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FDA Commissioner Scott Gottlieb, MD, has issued the following statement: "The increase in serious antimicrobial drug resistant infections is a critical public health concern and a growing threat to patients. According to our colleagues at the Centers for Disease Control and Prevention, each year in the U.S. at least 2 million people become infected with bacteria that are resistant to antibiotics and 23,000 people die each year as a direct result of these infections.
"As more and more bacteria grow resistant to currently available antibiotics, we must tackle the issue on all fronts and seek new approaches to this persistent and potentially deadly problem. This means helping to ensure good antibiotic stewardship and use in appropriate clinical scenarios. It also means spurring the development of new antibiotics, for instance, by pursuing novel incentive models for developers that take into consideration the challenging economic and usage dynamics of these products.
"Despite the growing incidence of these resistant strains of bacteria, there has unfortunately been an overall decline in antibiotic drug research driven largely by the significant obstacles to developing innovations in this category. This is especially true when it comes to developing new antibiotics that work through novel mechanisms that can evade existing patterns of resistance.
Consider patients who are hospitalized with life-threatening infections and need immediate treatment, but the severity and symptoms of the acute illness, such as delirium, may make obtaining informed consent from patients and performing other trial enrollment procedures difficult. This is just one example of the many challenges to conducting effective clinical trials in patients with serious bacterial diseases.
"Complicating matters further, many patients with serious infections may have already tried several currently available antibiotics before a clinical trial is considered. If patients have already received substantial treatment for their infection before enrolling in a clinical trial, this exposure to other treatments can make it more difficult to isolate the effects of an investigational drug.
"These are some of the scientific challenges. But there are also economic impediments.
"Developing new drugs is a costly endeavor. But the current reimbursement model, where drugs are reimbursed based on each episode of their use, presents incentives that run contrary to effective stewardship over new antibiotics that might be highly effective against very rare and dangerous pathogens. When such drugs become available, we try to use them sparingly, lest pathogens become over-exposed to a new mechanism of attack and develop resistance to it. So, providers have imposed understandable restrictions on the use of such drugs. While this represents responsible stewardship, it also means that a novel antibiotic may have a very limited market. If product developers know that they will not be able to recoup their investments, there may be reduced incentive to invest the significant money needed to discover and develop such a drug.
"The global effort to educate patients and providers about the importance of reducing the unnecessary and over-use of antibiotics is a crucially important means to slowing the rate of resistance. However, we must acknowledge that these essential antimicrobial stewardship programs do have an impact - as they should and aim to do - on the use of antibiotics and thus the amount of product sold. And as consequence, we must find ways to spur development and incentivize innovators. The FDA and other federal agencies are taking new steps to address each of these challenges, including new efforts to address the need for better economic incentives.
"One of those steps is implementing the set of special incentives that Congress created for antibacterial and antifungal drugs that treat serious or life-threatening infections. This includes the qualified infectious disease product (QIDP) designation. Under this program, new drug applications that are designated as QIDP can receive fast track designation, priority review designation and a possible five-year extension of any exclusivity that the application qualifies for upon approval.
"Even with these incentives, we recognize that challenges remain. As such, we continue to work with Congress, our partners at other agencies and the scientific community to find additional ways to create incentives for the development of novel antimicrobial drugs and strengthen the research and development pipeline.
"One idea that we’re currently discussing with other agencies such as the Centers for Medicare and Medicaid Services (CMS) would involve changing the model for reimbursement of certain new, anti-microbial drugs that meet critical, public health needs - principally their ability to effectively target dangerous, multi-drug resistant infections.
"Under such an approach, instead of paying for drugs that meet a narrow set of critical, public health criteria on a per use basis - for each prescription that’s written, as is done now - one might move instead to a licensing model. Under such a model, the acute care institutions that are most likely to prescribe these medicines would pay a fixed licensing fee for access to the drug, which would offer them the right to use a certain number of annual doses. This is similar to the way that software often gets reimbursed, where institutions pay a licensing fee for a fixed number of installations. We have been speaking with our counterparts at CMS as to whether such an approach is feasible, whether it can be formulated as a demonstration, and as a demonstration, whether it would have the intended public health benefits.
"These concepts are still being developed and we look forward to greater public engagement around these ideas. Adapting this licensing payment model to drugs that target dangerous, antimicrobial resistant organisms can help achieve two important public heath goals. First, such a model would create a natural market for drugs that meet certain public health criteria, by providing a predictable return on investment and revenue stream through more foreseeable licensing fees. Second, it would put the institutions fully in charge of stewardship of these important medicines. Once they purchase the ability to access a drug, they would be stewards of its use up to a certain number of annual doses, which could be tied to the number of beds an institution has or its likelihood of encountering certain organisms.
"This reimbursement model would address some of the investment challenges associated with the market for potent antimicrobials that target multidrug resistant organisms. These are drugs that we want to have available to us, but that we should keep in reserve and hope that we seldom have to use them. It is my belief that a licensing model might offer an effective “pull incentive” that attempts to create a predictable market for antimicrobial drugs that would meet a narrow set of critical, public health criteria.
"We are currently discussing these ideas as part of the FDA’s broader policy work in this area. We plan to release more information soon. Such an approach potentially de-links the return on investment on an important antimicrobial drug from the volume of that drug that’s used. This would achieve an important public health purpose since these are drugs that we would want to hold in reserve.
"We’re also taking other new steps to help advance development of improved antimicrobial drugs, through measures that make the development process more predictable and efficient.
"Toward these ends, another new program is the Limited Population Pathway for Antibacterial and Antifungal Drugs, or LPAD pathway; established by Congress under the 21st Century Cures Act. The FDA believes this program will advance development and approval of antibacterial drugs to treat serious or life threatening infections in limited populations of patients with unmet needs. Today 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. In reviewing an application submitted under the LPAD pathway, the FDA will consider the severity, rarity or prevalence of the infection that the drug is intended to treat. The agency will also consider the availability or lack of alternative treatment in the limited population.
"The guidance will also assist companies in developing labeling, including prescribing information, patient labeling and carton/container labeling, to inform the medical community that the drug was approved under the LPAD pathway based on a benefit-risk assessment in a limited population.
"We’ve already had meaningful, early interest by innovators in potentially developing drugs under this new pathway. We expect that development programs for drugs eligible for approval under the LPAD pathway will follow streamlined approaches to clinical development. This may involve smaller, shorter or fewer clinical trials. However, the LPAD pathway still requires these drug products meet the FDA’s approval standard for safety and effectiveness. Early and frequent communications between the FDA and drug companies interested in pursuing approval under the LPAD pathway for their products can help reduce overall product development times.
"While we hope our work will help advance the development of new antibacterial and antifungal drugs, this isn’t a problem that can be addressed by our agency alone. We’re collaborating with agency partners, the broader scientific and policy community, and medical product sponsors to address scientific challenges. Bacteria will continue to evolve. They will continue to chip away at the usefulness of available treatments - including the medicines that we have relied on for years.
"Many of the existing antibiotics are simply old. They were screened out of nature where they resided in soil for centuries, engaging in a natural battle with various bugs.
"More judicious use of antibiotics in health care and agriculture settings can help slow the rate at which bacteria become resistant to antibiotics. But even with prudent use, we will need to continuously encourage the development of new therapeutic options to keep pace with these challenges. The steps we’re taking, including the issuance of today’s draft guidance on the LPAD pathway and the discussion of new incentive models with our partners at other agencies, are some of the additional steps we’re taking toward strengthening the fragile antibacterial drug pipeline, as part of the larger effort to combat antibiotic-resistant bacteria."