Building a Strong FDA Workforce to Bring Scientific Advances to Patients

By: Scott Gottlieb, M.D.

The key to FDA’s public health mission, and its ability to bring innovative new therapies to patients, is the technical, scientific, and clinical expertise of its people. As the products that we’re asked to review become more complex and specialized, so do the technical demands on our workforce. Our staff must remain current with the dramatic advances in science and medicine and meet the increasing demands that globalization and other trends place on our core consumer protection functions.

Dr. Scott GottliebAs a result, FDA continually faces the challenges related to building and maintaining a diverse, talented, and dedicated professional workforce. However, we’re committed to doing what’s necessary to tackle these challenges and maintain a strong FDA — one that attracts and preserves world-class talent.

Most recently, I’ve requested a comprehensive effort to evaluate our hiring practices and procedures. We know that our traditional approach to recruiting and hiring is not as efficient as it should be to attract, hire, and retain the types of experts we need now and anticipate to need over the longer term. What’s more, we’re increasingly competing with better-resourced entities in the private sector for the same limited pool of people with very specific clinical and scientific skills and training. These are challenges that our current approach to hiring did not anticipate. It’s critical that we modernize the process for recruiting personnel into these specialized positions within our Agency’s programs.

As part of a new effort, and consistent with Secretary Price’s Reimagine HHS initiative, we’ll be piloting new hiring procedures aimed at better supporting the hiring goals required to meet FDA’s evolving needs. I’m very pleased that Melanie Keller, currently head of the Office of Management in our Center for Drug Evaluation and Research, has agreed to lead this effort on a full-time basis. She’ll be running the pilot from a newly created position inside the Office of Medical Products and Tobacco.

A central part of this new effort will involve more directly aligning the administrative hiring procedures and the scientific staffing objectives of our programs. Thus, the directors of the medical product centers participating in the pilot will be closely involved in overseeing the new initiative. They’ll help ensure that the scientific objectives of our review programs are more closely reflected in the recruitment and hiring process. We want to make sure that FDA’s existing experts are more personally involved in hiring our new experts. Although we face similar challenges across many of our programs, the pilot will initially focus on PDUFA- related positions in our drug and biologics programs while we develop our new model.

To take on this new effort, we’re establishing a dedicated group of full-time staff with the responsibility to ensure that we reliably and predictably identify, recruit, and efficiently hire the scientific personnel the Agency needs. Professional staff from our centers with experience recruiting specialized scientific and medical staffing will be key members of this new pilot effort. Staff from the Office of Operations will assist with the identification of potential candidates from key scientific disciplines.

The first order of business will be to address hiring into the positions supported by our PDUFA commitments. Too many of these positions remain vacant, and the backlog is substantial. Finding the right people and bringing them on staff quickly has proved difficult. Our goals will be to speed the hiring process while improving the retention of scientific and technical experts. We’ll aim to reduce and eventually eliminate the backlog of vacant positions while demonstrating the utility of our new hiring model. I encourage scientific professionals and technical experts who wish to join an outstanding workforce serving the public health to review the available job opportunities at FDA.gov.

I’m heartened by the progress FDA’s reauthorization legislation is making through Congress, and I look forward to its final passage. In the meantime, the new efforts I’ve outlined here will provide a solid foundation for recruitment and for responsibly managing our user fee resources. The reauthorization, coupled with key provisions in the 21st Century Cures Act— which give FDA the authority to bring on top candidates at competitive salaries — will greatly assist us as we modernize our recruitment policies, systems, and procedures. All of these efforts will strengthen FDA’s core functions, enabling us to ensure that safe and effective advances can reach the patients who need them as efficiently as possible.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

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

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

PRISM Identifies Vaccine Safety Issues

By: Azadeh Shoaibi, Ph.D., M.H.S.

The word “prism” might make you think of a triangular piece of glass that separates white light into a rainbow of colors.

Azadeh ShoaibiBut at FDA, it means a powerful, computer-based system that separates critical bits of information from vast streams of healthcare data in order to investigate adverse events and determine if there is a connection to a specific vaccine. And while the FDA prism–called Post-licensure Rapid Immunization Safety Monitoring System (PRISM)—might not have such a colorful name, it’s a bright light in the agency’s continual efforts to identify adverse effects in a timely manner.

PRISM is a cooperative effort between FDA’s Center for Biologics Evaluation and Research and its partners in the health care and medical insurance communities. It analyzes health insurance claims data from four national healthcare plans: Aetna, HealthCore (Wellpoint), Humana, and OptumInsight (United Healthcare).

Prism image

PRISM is a computer-based vaccine safety monitoring system that separates out critical information from vast streams of healthcare data. A part of the Sentinel Initiative of FDA, PRISM broadens the agency’s ability to monitor critical healthcare products in support of its mission to protect and advance public health.

Since it was first inaugurated in 2010, PRISM has made valuable contributions to public safety.

For example, FDA was able to use the system to reassure the public that there was no link between an influenza vaccine and increased risk of febrile seizure in children (convulsion or seizure brought on by a fever). Another PRISM study comprising more than 1.4 million doses of Gardasil doses found no evidence of venous thromboembolism after vaccination among females 9 to 26 years old. FDA also used PRISM to identify a link between a rotavirus vaccine (RotaTeq) and an increased risk of intussusception in infants.

These case studies, along with other information, were discussed at a public meeting in December called to discuss what the system has accomplished and how it’s used in the regulatory process. The purpose of the workshop was to describe the Sentinel Initiative (a national electronic system for medical product safety surveillance) and the PRISM program, illustrate how FDA uses PRISM for regulatory responsibilities, and discuss the future direction of PRISM, including its further integration into the regulatory review process.

Stakeholders, including manufacturers, academics, the public, and other federal agencies, who participated in the workshop had an opportunity to weigh in with their opinions about the system, discuss its limitations, and offer ideas for improving it.

PRISM is one component of FDA’s Sentinel Initiative, which monitors the safety of a variety of FDA-regulated medical products by examining information in electronic healthcare databases.

Sentinel performs what is called “active” surveillance, as opposed to “passive” surveillance. Passive FDA surveillance systems depend on industry, consumers, patients, and healthcare professionals to recognize and report suspected adverse events to an FDA web site, such as the Vaccine Adverse Event Reporting System (VAERS). This means that FDA might not become aware of potential problems related to a licensed product for months.

Unlike passive surveillance, Sentinel’s active surveillance lets FDA initiate its own studies using existing electronic healthcare data in a timely manner. Sentinel also lets FDA evaluate safety issues in targeted groups, such as children, or to evaluate specific conditions (e.g., heart attacks) that are not usually reported as possible adverse events of medical products through passive reporting systems.

So by adding an active surveillance capability to FDA’s toolbox, Sentinel broadens FDA’s ability to monitor the safety of a spectrum of licensed medical products in support of the agency’s mission to protect and advance public health.

Azadeh Shoaibi, Ph.D., M.H.S., is the Sentinel Lead at FDA’s Center for Biologics Evaluation and Research

This is Not a Test: RMAT Designation Goes Live

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

The field of regenerative medicine encompasses a wide scope of innovative products including cell therapies, therapeutic tissue engineering products, human cell and tissue products, and certain combination products using such therapies. Examples include genetically-modified cellular therapies, such as chimeric antigen receptor T-cells (CAR-T cells) and human tissues grown on scaffolds for subsequent use. These products hold great promise in addressing serious unmet medical needs. For example, data from a number of different published studies indicate the potential for CAR-T cells to treat certain relapsed or refractory blood cancers.

Peter MarksRecognizing the importance of this field, Congress included several provisions related to regenerative medicine in the 21st Century Cures Act, signed into law on Dec. 13, 2016. Building on the FDA’s existing expedited programs available to regenerative medicine products, one of these provisions established a new program to help foster the development and approval of these products: Regenerative Medicine Advanced Therapy (RMAT) Designation.

Sponsors of certain cell therapies, therapeutic tissue engineering products, human cell and tissue products, and certain combination products may obtain the RMAT designation for their drug product if the drug is intended to treat serious or life-threatening diseases or conditions and if there is preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for that disease or condition. Sponsors may make such a request with or after submission of an investigational new drug application and the agency then will take action on the requests within 60 calendar days of receipt.

Sponsors of RMAT-designated products are eligible for increased and earlier interactions with the FDA, similar to those interactions available to sponsors of breakthrough-designated therapies. In addition, they may be eligible for priority review and accelerated approval. The meetings with sponsors of RMAT-designated products may include discussions of whether accelerated approval would be appropriate based on surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites.

Once approved, when appropriate, the FDA can permit fulfillment of post-approval requirements under accelerated approval through the submission of clinical evidence, clinical studies, patient registries, or other sources of real world evidence such as electronic health records; through the collection of larger confirmatory datasets; or through post-approval monitoring of all patients treated with the therapy prior to approval.

The FDA’s Center for Biologics Evaluation and Research is committed to helping make regenerative medicine advanced therapies that are shown to be safe and effective available as soon as possible, particularly for patients with serious or life-threatening diseases or conditions lacking other treatment options.

We have started receiving RMAT designation requests and expect that, as with Breakthrough Therapy Designation, early and frequent communication facilitated by the RMAT designation will help reduce overall product development times. We very much look forward to continuing to work with sponsors of these products and other stakeholders to help make these exciting new therapies available to those in need.

Peter Marks, M.D., Ph.D., is the director of the Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration.

FDA-Patented Invention Earns 2016 Patents for Humanity Award for Impact on Global Public Health

By: Carolyn A. Wilson, Ph.D., and Alice Welch, Ph.D. 

In 2003, two scientists in FDA’s Office of Vaccines Research and Review within the Center for Biologics Evaluation and Research (CBER) developed a pivotal step in the manufacture of a vaccine now called MenAfriVac. This vaccine has since protected more than 235 million lives against recurring meningitis outbreaks in sub-Saharan Africa. The patented chemical method devised by these two researchers, Dr. Robert Lee and Dr. Carl E. Frasch, enabled the production of the inexpensive and highly effective MenAfriVac vaccine, earning FDA a 2016 Patents for Humanity Award from the U.S. Patent and Trademark Office.

Carolyn A. Wilson

Carolyn A. Wilson, Ph.D., Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

FDA’s scientific research doesn’t often grab headlines. But FDA’s research program is a critical part of the work we do to protect public health and speed innovations that make safe and effective medicines available. And sometimes FDA scientists make significant discoveries that are patentable inventions. When they do, FDA’s Technology Transfer program facilitates the transfer of such technologies to the private sector so they can become useful solutions to public health challenges. The MenAfriVac vaccine is a stellar example of such an FDA invention.

So it was with particular pride and satisfaction that we joined Drs. Lee and Frasch this past November as the U.S. Patent and Trademark Office honored them with a Patents for Humanity Award, in recognition of the critical contribution the patented technique made to the development of the MenAfriVac vaccine.

The story began in late 2003, when Dr. Lee devised a set of chemical reactions for a technique called “conjugation.” It is a method for efficiently linking one ingredient of a potential vaccine with a molecule that supercharges that ingredient’s ability to stimulate the immune system. That chemical joining, along with the collaboration with Dr. Frasch, became the basis of the FDA patent.

At the time, it was just another quiet development in the quest to make the production of certain types of vaccines more efficient. Little did the two researchers know that this patent would later help the Bill & Melinda Gates Foundation-supported non-profit PATH save tens of thousands of lives in the African meningitis belt.

Alice Welch

Alice Welch, Ph.D., Director of FDA’s Technology Transfer Program.

Just a couple of years earlier in 2001, the Meningitis Vaccine Project (MVP), a World Health Organization (WHO) and PATH partnership, had received Gates Foundation funding. Their goal was to produce an inexpensive, safe, and effective vaccine so that the affected countries could afford mass group A meningitis vaccination programs.

But MVP lacked access to a technique that was simple, efficient, and produced meningitis vaccines inexpensively. Thanks to the scientific accomplishment of these two scientists, CBER was able to provide its new technique to MVP via PATH, through a technology transfer agreement made with help from the National Institutes of Health. CBER also developed reagents to evaluate the performance and safety of the vaccine as well as methods to monitor the manufacturing process. And in December 2003, scientists from the Serum Institute of India Limited came to CBER to learn how to use the technique to make the vaccine on MVP’s behalf. The resulting vaccine didn’t need to be refrigerated, which greatly simplified deployment of this product in sub-Saharan Africa.

Awards Ceremony

Alice Welch holds the 2016 Patent for Humanity Award from the US Patent and Trademark Office.
Also in attendance for the ceremony were (left to right) Carolyn Wilson, Carl Frasch, and Robert Lee.

Early in December 2010, MVP initiated its vaccination campaign using MenAfriVac, first in Burkina Faso, then Mali, and then Niger. A year later, MVP extended the campaign to Cameroon, Chad, and Nigeria.

WHO is now helping countries transition from mass campaigns to routine immunization to establish sustainable disease control in the region. By 2020 the vaccine is expected to have protected more than 400 million people, preventing 100 million cases of meningitis A, 150,000 deaths, and 250,000 cases of severe disability.

In an era when established and emerging infectious disease outbreaks affect the lives of more people worldwide than ever before, the American public and the global community will increasingly depend on FDA to provide the kind of scientific research and expertise that have led to the successful development of medical countermeasures and vaccines like MenAfriVac.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

Alice Welch, Ph.D., is Director of FDA’s Technology Transfer Program.

21st Century Cures Act: Making Progress on Shared Goals for Patients

By: Robert M. Califf, M.D.

Today, President Obama signed into law the 21st Century Cures Act, which, I am pleased to report, builds on FDA’s ongoing efforts to advance medical product innovation and ensure that patients get access to treatments as quickly as possible, with continued assurance from high quality evidence that they are safe and effective.

Robert CaliffCures will greatly improve FDA’s ability to hire and retain scientific experts. One of our ongoing challenges has been recruiting and retaining the experts we need in specialized areas to allow us to get our work done and meet our growing responsibilities. This is an especially important need given the tremendous advances in biological sciences, engineering, information technology and data science. Preventive, diagnostic and therapeutic strategies will become more complex with much greater potential for benefit and in some cases greater risk if used without adequate evidence to exclude risks that exceed potential benefits.

This new law rightly recognizes that patients should play an essential role in the development of drugs and devices to diagnose and treat their disease, since patients are in a unique position to provide essential insights about what it is like to live with and fight their disease. That’s been our perspective as well, and it’s why FDA has continued to advance the science of patient input through our patient-focused drug development program and our partner with patients program for medical devices. As it is, Cures will enhance these ongoing efforts to better incorporate the patient’s voice into FDA’s decision-making.

Cures will also support our efforts to modernize and improve efficiency in clinical trial design. This has been an important FDA priority for decades, but exciting new approaches are now available, and we need to develop a common understanding of which designs should be used for which clinical issues. In cancer, for example, we’re already weighing the use of common control trials, which share a control arm, involve multiple different drugs for the same indication, and may even involve different companies. One of the benefits of using a common control arm is that the overall number of patients who need to be recruited and enrolled decreases, thereby optimizing clinical trial resources and potentially shortening the time it takes to get a new study off the ground

Even without the benefit of Cures, patients have been well-served by FDA’s program efficiencies, emphasis on early meetings, and use of expedited pathway programs to speed approval and delivery of new drugs and devices to patients. Rather than passively processing product applications, FDA works to advise companies and inventors from the earliest stages of the development process on the kinds of medical products needed, how to do the necessary research, and how to viably and effectively translate from concept to product. This not only means that important new products will be developed as efficiently as possible but also that medicines and devices with no chance of success are identified much earlier so that money isn’t wasted on futile development. These programs have been embraced by developers of medical products in this country, and they are making a real and positive difference.

In the United States, the FDA uses expedited programs (fast track, priority review, accelerated approval, and breakthrough therapy) for drugs and biologics more than comparable drug and biologic regulators in other countries use theirs and as a result FDA is the first to approve a majority of novel drugs compared to our foreign counterparts.

For devices, this past year was the first full year of operation for FDA’s expedited access pathway (EAP) program, which helps speed the development and availability of certain medical devices that demonstrate the potential to address unmet medical needs for life-threatening or irreversibly-debilitating diseases or conditions. So far, we have granted 24 devices access to this program. Cures builds on EAP by creating the breakthrough device pathway.

The law establishes other new programs as well. For instance, the Limited Population pathway will help streamline the development programs for certain antibacterials and antifungals intended to treat targeted groups of patients suffering from serious or life-threatening infections where unmet need exists due to lack of available therapies. Approvals of these antimicrobials are expected to rely on data primarily targeting these limited populations. The statement “Limited Population” will appear prominently next to the drug’s name in labeling, which will provide notice to healthcare providers that the drug is indicated for use in a limited and specific population of patients. The limited population statement, additional labeling statements describing the data, and FDA review of promotional materials, will help assure these drugs are used narrowly to treat these serious and life-threatening infections while additional evidence is generated to assess safety and effectiveness for broader use.

Cures also creates a new program for  the development of regenerative medicine products, an important and exciting new field that deserves this special focus. The program designates drugs as regenerative advanced therapies and takes appropriate actions to improve the efficiency of development and to enhance the exchange of information among FDA, researchers and developers. An especially important element of this program is the creation of a research network and a public-private partnership to assist developers in generating definitive evidence about whether their proposed therapies indeed provide clinical benefits that are hoped for.

Looking ahead, much still needs to be done to spur product development. There have yet to be successful therapies identified for certain diseases, such as Alzheimer’s disease, where underlying scientific knowledge is still lacking.  In addition, we are only at the early stage in building a national evidence generation system based on registries, claims data, and electronic health records that will be a rich source of post-market data and an avenue for conducting more efficient research. Last week we published a consensus of FDA leadership on the use of real world evidence in the New England Journal of Medicine, focusing on the misperception that randomized trials and real world data are incompatible.  In fact, the use of randomization within the context of clinical practice will constitute a major advance in evidence generation and we are actively encouraging proposals with this combination of randomized trials conducted in real world practice. Cures provides support for continued exploration of the use of real world evidence in the regulatory context.

The law also addresses drug firms providing healthcare economic information to payers and formulary committees. This complex area will require careful delineation of principles to guide information exchange to enable these entities to appropriately assess the value of drugs.

With Cures, great progress has been made towards our shared goal of advancing regulatory science so that we can continue to speed the discovery, development, and delivery of medical products to prevent and cure disease and improve health while sustaining the evidence framework that enables assurance to the public of the safety and effectiveness of medical products. We are excited about the major advances in NIH funding, and welcome the increasing focus on rigorous translational science and data sharing reflected in the bill. Furthermore the funding of opioid addiction treatment and mental health services is a major positive element for our country and consistent with tremendous needs that we recognize.

FDA now stands ready to work with Congress, our sister federal agencies and the medical products ecosystem to implement these important provisions as we continue to work on behalf of all Americans to protect and promote public health and promote innovation in this exciting time.

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

The Mutual Reliance Initiative: A New Path for Pharmaceutical Inspections in Europe and Beyond

By: Dara Corrigan, J.D.

Dara CorriganFor FDA professionals focused on drug quality and safety, the rapid increase in imported drugs from nations where we devote limited inspection resources is of great concern. One way to address this concern would be to create an expanded inspectorate, one where investigators and inspectors from FDA and trusted partners, such as those in the European Union, would work together, rely on each other’s inspections, avoid duplicating inspections, and conduct more inspections in areas where the increase in drug manufacturing has greatly increased, like in China and India.

To meet this challenge, FDA has responded with the Mutual Reliance Initiative (MRI). The concept is simple. EU country inspectors inspect in their respective countries, FDA inspects the manufacturing facilities in the U.S., and the EU and FDA would rely upon each other. This would avoid duplication, lower costs, and enable the regulators to devote more resources to other parts of the world where there is greater risk. The savings would be considerable – over the last 5 years, about 40 percent of FDA’s drug inspections were performed in the EU.

The Mutual Reliance Initiative

There is a history to U.S.-EU collaboration. In 1998, in an annex to a U.S.-EU trade agreement, the U.S. and the EU agreed to recognize each other’s good manufacturing practice drug inspections. However, the agreement was never fully implemented.

Since 1998, FDA has expanded its reach beyond U.S. borders by opening foreign offices in China, Europe, India, and Latin America. We conduct more foreign inspections now and have gathered more than 15 years of experience in collaborating with the EU.

Equally important was the 2012 passage of the Food and Drug Administration Safety and Innovation Act. Congress recognized that FDA cannot and should not monitor the world’s drug inventory by itself and authorized FDA to accept the findings of a foreign inspector when its drug inspectorate is capable of conducting inspections that meet U.S. standards.

Working With The EU Inspectorates

The MRI was launched in May 2014. As part of MRI, FDA and EU assembled dedicated teams to assess the risk and benefits of entering into a mutual recognition agreement. FDA was invited to observe the EU’s Joint Audit Programme, in which two EU nations audit the inspectorate – the regulatory authority – of another member. FDA first observed the audit of Sweden’s inspectorate by auditors from the United Kingdom and Norway. Since then, FDA has observed an additional 12 audits of drug inspectorates across the EU with more audit observations planned through 2017.

This unprecedented access allows FDA observers to gather firsthand knowledge of the laws that govern EU GMP drug inspections and how inspectorates manage the drug inventory within their respective borders. Also, interacting with auditors across the EU provides a unique opportunity to understand the regulatory framework in the EU. With 28 member states (27 after Britain leaves the EU), there can be differences FDA must understand.

And to clarify, the so-called “Brexit” has no impact on FDA’s relationship with our United Kingdom counterparts at this time. Once the UK finalizes its departure from the EU, FDA and the UK will reexamine existing commitments and, if necessary, renegotiate any existing agreements. According to reports, it is likely going to take the UK and EU two years to finalize the terms of the Brexit.

MRI is one of the key components of the pharmaceutical sector covered in the Transatlantic Trade and Investment Partnerships (T-TIP) but could also take another path if the initiative progresses more quickly than the trade negotiations.

The observation and analysis of the drug inspectorates in the EU has only been possible because of the extraordinary devotion and collaboration across FDA. Observers of the audits have included subject matter experts, management, and investigators from the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, the Office of Regulatory Affairs and the Office of Global Regulatory Operations and Policy. These same FDA employees, and others, guided FDA successfully through the EU’s audit of FDA in September 2015 when the EU visited three district offices, the main campus, and a drug laboratory as part of its assessment. The EU team applied the same criteria that it applies within the EU when it audits its own member states.

Looking Forward

What is next? We hope to sign an agreement with the EU soon and are working to complete assessments of the capability of the drug manufacturing inspectorates of two to four countries within the EU.

These first steps with the EU will lead toward our goal of an expanded inspectorate, containing investigators and inspectors from FDA and from across the EU. These collaborations will enhance our ability to evaluate risk, produce better data, and minimize public health risk globally. Indeed, the need to engage globally in different ways is imperative. With MRI, we are moving boldly forward in that direction.

Dara Corrigan, J.D., is FDA’s Associate Commissioner for Global Regulatory Policy

Combination Products Review Program: Progress and Potential

By: Nina L. Hunter, Ph.D., and Robert M. Califf, M.D.

Nina Hunter

Nina L. Hunter, Ph.D., FDA’s Associate Director for Science Policy in the Office of Medical Products and Tobacco

About a year ago, we shared with you our Combination Product Review, Intercenter Consult Process Study Report, which was developed by FDA’s Office of Planning. The report’s findings were derived from focus group studies with reviewers from FDA’s different Centers and included input from industry. Since then, we have built on foundational policies and processes to address many of the issues identified in the report.

The team has made tremendous progress toward the goal of modernizing the combination products review program by improving coordination, ensuring consistency, enhancing clarity, and providing transparency within the Agency as well as with all stakeholders. We are excited to share our progress with you now. The table below summarizes some key achievements from the past year, including publication of draft guidances, a variety of new processes, and a look at future goals.

Robert Califf

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

As technologies advance across multiple fields, the distinctions that previously allowed combination products to be neatly categorized by FDA’s medical product centers are blurring or even vanishing.

Combination products account for a growing proportion of products submitted for review, and FDA will continue to pursue new approaches to collaboration that ensure safe, effective and innovative medical products are made available to patients as quickly as possible. Continued collaboration with you, our stakeholders, will be critical as together we continue to make progress in this important area.

We are still listening and have much more work to do!

Combination Products Review Table

This table summarizes key Combination Product Review Program achievements from the past year. Click on table for PDF version.

The PDF version of the table is also located here: combination-products-review-program

Nina L. Hunter, Ph.D., is FDA’s Associate Director for Science Policy in the Office of Medical Products and Tobacco

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