To Fight Antimicrobial Resistance, Allow FDA To Approve New Drugs For Limited Populations

Over the past several months, microbiologists and public health experts around the world have been alarmed by the discovery of a gene conferring resistance to colistin, a so-called “last resort” antibiotic.

The gene, MCR-1, was discovered in China last year, and thereafter quickly identified in E. coli samples from six continents. Because this type of gene is highly transferable, it will, in all likelihood, spread to other hard-to-treat bacteria. What global health leaders have been warning of for years has now become reality.

Now, more than ever, there is an urgent need for action to spur the innovation of antibiotics to treat the most serious and life-threatening superbugs. The recent Declaration on Combating Antimicrobial Resistance, signed by more than 80 drug companies, is a promising sign of the growing international momentum to tackle this challenge. In the United States, Congress and the administration are bringing unprecedented attention to the problem, including significant funding increases for federal efforts to fight antibiotic resistance and conserve existing drugs.

However much remains to be done, including tackling major barriers in basic science and addressing the challenges of clinical trials necessary for antibiotic development. As the Senate considers a series of biomedical innovation bills in the coming weeks, it has the opportunity to pass legislation that would directly address a public health need by bringing drugs for resistant infections to market.

Specifically, the Promise for Antibiotics and Therapeutics for Health (PATH) Act would allow the Food and Drug Administration (FDA) to approve antibiotics for limited populations of patients with serious and life-threatening bacterial infections that are resistant to current treatments - in other words, the types of antibiotics that could treat superbugs such as MCR-1 and others that will surely follow. This “limited-population antibacterial drug” (LPAD) approach has broad and bipartisan, bicameral support, and was approved overwhelmingly by the House of Representatives last year as a part of the 21st Century Cures Act, known as the ADAPT Act. On April 6, the Senate Committee on Health, Education, Labor, and Pensions plans to advance a companion measure, called the PATH Act.

The Current Landscape

Already, the majority of infectious disease doctors report having treated patients who have infections that do not respond to any antibiotic. At the same time, there has been a void of nearly 30 years in the discovery of new types of antibiotics.

The Pew Charitable Trusts' most recent analysis of the antibiotic pipeline, updated in 2015, shows just 39 new antibiotics in clinical development - a promising number, perhaps, until one considers that only about one of every five drugs that enters human testing will ultimately receive FDA approval. That's not enough to meet the needs of today - or the increased rate of infections projected moving forward.

Further, there has been an exodus of major pharmaceutical companies from the antibiotics business and, with their departure, a loss of essential research and development expertise.

Although no single policy change will address all the myriad challenges facing antibiotic development, the LPAD pathway will help bring drugs to market for the most pressing public health needs and will do so in a way that reduces development costs.

The Challenge Of Clinical Trials For New Antibiotics

The antibiotics that patients most desperately need are also the antibiotics for which clinical trials are most difficult, often because only a small number of patients typically contract these hard-to-treat infections. Of that small number of patients, many have compromised immune systems or other pre-existing conditions that limit their participation in clinical trials. There are few rapid diagnostic tests for resistance, so patients with these infections have often received other antibiotics by the time their resistant pathogen is identified. This, too, disqualifies them from most clinical trials.

For these reasons, new antibiotics are typically studied in patients who have drug-susceptible, rather than drug-resistant, infections, and the trials are generally designed only to show that the drugs are comparable (“noninferior” is the technical term) to drugs that are already available. This combination of factors means that few drugs are evaluated specifically for use in patients with resistant infections, which is the problem LPAD seeks to address.

Origins Of The Concept

The limited-population antibacterial drug concept dates to 2012. Originally conceived as the “special medical use” (SMU) pathway, it was proposed as an alternative way to approve certain drugs to address unmet medical needs. FDA's Janet Woodcock spoke in favor of this approach at a congressional hearing that year, and the concept was endorsed by the President's Council of Advisors on Science and Technology (December 2012) and FDA (February 2013). Gradually, SMU evolved to focus primarily on antibacterial drugs, an area of great unmet need and significant and specific development challenges. This incarnation of the policy became known as the LDAP pathway.

Under the LPAD approach, FDA would, at the request of a drug company sponsor, evaluate a new antibiotic for potential use in a defined population of patients who have resistant infections, making a risk-benefit calculation specific to that population.

To determine whether this approach could address the problem of antibiotic development while also protecting patient safety, Pew convened a group of key stakeholders in January 2013 to evaluate and refine the idea. Participants included representatives from industry, academia, health insurance companies, physician organizations (including the Infectious Diseases Society of America), public health groups, and government. Together, the group considered the implications of LPAD for clinical trial design and for use in clinical settings. The group also explored how hospitals and insurers would be likely to ensure appropriate use of, and pay for, the drugs. The result was a set of core principles to shape the development of LPAD legislation.

Core Principles For An LPAD Pathway

The limited-population antibacterial drug pathway should be created through legislation based on the core principles outlined below. Specifically, the new law should:

1. Create a special designation and label (with logo) distinguishing products approved under the LPAD pathway from traditional antibiotics (e.g., drugs approved for more common infections or for infections for which satisfactory therapeutic options exist).


2. Acknowledge that the benefits of an antibiotic approved under the pathway outweigh the risks for the limited population for which the drugs are indicated based on smaller data sets. This calculation would take into account the seriousness of the infection and the unmet medical need. For purposes of the legislation, the definition of unmet need should allow for the approval of multiple antibiotics per indication to ensure the antibiotic pipeline is sufficiently diverse.


3. Include a mechanism to collect information in order to evaluate the utility of the pathway, preferably including FDA's Sentinel System and/or the Centers for Disease Control and Prevention's National Healthcare Safety Network.


4. Require FDA to issue guidance, within one year of enactment, on acceptable clinical trial designs to demonstrate the safety and effectiveness of antibiotics approved under the pathway.


5. Ensure that the option to pursue this pathway for limited approval be voluntary for drug sponsors.


6. Allow removal of the limited-population designation if FDA approves a broader indication sought by the sponsor under the traditional approval pathway.


7. Provide for submission and FDA review of promotional materials of products approved under this pathway, using the processes FDA has established for accelerated approval products.


8. Not attempt to regulate the practice of medicine.

Broad Support, Mixed With Criticism

Since creation of the LPAD core principles, numerous organizations have worked with FDA and Congress to shape and advance legislation; the PATH Act is consistent with those principles. It:

• Creates a voluntary pathway, available only for antibiotics that would address an unmet medical need. If drug companies think LPAD will be useful in the development of new antibiotics, they can use it. However, LPAD approvals will not be required for all antibiotics and indeed would be an option only for that subset intended to address unmet medical needs.


• Maintains the current FDA approval standard. As with drugs approved under FDA's traditional pathway, sponsors seeking approval of antibiotics via LPAD must demonstrate safety and provide “substantial evidence” of these drugs' effectiveness. Substantial evidence is defined in Section 505(d) of the Federal Food, Drug, and Cosmetic Actas “evidence consisting of adequate and well-controlled investigations, including clinical investigations.” Additionally, to approve any drug, FDA must find that the drug's benefits outweigh its risks. In the case of LPAD, FDA will be required to apply this same test, making the benefit-risk assessment for the specific, limited population of patients for whom the drugs would be used-those with few or no other remaining treatment options-not for a more general population that could be treated with existing drugs.


• Requires additional measures to help ensure that antibiotics approved under this pathway are used in the limited population for which they are intended. These provisions include (1) prominent, mandatory branding so that prescribing physicians understand that the drugs are intended for use only in specific patient populations; (2) mandatory FDA review of any marketing materials for LPAD drugs; and, (3) a requirement, once the drugs are on the market, that the Department of Health and Human Services evaluate whether they are generally being used as intended.

Several of these points have been cause for criticism or source of confusion, and so bear greater discussion here.

In particular, some stakeholders have pointed to language in the House version of LPAD permitting FDA to consider “alternative endpoints [such as] datasets of limited size; pharmacologic or pathophysiologic data; data from phase 2 clinical studies; and such other confirmatory evidence as the [agency] deems necessary” as evidence that the measure would lower the FDA approval standard. As is the case with all FDA-reviewed drugs, the agency would consider a wide range of data when determining whether to approve a new antibiotic for use in a limited population, including clinical and nonclinical data. While the legislation allows FDA to consider in vitro and in vivo data as part of the overall assessment of the drug's performance, the agency has been explicit that clinical data, including human clinical trials, will be expected for any antibiotics approved under LPAD.

The key point is to recognize that for antibiotics, as for disease areas such as cancer, patients who can't be treated adequately with existing drugs would be likely to view the potential benefits and risks of a new drug differently from patients who can be treated with other long-established therapies. FDA, in turn, might accept smaller clinical trials or greater uncertainty in the data when approving a therapy for an unmet medical need. The agency's “Guidance for Industry: Antibacterial Therapies for Patients With Unmet Medical Need for the Treatment of Serious Bacterial Diseases” is an excellent resource for the other critical questions FDA may consider when assessing whether a limited pathway drug meets the standard for approval. This maintains the benefit-risk standard for patients in that population but may allow for faster and more efficient drug development.

Another source of confusion has been the requirement in the proposed legislation for a post-market assessment of how LPAD drugs are used. This does not represent an effort to ensure that the drugs are not used off-label; indeed, the legislation is explicit that it does not restrict the practice of medicine nor seek to restrain clinical decision-making. However, it will be important to understand whether drugs approved for a limited population are generally used in the population for which they are intended.

For that reason, the legislation requires such an assessment, which might be carried out through a range of approaches, including use of the CDC's National Healthcare Safety Network, FDA's Sentinel program, or by some other means. These additional measures are important, because unlike other therapies for potentially life-threatening illnesses, antibiotics are often prescribed by nonspecialists.

The bipartisan PATH bill is supported by a wide range of stakeholders, including provider associations, public health groups, and pharmaceutical companies, which recognize that now is the time to advance a measure that helps address a public health need and the pressing challenge of antibiotic development. When MCR-1 or the next multidrug-resistant pathogen arrives, we should hope that there are new antibiotics ready for use.