FDA Proposes Subscription Model to Prod Antibiotic Development

Troy Brown, RN

September 17, 2018

The US Food and Drug Administration (FDA) hopes to combat drug-resistant bacteria by introducing a four-pronged approach that includes a hospital "drug subscription" plan aimed at easing the costs and risks of developing new antimicrobials by pharmaceutical companies. The 5-year plan includes promoting antimicrobial stewardship, improving antimicrobial resistance surveillance, and improving regulatory science.

Scott Gottlieb, MD, commissioner of the FDA, presented the plan on September 14 at a meeting at the Pew Charitable Trusts in Washington, DC.

Gottlieb said sustaining "a strong antibiotic drug pipeline" is critical to fighting antibiotic resistance, but antibiotic development is not profitable for most pharmaceutical companies.

"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," Gottlieb said in prepared remarks to the group.

"We don't have that today. As large companies pare their efforts back, the funding pool available for commercializing innovative projects is shrinking," he added. 

Part of the problem is that drugs that treat multidrug-resistant pathogens are usually saved for times when less expensive "first-line" drugs are ineffective.

"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," Gottlieb explained.

"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," he said.

Current Model "In Direct Conflict to Our Public Health Goals"

Holding back a newer antibiotic for last-line use decreases product revenues early in the drug's patent life, when those revenues are of most value to companies and investors. This is in direct contrast to markets for the new HIV and hepatitis C antiviral drugs, in which new drugs have quickly replaced many of the older drugs and become first-line treatments.

"When a new product...enters the market, the economic rewards are not to the point that they're able to sustain development in this area in the way that we need in order to be able to meet patient needs," Edward Cox, MD, MPH, director, FDA's Office of Antimicrobial Products, Center for Drug Evaluation and Research, said during a panel discussion at the meeting.

Reimbursement reforms could include a range of approaches such as milestone payments and licensing fees for companies that develop FDA-approved products with high economic and clinical value and efficacy against multidrug-resistant organisms.

"[A] subscription-based model for big institutions that are most likely to use drugs targeted to multidrug-resistant organisms...would provide a foundation of return on investment. It probably wouldn't encompass the entire market for a new drug, but it would provide enough of a...guaranteed market that would help more companies get over the 'hurdle rate' of making investments in new drug development in this area," Gottlieb told the group. 

"It's a concept that we used to pay for a lot of other things in the in-hospital setting. Software is paid for this way. A lot of durable medical equipment is paid for on a subscription-based model, so hospitals are used to paying for things on [this] model where they pay a flat fee for access to something and they might pay a variable fee based on the number of beds they have, or the number of admissions they have, or for a certain number of uses. These models are very well established and have just never been applied to the drug setting," Gottlieb explained to the group.

Other reimbursement approaches could include new technology add-on payments for certain new antibacterial medications that fill critical patient and public health needs.

The FDA is talking with agencies including the Centers for Medicare and Medicaid Services about these and other reimbursement approaches.

The Gates Foundation, Biomedical Advanced Research and Development Authority, and Center for Medicare and Medicaid Innovation could collaborate with commercial insurers to provide a natural testing ground for innovative payment models such as these, which could be tied to effective antimicrobial stewardship efforts by providers and manufacturers, Gottlieb said in his prepared remarks.

Incentives for Drug Development

Much of the focus has been on incentives to encourage product research and development, Gottlieb explained. The Generating Antibiotic Incentives Now (GAIN) Act passed in 2012 as part of the FDA Safety and Innovation Act (FDASIA), created incentives for companies to develop antibacterial and antifungal medications for serious or life-threatening infections. Under the GAIN Act, the FDA can designate certain antimicrobial medications as qualified infectious disease products (QIDPs). The FDA has designated 168 QIDPs from July 9, 2012, through August 2, 2018 — including approximately 83 novel drugs — and approved 15 QIDPs.

Congress enacted the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) in 2016 under the 21st Century Cures Act, to speed up the development and approval of antibacterial medications to treat serious or potentially lethal infections in populations of patients with unmet medical needs.

The FDA released draft guidance regarding the LPAD on June 12, 2018. "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," Gottlieb said in his prepared remarks.

"The FDA expects that preclinical 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," he added.

Antibiotic Use in Animals Under Scrutiny

The FDA announced new efforts to promote antimicrobial stewardship in veterinary settings on July 31, 2018.

"Importantly, the FDA has pledged to set evidence-based limits on the duration for which these drugs are used in animals. The agency must be held to its commitment to finalize the setting of these limits by 2023. The FDA has also made a key commitment to bring all animal antibiotics under veterinary oversight and to implement a strategy to promote antimicrobial stewardship in companion animals. These critical steps forward cannot be delayed: there simply is no time to waste," Peter G. Lurie, MD, MPH, president, Center for Science in the Public Interest, said in a news release.

"FDA could improve its strategy by providing concrete metrics for each of the goals it has identified. As these and other changes take effect, it will be important for Americans to have a clear means to assess whether the FDA's efforts will have been successful in reducing inappropriate antibiotic use in animals and, ultimately, in reducing antibiotic resistance itself," Lurie added.

Antibiotics are still needed to address certain diseases in animals, William Flynn, DVM, MS, deputy director, science policy, FDA's Center for Veterinary Medicine, said during the panel discussion. "We're trying to focus on the driver; in other words, what is the underlying disease condition that is driving the need for using this product...and working with the industry — both the [agriculture] industry and the veterinary community to figure out [whether there are] better ways or alternative ways we can manage that disease condition so that we do not have to rely on these antibiotics as much as we currently are," he explained.

"Astounding" Progress in Diagnostics

"The progress that we've seen in the last decade in diagnostics is nothing short of astounding...the new diagnostics we have out there are teaching us so much more," Steven Gitterman, MD, PhD, FDA deputy director, Division of Microbiology Devices, Center for Devices and Radiological Health, said during the panel discussion. Newer diagnostic tests enable clinicians to distinguish viral from bacterial infections and determine whether a condition is infectious or noninfectious — for example, whether a skin disorder is poison ivy or cellulitis. This will help avoid inappropriate antimicrobial use. Such diagnostics can also assist researchers when selecting patients for clinical trials, he added.

Nontraditional Therapeutics

The FDA's biologics center is also assisting with the development of nontraditional products including bacteriophage, live biotherapeutic products, and fecal microbiota for transplantation.

"We currently view that the current regulatory pathways provide sufficient flexibility to support licensure of these nontraditional therapeutics, as long as you can generate data that support the safety, efficacy, and the potency. Obviously, we're continuing to watch how these types of therapies are being developed, the data from clinical trials, and we'll reassess that," Carolyn Wilson, PhD, associate director, research, FDA's Center for Biologics Evaluation and Research, said during the panel discussion.

The FDA has introduced a new webpage they're calling a "one-stop shop" for keeping abreast of the FDA's work on antimicrobial resistance.

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