FDA’s Comprehensive Effort to Advance New Innovations: Initiatives to Modernize for Innovation

By: Scott Gottlieb, M.D.

Our longstanding goal for medical care is to ensure that the right drug or device is delivered to the right patient at the right time. This vision is increasingly possible with the innovative products that are becoming available. Many of these opportunities are enabled by new technology platforms such as digital health, targeted medicines, and regenerative medicine, including cell and gene therapies. These new technologies offer transformative opportunities. But they also challenge the U.S. Food and Drug Administration (FDA) to modernize its approach to evaluating new innovations. In many cases, we’ve had to refashion our regulatory approach to create more modern platforms that are better suited to the efficient evaluation of these advances.

Dr. Scott Gottlieb, Commissioner of the U.S. Food and Drug AdministrationIn short, we’ve had to modernize our overall approach to regulation to effectively advance the kinds of innovations that are becoming available. This includes modernizing how we organize our medical product review programs. These initiatives are part of our comprehensive Medical Innovation Access Plan.

These efforts are strengthened by new authorities and resources made possible by bipartisan legislation like the 21st Century Cures Act, as well as the recent re-authorization of the FDA’s user fee agreements. The actions that we’re taking have additional support from the President’s Fiscal Year 2019 budget. Together, these efforts will enable the FDA to fund the creation of a cross-cutting data enterprise for the generation of evidence, and a more modern and integrated approach to the evaluation of this information, to make sure that our regulatory decisions are as flexible and sophisticated as the science driving these advances.

And we’re not doing it alone.

We’re working closely with our public and private sector partners to better meet shared public health goals and address cross-cutting scientific and technical challenges, while making regulatory decisions more transparent and predictable for all stakeholders. My recent written testimony on how the FDA is implementing the 21st Century Cures Act contains an overarching picture of the agency’s many activities related to our new policies aimed at advancing innovative products.

I’d like to use this opportunity to reflect on how the FDA is creating a new operating system for innovation by modernizing clinical trials, streamlining the FDA’s organization and processes to advance regulatory science, and expanding the FDA’s capacity to analyze complex real-world data streams to detect early safety and efficacy signals. And to describe the new policies we plan to announce to advance these goals. These mutually reinforcing efforts will help the FDA meet its mission of promoting and protecting public health, and they will help unlock the full public health potential of America’s public and private investments in medical research.

Modernizing Clinical Trials for Drugs and Devices

Prospectively randomized, placebo controlled clinical trials are often the most powerful tool that we have for answering fundamental questions about the safety and efficacy of new medical products. But greater efficiency is needed, as clinical trials are becoming more costly and complex to administer. Moreover, many of the new products that we’re being asked to evaluate aren’t easily evaluated using these traditional approaches. At the same time, new technologies and sources of data and analysis make better approaches possible.

Added complexity can not only make medical product development more uncertain, expensive, and time consuming; overly complex trials and unnecessary data collection can deter patient enrollment, exhaust investigators, and delay completion of studies so long that their findings aren’t relevant. They can also discourage the development of second and third-to-market innovations, meaning that first-in-class drugs enjoy monopolies for longer periods of time. This can reduce competition that lowers prices, and limit therapeutic diversity.

The FDA is working across its medical product centers, in collaboration with the Clinical Trials Transformation Initiative (CTTI) and the Medical Device Innovation Consortium (MDIC), to facilitate innovative trial designs and patient-centered endpoints for drugs and medical devices that can make clinical trials more efficient. These approaches can also be more rigorous. Developing more efficient strategies for generating critical evidence relating to the safety and efficacy of drugs and devices in specific populations (for instance, through seamless trial designs, and the use of master protocols and basket trials) can help make the clinical development process more efficient. It can enable investigators to learn more about a product’s efficacy and safety, and help regulators and sponsors detect efficacy and safety signals earlier in the development process.

Lowering the cost and time needed to conduct trials can promote market competition, help check drug prices, and bring patients innovative medical products earlier. These approaches can lower costs by making it more economical for second or third- in- class products to compete with first entrants. Right now, when it comes to drugs targeted to unmet needs, we’re seeing a trend where second and third-to-market competition is taking longer to reach patients. There are complex reasons for this. But one is the difficulty of conducting traditional clinical trials in settings where there is an available therapy, but still significant unmet medical need – for instance, in some rare diseases.

We studied these trends. A new FDA analysis considers the number of drugs or biologics that CDER has approved in the same class. They’re drugs that use the same mechanism to produce a physiological change in the same or related condition. We found that new competition isn’t entering the market as quickly for these drugs. In other words, when a novel sole source drug wins approval it faces no competition from other drugs in the same class. Follow-on drugs and biologics to compete with the first-in-class have been arriving more slowly.

Here are some results from the data we reviewed. We plan to publish the full analysis soon.

For non-orphan pharmaceuticals, which treat conditions affecting larger patient populations, 41 percent of the first-in-class products approved between the years of 1991 and 2000 had at least one competitor in the same class within five years. This rate dropped sharply over the next decade. For the years from 2001 to 2010, for the same kind of cohort of medicines – first-in-class products that were approved to treat patients with prevalent conditions – only 18 percent of these drugs had a within-class competitor after five years. Another way of interpreting the data is to describe the lag in any competition.  For the older classes, where the first-in-class was approved in 1991 to 2000, nearly a quarter had a competitor within two years. For the cohort where the first-in-class was approved in 2001 to 2010, it took an additional five years for there to be nearly as much competition. By year seven, competition still lagged the previous cohort, with only 22 percent of classes having any competitor. We see similar patterns in most rare disease treatments.

Consider first-in-class orphan drugs and biologics for non-cancer indications. For drugs approved between 1991 and 2000, 26 percent had at least a competitor within five years. The comparable rate for the 2001 to 2010 cohort was 13 percent. These trends mean that costlier, branded drugs may enjoy longer periods without facing competition from products in the same class. This may increase their pricing power. For orphan drugs, where conducting clinical trials can be difficult, these periods can sometimes extend long after patents and other exclusivities lapse.

We’re taking steps to facilitate more efficient clinical development programs. The Center for Devices and Radiological Health’s (CDRH’s) work with MDIC, for example, is improving efficiency in trial site contracting, first in patient studies, and Institutional Review Board (IRB) approval. These are three of the costliest factors in device trials and can pose barriers to developing innovative products. Similarly, the FDA has advanced efforts to modernize clinical trials by pioneering Master Clinical Trial Protocols (MAPs) such as basket, umbrella, and platform trials. These approaches can increase trial efficiency and lower costs.

MAPs move away from one-drug, one-disease trials. They involve one or more interventions in multiple diseases or a single disease with multiple interventions, each targeting a biomarker-defined population or disease subtype. A key feature of master protocols is the use of a common clinical trial infrastructure to streamline trial logistics, improve data quality, and facilitate data collection and sharing.

In the coming weeks, we’ll be issuing additional guidance on MAPs and efficient trial design strategies to help expedite the development of oncology drugs and devices. We’ll also be issuing guidance on the use of adaptive trial designs, and innovative endpoints like minimal residual disease in hematologic cancers. We recently issued draft guidance on the use of placebos in randomized trials in oncology. Advances in care, and trial design, can make it unethical and infeasible in some circumstances to use placebo controls in cancer trials. At the same time, the FDA is advancing the development of natural history models for rare diseases. These models may obviate the need for placebo arms in some trials by allowing researchers to replicate the behavior of patients who otherwise are left untreated.

As part of this effort, we’re also launching a complex innovative designs (CID) pilot meeting program to facilitate the advancement and use of novel clinical trial designs. The CID pilot will offer medical product developers an early opportunity to meet with FDA experts in all relevant disciplines from the agency’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) to discuss regulatory approaches to novel trial designs.

Medical devices present a different set of technical challenges and opportunities compared to drugs. But we’re employing the same principles to facilitate the agile development and review of innovative devices. For example, in the FDA’s Breakthrough Devices Draft Guidance, we proposed the use of “sprints” in which the sponsor of a breakthrough device identifies a regulatory challenge they need to solve. We then work interactively with the sponsor to address that challenge within a short timeframe — often just a few weeks. These early interactions have resulted in the development of flexible clinical study designs for certain breakthrough devices and in more FDA review team support and senior management engagement earlier in the development and review process. All of these steps are intended to enable the FDA to evaluate, and the sponsor to develop, innovative devices more efficiently. The FDA has granted 72 breakthrough device designation requests and, as of June 1, 2018, has approved or cleared six breakthrough devices.

As part of these efforts, CDRH continues to apply the “least burdensome” approach to all activities – exceeding what has been mandated in statute – related to medical device regulation. This concept will ensure that regulators and sponsors align on the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most efficient manner at the right time. This culture helps to further reduce the time and cost required to develop and market safe and effective new devices.

Together, the FDA’s Breakthrough Device program, least burdensome principles, and acceptance of greater uncertainty in appropriate circumstances are already making a dramatic difference in the health of millions of American patients. Just some examples of products that have come to market as a result of CDRH’s streamlined approaches include: an innovative device for  transcatheter aortic valve replacement (TAVR), the “artificial pancreas” (and subsequent expansion of approval to include individuals aged 7 to 13), the world’s smallest heart valve for newborns, first blood test in the world to evaluate mild traumatic brain injury, the first breakthrough-designated next generation sequencing (NGS) based IVD to detect cancer mutations in 324 genes, the first artificial iris in the United States, and the first mobile medical app to help treat substance abuse disorders.

Modernizing FDA’s Organization and Breaking Down Outdated Silos

Building on the FDA’s success in standing up the Oncology Center of Excellence, we’re also modernizing our organizational structure, flattening our review process, and breaking down review silos between different scientific disciplines that are important components of the medical product review process. The goal is to enable FDA review teams to be more disease focused, more integrated across the disciplines involved in drug review, and better able to evaluate and analyze data from agile clinical trials through a more structured approach to data review.

For instance, CDER has proposed an important series of new steps to modernize the organization and functions of CDER’s Office of New Drugs. Part of this involved structural changes. Other elements are aimed at process improvements that make the review process more predictable, consistent, and structured. The idea is to make the review of data more structurally consistent and improve the productivity of our clinical staff. This effort is starting with how we can more carefully and rigorously evaluate safety.

We’re implementing a more standardized, efficient, and comprehensive process for review of drug safety. This new process will leverage staff expertise in data analytics to develop more standardized approaches and templates for how we evaluate safety data as part of new drug applications. This process fully leverages the standard datasets that must be submitted in drug applications. It also brings in added quantitative and programming expertise in the conduct of safety analyses to support the medical team’s efforts. As part of this effort, we’re looking to make the review process more integrated, multi-disciplinary, and problem-focused; and to develop a review document that reflects this multi-disciplinary, problem-focused approach. By enhancing efficiency and providing greater support for the application review, we intend to “front load” this process. This approach should result in more time during the review cycle for key discussions, such as on labeling and on post-market requirements and commitments. These new processes should align well with our ongoing efforts to base our regulatory decisions on an informed assessment of the benefit-risk balance – by providing a deeper understanding of the risks, along with a comprehensive assessment of benefit, incorporating the patient’s perspectives and preferences.

These new approaches will bring added efficiency to our processes and improve our internal productivity. One benefit will be reducing routine administrative burdens on our new drug staff, elevating the role of our scientists and medical officers to take on even more thought leadership in their fields. We’ll use the productivity gained to channel more of the intellectual resources of our clinical staff into thought leadership activities that help advance the principles of regulation. As part of this effort, for example, we’re considering creating many new therapeutic-specific divisions that’ll have more ability to engage in discrete areas of medicine. The goal is to make sure that the drug review divisions are therapeutically focused to promote efficient review and provide greater scientific leadership to academic, industry and patient groups. The Office of New Drugs modernization will give our subject matter experts more time, better analytic tools, and more knowledge management support to advance the clinical and regulatory principles we rely on to evaluate the safety and efficacy of innovative products

This should allow the FDA to issue many more product-specific guidance documents. We plan to develop hundreds of new clinical guidance documents and make sure they stay up-to-date to reflect the latest science. We’ve already issued nearly 100 guidance documents in 2018 alone. Another goal is to allow the FDA’s staff to engage with stakeholders on new technologies like continuous manufacturing of drugs and biological products through the FDA’s Emerging Technology Program, designed to help industry implement innovative technologies that can improve product quality.

The FDA’s Device Center is undertaking a similar modernization of its approach. CDRH has explored, piloted, and developed implementation plans that will help CDRH improve information sharing, decision making, and work efficiency by instituting a Total Product Life Cycle (TPLC) approach to many of the core medical device review activities. TPLC will also enable CDRH experts to leverage their knowledge of pre- and postmarket information to optimize regulatory decision-making. Efforts underway at the FDA’s Device Center share a similar goal with the OND reform. The aim of FDA’s TPLC approach is to ensure not only that devices meet the gold standard for getting to market, but also that they continue to meet this standard as we get more data about devices and learn more about their benefit-risk profile in real world clinical settings.

Harnessing Real World Evidence              

As part of these efforts, the FDA is also actively working to evaluate the use of real-world evidence (RWE) to support regulatory decisions. This includes data captured from sources such as electronic health records, registries, and claims and billing data. Real world evidence can help answer questions that are relevant to broader patient populations or treatment settings where information may not be captured through traditional clinical trials. We are expanding our ability to use RWE for post-marketing safety surveillance, and exploring its potential to help support expanded label indications.

FDARA provided important funding to evaluate how RWE can be generated, and its potential use in product evaluation. The funding included significant new resources to enhance the FDA’s Sentinel system. To date, Sentinel has been used to assess safety. The FDA is now supporting the first randomized prospective intervention trial that makes use of information in the Sentinel system. To take one practical new example of this application, the IMPACT-Afib trial will test an educational intervention to address the important public health problem of underuse of effective medications to reduce the risk of stroke in patients with atrial fibrillation. This proof-of-concept trial can serve as a prototype for future RWE trials. At the same time, in another proof of concept study, the FDA is also funding a project to examine whether real world evidence that’s generated using observational data can replicate the results of approximately 30 randomized controlled clinical trials for drugs.

CDRH has also made one of its top priorities the development of a system of active surveillance for medical devices by building out the National Evaluation System for Health Technology (NEST). The goal is for this to ultimately help drive the development of safer, more effective devices, and timelier patient access to those devices. It will also increase the value and use of real-world evidence to support the needs of multiple stakeholders in our health care system, including the detection of emerging safety signals. NEST may also eventually be used to facilitate reimbursement (the Centers for Medicare and Medicaid Services serves on the NEST Governing Committee) as improved data collection can help encourage coverage with evidence development (CED).

FDA’s Role in Curating Standards for Novel Technologies

The agency’s role in curating standards for medical technologies can help advance innovation in areas that may lack consensus standards now. One example is through software-based platforms that are playing an increasingly central role in managing patient health. These tools can help more patients gain more control over their own health.

These software tools are becoming more sophisticated, enabling a broader set of opportunities. Artificial intelligence (AI), for example, holds enormous promise for the future of medicine. We’re actively developing a new regulatory framework to promote innovation in this space and support the use of AI-based technologies. So, as we establish and apply our Pre-Cert program – where we will focus on a firm’s underlying quality in assuring software products meet safety and effectiveness standards – we’ll consider how to account for one of the greatest benefits of machine learning – that it can continue to learn and improve as it is used.

We know that to support the widespread adoption of AI tools, we need patients and providers to understand the connection between decision-making in traditional health care settings and the use of these advanced technologies. One specific area that we’re exploring with stakeholders is how we can benchmark the performance of AI technologies in the field of radiogenomics, where AI algorithms can be taught to correlate features on a PET or MRI scan with the genomic features of tumors. This provides an opportunity to improve patient prognosis, identify early response to treatment, or develop novel imaging biomarkers that could be used to triage high risk patients who may need more frequent screening.

Toward these goals, the FDA is exploring the use of a neutral third party collect large annotated imaging data sets, for example highly annotated radiology scans used in a variety of clinical trials for specific disease indications, for purposes of understanding the performance of a novel AI algorithm for a proposed indication. Such a capability would enable a transparent benchmarking system for AI algorithm’s performance, and help providers and payors compare AI systems with the best human standard of care.

The FDA is also one of many stakeholders deeply interested in advancing the assessment and quantification of symptom and functional outcomes in cancer patients through clinical outcome assessments (COAs). COAs, in layman’s terms, are measures that describe or reflect how a patient feels, functions, or survives. Several technological advances hold promise to revolutionize how we can capture patient-centered clinical outcomes in controlled trial and real-world settings. One traditional COA is a survey that collects patient reported outcomes (PROs) through a questionnaire.

Electronic capture of PRO data (ePRO) is also becoming standard, providing a rich pipeline of structured clinical data. In addition to ePRO, mobile wearable technologies can complement traditional PRO surveys by generating objective, continuous activity and physiologic data. Obtaining reliable wearable device data on activity level, coupled with direct patient report on their ability to carry out important day to day activities, can provide information on physical function that is directly relevant and important to the quality of life of cancer patients.

Medical products are becoming increasingly sophisticated. The advent of advanced computing and systems biology will continue to help make health care more personalized, while connected technologies break down barriers between clinical research and real-world patient care. New platforms like targeted medicine, cell and gene therapy, and regenerative medicine hold more curative opportunities.

To facilitate these opportunities, and help make sure these innovations are able to improve public health, we’ve undertaken a comprehensive effort to make sure that our organization and policies are as modern as the technologies we’re being asked to evaluate, and that we’re able to efficiently advance safe, effective new innovations.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

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

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

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

Mission Possible: Moving the Needle Forward to Advance Health Equity

By: CAPT Richardae Araojo

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

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

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

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

Getting culturally sensitive messages out to minority communities

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

Ensuring minority representation in clinical trials

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

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

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

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

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

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

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

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

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

Arianna Simonetti

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

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

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

Richard Forshee

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

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

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

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


Blood Availability: A Model of Supply and Demand

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

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

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

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

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

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

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

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

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

Predicting Stem Cell Activity to Ensure Safe and Effective Therapies

By: Steven R. Bauer, Ph.D.

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

Steve Bauer

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

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

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

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

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

Stem Cell lab photo

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

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

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

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

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

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

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

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

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