot of the uncertainty is in how these products are manufactured. So, switching between different manufacturing platforms can create risk.

Applying continuous manufacturing approaches to these products could allow for the development of a quality manufacturing process that could support the production of enough commercial grade product to conduct an initial clinical trial as small as 10 to 20 patients. This would represent one production “cassette.”  Using continuous manufacturing, the scaling of manufacturing for larger trials wouldn’t require the build out of a completely new manufacturing facility. It would just require the introduction of additional “cassettes” into the closed system. Subsequently, if the clinical trial produced definitive data on safety and efficacy, then marketing could commence with product produced by making use of additional manufacturing cassettes. This could have a transformational effect on the costs and feasibility of applying gene therapy to rare diseases.

These manufacturing technologies are not only suited to emerging technologies, but also help address old challenges, like issues with drug shortages and pharmaceutical quality.

Drug shortages are a serious public health issue. What’s not widely known is that quality issues cause the majority of drug shortages. These quality issues are often related to facility remediation efforts and product manufacturing issues. Drug shortages have consequences for patient access to critical and lifesaving drugs. They also can cause prices to rise, in some cases substantially.

Continuous manufacturing systems may be far less prone to the shortcomings that trigger many drug shortages. This technology also reduces the number of steps in the manufacturing process and centralizes all manufacturing steps in one location. Simplification and centralization, in turn, allows for issues to be identified – and remedied – more quickly. In this way, continuous manufacturing helps address the primary root causes of drug shortages. Advanced manufacturing techniques also allow for more flexible manufacturing capacity, which enables manufacturers to respond to drug shortages faster. With these systems, drug makers can more quickly adjust volumes based on product demand and therefore release product to the market more quickly.

This flexibility – and the capacity to increase production easily – could also be important for vaccines; both for seasonal flu and vaccines to combat new outbreaks.

For example, egg-based vaccine manufacturing requires about six months to meet demand, which requires the World Health Organization and public health agencies to predict the flu strand six months prior to the flu season. In contrast, advanced manufacturing has the potential to expedite the process, shortening the amount of time between when the flu strain is selected and distributed.

This can allow us to produce the vaccine closer to the flu season, when we might have more certainty about the circulating strain. It also allows us to switch the strain more easily in the event of an unforeseen change. Or to produce a new vaccine in the event of a pandemic. These approaches also enable easier scaling of manufacturing if vaccine supplies should run short.

This additional flexibility when it comes to manufacturing can also provide a critical boost for emergency preparedness products, enabling manufacturing that can be more easily scaled to quickly respond to new threats. Consider when access to a vaccine is a key strategic need; for example, a vaccine to guard against a bioterror threat. Instead of stockpiling massive volumes of the vaccine; we would instead be able to mothball a just-in-time continuous manufacturing platform. The system could then scale up production in the event of an infectious threat.

Advanced manufacturing also provides an opportunity for the U.S. to regain a leadership position in pharmaceutical manufacturing and bring more high-quality manufacturing jobs back to this country. Many of the products that would benefit from advanced manufacturing are breakthrough-designated drug products that are usually first approved and marketed in the U.S. But many are still manufactured overseas. The traditional approach to manufacturing drugs requires large facilities and a lot of manual labor. Drug makers have made a calculation that these manufacturing sites can be operated more cheaply in countries with lower labor costs.

Continuous manufacturing changes this calculus.

These advanced platforms are small footprint operations. They require a reduced complement of more highly skilled workers. It’s the sort of manufacturing where America excels.

The U.S. is the current pioneer for advanced manufacturing. Our investments in educating engineers and establishing a research base for the development of domestic facilities will ensure that we maintain our lead in the world. Many U.S. universities have already established advanced manufacturing academic programs that train on these approaches. Some are funded through grants from the FDA that were authorized in 21st Century Cures. These approaches have also been applied with success to other fields, such electronic devices and chemical industries.

Producing more drugs domestically doesn’t just mean more American jobs. It could also reduce import costs for manufacturers and increase security of our supply chain.

Continuous manufacturing technologies could save 30 percent in manufacturing costs. This estimate does not include the savings from potential future technologies. That totals $60 billion per year in savings in the United States. This can help reduce drug costs. PCAST estimates that “Continuous manufacturing may reduce manufacturing costs, which currently consume as much as 27 percent of the revenue for many pharmaceutical companies, by up to 40 to 50 percent.”

One example of promising investment in these technologies is recent efforts by General Electric to “launch prefabricated manufacturing units for producing virus-based gene and cell therapies, novel anti-cancer treatments and vaccines.” Innovations like these could make it more feasible for small, innovative biotech companies to enter the market and compete against larger pharmaceutical companies, especially for gene and cell-based cancers. This could provide a broader array of innovation, and infuse more competition into these promising therapeutic areas.

The agility of continuous manufacturing platforms should ultimately reduce costs of drug manufacturing and could provide savings to our health system. But the efficient adoption of these approaches will require a paradigm change in the regulation of manufacturing. And that will require an investment to write new principles for how the FDA oversees these tasks. This is the opportunity before the FDA, and the heart of the proposal in the President’s budget.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Additional Resources:

“Continuous Manufacturing” -Common Guiding Principles Can Help Ensure Progress

Establishment of a Public Docket-Submission of Proposed Recommendations for Industry on Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing

Spotlight on CDER Science: Modernizing the Way Drugs Are Made: A Transition to Continuous Manufacturing

Emerging Technology Program

FDA Budget Matters: A Cross-Cutting Data Enterprise for Real World Evidence

By: Scott Gottlieb, M.D.

Over time, as our experience with new medical products expands, our knowledge about how best to maximize their benefits and minimize any potential risks, sharpens with each data point we gather. Every clinical use of a product produces data that can help better inform us about its safety and efficacy.

Dr. Scott GottliebThe FDA is committed to developing new tools to help us access and use data collected from all sources. This includes ways to expand our methodological repertoire to build on our understanding of medical products throughout their lifecycle, in the post market. We don’t limit our knowledge to pre-market information, traditional de novo post-market studies, and passive reporting. Newer methodologies enable us to collect data from routine medical care and develop valid scientific evidence that’s appropriate for regulatory decision making to help patients and health care providers prevent, diagnose, or treat diseases.

This includes our ability to leverage what’s often referred to as “real world data.” Real world data consists of data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources, including information obtained at the point of care. By using this information, we can gain a deeper understanding of a medical product’s safety and benefits, its additional treatment implications, and its potential limitations. By better leveraging this information, we can also enable more efficient medical product development by integrating greater complements of safety and benefit information gleaned from clinical care. This is especially true when it comes to our important obligation to continue to evaluate products in the post-market setting.

Traditional randomized clinical trials can provide key information on a medical product’s performance to support regulatory marketing decisions and health care decisions made by patients and providers. However, traditional clinical trials have their own limitations. The FDA, along with others, sometimes benefit from more information than these trials can provide about how medical products are used in medical practice.

For example, traditional clinical trials have patient inclusion and exclusion criteria that often narrow the patient population that can participate in a traditional trial. So, patients who’ve undergone another treatment, or who are taking other medications, may not qualify for a certain trial that’s looking for patients who haven’t been treated for that disease or condition, or who are taking certain medications.

When this product comes to market, it’s possible that patients who pursued other treatments or patients taking medications for other conditions will be prescribed this therapy. Because these patients weren’t studied, there’ll be no clinical trial evidence available showing how these other factors may affect the safety or efficacy of this product. Clinical trials provide a picture of a medical product’s potential in a narrow and highly controlled setting. But they do not provide a complete picture as to how a product works outside of that setting. This can limit our broader understanding of how a new product will work in “the real world.”

Real World Evidence diagramThe FDA is uniquely positioned and qualified to lead the effort to expand the use of real world data to address these knowledge gaps. Over the past decade, through the FDA’s Sentinel System and the National Evaluation System for health Technology (NEST), the FDA has begun to harness formerly untapped information to help us answer some of the most pressing questions facing patients and providers about the use of medical products. This use of real world data is referred to as “real world evidence.” This is meant to express the use of real world data to generate practical clinical evidence regarding the potential benefits or risks of a product. In this case, the evidence is derived from analysis of real world data.

We’re working to promote and expand the use of both real world data and real world evidence in medical product development and regulatory science. And not only for FDA uses, but also for others that seek to answer critical questions about health care delivery. To accomplish this goal, the FDA will leverage our knowledge and skills from building and using the Sentinel System and further supporting the development of NEST. Most importantly, we must develop the means to govern the responsible use of these data and to provide timely access to a broad group of public and private entities through the creation of a national resource. All the while, we must maintain strict data security and privacy of personal information.

To these ends, as part of the President’s Fiscal Year 2019 Budget, we’ve put forward a $100M medical data enterprise proposal to build a modern system that would rely on the electronic health records from about 10 million lives. This system would expand the data enterprise that we already maintain by incorporating new information from electronic health records, and other sources that would allow us to more fully evaluate medical products in the post-market setting.

This is the next evolution in the Agency’s development of a comprehensive data enterprise to improve medical product regulation and better inform us on the safety and benefits of new innovations.

Post-Market Data Sources: Claims Data vs. EHRs

Previously, our investments in post-market data have mostly focused on the development of systems to consolidate and analyze information derived from healthcare payer claims. This was a key advance in our regulatory system. And relying on health claims information was the state of the art at the time that we built these systems. Now we have the capacity to use clinical data derived from electronic health records to develop faster reporting on the performance of medical products in real world medical settings.

Claims data provides important insights. But it also has some limitations. For example, there’s an inherent lag between when a medical event occurs, and when it’ll show up in payer claims. There’s also some ambiguity in this process. It’s not always clear, by looking at claims data alone, what actually happened to the patient and whether the medical product was a factor. So, in the current system, we need to make certain assumptions when we evaluate claims data, to draw conclusions from this information. And some of these assumptions can inject uncertainty. The FY 2019 Budget request seeks to address some of these limitations by giving the Agency the ability to access the clinical medical information contained in de-identified electronic health records.

Investments in such a system can become a national utility for improving medical care, and allowing the FDA to optimize its regulatory decisions. It would give patients and providers the access to near-real-time, post-market information that can better inform their decisions. Such an enterprise can not only support our evaluation of safety and benefit using data derived from real-world settings, but it can also make the development of new innovations more efficient. If we have more dependable, near-real-time tools for evaluating products in real-world settings, we can allow key questions to be further evaluated in the post-market setting. This can allow some of the cost of development to be shifted into the post-market, where we can sometimes access better information about how products perform in real-world settings.

Establishing a System that can Leverage All Data Sources

Real world data can come from many sources. It not only can include electronic health records, but also claims and billing activities, product and disease registries, patient-related activities in out-patient or in-home use settings, and mobile health devices. It’s key that the sources of these data elements, such as different health care systems, be able to communicate electronically. This requires full “interoperability” and the elimination of any silos. The FY 2019 Budget request seeks to establish these building blocks, and assemble the data into an interoperable platform. There are several foundational steps that we’re already undertaking to build a strong programmatic basis for using real world data and evidence.

Achieving interoperability and establishing data standards, while conceptually obvious, is by no means easy to accomplish. Different groups may collect the same information in different ways. Consider that one group collects temperature using Celsius and another uses Fahrenheit. The group that uses Celsius may document a temperature of 37 degrees, while the one that uses Fahrenheit would document a temperature of 98.6 degrees. While these both are the same finding, in the absence of data standards, they would appear drastically different. Therefore, one key to this effort is the development of data standards and agreed upon definitions that allow different groups to meaningfully share their data.

Additionally, as noted above, there are many potential sources of real world data. Our familiarity and ability to harness these data varies across these sources. For example, the Sentinel System has taken advantage of a well-established source of real world data, claims and billing data. But claims and billing data, while well established and characterized, don’t necessarily capture the full scope of actual patient treatment. When it comes to medical devices, these claims data may not include the Unique Device Identifier which can limit the utility of the information. In addition, physicians may not be recoding every treatment in claims and billing data because of payment bundles, so the exact treatment is not known.

In comparison, electronic health records capture more of the patient experience and have the potential to provide more “real-time” information. But the information is also captured in a much less standardized way. Often key information is documented in unstructured ‘free text’ as part of a provider’s note. So, standardizing this information — and assembling it into formats that can allow for easier analysis and integration — will take additional investment in systems that can consolidate this information and make it interoperable.

Part of our proposed investment will go toward building these new capabilities to assemble real world data into formats to make this information more accessible. Ultimately, our goal is that such a tool can become a national utility that can be accessed by qualified research partners to inform a host of important clinical questions.

Improving Clinical Trials

The development of such a tool can also make the entire clinical trial process much more efficient. And it can enable us to enroll more patients from more diverse backgrounds into trials.

For example, real world data can be used to more efficiently identify and recruit patients for a clinical trial. Key design considerations, such as randomization, can be integrated across clinical care settings, introducing a much more diverse population into the clinical trial system. Innovative statistical approaches — such as Bayesian and propensity scores methods — can combine information from different sources and potentially reduce the size and duration of a clinical trial while expanding the scope of healthcare questions that we’re able to evaluate. This will enable a modern clinical trial system that improves upon trials being conducted in large medical care centers. It could enable more clinical trials at smaller community-based health care providers. Such a system can expand the number of patients we’re able to evaluate, and broaden the information that we’re able to collect, while at the same time reducing the cost of developing this information. We can have more and better information, and a less costly process.

All of this is contingent upon our ability to have confidence in the quality of data we’re accessing to make decisions, be that regulatory or derived from individual patient care.  We’re working with public and private partners to ensure optimal data quality, validity, and utilization. Our goal is to develop better data standards, to promote interoperability, and improve data quality.

Investing in Tools to More Wisely Use Data to Improve Health

Data quality has different impacts when considering the use of this data for individual patient care as opposed to broader public health evaluations. However, our capacity to make effective use of real world data and real world evidence will have a profound impact on individual patients and the public health.

Investing in the creation of a national resource that leverages real world data, establishes data standards to facilitate interoperability, and promotes data quality for the integration of this evidence into medical product development and clinical care is a key national investment. It’ll improve patient care, and make the process for developing safe and effective new medical innovations more efficient. It’ll give us a near real-time tool for monitoring the post-market safety of medical products, and will help inform better and more timely regulatory decisions.

Most importantly, such a system will provide patients with better care and more informed treatment decisions. The wider use of real world data could decrease the cost of product development, while increasing our understanding of how, when, and in whom, to use medical products. It’ll allow us to use the post-market period to refine our understanding of medical products. And it’ll allow us to make reliable post-market information available to providers and patients to better inform their treatment decisions.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

The American Chamber of Horrors

By: Vanessa Burrows, Ph.D., Suzanne Junod, Ph.D., and John Swann, Ph.D.

In the early 20th century, Americans were inundated with ineffective and dangerous drugs, as well as adulterated and deceptively packaged foods.

A cosmetic eyelash and eyebrow dye called Lash Lure, for example, which promised women that it would help them “radiate personality,” in fact contained a poison that caused ulceration of the corneas and degeneration of the eyeballs. An elixir called Banbar claimed to cure diabetes as an alternative to insulin, but actually provided no real treatment and caused harm to those patients who substituted this for effective insulin therapy. Food producers short-changed consumers by substituting cheaper ingredients. Some products labeled as peanut butter, for instance, were filled with lard and contained just a trace of peanuts, and some products marketed as “jellies” had no fruit in them at all.  Unscrupulous vendors even sold products to farmers, falsely promising they could treat sick animals – in at least one case, a product called Lee’s Gizzard Capsules killed an entire flock of turkeys instead of curing them.

Although the FDA sought to remove these unsafe and misleading products from commerce, it was severely limited in its efforts by the 1906 Pure Food and Drugs Act.  That law laid the cornerstone for the modern FDA and marked a monumental shift in the use of government powers to enhance consumer protection by requiring that foods and drugs bear truthful labeling statements and meet certain standards for purity and strength.

Over time, however, the shortcomings of the Pure Food and Drugs Act became apparent, as it failed to take into account the extraordinary changes in industries, products, markets, and advertising tactics. Dangerous drugs were a particular problem. As long as a drug met the law’s labeling requirements, the agency did not have the authority to remove even clearly dangerous products such as radium water and drugs with poisonous ingredients from the market because legal action against a drug product required a finding of fraud. If a drug’s maker could convince a court that he truly believed his own therapeutic claims, he won his case. In addition, the law provided no authority over cosmetics or medical devices, and did not specifically authorize standards for foods, which limited the agency’s ability to take action on behalf of consumers.

A popular book of the day, “100,000,000 Guinea Pigs: Dangers in Everyday Food, Drugs, and Cosmetics,” claimed that consumers were being used as guinea pigs in a giant experiment by food companies and makers of patent medicines, with the authors blaming the FDA for failing to act. But the critics failed to acknowledge the limits of the agency’s authority under the law at the time.

In an effort to inform the public about the 1906 law’s shortcomings, the FDA’s Chief Education Officer, Ruth deForest Lamb, and its Chief Inspector, George Larrick, led the creation of an influential traveling exhibit in 1933 to highlight about 100 dangerous, deceptive, or worthless products that the FDA lacked authority to remove from the market.

The exhibition was put on display at events like the 1933 World’s Fair in Chicago, at state fairs, and on Capitol Hill. It was so shocking that it was dubbed the “American Chamber of Horrors” by a reporter who accompanied First Lady Eleanor Roosevelt to view the exhibit. Lamb also adapted the exhibit into a 1936 book in which she explained, “All of these tragedies…have happened, not because Government officials are incompetent or callous, but because they have no real power to prevent them.”

The exhibit, which was viewed by millions, was an enormous success, helping promote greater awareness and understanding about the FDA’s role in protecting the public and the need for greater consumer protection and the limitations on its power to do so. To this end, it played an important role in moving Congress to enact a stronger food and drug law – the 1938 Food, Drug, and Cosmetic Act.

The 1938 law, which has been amended many times and remains the law of the land today, brought cosmetics and medical devices under the FDA’s authority, and required that drugs be labeled with adequate directions for safe use. It also mandated pre-market approval of all new drugs, such that a manufacturer would have to prove to the FDA that a drug was safe before it could be sold. And it prohibited false therapeutic claims for drugs. The Act also corrected abuses in food packaging and quality, and it mandated legally enforceable food standards. It formally authorized factory inspections, and added injunctions to the agency’s enforcement tools. In short, it gave the FDA many of the means it has today to protect the American public.

Many of the products from the original Chamber of Horrors exhibit are in the FDA’s permanent collection, and, to commemorate the 80th anniversary of the 1938 law, they are part of a special display currently on exhibit at the FDA. The objects provide a compelling visual record of how far science has brought us from the worthless and dangerous elixirs, foods, and other consumer products of the early 20th century, as well as underscoring the essential role the FDA today plays in protecting and promoting American health.

Vanessa Burrows, Ph.D., Suzanne Junod, Ph.D., and John Swann, Ph.D., are FDA Historians

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

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

 

 

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