How FDA Plans to Help Consumers Capitalize on Advances in Science

By: Scott Gottlieb, M.D.

We’re at a point in science where new medical technologies hold out the promise of better treatments for a widening number of vexing conditions. Over the last few decades, science has enabled fundamental advances in our understanding of the genetic and protein bases of human disease. These developments are already being translated into new medicines. In more cases, these treatments target the underlying mechanisms that drive different diseases. These advances hold out the promise of arresting and even curing a growing number of diseases.

Dr. Scott GottliebTo build upon such opportunities, FDA will soon unveil a comprehensive Innovation Initiative. It will be aimed at making sure our regulatory processes are modern and efficient, so that safe and effective new technologies can reach patients in a timely fashion. We need to make sure that our regulatory principles are efficient and informed by the most up to date science. We don’t want to present regulatory barriers to beneficial new medical innovations that add to the time, cost, and uncertainty of bringing these technologies forward if they don’t add to our understanding of the product’s safety and benefits.

This imperative is driven by our mandate to promote the public health. It includes a responsibility to make sure that we’re taking steps, within the scope of our existing responsibilities, to also help facilitate access to new innovations once FDA approves them. Access to advances in medical care is a critical component of public health. And the price of new technology affects the ability of people to access these new treatments. We therefore need to be mindful of the costs of our regulatory processes, to the degree that these costs also affect the availability of new innovations, and the way that they are ultimately priced.

New medical innovations are ultimately priced to a measure of the cost of the capital it takes to develop these technologies. This is true not only when it comes to the direct costs of research and development. Cost is also a function of the time and uncertainty of these endeavors.

For these reasons, as part of our public health mandate, we need to make sure that we’re taking a risk-based approach in everything we do. The 21st Century Cures Act gave FDA many new authorities and resources to accomplish this mission. “Cures” provides FDA with tools aimed at modernizing our regulatory programs. The goal of many of these efforts is to make sure that we’re taking every appropriate step to facilitate access to safe and effective new innovation.

Today we announced our detailed work plan for the steps we’re taking to implement different aspects of Cures. I want to highlight one example of these steps, which we’re investing in, and will be expanding on, as part of our broader Innovation Initiative. It’s the use of in silico tools in clinical trials for improving drug development and making regulation more efficient.

In silico clinical trials use computer models and simulations to develop and evaluate devices and drugs. Modeling and simulation play a critical role in organizing diverse data sets and exploring alternate study designs. This enables safe and effective new therapeutics to advance more efficiently through the different stages of clinical trials. FDA’s efforts in modeling and simulation are enabled through multiple collaborations with external parties that provide additional expertise and infrastructure to advance the development of these state-of-the-art technologies.

FDA’s Center for Drug Evaluation and Research (CDER) is currently using modeling and simulation to predict clinical outcomes, inform clinical trial designs, support evidence of effectiveness, optimize dosing, predict product safety, and evaluate potential adverse event mechanisms. We’ll be putting out additional, updated guidance on how aspects of these in silico tools can be advanced and incorporated into different aspects of drug development.

A variety of drug development, regulatory, and therapeutic questions are addressed by CDER through modeling and simulation strategies. CDER’s Office of Translational Sciences (OTS) uses these same strategies in the review of Investigational New Drugs Applications (INDs) and New Drug Applications (NDAs). To take just one example of the benefits of these approaches, as we enter an era of drug individualization, modeling and simulation that incorporates aspects of individual physiology and genetics in drug metabolizing enzymes is being used to identify patient subgroups that need dose adjustments. These approaches are incorporated to assess the combined effect of drug interactions, renal impairment, and hepatic insufficiency in patients, with clinical management strategies described in drug labeling where appropriate.

Another example is the use of modeling and simulation to assist in the creation of natural history databases to support model-based drug development. This could make clinical trials more efficient—for example, by enabling FDA to model some aspects of the behavior of the placebo arm in clinical trials. Right now, FDA is collaborating with scientists to develop such natural history models in Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and muscular dystrophy. An important objective of modeling and simulation is to better evaluate the behavior of new treatments in rare disease populations that are inherently hard to study due to their small size.

To advance these opportunities, we need to continue to invest in high performance computing. These computing capabilities are becoming a key requirement to the ability of our review staff to manipulate the large data sets that are now a common feature of drug applications. FDA is actively working to expand the agency’s capabilities in high performance computing, and to explore modeling approaches and enhance their regulatory impact, through an effort enabled by the work of the agency’s Scientific Computing Board.

FDA’s device center is also an integral part of this work. The Center for Devices and Radiological Health (CDRH) is also building in silico regulatory models for product design and evaluation, including the development of a digital library of models and a family of “virtual patients” for device testing. An important goal is consistency. We need to make sure that the adoption of these strategies is consistent across different medical products and across the agency.

FDA is working hard to maximize the authorities and resources Congress granted us to advance medical innovation for patients. To ensure smooth coordination and communication across the agency, we established an intra-agency Cures Steering Committee. Since enactment of the nearly 1,000-page law on December 13, 2016, the team has conducted a detailed analysis of the law’s provisions, compiled a list of all of its FDA-related requirements, and is helping to advance the work teams that will enable FDA to deliver on the law’s opportunities. Today, we’re posting an initial list of our Cures deliverables. It will eventually become a tracking tool to help the public follow our progress.

As you can see from the list, we’ve already implemented several important Cures provisions. Section 1002 of Cures authorized $500 million in new funding over 9 years to help FDA cover the cost of implementing certain parts of the law. Consistent with the law’s requirements, we developed a draft work plan demonstrating how FDA would use that funding, subject to annual appropriations. We submitted the draft work plan to FDA’s Science Board for its consideration at a public meeting in May. Today we’re posting the final work plan that we delivered to Congress on June 9th. It includes the recommendations from FDA’s Science Board.

Among some of the other noteworthy actions that we’re pursuing under Cures:

  • Our Center for Biologics Evaluation and Research (CBER) is implementing the Regenerative Medicine Advanced Therapy, or RMAT designation. This new process provides another pathway to access FDA’s existing expedited programs, and is available for certain cell therapies, therapeutic tissue engineering products, and certain combination products. The goal of these efforts is to help foster the development and approval of these novel products. We’ve already received almost two dozen requests for RMAT designation and granted four such designations to date. To continue to advance these opportunities, we’ll be announcing this September a comprehensive framework for the development and proper FDA oversight of regenerative medicine. This new policy effort will comprise a series of new guidance documents covering many aspects of the regulation of regenerative medicine products. It will be announced as part of our Innovation Initiative. It will delineate our policies for appropriate and efficient regulatory oversight of regenerative medicine products, in order to demonstrate their safety and effectiveness. It will also create an accessible framework that will enable providers to more easily collaborate on proving these principles for regenerative products that are advanced within local medical institutions. We want to help facilitate these scientific advances, which hold out tremendous potential for treating and even curing diseases. To achieve these goals, we need to make sure that we have a modern regulatory framework in place that can allow innovators to meet the statutory requirements for demonstrating safety and effectiveness.
  • The newly established Oncology Center of Excellence is the first inter-center institute at FDA that focuses on a specific disease area rather than type of product. It’s designed to take advantage of the synergies that can be achieved by coordinating the clinical review of products across FDA’s drug, device, and biologic centers to make the development of oncology and hematology medical products more efficient. This new center will allow our expert review staff to work together and take a life-cycle approach to the development and post-market regulation of new cancer treatment options.
  • Under provisions of Cures, CDRH exempted more than 70 Class I device types from the requirement to submit to FDA a 510(k) submission. CDRH also proposed exempting another 1,000+ Class II device types from having to submit a 510(k) submission based on an initial determination that premarket review is not necessary to provide a reasonable assurance of safety and effectiveness. This action will decrease regulatory burdens on the device industry and eliminate private costs and expenditures.
  • To further align our regulatory requirements with the provisions of Cures, CDRH also amended its current regulations to allow more devices to qualify for a humanitarian device exemption for small patient populations. We’ll allow researchers to seek approval for device clinical trials through a central institutional review board rather than mandating the use of local review boards. Under the provisions of Cures, CDRH has also published the list of reusable device types for which FDA will require validated instructions for use and validation data regarding cleaning, disinfection, and sterilization in 510(k)s. These new requirements go into effect on August 8, 2017.
  • Finally, last month CDER, working with CBER, issued a plan for the development and issuance of patient-focused drug development guidances. The workshops and the new guidance will set forth our plan to facilitate a more systematic approach to gathering and using patient perspectives to inform FDA’s regulatory decision-making.

We’re at the beginning of a transformative era in science and medical technology. Through our implementation of Cures, and our efforts to build on its provisions through a new Innovation Initiative, we hope that our collective efforts will help consumers benefit from this new progress. FDA’s headway in pursuing the opportunities enabled by Cures illustrates the agency’s enthusiasm and commitment to the law—both its letter and its spirit. Please bookmark the Cures web page and our tracker to follow our progress as we work to vigorously advance these shared goals.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

FDA Science: Working at the Speed of Emerging Technologies

By Luciana Borio, M.D.

Let’s face it, we’ve all gotten used to nearly instant access to almost anything.

Today, with a tap of an app, we order a car ride, a book, or pizza for dinner. Need to navigate past traffic in downtown city streets? No problem. There’s an app for that, too.

Some may wonder: Why hasn’t rapid medical product development partaken of this need for speed that has reshaped other sectors of our economy? Well, in many ways, it has.

Innovation is happening extraordinarily fast in the biomedical sciences and at FDA. As FDA’s Acting Chief Scientist responsible for leading and coordinating FDA’s cross-cutting scientific and public health efforts, I see close up that years of scientific research, collaboration, and investment are paying off.

FDA Acting Chief Scientist Lu Borio

FDA Acting Chief Scientist Luciana Borio

When I testified at a congressional hearing recently, my colleague, Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, gave a tangible example of what I mean. He said it took his team about three months to begin clinical testing of a Zika vaccine candidate developed from scratch. In 2003, it took the same team 18 months to develop a candidate vaccine to address the SARS outbreak and begin clinical testing of that product.

And in just over two decades, a disease like multiple sclerosis has gone from being untreatable to one for which clinicians are nearly “flummoxed by the options,” according to a headline I saw recently.

There is a reason for this success. In the last several years, scientists have identified and begun using “safety-risk biomarkers.” Rather than those for efficacy, these biomarkers identify which patients are at highest risk for certain adverse events. They have opened up an array of therapeutic options for patients who might do just fine with some treatments that may not otherwise have been developed due to our previous inability to properly assess their risk.

None of these successes would be possible without our FDA product reviewers working at breakneck pace to guide these innovative development programs.

It’s not always fully understood that FDA scientists play an essential role in advancing many biomedical innovations. That’s why we invite the public to participate in a two-day Science Forum at FDA every other year to showcase the agency’s robust scientific research and the important work done by our 11,000 scientists.

Just as industry focuses on product development research and academia focuses on the scientific foundation, FDA research concentrates on creating test methods and developing knowledge of processes to ensure that our products are safe and effective or, with tobacco, at least with reduced harm.

I like to think that this year’s Science Forum was better than ever. Over two days, hundreds of participants were treated to 230 scientific posters and some 50 presentations by FDA scientists and others, organized under eight broad categories:

  1. Identification and Evaluation of New Biomarkers;
  2. FDA Response to Urgent Public Health Needs;
  3. Microbiome and Human Health;
  4. Advanced Manufacturing and 3D Printing;
  5. Omics Technologies at FDA;
  6. Patient and Consumer Engagement and Communication;
  7. Computational Modeling and Simulation at FDA; and,
  8. Current Progress in Nanotechnology Research at FDA.

Four poster sessions during the two days augmented the presentations that featured the authors of studies describing the methodology, challenges, and results of their research one-on-one with those at the forum. Among the meaty topics discussed were:

  • The emerging technology of additive manufacturing and medical devices, produced by 3D printing. Bioengineers at FDA’s Center for Devices and Radiological Health have positioned themselves at the forefront of knowledge and research about this cutting-edge manufacturing process, by looking into patient matching, imaging, and phantoms. With our proactive posture, FDA is paving the way for safe and effective innovation that will usher in life-saving advanced treatments for patients.
  • The growing use in medical products of nanomaterials – equal to about one-billionth of a meter – so small that they can’t be seen with a regular microscope. Silver nanoparticles are now used in wound dressing for their antimicrobial properties. And liposomal nanoparticles are used as drug carriers to reduce toxicity and increase circulation time in the blood. Characterizing these complex nanomaterials is challenging. FDA scientists highlighted their analytical methods for characterizing nanomaterials in over-the-counter FDA-regulated products. This will help us with assessing risk, developing industry guidelines for characterizing nanomaterials, postmarket surveillance, and determining shelf life of nanomaterials in consumer products.
  • In the area of food safety, FDA has contributed to enhancing antimicrobial resistance monitoring in a collaborative effort with USDA and the Centers for Disease Control and Prevention. And, genomics studies conducted by FDA scientists have demonstrated that we can use the emerging technology whole genome sequencing as an effective tool for predicting antimicrobial resistance of certain foodborne pathogens.

Not all of our essential research deals with cutting-edge technology. Scientists from FDA’s Center for Tobacco Products (CTP) shared their work on water pipe, or hookah, smoking. Water pipes, a centuries-old method of smoking, are becoming an increasingly common method of tobacco smoking in young adults. A rare and serious lung disease – water pipe-induced acute eosinophilic pneumonia – has been reported among these smokers. One of the forum’s posters described how CTP scientists identified the disease and made physicians aware of it.

And, as a sign of the times, mobile communications also were part of the poster sessions. Healthy Citizen @FDA will be a holistic, citizen-centric mobile platform for FDA to collaborate and communicate with citizens to improve public health outcomes and to receive timely FDA alerts.

Of course, events like these are equally valuable for what happens before and after the formal presentations. From the snippets of conversation I picked up in the hallways, FDA and outside scientists had plenty of opportunity to interact, share ideas, and even discuss potential collaborations.

Those who attended the 2017 Science Forum gained a deeper understanding of the cutting-edge science we do at FDA to protect and promote the public health. And those who missed the Forum have the option of watching the recorded presentations on FDA’s website. We look forward to future opportunities to share more of the exciting advances we’re making with our partners in the scientific community.

Luciana Borio, M.D., is FDA’s Acting Chief Scientist

Fostering Medical Innovation: A Plan for Digital Health Devices

By: Scott Gottlieb, M.D.

It is incumbent upon FDA to ensure that we have the right policies in place to promote and encourage safe and effective innovation that can benefit consumers, and adopt regulatory approaches to enable the efficient development of these technologies. By taking an efficient, risk-based approach to our regulation, FDA can promote health through the creation of more new and beneficial medical technologies. We can also help reduce the development costs for these innovations by making sure that our own policies and tools are modern and efficient, giving entrepreneurs more opportunities to develop products that can benefit people’s lives.

Dr. Scott GottliebTo this end, FDA will soon be putting forward a broad initiative that is focused on fostering new innovation across our medical product centers. I will have more to say on many elements of this initiative soon. However, today I want to focus on one critical aspect of this innovation initiative: A new Digital Health Innovation Plan that is focused on fostering innovation at the intersection of medicine and digital health technology. This plan will include a novel, post-market approach to how we intend to regulate these digital medical devices.

According to one estimate, last year there were 165,000 health-related apps available for Apple or Android smartphones. Forecasts predict that such apps would be downloaded 1.7 billion times by 2017. From mobile apps and fitness trackers to clinical decision support software, innovative digital technologies have the power to transform health care in important ways, such as:

  • Empowering consumers to make more and better decisions every day about their own health, monitor and manage chronic health conditions, or connect with medical professionals, using  consumer-directed apps and other technologies to  help people  live healthier lifestyles through fitness, nutrition, and wellness monitoring;
  • Enabling better and more efficient clinical practice and decision making through decision support software and technologies to assist in making diagnoses and developing treatment options; managing, storing, and sharing health records; and managing schedules and workflow;
  • Helping to address public health crises, such as the opioid epidemic that is devastating many American communities. In fact, FDA conducted a prize competition to encourage the development of a mobile app to help connect opioid users experiencing an overdose with nearby carriers of the prescription drug naloxone for emergency treatment.

For these and other digital technologies to take hold and reach their fullest potential, it is critical that FDA be forward-leaning in making sure that we have implemented the right policies and regulatory tools, and communicated them clearly, to encourage safe and effective innovation. In this rapidly changing environment, ambiguity regarding how FDA will approach a new technology can lead innovators to invest their time and resources in other ventures. To encourage innovation, FDA should carry out its mission to protect and promote the public health through policies that are clear enough for developers to apply them on their own, without having to seek out, on a case-by-case basis, FDA’s position on every individual technological change or iterative software development.

Congress has already taken a major step to advance these goals in the 21st Century Cures Act. Expanding upon policies advanced by FDA’s Center for Devices and Radiological Health (CDRH), the Act revised FDA’s governing statute to, among other things, make clear that certain digital health technologies—such as clinical administrative support software and mobile apps that are intended only for maintaining or encouraging a healthy lifestyle—generally fall outside the scope of FDA regulation. Such technologies tend to pose low risk to patients but can provide great value to the health care system. FDA, led by CDRH, is working to implement the digital health provisions of the 21st Century Cures Act and, in the coming months, will be publishing guidance to further clarify what falls outside the scope of FDA regulation and to explain how the new statutory provisions affect pre-existing FDA policies.

FDA will provide guidance to clarify our position on products that contain multiple software functions, where some fall outside the scope of FDA regulation, but others do not. In addition, FDA will provide new guidance on other technologies that, although not addressed in the 21st Century Cures Act, present low enough risks that FDA does not intend to subject them to certain pre-market regulatory requirements. Greater certainty regarding what types of digital health technology is subject to regulation and regarding FDA’s compliance policies will not only help foster innovation, but also will help the agency to devote more resources to higher risk priorities.

In addition to these efforts, we are also announcing today a new initiative that FDA is undertaking. This fall, as part of a comprehensive approach to the regulation of digital health tools and in collaboration with our customers, FDA will pilot an entirely new approach toward regulating this technology. This will be the cornerstone to a more efficient, risk-based regulatory framework for overseeing these medical technologies.

While the pilot program is still being developed, we are considering whether and how, under current authorities, we can create a third party certification program under which lower risk digital health products could be marketed without FDA premarket review and higher risk products could be marketed with a streamlined FDA premarket review. Certification could be used to assess, for example, whether a company consistently and reliably engages in high quality software design and testing (validation) and ongoing maintenance of its software products. Employing a unique pre-certification program for software as a medical device (SaMD) could reduce the time and cost of market entry for digital health technologies.

In addition, post-market collection of real-world data might be able to be used to support new and evolving product functions. For example, product developers could leverage real-world data gathered through the National Evaluation System for health Technology (NEST) to expedite market entry and subsequent expansion of indications more efficiently. NEST will be a federated virtual system for evidence generation composed of strategic alliances among data sources including registries, electronic health records, payer claims, and other sources. The Medical Device Innovation Consortium (MDIC), a 501(c)(3) public-private partnership, is serving as an independent coordinating center that operates NEST. In the coming weeks, MDIC will announce the establishment of a Governing Committee for the NEST Coordinating Center comprised of stakeholder representatives of the ecosystem, such as patients, health care professionals, health care organizations, payers, industry, and government. Although FDA does not own or operate NEST, we have been establishing strategic alliances among data sources to accelerate NEST’s launch with the initial version of a fully operational system anticipated by the end of 2019.

Applying this firm-based approach, rather than the traditional product-based approach, combined with leveraging real-world evidence, would create market incentives for greater investment in and growth of the digital health technology industry. Such processes could enable developers to deploy new or updated software more rapidly and would help FDA to better focus our resources.

Through these and other steps, FDA will help innovators navigate a new, modern regulatory process so that promising, safe and effective developments in digital health can advance more quickly and responsibly, and Americans can reap the full benefits from these innovations. These efforts are just one part of a much broader initiative that FDA is currently undertaking to advance policies that promote the development of safe and effective medical technologies that can help consumers improve their health. Our goal is to make sure that FDA has the most modern and efficient regulatory approaches when it comes to evaluating new, beneficial technologies.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

How Creative FDA Regulation Led to First-in-the-World Approval of a Cutting-Edge Heart Valve

By: Jeffrey Shuren, M.D., J.D., and Bram Zuckerman, M.D.

Jeffrey Shuren

Jeffrey Shuren, M.D., J.D., Director of FDA’s Center for Devices and Radiological Health

Nearly six years ago FDA approved an artificial transcatheter heart valve (THV) to treat patients having severe symptoms and life-threatening heart problems such as fainting, chest pain, heart failure, irregular heart rhythms, or cardiac arrest, because one of the valves in their heart (the aortic valve) was no longer working properly and they were too sick for surgery.

Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of these patients.  But the U.S. wasn’t the trendsetter – in fact, it was the 42nd country to approve the first TAVR device, the Edwards Sapien THV.

Since that approval, FDA has sharpened its focus on patient access to innovative medical devices. On June 5th, 2017, FDA became the first regulatory body in the world to approve the most recent iteration of the Sapien valve, the Sapien 3, to treat high-risk patients whose surgically-placed aortic or mitral bioprosthetic valves were old and worn out. The Sapien 3 is intended to slip into these valves using a so-called “valve-in-valve” option, a procedure that can be done without open heart surgery through a patient’s blood vessel or a small cut in the chest.

Sapien 3

SAPIEN 3 Heart Valve Device

To narrow the gap from 42nd to first required creativity and commitment. The FDA Heart Valve Review Team first streamlined FDA’s expectations for nonclinical testing – something that had been a huge rate-limiting factor for translating innovative TAVR devices from bench to bedside. We became more consistent, predictable, and transparent about our expectations, which helped significantly reduce the total time to initiating clinical studies. And we worked closely with the industry on creative clinical trial designs and the use of other sources of clinical evidence that could demonstrate that the device is safe and effective when used in the intended patient population.

Bram Zuckerman

Bram Zuckerman, M.D., FDA’s Director, Division of Cardiovascular Devices, Center for Devices and Radiological Health

This latest approval is the most recent example of our increasing use of real-world evidence, made possible in this case by the Transcatheter Valve Therapy (TVT) Registry, a partnership of the American College of Cardiology and the Society of Thoracic Surgeons. The TVT registry collects clinical data on the performance of transcatheter valve replacement procedures performed in the U.S. once a product goes to market – including both on-label and off-label uses – making it possible, under certain circumstances, to accumulate more data faster, without the need for costly and time-consuming formal clinical trials.

Some 100,000 patients have received TAVR since FDA’s first approval in 2011, including more than 600 patients for what were then off-label, valve-in-valve uses. FDA relied on real-world evidence to evaluate the benefits and risks of this off-label use — such as the safety of the procedure, the function of the valve, and the improvement of patient symptoms – to approve the new indication for Sapien 3. This is a promising approach for the expansion of indications for other devices, provided robust registries are available.  FDA is working to broaden and improve the opportunities to leverage real-world evidence for many types of devices through the establishment of the National Evaluation System for health Technology, or NEST, which will integrate data from clinical registries, electronic health records, and medical billing claims to gather more comprehensive evidence of medical device safety and effectiveness.

CDRH Sapien 3 Reviewers

John C. Laschinger, M.D., Medical Officer, and Changfu Wu, Ph.D., Lead Reviewer, Members of FDA’s Structural Heart Devices Branch

And we’re not stopping here. U.S. medical device companies have long been accustomed to going overseas to conduct early feasibility studies (including first-in-human studies) for new heart valve devices, securing marketing authorization in other countries, and then returning to the U.S. for pivotal clinical trials before FDA approval. We’re trying to break that model with a new program that encourages early feasibility studies for new medical devices in the United States. These studies allow for early clinical evaluation of devices to provide proof of principle and initial clinical safety data, and may be appropriate early in device development when clinical experience is necessary because nonclinical testing methods are not available or adequate to provide the information needed to advance the developmental process.

Many heart valve device companies have already responded. Rather than traveling to other countries, they’re staying put in the U.S. for their early feasibility studies, saving on travel costs, enjoying more convenient communications with the investigators, and benefiting from early interactions with FDA.

These steps – along with our other reforms – will ensure that cutting-edge treatments get to U.S. patients as quickly as possible.

Jeffrey Shuren, M.D., J.D., is FDA’s Director of the Center for Devices and Radiological Health

Bram Zuckerman, M.D., is FDA’s Director, Division of Cardiovascular Devices, Center for Devices and Radiological Health

‘Radiating Shoe Sales’

By: Vanessa Burrows

Since the discovery of X-rays in the late 19th century, the technology has enhanced health care in a variety of ways. Like many cutting-edge scientific developments, however, it also has inspired uses of uncertain therapeutic value. That was the case with the shoe-fitting fluoroscope, the subject of the latest episode of FDA’s history video series.

Vanessa Burrons

Vanessa Burrows, FDA Historian, next to a shoe-fitting fluoroscope

Marketed as a scientific method for optimizing shoe fit, the fluoroscope appeared in shoe stores nationwide from the 1920s to the 1960s. But the machines not only didn’t do what they promised, they also exposed children, their parents, and store clerks to unhealthy doses of radiation.

In the late 1940s, scientists and regulators began to raise serious concerns about the dangerous levels of radiation. Over the next two decades, individual states gradually took action to either ban or restrict the use of the device.

By the 1970s, concerns grew about radiation emitted from common appliances, such as televisions and microwave ovens. And in 1971, FDA was given authority to regulate radiation-emitting devices. The agency continues this oversight, working to protect consumers from harmful novelty devices like the shoe-fitting fluoroscope. FDA also sets standards for medical imaging, surgical and therapeutic equipment, security systems, and consumer products – all for the protection of the health of American consumers.

We hope you enjoy your visit to FDA’s HistoryVault.

Vanessa Burrows is an FDA Historian

FDA and NIH Release Final Template for Clinical Trial Protocols

By: Peter Marks, M.D., Ph.D.

A little more than a year ago, FDA and NIH announced the availability of a draft template for investigators to use when organizing clinical trial protocols, which are essentially roadmaps for conducting a clinical trial.

Peter MarksToday, we are excited to announce that the NIH-FDA Joint Leadership Council has issued a final version of the template, a development which is likely to contribute important efficiencies to the process of protocol development, saving medical product development time and money.

The final version is intended for clinical investigators who are writing protocols for phase 2 and phase 3 NIH-funded studies requiring investigational new drug or investigational device exemption applications, but could also be helpful to other investigators conducting studies of medical products that are not regulated by FDA. It provides both instructional and sample text and reflects input from the public, consisting of nearly 200 comments from over 60 individuals. Importantly, it also has been harmonized with a separate protocol template that was recently developed by the private sector organization, Transcelerate Biopharma, for industry-sponsored research.

Clinical trial protocols are critical components of any medical product development program, describing trial objectives, trial design, methodology, statistical considerations, and trial organization.

Having a standard protocol format will facilitate review of protocols by regulators and others (e.g., institutional review boards). We believe that the template will help investigators prepare protocols that are consistent and well organized, contain all the information necessary for the clinical trial to be properly reviewed, and follow the International Conference on Harmonisation (ICH) E6 Good Clinical Practice guidelines. By clarifying expectations, the template will contribute important time and money-saving efficiencies.

Guidance is available from FDA on the content that should be included in a protocol to help ensure human subject protection and high data quality, but the guidance does not describe a standardized format for presenting this information. Placing relevant information in a standardized location in a clinical trial protocol can expedite the development and review of protocols thus enabling a quicker start of a clinical trial, potentially leading to more timely completion of studies and getting important new treatments to patients more quickly. What’s more, with the increased complexity of clinical development, such as use of combinations of different medical products, it is more important than ever that investigators understand protocol development expectations and capture important components right from the start.

NIH, which supports and conducts biomedical research, and FDA, which evaluates the safety and effectiveness of medical products and depends on high-quality research to inform its decisions, agreed that developing a protocol template would be an excellent opportunity to help improve the design of clinical trials. Our agencies believe that the availability of this template and accompanying instructional information will be very useful to investigators in creating well-organized, high-quality protocols — a benefit to everyone involved in medical product development.

Peter Marks, M.D., Ph.D., is the Director of FDA’s Center for Biologics Evaluation and Research

Working to Raise Awareness and Reduce Health Disparities

By: Jonca Bull, M.D.

Minority Health Month imageApril is National Minority Health Month and this year’s theme is “Bridging Health Equity Across Communities.”

FDA’s Office of Minority Health (OMH) is committed to the HHS mission of advancing health equity, and our office works year-round to advance FDA’s message of ensuring the safety and efficacy of our nation’s food supply and medical products to all communities, but with a focus on minority groups. The first HHS Office of Minority Health was established nearly three decades ago and FDA’s own office came into being in 2010.

Jonca Bull, M.D., is Director of FDA’s Office of Minority HealthIn the intervening years, we have made significant progress. But we are reminded daily that there is still more to be accomplished in the fight to reduce and eliminate health disparities.

Today, minority communities and those at the lower socioeconomic rungs still remain disproportionately burdened by chronic disease and are much more likely to succumb to certain illnesses.

Within the past year, we have worked diligently to connect our communities to resources to help educate and raise awareness about these issues. Highlights from our two programmatic teams include:

Outreach and communications –

Released English and Spanish language videos to encourage minority participation in clinical trials, with the most recent video being released this month;

  • Worked closely with the health fraud team in the Office of Regulatory Affairs to raise awareness about tainted and fraudulent products that target some ethnic groups;
  • Exhibited and presented at nearly a dozen conferences throughout the year; and,
  • Spearheaded the agency’s Language Access plan to help ensure that FDA materials are available to all consumers in their native language.

Research and Collaboration –

  • Worked with FDA centers and external partners to support research studies around minority health and health disparities. Projects included: Racial Disparities in Multiple Myeloma, Underutilization of Generic Medications in Underserved Patients, and Advertising and Promotional Labeling in Adult Immunization Disparities.
  • Funded multiple Centers for Excellence in Regulatory Research Science and Innovation (CERSI) projects with Georgetown University (Targeting triple negative breast cancer in African American women), University of California San Francisco/Stanford (Safer Labeling of Pediatric Medications: Reducing Literacy-related Health Disparities among Chronically Ill Adolescents), Johns Hopkins University (Workshop Clinical Trials: Assessing Safety and Efficacy for a Diverse Population);
  • Supported a genomics and health disparities fellow at Harvard University School of Medicine; and,
  • Hosted more than half a dozen fellows and pharmacy students from Howard University, the University of Washington, and Florida Agricultural and Mechanical University, among others.

In addition, last fall, OMH issued a draft guidance document titled, Collection of Race and Ethnicity Data in Clinical Trials-Guidance for Industry and FDA Staff with the goal to ensure that subpopulation data is collected consistently by industry. This document outlines FDA’s expectations for, and recommendations on, the use of a standardized approach for collecting and reporting race and ethnicity data in submissions for clinical trials for FDA regulated medical products conducted in the United States and abroad. We also hosted a webinar to walk through the document.

Working collaboratively within FDA and with external stakeholders, we will continue promoting and protecting the health of diverse populations through research and communicating of science information that addresses health disparities.

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

For more information read: The FDA Supports Research to Reduce Health Disparities

America’s Got Talent – Regulatory Science Style

By: Stephen Ostroff, M.D.

Veni Vidi Vici. It translates into English as “I came, I saw, I conquered.” It also happens to be the name chosen by one of the winners of the recently held America’s Got Regulatory Science Talent Competition.

America's Got Regulatory Science Event

Dr. Ostroff and FDA staff discuss projects with students from the University of Maryland CERSI.

FDA recognizes that young scientists are our future. Now in its fifth year, America’s Got Regulatory Science Talent is one of a number of initiatives FDA supports to encourage young scientists to pursue careers in the rapidly maturing field of regulatory science.

Each year, teams from the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (CERSI), and the University of Rochester’s Clinical and Translational Science Institute (CTSI), compete by presenting their proposed solutions to a current challenge in regulatory science. The students identify the needs by consulting eight priority areas identified in FDA’s Strategic Plan for Regulatory Science.

Winners are decided by a panel of judges after evaluating each presentation for its quality and novelty, and the proposed solution’s potential significance and feasibility. The winning teams come to FDA to formally present their ideas and have discussions with Agency scientists who are working in their project area. The event, held on April 12th, was sponsored by the Office of Regulatory Science and Innovation (ORSI) which is located in the Office of Chief Scientist. The winning teams certainly came, saw, and conquered.

This year’s winners are:

University of Maryland CERSI

Dr. Ostroff with the University of Maryland teams

Dr. Ostroff with the teams from the University of Maryland CERSI

1st Place Team – Veni Vidi Vici

A high-visibility universal labelling system to communicate risks of hazardous drugs. Wonder if your prescription medication has some dangerous side effects that may be noted in “fine print” – or even nowhere – on the label? A universal symbol in red and yellow in a prominent place on the label is the “Veni Vidi Vici” Team’s solution.

2nd Place Team – Biomarker Boys

Platform to improve transparency for biomarker integration in Accelerated Approval pathway. Tackling a challenge experienced in this growing area of biomedical innovation, the “Biomarker Boys” created a form that facilitates transparent and structured integration of biomarkers into rare disease state drug development.

University of Rochester CTSI

Dr. Ostroff with the University of Rochester teams

Dr. Ostroff with the teams from the University of Rochester CTSI

1st Place Team – Simple English Explanation Directive (SEED)

Making clinical trial results more accessible and functional. Team “SEED” takes the incredibly complicated language that is often found when describing a clinical trial, and puts it in easy-to-understand form.

2nd Place Team – 3-Defining Patient Matched Implants

A streamlined process to test 3-D printed personalized implants. The “3-Defining Patient Matched Implants” Team decided that a quality systems approach is needed to streamline the process of validating the integrity of individual patient-matched 3-D printed implant systems. Their proposal introduces an alternative approach to the current method used in 3-D printing to ensure implants are safe for implantation.

This competition reminds us that good science makes for good regulation. And it was great to see the outside-the-box thinking and innovative approaches these contestants took in addressing some of the challenges that FDA faces with the products we regulate. It’s also a good reminder that the future of regulatory science depends on training and education – and we cannot underestimate the importance of educational activities like these.

The innovative approaches from this year’s teams also show the power of collaboration, mirroring the collaborative approach FDA takes in leveraging the brainpower of our teams of scientists, engineers, statisticians, social and behavioral scientists, medical officers, communicators, and others. The teams from the University of Maryland and the University of Rochester demonstrate just how teamwork produces great results.

Congratulations to the schools for organizing the competitions and to the FDA mentors who encouraged the competitors. Each year the quality of the work improves and I’m certain it will benefit patients and consumers over the coming years. Please check out this year’s talent –including a presentation from a freshman at Maryland. Who knows? Maybe one of these students will be FDA Commissioner some day!

To see the finalists present their innovative solutions to regulatory science challenges, visit FDA’s America’s Got Regulatory Science Talent web page.

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

FDA flickr photos from FDA’s America’s Got Regulatory Science Talent 

FDA: Helping Small Businesses Get Big Results

By: Brenda Stodart, Pharm.D., and Renu Lal, Pharm. D.

It is well known that small business is vital to the success of the American economy. Less known, though, is how instrumental it has been to the growth and innovation in drug development.

Brenda Stodart

Brenda Stodart, Pharm.D. Captain, United States Public Health Service, Program Director at the FDA’s CDER Small Business and Industry Assistance Program, Division of Drug Information

We may think of the pharmaceutical industry in terms of giant corporations, but the fact is that there are hundreds of small firms – with very few employees – that are developing many of the important drugs that we use every day. FDA defines a small business as one with fewer than 500 employees (including employees of affiliates), but many are much smaller.

Industry sources indicate that, over the past decade or so, more than half of the novel drugs (i.e., those not previously marketed in the United States) developed in this country and approved by FDA, have been developed by small companies. Small companies also impact the generic drug industry creating market choice, competition, and increased access. According to FDA data, of the 2,176 new and generic drug applications submitted to the agency in 2014-2015, at least 639, or about 29 percent, were submitted by firms with fewer than 500 employees.

Small companies have certain advantages. They can be nimble with decision-making and can quickly progress with new ideas. A smaller drug development pipeline allows them to focus on a single or few products. But they also have unique challenges. A small workforce tends to require employees to wear multiple hats, as opposed to their larger counterparts who typically employ teams of specialists. And because many small companies are focused on developing one drug at a time, they often operate on a “high reward-high risk” model. There is a smaller margin for error for a small company that has invested all its resources in developing one drug than for a large company that is able to spread its risk across several products it is developing simultaneously.

Renu Lal

Renu Lal, Pharm.D., pharmacist at FDA’s Division of Drug Information, CDER Small Business and Industry Assistance Program

For many years, to help level the playing field, FDA has been assisting small pharmaceutical companies to maximize their opportunities for success. The Generic Drug Forum on April 4-5, 2017, is one example of the work we do to support small businesses. Organized by FDA’s Center for Drug Evaluation and Research Small Business and Industry Assistance (SBIA) staff, representatives from a wide range of pharmaceutical companies will gather to learn about the development, testing, review, and approval of generic drugs. CDER SBIA holds at least four meetings a year as part of a series called the Regulatory Education for Industry (REdI) conferences.

REdI conferences typically attract significant international attendance (in-person or via webcast). This global reach is important, as about 80 percent of active pharmaceutical ingredients used in U.S-manufactured drugs come from more than 150 different countries. The map below shows the geographic distribution of our most recent REdI conference registrants. Thirty percent of registrants were from outside the U.S., representing 55 countries worldwide.

CDER SBIA Conference Map

International participation at CDER SBIA REdI Conference [September 2016]

Many of these companies have never submitted an application for approval to FDA. Whether new or experienced, many are very early in the drug development process. In CDER’s SBIA program, 43 percent of the companies we work with have fewer than 100 employees, and 17 percent have fewer than 10 employees.

Although the mission of CDER SBIA is to help small business, our educational products are available to the entire pharmaceutical industry. In addition to REdI conferences, SBIA also offers webinars with live question and answer sessions by FDA subject matter experts on timely topics of interest to small companies.

SBIA recently held a half-day live webinar, which featured CDER experts from the Office of Pharmaceutical Quality (OPQ) discussing specific microbiology issues. CDER SBIA also provides a variety of helpful resources including a bimonthly electronic newsletter, CDER SBIA Chronicles, an audio podcast, CDERLearn, and online tutorials developed by CDER subject matter experts. We also interact with our constituents through our presentations and exhibits at conferences, and we are always available to help out via phone and e-mail. All slides, webcasts, and documents that we develop to help small companies are posted on the CDER SBIA Learn webpage after the event. REdI conferences and all other SBIA services are available at no cost to all who wish to attend and participate, which is particularly helpful to smaller companies with limited resources.

At a time when quality manufacturing and the safety and effectiveness of drugs in development is as important as ever, CDER understands that providing support to small businesses through education and resources is vital to advancing innovation and protecting public health.

Brenda Stodart, Pharm.D., Captain, United States Public Health Service, is a Program Director at FDA’s CDER Small Business and Industry Assistance Program, Division of Drug Information

Renu Lal, Pharm.D., is a pharmacist at FDA’s Division of Drug Information, CDER Small Business and Industry Assistance Program

FDA Advisory Committees: Independent, Informed, Essential, and Evolving

By: Robert M. Califf, M.D.

One of the most common concerns raised when I meet with medical leaders is the need to improve the function of FDA’s Advisory Committees (ACs). ACs play a key role in FDA’s decision-making process by providing independent expert advice on extraordinarily complex issues. Just as importantly, they offer a forum for open and transparent discussion about these processes. As their name suggests, ACs are only advisory, but they can yield unique insights into understanding the balance of benefits and risks of products.

Not every product is brought to an advisory committee — when the answers are clear, the FDA makes decisions without consulting an AC. But when products present challenging issues or involve developing areas of science, the views of experts in relevant fields can provide essential perspective needed to make good decisions.

They also provide a barometer for the public on Agency thinking in a given field and offer insight into Agency decision-making and requirements for successful product development in a particular setting. The views expressed and votes taken can have financial impacts on companies and can lead to changes in how investments are made in therapeutic areas. So it is not surprising that the deliberations and views of ACs often receive significant media attention.

ACs have been the subject of ongoing discussions concerning their impartiality, their transparency, and how they affect decisions made about FDA-regulated products. In response to these concerns, the FDA is taking a closer look at the AC meeting process to determine what changes may be needed to ensure that ACs remain able to provide crucial expert advice relevant to the uncertainties that prompt such meetings.

Robert Califf

The process of engaging the expertise needed for ACs requires careful consideration, and the goal of ensuring that such a critical function leads to the best advice with optimal public trust by eliminating or managing conflicts is embedded in both law and culture at FDA. Experts who comprise ACs generally are classified as “special government employees” (SGEs) of the FDA. As such, they must declare any potential conflicts of interest and undergo a rigorous financial screening to ensure that they do not have a conflict or apparent conflict that could preclude their participation. SGEs are also expected to be free of intellectual bias that may foreclose their ability to consider the data and questions with an open mind.

Sometimes, a compelling interest can justify allowing a SGE with a potential conflict to participate. In such a case, the prospective AC member must be granted a waiver or appearance authorization, which provide a mechanism for clearly delineating the reasons for allowing that person to participate and requires disclosing the conflict. This aspect of the AC process has evolved over time, becoming increasingly complex and burdensome.

In 2007, the Food and Drug Administration Amendments Act (FDAAA) restricted the FDA’s ability to use waivers for SGEs as part of an effort to reduce bias among AC members by allowing minimal or no financial conflicts. This led to concerns from multiple stakeholders about whether the FDAAA provision was in fact discouraging the most qualified experts from serving on ACs and thus depriving FDA of the best possible guidance on important scientific issues.

In response to these concerns, Congress included a provision in the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) that encouraged FDA to weigh an AC member’s conflicts against the need for that participant’s scientific expertise. However, despite this added flexibility, there are many who believe FDA has not been aggressive enough in advocating for waivers — a circumstance that they believe has sometimes resulted in difficulty obtaining the optimal expertise needed to address the complex problems typically brought to ACs. And some outside the Agency have wondered whether this means FDA is moving to reduce use of ACs.

The process for AC participation itself has led to other criticisms. Across academia, the AC system is seen as overburdened with unnecessary paperwork. Additionally, FDA has faced criticism that the concept of an “imputed interest” is interpreted so that academic leaders with significant experience and insight are considered to have conflicts relating to grants and contracts held by faculty members at the same institution — even if they themselves have no involvement with the project. The proliferation of roadblocks to serving as an SGE has led some within FDA and key leaders in various scientific fields to question the value of ACs in their current form.

After indepth discussion with the medical product and tobacco Centers, OMPT initiated a process improvement evaluation using Lean concepts, which comprise an industrial engineering toolset used for process improvement. These tools were applied to the AC process to fully understand the administrative requirements for planning meetings and screening potential SGEs. We are confident that administrative processes, both inside FDA and for SGEs, will be streamlined as a result.

The next step will be to evaluate current policies and identify areas where the evaluation of conflicts of interest for SGEs can be modernized. We must consider questions such as the criteria for disqualifying AC members from specific activities, the appropriate scope of “imputed interests,” and the interrelationship between the advisory role of AC members and the decisional role of Agency employees.

Even more importantly, we must engage in wide-ranging discussions inside and outside FDA about the best ways for the Agency to get the advice it needs to make critical decisions that protect and promote the health and safety of all Americans. To obtain the best expertise possible, we must optimally configure and administer our ACs.

There is no question that we must appropriately address potential conflicts for our SGEs.  However, we must also ensure that experts working in their fields are not unnecessarily foreclosed from participation in the AC process. As we continue to improve the mechanics of ACs and to reduce unnecessary administrative burdens, we must also address the appropriate mix of expertise on committees, so that FDA scientists and staff get the advice they need to make the best decisions on behalf of the American public.

Robert M. Califf, M.D., is Commissioner of the U.S. Food and Drug Administration