On August 5, FDA issued its final guidance on the limited population pathway for antibacterial and antifungal drug approval (LPAD Pathway). While the LPAD Pathway final guidance is largely unchanged from the June 2018 draft guidance, FDA has added some important content to help clarify information regarding standards for approval, relationship to other programs, labeling guidelines, LPAD Pathway program limitations, and pre-dissemination requirements.
What is the LPAD Pathway in FDA Drug Approval?
In response to the growing need for new antimicrobials, in 2012, the government enacted the Generating Antibiotics Incentives Now (GAIN) provisions under the Food and Drug Administration Safety and Innovation Act. GAIN provisions offer incentives for the development of antimicrobials to treat serious or life-threatening infections. Those incentives include priority review, fast track designation, and a five-year exclusivity extension for certain applications.
In addition to GAIN, in June 2018 the FDA published guidance for its Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) as part of the 21st Century Cures Act. LPAD outlines a streamlined development program for drugs intended to treat serious or life-threatening infections in a limited population of patients with unmet needs.
Drugs eligible for approval under the LPAD Pathway may follow the streamlined approaches allowing for significantly smaller, shorter, or fewer clinical trials. In exchange for regulatory approval based on smaller clinical trials, the drug may receive a narrow indication focused only on high-risk patients for whom benefits are shown to outweigh risks.
In September 2018, the FDA granted Insmed, Inc. of Bridgewater, NJ its first drug approval under LPAD for Arikayce (amikacin liposome inhalation suspension) in the treatment of Mycobacterium avium complex infection - nontuberculous mycobacteria.
What Drugs Are Eligible for the LPAD Pathway?
In general, three conditions must apply for FDA to approve an antibacterial or antifungal drug (alone or in combination with other drugs) under the LPAD Pathway:
- The drug is intended to treat a serious or life-threatening infection;
- The drug is intended to treat a limited population of patients; and
- The drug is intended to treat patients with unmet medical needs.
1. Serious or life-threatening infection
A drug is “intended to treat a serious or life-threatening infection” if the drug is intended to affect a serious condition or serious aspect of a serious or life-threatening condition, such as a direct effect on a serious symptom or other intended effects. A “direct effect” may include diagnosis, prevention, and/or treatment of a serious aspect of an infection.
2. Limited population
A drug must be intended for use in a group of patients that is limited in a way that is clinically relevant to health care providers. The limited population may be the only group of patients for whom the drug is effective, or it may be a subgroup of a larger population for whom the drug could potentially be effective.
If the drug is intended as a preventative, FDA decides whether the population is limited in a clinically relevant way by looking at the number of patients for which the drug is intended to be prescribed, not the expected incidence of prevention.
In general, FDA does not consider a population to be limited simply because the drug intends to treat a serious infectious disease that occurs infrequently or rarely. In the final guidance, FDA adds an example of what would and would not qualify for the LPAD Pathway to further explain its interpretation of “limited population.”
FDA states, “For example, an antibacterial drug that would have a role in the preventive armamentarium for only a select patient population (e.g., mechanically ventilated patients) with no other options may be an appropriate candidate for the LPAD Pathway; in contrast, an antibacterial drug intended for broad population-level prevention of an infrequently or rarely occurring serious or life-threatening disease generally would not be an appropriate candidate for the LPAD Pathway.”
3. Unmet medical need
FDA interprets the term “unmet medical need” as a condition whose treatment or diagnosis is not addressed adequately by available therapy - whether an immediate need for a specific population or a longer-term societal need.
Serious conditions with no available therapy are unmet medical needs. If a therapy does exist, the new treatment would have to offer some mechanistic, efficacy, or safety advantage over available therapies, such as an effect on the condition that available therapies do not have, an improved effect, an effect for patients unable to tolerate or respond to existing therapies, lower toxicity, mechanistic diversity, improved compliance, or address an anticipated or emerging or public health need.
In the final guidance, FDA refers sponsors to the guidance on Antibacterial Therapies for Patients with an Unmet Medical Need for the Treatment of Serious Bacterial Diseases for further concepts on streamlined development programs. FDA states that this guidance is “applicable to drugs that are eligible for the LPAD Pathway.” The Unmet Medical Need Guidance offers insights into clinical trials using noninferiority designs and superiority clinical trials in limited populations “nested within a noninferiority clinical trial in a broader population.”
Does LPAD Pathway Conflict with Other FDA Designation or Approval Pathways?
Applicants seeking approval under the LPAD Pathway are still able to pursue designation or approval under other programs, including accelerated approval, fast track designation, priority review designation, breakthrough therapy designation, qualified infectious disease product (QIDP) designation, or orphan drug designation.
However, if a drug qualifies for approval under the traditional or accelerated approval pathway alone, FDA states it will approve the application, but not under the LPAD Pathway.
In the final guidance, FDA adds an example to further clarify this point. FDA states, “For example, a drug for which the sponsor conducts a streamlined development program may be eligible for traditional approval if the clinical data support approval in a broader population.”
LPAD Pathway Approval for Multiple Indications
FDA’s final guidance adds several statements to help clarify how sponsors should go about seeking approval for multiple indications when not all of those indications are LPAD Pathway eligible. In some cases, certain drug indications may qualify for LPAD Pathway approval while other indications do not.
FDA explains that written requests for approval under the LPAD Pathway for multiple indications should specify which indications are proposed for approval under the LPAD Pathway. If approval under the LPAD Pathway is pursued for less than all indications when multiple indications are approved or proposed, FDA recommends that applicants “consult the review division for advice regarding how to incorporate LPAD Pathway-related information into labeling.”
LPAD Pathway Applicant Pre-Dissemination Requirements
Under 506(h)(3)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), sponsors of drugs approved under the LPAD Pathway must submit all promotional materials related to the drug within at least 30 days before those materials are circulated.
FDA expands on this pre-dissemination requirement in the final guidance. Specifically, FDA states that applicants should:
The final guidance clarifies that day 1 of the 30-day clock begins the day the Agency receives the complete submission. The pre-dissemination requirement is then satisfied on day 31 - after 30 calendar days.
Further, for the pre-dissemination requirement to be met, all promotional materials must be truthful and nonmisleading. Applicants must comply with FD&C Act postmarketing requirements and regulations and must submit labeling or advertising devised for promotion of the drug product at the time of initial dissemination or publication.
Drug Sponsors Can Terminate LPAD Pathway Limitations
Finally, the final guidance on the LPAD Pathway explains how sponsors can use an efficacy supplement to terminate LPAD Pathway limitations when clinical data supports drug use in a broader population.
Under section 506(h)(7) of the FD&C Act, when FDA determines that clinical data shows the drug is safe and effective for a broader indication, FDA may terminate the limitations associated with an LPAD. Additional clinical data can prompt the FDA to conclude that labeling and other conditions of LPAD pathway approval are no longer necessary.
When determining whether to terminate limitations, FDA intends to consider differences in indicated patient populations; conditions of use; and dosage, duration, and strength between the proposed broader indication and the LPAD approved indication.
FDA will indicate the termination of LPAD Pathway limitations in the approval letter. Upon approval, the LPAD pathway language will be removed from the labeling and the pre-submission of promotional materials will no longer be required.