FDA: A Great Place for Science…and for Scientists on the New Frontier of Regulatory Science

By: Robert M. Califf, M.D.

Robert CaliffAs FDA Commissioner, I’m proud of our agency’s extraordinary commitment to using the best available science to support our mission to protect and promote the health of the American public. This is especially critical today, as rapid scientific and technological advances are helping to expand our understanding of human biology and underlying disease mechanisms and to identify the molecular profile of a food contaminant.

These breakthroughs offer unprecedented opportunities for us to develop new treatments and cures and to protect our food supply with a robust system that meets the challenges of globalization.

But there’s another benefit that derives from our application of cutting-edge science to the challenges we face, which has become increasingly evident to me through my conversations with some of FDA’s more than 10,000 scientists. And that’s the deep personal and professional satisfaction gained from working in FDA’s state-of-the-art laboratories on front-line issues that make a real difference in the lives of all Americans. As one FDA scientist commented, “At FDA, your work is really at the crossroads of cutting-edge technology, patient care, tough scientific questions, and regulatory science.”

Being Part of a Vibrant Collaborative Scientific Environment

Whether you’re a biologist, chemist, epidemiologist, pharmacist, statistician, veterinarian, nurse, physician, or an engineer and whether you’re a recent graduate or a seasoned scientist, FDA offers an unmatched opportunity to be a part of a vibrant, collaborative culture of regulatory science.

FDA scientists gain a bird’s eye view of the pharmaceutical and food industries, and develop a thorough familiarity and understanding of the regulatory structure that guides these industries. As one young FDA scientist recently commented, “We see a tremendous breadth of different products here, which helps us learn quickly and makes our jobs interesting and challenging.” Another newly trained FDA scientist shared, “We have the chance to work with highly trained colleagues, within and across disciplines, to build and keep our scientific training cutting-edge.”

While the work of FDA scientists helps to advance scientific understanding, it goes much further than that. That’s because our work is directly tied to regulatory decisions. As such it has a powerful and immediate effect on the health of millions of Americans. As another FDA scientist explained, “We get to see how these basic science and clinical advances get applied to producing medical treatments and devices and how these can make differences in people’s lives.”

FDA offers a number of fellowship, internship, graduate, and faculty programs through which newly-minted scientists can join FDA and continue to apply and develop their skills. Many of these individuals remain on as full-time FDA scientists. One former FDA Fellow said they appreciate how “FDA makes room for and respects voices of young, qualified scientists.”

Tackling the Most Challenging Scientific Issues

So, although I may frequently boast about FDA’s responsibility and ability to do rigorous scientific research and its importance for the American public, I’m speaking as much about our scientists as our science. And I hope that when other young talented scientists consider these testimonies from our multifaceted scientific workforce they will be encouraged to join us.

I want to see more professionals take advantage of the opportunities FDA offers to collaborate on some of the most transformative scientific issues of our times – both for their benefit and for the nation’s. We need the best scientific minds to tackle the challenges of food safety, medical product development, and to evaluate how emerging technologies are affecting FDA-regulated products so that our reviewers can make science-based decisions about a product’s benefits and risks.

That’s why we’ve successfully added thousands of qualified new employees over the last several years and worked hard to fill mission-critical positions. It’s also why we continue to seek more hiring flexibilities and other ways that enable us to be more competitive with private-sector salaries for these positions.

The career opportunities at FDA are enormous, and I look forward to welcoming the next generation of scientists of every stripe to help us fulfill our mission. It’s not only good for science and essential to FDA’s ability to protect and promote public health; it’s a unique opportunity for these talented scientists and their careers.

FDA Scientists Discuss Their Cutting-Edge Research in FDA Grand Rounds Webcasts

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

FDA Celebrates the 40th Anniversary of the Medical Device Amendments

By: Jeffrey Shuren, M.D., J.D.

In 1976, Steve Jobs and Steve Wozniak founded Apple and a gallon of gas was $.59. And in another action that has had long term impact, President Ford signed the Medical Device Amendments that closed the dangerous gap between what he called FDA’s “horse and buggy authority” and “laser age problems.”

Jeffrey Shuren, M.D., J.D.

Jeffrey Shuren, M.D., J.D., FDA’s Director of the Center for Devices and Radiological Health, speaking at FDA’s Celebration of the 40th Anniversary of the Medical Device Amendments

Unlike the pharmaceutical industry, which was born from large chemical companies that discovered medical uses for the products they made, the device industry sprung to life as a scrappy sibling—mostly mom-and-pop businesses addressing the needs of individual patients and physicians through invention.

Although Congress had first given FDA explicit authority over medical devices in the 1938 Food, Drug, and Cosmetic Act, the focus was on fraudulent products. Efforts to extend FDA’s oversight on medical devices failed in 1962 and again in 1970.

Then in 1975, reports emerged that thousands of women had been harmed, some even died, from pelvic inflammatory disease, as the result of using the Dalkon Shield, an intrauterine device for contraception. Congress responded the following year by enacting the Medical Device Amendments, which authorized FDA to classify all medical devices based on risk into one of three classifications, to require premarket approval for Class III devices, and for devices to comply with reporting and GMP requirements.

The law ushered in a new era for medical technology innovation, patient access, and patient safety, but also created a tension, contributing to a political environment where the pendulum continues to swing between these objectives, defining and driving the medical device ecosystem ever since.

In signing the legislation, President Ford noted that, when “well designed and well-made and properly used” medical devices “support and lengthen life.” But when medical devices are “poorly designed, poorly made, and improperly used” they can “threaten and impair” life.” His words still ring true today.

The initial Medical Device Program started with about 180 people. Today, FDA’s Center for Devices and Radiological Health (CDRH) is 1,700 strong; a vibrant family of individuals with a wide range of scientific, clinical, engineering, legal, and other expertise, who hail from a variety of backgrounds, and who are ready to tackle the latest scientific advancement.

And the mom and pop industry has transformed into a world of sophisticated software algorithms, miniaturization, combination products, wearable sensors, non-invasive procedures and diagnostics, robotics, and artificial intelligence.

Along the way, CDRH has adapted its expertise and regulatory approaches to meet the needs of such rapidly evolving innovation. While we will continue to adapt, more importantly, we are focusing on proactively anticipating where we need to be so that regulatory innovation is out in front of medical device innovation. We’re doing this now in the digital health space, by designing regulatory frameworks around the type of technology and its unique evidence generation and innovation cycle rather than applying a one-size-fits-all approach.

We are implementing new models for evidence generation. They include the establishment of a National Evaluation System for health Technology, or NEST, that could transform the historical tension between device innovation, patient access and patient safety into an alignment of interests to drive the development and more timely access to life-saving, life-enhancing, and life-advancing devices. This is consistent with our vision: That patients in the U.S. have access to high-quality, safe and effective medical devices of public health importance first in the world.

And we are also going to new places with patients by establishing a foundation for engaging with them as our partners and routinely incorporating their perspectives in our decisions. And that’s fitting because improving the health and the quality of life of patients by assuring they have timely access to medical technologies that will benefit them is at the heart of who we are and what we do.

As we look ahead to the future, it is our work, our care and our dedication that will allow us to reach our vision.

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

For more information read: Remarks at FDA’s Celebration of the 40th Anniversary of the Medical Device Amendments, by Jeffrey Shuren, M.D., J.D.

Be A Champion for Clinical Trial Diversity

By: Jonca Bull, M.D.

The FDA is launching a campaign to encourage minorities to participate in clinical trials for all medical conditions.

Jonca Bull, M.D., is Director of FDA’s Office of Minority HealthThe first part of the campaign will be launched on June 19, 2016, World Sickle Cell Day, observed annually to help increase public knowledge and raise awareness of Sickle Cell Disease, which primarily affects people of African and Hispanic descent. We want to encourage diverse communities to learn more about how they can become a part of the research process to bring new therapies to the market.

Clinical trials are a critical step in making new medical products available. Medical products—from vaccines to drugs for blood pressure or diabetes management — are tested in clinical trials.

Although FDA generally does not conduct clinical trials, we do the critical work in reviewing the data to assess the safety and efficacy of medical products before they can be used in medical practice. None of this is possible without clinical trials and the patients who go the extra mile by being research participants.

In order to help ensure that medical products are safe for everyone, we need a diverse pool of research participants—racial and ethnic minorities, women, even the elderly.

We know that certain diseases impact some populations differently. For example, diabetes occurs  more frequently in blacks and Hispanics, high blood pressure and heart failure occurs more frequently and severely in blacks; and, Asian American communities experience more hepatitis B.

Clinical trials participants need to more closely mirror the patients who will ultimately use the medicine. This is especially important when considering health disparities — diseases that occur more frequently or appear differently in non-white populations. But most clinical trials participants are white and male. That means we may miss vital data that could be used to be make better evidence-based, regulatory decisions. If we do not develop a more diverse pool of research participants, health disparities may persist because we will not know if a medical product is safe and effective in the actual population that will ultimately use it.

And that’s why we’re launching our campaign, which includes a series of educational aids such as videos, a blog, and an infographic. In these videos Shirley Miller, who lives with sickle cell disease, talks about her experience participating in clinical trials and encourages her peers to learn more about research studies.

In another video Dr. Luciana Borio, FDA’s Acting Chief Scientist, discusses why clinical trial diversity matters from FDA’s perspective.

This campaign is taking us one step closer to a world where health equity is a reality for all. It supports FDA’s initiative: “The Year of Clinical Trial Diversity.”

It is a part of our larger effort to improve clinical trials diversity — we also work with stakeholder groups, support research, develop multi-lingual resources, and use social media to promote a community of “Clinical Trials Champions.”

You can be a “Champion” by watching and sharing the videos and related resources.

Everyone has a stake in the game —health care providers, researchers, and patients. Share these videos and other materials. Start a conversation today.

Videos:

More information about this campaign and FDA’s OMH can be found here: www.fda.gov/minorityhealth

Follow us on Twitter @FDAOMH

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

Globalization and FDA’s New Partnerships to Ensure Product Safety

By: Howard Sklamberg

Globalization is posing challenges for public health. For FDA, part of that challenge is the ever-increasing volume and complexity of FDA-regulated products coming to America’s shores.

Howard SklambergIn fiscal year 2015, there were more than 34 million shipments of FDA-regulated products into the United States, up from just 15 million shipments a decade ago. These products are handled by 130,000 importers, and are manufactured, processed, or packaged at more than 300,000 foreign facilities.

We know this global trade expansion has ramifications for our nation’s public health. We also know we cannot be the inspectors for the world. Hence, we need to effectively direct our resources in a risk-based manner as we grapple with this tremendous volume of imported goods.

How? One way is to identify foreign regulators whom we can rely upon to partner with in verifying that safety standards are being met and then construct an approach that will meet the requirements of multiple regulatory jurisdictions. We are currently engaged in three innovative programs that meet this challenge.

The Medical Device Single Audit Program

The Medical Device Single Audit Program, or MDSAP, is an international approach to the auditing and monitoring of the manufacture of medical devices to ensure their safety and efficacy. This audit program will allow a single regulatory audit of a medical device manufacturer’s quality management system that satisfies the requirements of multiple regulatory jurisdictions.

Currently, five nations – Australia, Brazil, Canada, Japan, and the U. S. – are participating in the MDSAP Pilot. It began 18 months ago and will run through the end of 2016. The program’s goals include:

  • Enabling regulatory oversight of medical device manufacturers’ quality management systems;  and,
  •  Promoting more efficient use of regulatory resources through work-sharing and mutual acceptance among regulators.

Mutual Recognition Agreements

In 2014, FDA launched the Mutual Reliance Initiative (MRI), a strategic collaboration between the FDA and the EU Member States. The goal of the program is to determine if the FDA and EU can agree to recognize each other’s drug Good Manufacturing Practice (GMP) inspections, a potentially time-saving approach.

If successful, we could rely upon EU experts to inspect facilities within their own borders, a more practical way of overseeing the large number of drug manufacturing sites outside of the United States. And it would be similarly more practical if the EU relied on FDA experts to inspect facilities within the United States.

Both the EU and the FDA are in the process of evaluating each other’s processes. The EU has visited several of FDA’s district offices in the United States and one drug laboratory and evaluated the work they do. The FDA has a different challenge since each country in the EU has at least one inspectorate, and in Germany, each state has their own inspectorate. To date, FDA has observed eight audits – in Sweden, Greece, Croatia, Germany, Hungary, Italy, the Czech Republic, and the United Kingdom – and will continue to observe audits of other Member States this year and in 2017.

Food Safety Systems Recognition

Preventing problems at relevant points along the global food supply chain can be a daunting job. FDA is soliciting help by leveraging foreign food safety systems that are similar to our own.

The agency’s Systems Recognition program determines whether another country has comparable regulatory programs and public health outcomes to what we have in place in the U.S.

A major advantage of Systems Recognition is that it allows FDA to be more risk-based in its oversight of imported food and we can more wisely plan our overall inspection activities, including foreign facility inspections, import field exams, and import sampling.

Thus far, we’ve completed: New Zealand and the U.S. signed a Systems Recognition Agreement (in 2012) and recently another agreement was signed with the Canadian Food Inspection Agency.

What’s Next? 

The three initiatives I’ve briefly outlined represent the best of FDA innovation and expertise in grappling with the increasing amount of imported FDA-regulated products. Our work will focus on a continued careful reliance on trusted foreign partners; a move away from duplicative work; more risk-based inspections; better data; and the minimization of public health risks globally.

Howard Sklamberg is FDA’s Deputy Commissioner for Global Regulatory
Operations and Policy

Celebrating a Year of the Expedited Access Pathway Program for Medical Devices

By: Erin Cutts, B.S., Owen Faris, Ph.D., and Jeffrey Shuren, M.D., J.D

The U.S. Food and Drug Administration (FDA) is committed to supporting patient access to high-quality, safe, and effective medical devices of public health importance — as quickly as possible.

Erin Cutts

Erin Cutts, B.S., Policy Lead, Q-Submission Program (acting), Office of Device Evaluation in FDA’s Center for Devices and Radiological Health

For patients suffering from life-threatening conditions and who have few, if any, options, this access becomes critical. About a year ago, FDA’s Center for Devices and Radiological Health created the voluntary Expedited Access Pathway (EAP) program to facilitate the development of and access to new technology for these patients who desperately need them.

The EAP program represents a collaborative approach to help manufacturers with product development and evaluation. Products in the EAP program ultimately undergo either Premarket Approval (PMA) or de novo review.

Other device programs may focus specifically on premarket review once a submission has been made. But EAP allows FDA and sponsors to focus on the early stages of product development, which can be helpful for new products that address the unmet — and critical — life-threatening patient needs. In fact, we think the EAP program will have most impact when sponsors request EAP designation prior to beginning an IDE pivotal study. That way we can work with the sponsor to make sure the data being collected in the pivotal study are appropriate to include in the device’s manufacturing submission.

Owen Faris

Owen Faris, Ph.D., Clinical Trials Director, Office of Device Evaluation in FDA’s Center for Devices and Radiological Health.

For the devices in the EAP program, FDA, including senior leadership, maintains a high level of interaction with sponsors and provides advice on efficient device development. What does this mean? While working with the device sponsor, FDA carefully considers the risks and benefits of the new device, as well as the risks of delaying a new therapy to patients who have few or no other options. It may be appropriate to accept more initial uncertainty for devices in the EAP program so that an important technology can reach patients sooner. This uncertainty can be further addressed by collecting additional data once the device is on the market.

Jeffrey Shuren

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

Over the past year, FDA has made 29 decisions on requests for EAP designation: 17 have been accepted into the program, and 12 have been denied. These decisions were typically made in 30 days.

EAP designation requests have included devices for the heart, brain, and kidneys that are manufactured by small start-up companies and large corporations. We expect that our resources and focus on these promising technologies under the EAP program will allow them to be evaluated and enter the market more quickly, therefore providing options to the patients who need them most.

Projects should meet certain criteria to qualify for the EAP program:

  • The device should treat or diagnose a life threatening or irreversibly debilitating disease or condition;
  • The device should address an unmet need, which is usually shown by comparing the device to other available options; and,
  • The company should have a Data Development Plan outlining what will be included in future submissions to FDA. This plan helps FDA and the company agree on the high level items up front to prevent confusion and delays later in the FDA review process.

As the program has grown in the past year, we’ve  learned that companies who benefit most from this program are those that have a preliminary proof of principle for how their device works, but haven’t undertaken formal studies to support future submissions to FDA. For these companies, discussing their Data Development Plan with the FDA and agreeing on a roadmap to their marketing application and beyond is an important part of a successful review.

So what’s next? As we look forward to the EAP program’s second year,we remain excited about the possibilities it presents – and to be working with industry to quickly bring new and innovative devices to patients.

Erin Cutts, B.S., is Policy Lead, Q-Submission Program (acting), Office of Device Evaluation in FDA’s Center for Devices and Radiological Health.

Owen Faris, Ph.D., is Clinical Trials Director, Office of Device Evaluation in FDA’s Center for Devices and Radiological Health.

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

From Competition to Collaboration: precisionFDA Challenges

By: Taha Kass-Hout, M.D., M.S., Zivana Tezak, Ph.D., and Elaine Johanson

Next week, we will announce the winners of the first precisionFDA challenge.

Taha Kass-Hout

Taha A. Kass-Hout, M.D., M.S., FDA’s Chief Health Informatics Officer (CHIO) and Director of FDA’s Office of Health Informatics

We set up precisionFDA as an online, cloud-based, virtual research space to allow scientists from academia, industry, health care organizations, and government to work together on creating tools to evaluate a method of “reading” DNA known as next generation sequencing (or NGS). The ultimate goal of precisionFDA is to foster innovation and develop regulatory science around NGS tests, which are essential to achieving the promise of President Obama’s Precision Medicine Initiative. So far, the response to precisionFDA has been gratifying, with participants calling precisionFDA “refreshing”, “innovative,” and “a new paradigm in regulatory science.” The community currently boasts more than 1,500 users from 600 organizations, with more than 10 terabytes of genetic data stored.

To engage users and encourage sharing of data and ideas, precisionFDA has offered two competitions to date. These competitions are motivating community members to demonstrate the effectiveness of their tools, test the capabilities of the precisionFDA platform, and engage the community in discussions and data analysis that will provide new insights and serve as a comprehensive source of information about reference data and software pipelines used to analyze sequencing results.

Zevana Tezak

Zivana Tezak, Ph.D., Associate Director for Science and Technology at FDA’s Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health

The first precisionFDA challenge, the Consistency Challenge, closed in April 2015, with 21 entries from 17 submitters. Participants were given two datasets of whole genome sequences from a known human sample, sequenced at two different sites and generously donated to precisionFDA by Garvan Institute of Medical Research and Human Longevity, Inc. Challenge participants were instructed to use the informatics pipeline (software) of their choice to identify genetic variants and check for consistency between results in the provided datasets. The top performers will be announced in person by FDA Commissioner Robert Califf on May 25, 2016. At the time of his announcement, we will post detailed information here on all the recognitions and how the top performers were selected. So stay tuned!

The second challenge, the Truth Challenge, closes on May 26, 2016, and was designed in collaboration with the Genome in a Bottle consortium and the Global Alliance for Genomics and Health. Participants are expected to identify genetic variants in one known and one unknown sample dataset. The goal is to see how close they come to the truth when analyzing data from a human sample with variant results unknown to them, which we will reveal at the end of the challenge. An exciting characteristic of this challenge is that the Genome in a Bottle consortium will release for the first time new high confidence variant calls for the unknown sample dataset (we refer to in this challenge as “truth dataset”) for the human sample at the end of the contest.

Elaine Johanson

Elaine Johanson, precisionFDA Project Manager and Deputy Director of FDA’s Office of Health Informatics.

The knowledge generation potential for precisionFDA is immense, and leverages the collaboration of the global community to help solve challenges that will ultimately provide insight to regulation to ensure the safety and efficacy of genetic tests. The platform offers users the ability to assemble and run apps, learn from other experts, share lessons learned, participate in competitions, and help to develop standards for assessing the effectiveness of genetic tests.

With new challenges and opportunities for ongoing discussions and collaborations between FDA and the global community, we look forward to the precisionFDA community facilitating and advancing development and assessment of new tools and tests in this fast growing field of genetic testing.

 

Taha A. Kass-Hout, M.D., M.S., is FDA’s Chief Health Informatics Officer (CHIO) and Director of FDA’s Office of Health Informatics

Zivana Tezak, Ph.D., is Associate Director for Science and Technology at FDA’s Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health

Elaine Johanson, is precisionFDA Project Manager and Deputy Director of FDA’s Office of Health Informatics

What We Mean When We Talk About EvGen Part II: Building Out a National System for Evidence Generation

By: Rachel E. Sherman, M.D., M.P.H., and Robert M. Califf, M.D.

In an earlier FDA Voice blog post, we discussed a pair of concepts – interoperability and connectivity – that are essential prerequisites for the creation of a successful national system for evidence generation (or “EvGen”). In this post, we take a look at how we would apply these constructs as we go about building such a system.

Building EvGen

Rachel Sherman

Rachel E. Sherman, M.D., MPH, is FDA’s Associate Deputy Commissioner for Medical Products and Tobacco

Creating knowledge requires the application of proven analytical methods and techniques to biomedical data in order to produce reliable conclusions. Until recently, such analysis was done by experts operating in centers that typically restricted access to data. This “walled garden” approach evolved for several reasons: the imperative to protect the privacy and confidentiality of sensitive medical data; concern about the negative consequences that could arise from inappropriate, biased, or incompetent analysis; and, the tendency to see data as a competitive asset. Regardless of the specific reason, the result has been the same: widespread and systemic barriers to data sharing.

If we are to reverse these tendencies and foster a new approach to creating evidence of the kind envisioned for EvGen, we must bear in mind several critical principles:

  1. There must be a common approach to how data is presented, reported and analyzed and strict methods for ensuring patient privacy and data security.
  2. Rules of engagement must be transparent and developed through a process that builds consensus across the relevant ecosystem and its stakeholders.
  3. To ensure support across a diverse ecosystem that often includes competing priorities and incentives, the system’s output must be intended for the public good and be readily accessible to all stakeholders.

What Would EvGen Look Like in Practice?

Robert Califf

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

What would a robust national platform for evidence generation look like? It may be helpful to envision EvGen as an umbrella for all activities that help inform all stakeholders about making treatment decisions.

The task of evaluating drugs, biologics, or devices encompasses different data needs and methods. However, all share a common attribute: the characterization of individuals and populations and their associated clinical outcomes after they have undergone diagnostic or prognostic testing or been exposed to a therapeutic intervention.

Moreover, when medical practice itself is part of the evaluation, characterization of the organization and function of delivery systems is critical. In other words, the kinds of evidence needed to evaluate medical products for safety and effectiveness and the kinds of evidence needed to guide medical practice overlap substantially.

Over the last decade, there has been enormous progress in the area of “secondary use,” in which data collected for one purpose (for instance, as part of routine clinical care) can be reused for another (such as research, safety monitoring, or quality improvement).

The Sentinel Initiative, launched in response to a Congressional mandate to develop an active postmarket risk identification and analysis system, is one example. Modeled after successful programs such as the Centers for Disease Control and Prevention’s Vaccine Safety Datalink, Sentinel allows FDA to conduct safety surveillance by actively querying diverse data sources, primarily administrative and insurance claims databases but also data from electronic health record (EHR) systems, to evaluate possible medical product safety issues quickly and securely.

Another example, the National Patient-Centered Clinical Research Network (PCORnet), is a national system that includes many of the attributes needed for EvGen. PCORnet includes participation from government, industry, academia, and patients and their advocates. Whereas FDA’s Sentinel system is built primarily on claims data repurposed for safety surveillance, PCORnet is designed to leverage EHR data in support of pragmatic clinical research.

The NIH’s Health Care Systems Research Collaboratory has demonstrated through its Distributed Research Network that the concept of secondary data use can be extended into the realm of prospective pragmatic interventional trials. The NIH Collaboratory program, which includes many of the same health care systems involved in Sentinel and PCORnet, has 10 active trials underway.

In addition, the Reagan-Udall Foundation Innovation in Medical Evidence Development and Surveillance (IMEDS) Evaluation Program is exploring governance mechanisms to ensure that private-sector entities, notably regulated industry, can collaborate with Sentinel data partners to sponsor safety queries about marketed medical products. Such measures have the potential to expand the involvement of private-sector partners beyond the arena of methodology, further helping to ensure that Sentinel continues its expansion into a national resource.

Similarly, efforts are underway to establish a National Device Evaluation System (NDES). As currently envisioned, the NDES would be established through strategic alliances and shared governance. The system would build upon and leverage information from electronic real-world data sources, such as data gathered through routine clinical practice in device registries, claims data, and EHRs, with linkages activated among specific data sources as appropriate to address specific questions.

As substantial work already is being done in all of these areas, valuable experience is being gained. The next step is to ensure that these pioneering efforts coalesce into a true national resource. More on that in future postings.

Rachel E. Sherman, M.D., M.P.H., is FDA’s Associate Deputy Commissioner for Medical Products and Tobacco

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

Strengthening Partnerships: FDA’s China Office Engages in Key Outreach with Chinese Provincial FDA, Academia, and Industry

By: S. Leigh Verbois, Ph.D.

独木不成林,单弦不成音

Dú mù bù chéng lín, dān xián bù chéng yīn

‘A single tree makes no forest, one string makes no music.’

“A single tree makes no forest, one string makes no music.”This old Chinese proverb inspired FDA’s China Office, as members of our staff embarked on a five-day trip to meet with provincial FDA regulators, industry, and academia in China’s Yangtze River Delta region.

FDA Staff with Zhejiang FDA

FDA Staff Meets with Zhejiang FDA
Hangzhou, China
Front Row, Left to Right: Gang Wang (FDA China Office), Bo Ju (Zhejiang FDA), Yuanchang Shao (Zhejiang FDA), Leigh Verbois (FDA China Office), Jue Chen (Zhejiang FDA), Chiang Syin (FDA China Office), William Sutton (CDRH),
Back Row, Left to Right: Jinfeng Liang (Zhejiang FDA), Wenhua Zheng (Zhejiang FDA), Yini Ye (Zhejiang FDA), Lixin Shen (Zhejiang FDA), Nicole Taylor Smith (FDA China Office), Lixia Wang (FDA China Office)

The Yangtze River Delta region is an economic area that encompasses the Shanghai municipality, Zhejiang and Jiangsu provinces. The commercial epicenter, which accounts for 20 percent of China’s gross domestic product, is home to a significant number of FDA-regulated medical product manufacturers.

We traveled more than 3,300 kilometers (1,980 miles) to meet with key leaders and experts to strengthen partnerships, share information, and build the foundation for future cooperative engagement. Our first stop was Shanghai, where I had the great fortune to be able to address hundreds of students and faculty at East China University of Science and Technology’s School of Pharmacy and China Pharmaceutical University.

My message to the students was that they are the future leaders who will be in charge of the next generation of pharmaceutical innovation and data integrity.

In Shanghai, we also had the opportunity to sit down with U.S. Embassy Consul General Hanscom Smith to compare notes and to talk about current FDA priorities underway in the region.

China Pharmaceutical University (CPU)

China Pharmaceutical University (CPU)
Nanjing, China
CPU Faculty and Students attending Dr. Leigh Verbois’s Presentation on “CDER’s Novel Drug Approvals and Priorities”

The team then rode a high speed bullet train to Nanjing to meet with Jiangsu FDA, the regional regulator. This type of information sharing between the provincial FDA and the FDA China Office supports our shared mission of assuring that medical products produced in China meet U.S. safety standards.

On day three, we traveled again by bullet train to Suzhou where we partnered with China’s Association for Medical Device Industry to hold a two-hour, town hall meeting with almost 200 of China’s big device manufacturers that export products to the United States.

Working with FDA’s Center for Devices and Radiological Health (CDRH), our team provided information on Unique Device Identification (UDI) requirements. In the greater China region, it is estimated that there are nearly 4,000 medical device establishments affected by these requirements.

Hangzhou, China

Hangzhou, China
One of the many bridges in Hangzhou to symbolize “Building Bridges” between the FDA China Office and our Chinese stakeholders

The next morning, we headed for Hangzhou. After about two hours by train, we arrived in Hangzhou ready to meet with provincial FDA officials. Our meeting focused on specific ways we could collaborate on future medical device and drugs outreach, and more effectively share information.

The final day of our weeklong journey started with an industry roundtable focused on pharmaceuticals, held in partnership with Zhejiang FDA. As fellow regulators, we joined together to engage in substantive discussion with representatives from major manufacturers located in the Zhejiang, Jiangsu, and Shanghai regions, many of whom were interested in recent data integrity efforts in China. The FDA team then boarded our last train back to Shanghai for a final meeting with local officials that focused on our mutual priorities, as well as ways to expand and leverage efforts going forward.

The team flew back to Beijing feeling very satisfied that we accomplished much and clearer than ever that continued collaboration with Chinese regulators, industry and academia will help to ensure that medical products manufactured for the U.S. market are safe and effective. After all, one tree alone does not make a whole forest.

Leigh Verbois, Ph.D., is Director of FDA’s China Office in the Office of International Programs

What We Mean When We Talk About EvGen Part I: Laying the Foundation for a National System for Evidence Generation

By: Rachel E. Sherman, M.D., M.P.H., and Robert M. Califf, M.D.

Rachel Sherman

Rachel E. Sherman, M.D., M.P.H., is FDA’s Associate Deputy Commissioner for Medical Products and Tobacco

Across the clinical research enterprise, there is a growing awareness of serious shortfalls in the current paradigm of generating the scientific evidence that supports medical product evaluation and clinical care decisions and the need to modernize methods and expectations surrounding this evidence base.

We know, for instance, that most clinical practice guideline recommendations are not based on high-quality evidence, typically derived from appropriately designed randomized controlled trials. We also know that adherence to standards supported by such high-quality evidence results in better outcomes for patients.

There is reason to believe that we’ve arrived at a tipping point where previously separate, “siloed” efforts can be linked to create a national system for evidence generation (EvGen). In this first of a series of posts, we’ll take a look at the elements required to build such a national system, beginning with a pair of foundational concepts—interoperability and connectivity.

Interoperability

Robert Califf

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

Put simply, interoperability is the idea that different systems used by different groups of people can be used for a common purpose because those systems share standards and approaches. To take one example: modern train tracks employ agreed-upon standards in terms of track gauge and other specifications so that many different kinds of vehicles can safely use the rail system.

In similar fashion, a national system for evidence generation that applied common data standards and definitions could “lay the track” for significant improvements in the exchange of biomedical data. Patients, consumers, professional groups, payers, the medical products industry, and health systems all stand to benefit from potential gains in efficiency and reductions in cost that would accompany standardized approaches to data collection, curation, and sharing, once up-front investments are absorbed. Then, with these standards in place, effort could be devoted to generating actionable knowledge rather than simply managing data.

Connectivity

Establishing interoperable systems is a critical step in building a national system for evidence generation. An equally important step is to enable collaboration among the many groups that generate data, for example patients, clinicians, hospital systems, health insurance organizations. Evidence is derived from high-quality data that often originates from many different sources or settings. We can create an interconnected environment that leverages all the available data to provide answers to important public health questions. A defining characteristic of such a network is the ability to leverage all available data for different tasks as needed, allowing the network to integrate complex relationships between data input and output. Coupled with interoperable standards, a national system for evidence generation based on these principles will be capable of generating very large quantities of data and enabling those data to flow among system components.

The result? Researchers will be able to distill the data into actionable evidence that can ultimately guide clinical, regulatory, and personal decision-making about health and health care.

These two core constructs represent the essential scaffolding that must be developed and put in place to support a national system for evidence generation. In our next posting, we’ll examine ways we can begin building and continuously improving such a system for the benefit of all stakeholders.

Rachel E. Sherman, M.D., M.P.H., is FDA’s Associate Deputy Commissioner for Medical Products and Tobacco

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

Developing a Consensus Voice: The Combination Products Policy Council

By: Nina L. Hunter, Ph.D., and Rachel E. Sherman, M.D., M.P.H.

We recently announced the launch of lean process mapping to build a better system for combination products review – one that is more cohesive, more collaborative, more systematic, and more predictable. We look forward to providing an update on this effort soon.

Nina Hunter

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

In the meantime, we’re delighted to announce the creation of FDA’s first Combination Products Policy Council. Building on successful cross-cutting efforts such as the Biosimilars Implementation Committee and the Medical Policy Counsel in the Center for Drug Evaluation and Research (CDER), the Council will be a senior-level, agency-wide forum for discussing, resolving, and implementing product and policy issues. Because of the multiple FDA organizations involved, this council will have decisional authority on issues relating to combination products, cross-labeled products, and medical product classification.

The different parts of a combination product and the different product types labeled for use together in premarket applications for combination products and cross-labeled products can create complexities for reviewers and require expertise from multiple centers.

Rachel Sherman

Rachel E. Sherman, M.D., M.P.H., is FDA’s Associate Deputy Commissioner in the Office of Medical Products and Tobacco

Currently, the lead center manages the review process using procedures associated with the center-specific application type and user fee goal dates. But differences in statutory and regulatory requirements for different application types, including evidentiary standards, data requirements, and review limitations, make it challenging to coordinate reviews and ensure alignment and consistency in addressing issues across centers.

In response to these complexities, we are creating a key component in the Office of the Commissioner that can convene parties across centers, foster understanding and consistent application of requirements, and develop a unified FDA position on issues that arise. Although this process will not replace the existing formal appeal process, we anticipate that many issues can be resolved before reaching that stage.

Council Mission

  • Modernize the inter-center consultation process and related aspects of combination product and cross-labeled product review;
  • Promote development of innovative, safe, and effective combination products and cross-labeled products; and
  • Promote alignment in addressing challenging medical product classification issues.

The Council will be composed of representatives from relevant centers and offices. In addition, experts from within centers and other FDA offices will provide expertise as needed for specific policy topics under consideration.

In addition to serving as a communications hub, the Council will be involved in the development of agency-wide and external communications such as draft guidances, publications, and blog posts on policy decisions. FDA envisions a variety of topics may be relevant for consideration by the Council, including such “front-burner” items as product jurisdiction and designation practices, application of evidentiary standards for clearance/approval to combination products and cross-labeled products, and regulation of novel products.

We’ve heard that many stakeholders desire a voice in modernizing the combination review program, and we’re listening! In addition to the topics listed above, one of the Council’s priorities will be to consider how best to seek input from external stakeholders on various issues. We would hope that such comments include policy issues recommended for discussion and recommendations on how the policy issue could be addressed or implemented.

We are confident that the Council’s efforts will ensure transparency and consistency in our approach to combination product policy development and implementation, ultimately helping to ensure that innovative combination products marketed to the American people are safe, effective, and appropriately labeled. We look forward to providing updates about the Council, as well as additional modernization efforts in this important area.

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

Rachel E. Sherman, M.D., M.P.H., is FDA’s Associate Deputy Commissioner in the Office of Medical Products and Tobacco and the Chairperson of the Council