- Speech by
Scott Gottlieb, M.D.
The Pew Charitable Trusts
September 14, 2018
(Remarks as prepared for delivery)
Good morning. I’d like to thank Pew for hosting today’s event.
You’re all here today because you understand the importance of addressing antimicrobial resistance (AMR) to maintain and advance the tools of modern medicine. Not only for this generation, but for many generations to come.
The CDC estimates that in the United States alone, every year at least 2 million people develop serious infections caused by antimicrobial-resistant pathogens, like MRSA. And, at least 23,000 people die as a direct result of these infections.
We can’t count on outracing drug resistance. But we can use stewardship and science to slow its pace and reduce its impact on human and animal health.
To do so, we need an all-hands-on-deck approach to combating AMR in both human and veterinary settings. We need an all-of-the above strategy.
Today, I’m announcing the FDA’s 2019 Strategic Approach for Combating AMR. This is an ongoing, agency-wide initiative to build on our past efforts, and to coordinate policy and external partnerships to help confront AMR.
This strategy has been developed by agency and center leadership in the FDA’s Center for Devices and Radiological Health (CDRH), our Center for Drug Evaluation and Research (CDER), our Center for Biologics Evaluation and Research (CBER), our Center for Veterinary Medicine (CVM) and our National Center for Toxicological Research. The agency’s Office of the Chief Scientist is also helping to coordinate many of these efforts.
We’re also introducing a new web page today, which will provide our stakeholders a one-stop shop for following the FDA’s work on AMR.
We’re launching it in tandem with the release of the Center for Veterinary Medicine’s five-year plan for Supporting Antimicrobial Stewardship in Veterinary Settings.
My remarks today are focused on the FDA’s role in combating AMR. But we don’t undertake this work alone. We work closely with government partners and also with many stakeholders. We’re deeply appreciative of these collaborations.
The FDA plays a unique role in advancing human and animal health. Our regulatory goals put us in a key position to help coordinate and advance a shared purpose.
When we talk about promoting and protecting public health in the context of product development, we often talk about addressing the full continuum of product development and use. This comprehensive approach spans the entire life cycle of the product, from pre-market development, to clinical trials, to the need for post-market safety surveillance. Across this entire continuum, the FDA works to ensure that products are safe and effective for their intended use.
In addressing AMR, the FDA is also adopting a comprehensive approach with four major components that address the full continuum of product development and use. This includes steps to better facilitate product development and efforts to promote product stewardship, support antimicrobial resistance surveillance and advance regulatory science. We aim to address all aspects of this challenge.
Because of the FDA’s statutory responsibility for assuring safe and effective products that promote and protect both human and animal health, we have a unique vantage point for coordinating all of these aspects of a product’s development and application to health. And, different centers within the FDA have varied roles for assisting in this comprehensive approach to safety and proper stewardship.
CDER and CBER, for example, have a large role to play in helping to bring to market new antimicrobials and non-traditional alternatives to small molecule antimicrobial drugs. Most existing antibiotics are as old as the earth. They were screened out of nature where they resided, doing battle with bugs for centuries. We need to find new ways to safely accelerate this evolution in our laboratories.
CDRH has a key impact on stewardship by helping to bring new diagnostic devices to the market. These tools can help us rapidly test a patient to tailor treatments responsibly and effectively, targeting the right drug to the right bug.
And, CVM plays a role in all portions of this product lifecycle. But they have an especially important and unique role to play within the FDA when it comes to helping advance better stewardship efforts in veterinary settings.
Our new, comprehensive strategy is aimed at bringing all our centers work together, via one platform, to address four key areas:
First, we’re facilitating product development to ensure a robust pipeline of safe and effective treatments that can combat resistant organisms.
Second, we’re promoting antimicrobial stewardship. Careful stewardship across human and animal health can help preserve the effectiveness of available treatments and may help slow the development of antimicrobial resistance.
Third, we’re supporting the development of tools for surveillance of antimicrobial use and for determining when pathogens develop resistance.
Finally, we’re advancing scientific initiatives to help all stakeholders answer critical questions related to antimicrobial resistance. This includes research that can support the development of alternative treatment approaches. These can include bacteriophages, fecal microbiota transplants and live biotherapeutic products.
We don’t have much time today, so I’m only going to touch briefly on each of these four areas. I trust that the expert panel that follows my remarks will build on these ideas and fill in some of the details on our new efforts.
Facilitating Product Development
First, let’s talk about facilitating product development.
To sustain a strong antibiotic drug pipeline, we need a combination of “push” incentives to support product research and development, and “pull” incentives to attract more investment. A lot of the focus, so far, has been placed on developing push incentives. I think much more emphasis needs to be placed on developing pull incentives. These can create natural markets for drugs targeted to rare but dangerous, multi-drug resistant pathogens that can threaten human health.
We’ve already seen some successes from both approaches.
The Generating Antibiotic Incentives Now (GAIN) Act is one example. It was passed in 2012 as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). GAIN was designed to stimulate the development and approval of new antibacterial and antifungal drugs. The Act created incentives for sponsors to bring antibacterial and antifungal drugs to market that are intended to treat serious or life-threatening infections. It allows the FDA to designate certain antimicrobial drugs as qualified infectious disease products (QIDPs).
The FDA began granting QIDP designation to qualifying products immediately following the enactment of GAIN in 2012. From July 9, 2012 through August 2, 2018, the FDA has designated 168 QIDPs. This includes about 83 novel drugs. And since the enactment of GAIN, 15 QIDPs have been approved by the FDA.
The Limited Population Pathway for Antibacterial and Antifungal Drugs, or LPAD, was a piece of legislation enacted by Congress in 2016 under the 21st Century Cures Act. LPAD was created to advance the development and approval of antibacterial drugs to treat serious or life-threatening infections in limited populations of patients with unmet medical needs.
Three months ago, the FDA issued a draft guidance to assist in the development of drugs using this additional, important pathway. This draft guidance, when finalized, will support drug development by describing the criteria, processes and other general considerations for drugs approved under the LPAD pathway.
We’re encouraged that we’ve already seen meaningful, early interest by innovators in potentially developing drugs under this new framework.
The FDA expects that pre-clinical and clinical programs for drugs eligible for approval under this pathway will follow streamlined approaches to clinical development. This includes smaller, shorter or fewer clinical trials.
But we continue to see a need for additional pull incentives in the form of reimbursement reforms that allow innovators to capture more of the long-run social and economic value generated from the development of new antibiotics.
Large pharmaceutical companies have, for the most part, exited from antibiotic research. And while some small, venture-backed, start-up companies remain engaged, these companies are not as well positioned to fund the larger confirmatory trials required for regulatory approval. What we’d like to see is a balanced level of investment, and more interest in these opportunities. We’d like to see a more robust market for these products, complemented by a robust pipeline.
We don’t have that today. As large companies pare their efforts back, the funding pool available for commercializing innovative projects is shrinking. We’ve recently seen news that some big companies are getting out of this space.
I’m deeply concerned that without stronger “pull” incentives that encourage more research and development, we’ll see a far less robust pipeline of products than we need to address antimicrobial resistance. The problem is that the ideal drug is one that will be seldom used.
Under the current reimbursement scheme for drugs, profits are driven off of the number of prescriptions that get written for a drug.
But when it comes to developing a medicine to treat multi-drug resistant microbes, the goal is to hold such a drug in reserve and try not to use it. In other words, the reimbursement scheme is in direct conflict to our public health goals.
And what we’re seeing, as a result, is a classic externality problem.
Creating new antibiotics isn’t any easier than developing any other drug class. And, the commercial challenges are more daunting. Generic antibiotics are also inexpensive and widely effective, making them first line treatments. Medicare’s in-patient prospective payment system for hospital care is pegged to the price of generics.
So novel drugs eat into the profits of hospitals. And when new and better antibiotics are available, these novel drugs are reserved for “last-line” cases when their unique profiles, and higher prices, are justified because “first-line” drugs have failed.
This is completely justifiable behavior. If a new product is overused, it can reduce effectiveness by increasing antimicrobial resistance. In-hospital stewardship has improved a lot.
This is all good news.
But holding a drug in reserve also shrinks product revenues early in its patent life, when those revenues are most valuable to companies and investors. So the economics of this category, and our public health prerogatives, are not entirely in sync.
Contrast this with markets for new antivirals for HIV and Hep C, where new medicines have rapidly replaced a number of older drugs, becoming first-line treatments.
And investment has followed these economic realities.
If we want to maintain a robust pipeline for antibiotics, it is necessary to change the perception that the costs and risks of antibiotic innovation are too high relative to their expected gains—without weakening antibiotic stewardship.
It is important to pursue new policies and reimbursement approaches now, to shift the investment landscape right away. And it is important to develop these products now, so they’ll be available when we need them later.
One constructive way to start would be to develop innovative payment mechanisms that allow companies to capture a greater upfront share of the social value of antibiotic drug development.
The long run human and economic cost of antimicrobial resistance is enormous, including: death and disability from sepsis; extended and expensive hospital stays; and the need for dialysis or organ transplant in the wake of systemic infections.
The CDC estimates that the direct costs of antimicrobial resistance on the U.S. economy is $20 billion annually. When you factor in the economic consequences of lost productivity, it adds an additional $35 billion in costs.
Reimbursement reforms could include a mix of milestone payments and subscription fees for developers of FDA-approved products with high economic and clinical value, targeted at multi-drug resistant organisms and linked to proven clinical outcomes.
A subscription-based model could see hospitals paying a flat rate for access to a certain number of doses of an important new antimicrobial. These subscription fees could be priced at a level to create a sufficient return on the investment to develop drugs with a certain profile. This should have the effect of creating a natural market for drugs that meet certain important specifications.
The FDA is discussing potential approaches, and continued innovation in similar payment pilots, with other agencies, including CMS. New approaches to reimbursement that could be explored might also include new technology add-on payments for certain new antibacterial drugs that meet critical patient and public health needs.
The Gates Foundation, BARDA, and the Center for Medicare and Medicaid Innovation could join with commercial insurers to provide a natural testing ground for these kinds of innovative payment models. These might include the subscription-based models I spoke about. These incentives can be linked to the promise of effective stewardship efforts by providers and manufacturers.
The FDA is also committed to facilitating innovation through proactive engagement with sponsors and researchers to identify and address challenges to the development and approval of novel and non-traditional antibiotic products. The FDA’s biologics center is actively promoting development of non-traditional products in three major categories. These include bacteriophage, live biotherapeutic products and fecal microbiota for transplantation.
Other relevant biological products include vaccines to prevent primary or secondary infections caused by AMR microbes. The best way to prevent resistant microbes is to prevent patients from getting infections in the first place. By reducing hospitalizations that put patients at an increased risk of acquiring AMR infections, vaccines can be a critical tool in reducing the overall burden of AMR.
Academic investigators, small and medium enterprises, and even large companies may have questions about the development pathway for their biological products. Some of those questions benefit from early discussion with CBER to facilitate product development. We saw this, for example, when it came to development of fecal microbiota for transplantation.
These discussions can help answer important questions, remove roadblocks and ultimately help create a clearer route to getting safe, effective products to patients.
CBER’s INTERACT meeting program was recently created for sponsors to engage with CBER staff and obtain advice on a specific topic or issue that’s critical to early product development. The advice provided by CBER staff to a potential sponsor during an INTERACT meeting may help streamline development by, for example, helping sponsors avoid unnecessary preclinical studies.
The FDA will continue to advance new ways to facilitate development of non-traditional antimicrobials, including through a number of planned guidances.
Supporting Antimicrobial Stewardship
The next phase of the product continuum, and another key part of our comprehensive approach, is implementing good antimicrobial stewardship.
As all of you know, antimicrobial stewardship activities span the work of many federal agencies. We especially rely on the great work of the CDC in this area.
But we also have responsibility for a critical component of stewardship in veterinary settings. These settings are an area where, as a nation, we’ve made important progress over the past few years in improving antimicrobial stewardship.
Since becoming Commissioner 17 months ago, conversations with my colleagues in CVM have made clear to me that this progress is the result of close collaboration amongst a variety of our stakeholders.
The FDA’s two Guidances for Industry, GFI #209 and GFI #213, combined with our updates to the veterinary feed directive (VFD) regulation, laid out a clear path for CVM to work with industry to revise the labels of all medically important antimicrobials used in the feed and water of food-producing animals. The aim was to eliminate production uses of antibiotics, such as growth promotion. And, the goal was to bring all remaining therapeutic uses under the oversight of licensed veterinarians.
The successful implementation of these changes depended heavily on the commitment of key partners and stakeholders to work with the FDA. This included the animal pharmaceutical and feed industries, the animal agriculture community, the veterinary community, and other federal and state agencies.
We’re pleased to see such a high level of collaboration and support to implement these changes. Ultimately, we were able to reach our goal to successfully update 100 percent of the nearly 300 affected products. And because of this work, about 95 percent of the total quantity of medically important antimicrobials sold or distributed for use in food-producing animals are now under veterinary oversight. This is significant public health progress.
Our work, combined with the steps many of you in this room have taken to create your own stewardship initiatives, your own new product lines and new marketing campaigns, has together resulted in a very different landscape in how antibiotics are used now versus how they’ve been used for decades.
However, there’s still a lot of work to be done.
Today, we’re announcing plans to address remaining areas where there can be further alignment with the principles of antimicrobial stewardship.
One area of focus we’re announcing today is our intention to work with the industry to bring the remaining five percent of medically important antimicrobials approved for use in animals, such as certain injectable antimicrobials, under veterinary oversight. Toward these goals, we’ll release a draft strategy by the end of fiscal year 2019, likely as a guidance document, to assist industry in making needed changes to their products.
Another important area of focus is ensuring that medically important antimicrobials are labeled with appropriately defined durations of use.
The FDA has determined that about 40 percent of approved medically important antimicrobial drugs used in the feed and water of food-producing animals include at least one indication that doesn’t have a defined duration of use. That’s why the FDA is announcing today our plans to develop and implement a strategy to address this issue.
Implementing this change to all of these drugs will take time. To advance these goals, we’ll be releasing a draft strategy, likely as a new guidance for industry, by the end of fiscal year 2020. We recognize that stakeholder feedback will be crucial in finding a workable solution.
In the animal stewardship space, we’re also committed to working with key stakeholders both domestically and globally to help users of antimicrobial products have the information they need to use these products in a judicious manner.
Toward these ends, we’re renewing our commitment to work in consultation with our partners at USDA and to collaborate with stakeholders to identify ways to develop and disseminate information on antimicrobial stewardship.
This ranges from collaborating with producer groups to provide information on stewardship, to working with veterinary medical associations and academic institutions to create veterinary curricula with the most up-to-date information available.
We’re also taking new steps to support stewardship in human medicine. To advance these goals, the FDA has worked with manufacturers on the development and availability of new generation devices that can identify bacteria or fungal pathogens directly from specimens such as blood, spinal fluid, stool or sputum, and without the need to wait for growth in cultures.
In many cases, these tools can reduce the time for diagnosing the precise cause of disease from days to hours.
Several tests can also identify the presence of antimicrobial resistance genes, significantly enhancing the ability to select a targeted treatment regimen, reducing broad spectrum antibiotic use and improving patient outcomes.
Lastly, the FDA is working closely with manufacturers and academia on the next generation of biomarkers to rapidly identify whether a patient’s symptoms are due to a bacterial infection. Or, for example, when antibiotics can be stopped, thereby avoiding substantial unnecessary antibiotic use.
Enhancing Antimicrobial Resistance Surveillance
I want to move on to the third component of our comprehensive approach, gathering data on antimicrobial use and resistance. This is essential to understanding the drivers of resistance in human and veterinary settings and formulating appropriate responses.
But acquiring this data is complicated. It requires collaboration and coordination across multiple government agencies. The FDA is especially grateful to our colleagues at USDA and CDC, who partner with us on many of these data collection efforts.
We also appreciate Congress’s interest in the FDA’s surveillance efforts, and we’re committed to making the most of the funds appropriated for these activities. One such activity is the National Antimicrobial Resistance Monitoring System (NARMS), co-managed by FDA, USDA, and CDC.
Our veterinary center released a plan today that discusses further improvements we plan to pursue to NARMS. For example, we’ll be expanding NARMS sampling, supporting research in advanced genomic technologies and bioinformatics and building our domestic capacity to monitor AMR in previously underexplored pathogens to include companion animals and animal feed.
We’re also working to further refine industry reporting of antimicrobial sales data. And, we’re seeking to gain a better understanding of how these products are actually used on farms. This includes continuing to fund several pilot projects to help us better understand on-farm use. We plan to publish reports of this work.
In human medicine, it’s been long recognized that differences in hospital reporting on which specific AMR tests were conducted—and how results of these tests have been reported—has substantially hindered the ability to track antimicrobial resistance and implement decision support for treating physicians.
Working in partnership with more than 40 other stakeholders—including CDC, National Library of Medicine, pharmaceutical and device industries, and others—our device center’s Office of In Vitro Diagnostics and Radiological Health has led the development of interoperable data standards for the transmission of device codes from manufacturers to clinical laboratories.
This work has supported the development of a microbiology-coding manual. This new resource describes the effective implementation of about 12,000 microbiology LOINC codes into consistent electronic diagnostic results.
Reducing inconsistency in reporting test results should substantially improve the reporting of antimicrobial resistance. Continued development of this program, called the Systemic Harmonization and Interoperability Enhancement for Lab Data, or SHIELD, effort, should unlock the ability for real-time clinician support across all electronic health record systems.
It’ll enable efficient tracking of prevalence and spread of AMR within and across institutions. And, it’ll also advance the development of real world evidence for different treatment approaches.
Our Office of In Vitro Diagnostics and our drug center colleagues have also published a draft guidance titled “Coordinated Development of Antimicrobial Drugs and Antimicrobial Susceptibility Test Devices.” This policy can facilitate the availability of diagnostic devices to test organisms for antimicrobial susceptibility at the same time or very shortly after approval of a new antimicrobial drug.
We’ll be working to finalize this guidance soon.
Coordinated product development between drug and device developers can be very effective in streamlining the regulatory pathway. Such coordination has resulted in antimicrobial susceptibility devices being available almost immediately or within weeks of three recent new drug approvals. In addition, the FDA has received more than 13 pre-submissions from antimicrobial susceptibility testing (AST) device developers.
Recognizing that the availability of antimicrobial resistant bacterial strains has been a significant challenge to developers of diagnostics to detect antimicrobial resistance, the FDA and CDC collaborated to create the Antimicrobial Resistance Isolate Bank.
This is a publicly available resource that provides panels of curated bacterial and fungal strains to device developers, academic researchers, pharmaceutical companies, clinical laboratories, and others.
The AR Isolate Bank is an invaluable national resource. To date, it has provided more than 2,000 panels for use in device development, drug development, research, or laboratory use. Each panel has been developed to focus on an important clinical concern.
This bank has contributed to 13 clearances or approvals for AST devices along with the development of other infectious disease test submissions since its launch in 2015.
Advancing innovative AST devices and diagnostic tools, and enhancing interoperability of IT systems, will bring us much closer to a real time surveillance system for antimicrobial resistance. This will enable clinicians and policymakers to monitor local and national trends, and design agile clinical trials testing targeted treatment approaches, without waiting days or months for reliable data.
Enhancing Regulatory Science
Finally, we’re also pursuing our own intramural regulatory science initiatives. For instance, the FDA is developing methods to assess medical countermeasures and validating next generation in vitro diagnostics platforms. In addition to these efforts, the FDA also works with a variety of public-private partnerships to inform approaches to drug development, facilitate guidance development and provide recommendations to streamline the efficient development of new antibiotics.
To take one example, the Biomarkers Consortium of the Foundation for the NIH has brought together industry, FDA, NIH and academia to advance the science of clinical trial endpoint development for antimicrobials. The Clinical Trials Transformation Initiative is another example. This program is supporting research and expert meetings on streamlined development of drugs for serious bacterial infections with unmet medical need. Through this effort, we’re developing consensus driven recommendations to streamline clinical trials for hospital-acquired and ventilator-associated pneumonia.
And today, the FDA is releasing a Request for Information to obtain additional, external input on how best to develop an annual list of regulatory science initiatives specific for antimicrobial products. This input will help the Office of Antimicrobial Products develop the FDA’s fiscal year 2019 Regulatory Science Initiatives.
This will help the FDA identify research areas where regulatory science can support new antibacterial drug development. This includes new efforts to create drug development tools or standards for use by industry or other stakeholders, to better meet patient needs.
There’s more work we’re doing at the FDA to combat antimicrobial resistance that my colleagues will discuss shortly.
We are confronting a global public health threat.
We need to harness science and policy to help our public health systems and researchers become nimbler in the battle against drug resistant pathogens.
I’m confident that efforts we’re launching today, and the ones that we’ll continue in the months and years to come, will help us achieve our goal of facilitating stewardship and advancing innovation across human and animal health, within our borders and across them.