GAO: Pathway for antimicrobial drug development leads to few approvals

Regulatory NewsRegulatory News
| 22 November 2021 | By Mary Ellen Schneider 

A regulatory pathway to encourage development of drugs to combat antimicrobial resistant infections – the limited population pathway for antibacterial and antifungal drugs (LPAD) – has resulted in just two drug approvals by the US Food and Drug Administration (FDA) since 2016, according to a new report from the Government Accountability Office (GAO).
The GAO report, released on 19 November 2021, suggested that the LPAD pathway does not address the underlying economic challenges in developing antimicrobial drugs for limited populations, namely that the sales revenue is insufficient to cover the drug development costs.
GAO reiterated its recommendation from a March 2020 report that HHS develop a strategy to spur the development of new treatments for antibiotic-resistant infections by using postmarket financial incentives that include rewards for market entry or reimbursement reform. HHS did not agree with the recommendation at the time, noting that it was conducting its own analysis for an upcoming strategic framework.
“We maintain that it is important that HHS not delay the development of such a strategic framework, which would be the initial step toward the creation of these incentives. As of June 2021, the agency indicated that it was still examining the issue and this recommendation had not been implemented,” GAO officials wrote.
The GAO audit, conducted from February to November 2021, included a review of FDA guidance documents, documentation from the approval process and written statements from drug developers to FDA and investors, as well as interviews with FDA officials and industry stakeholders. The Department of Health and Human Services (HHS) provided technical comments on the draft that were incorporated into GAO’s final report.
How LPAD works
The LPAD pathway was created as part of the 21st Century Cures Act in 2016. The FDA issued draft guidance to industry on the program in June 2018 and finalized the guidance in August 2020 (RELATED: LPAD pathway: FDA finalizes guidance, Regulatory Focus 05 August 2020)
The program is aimed at the development and approval of antibacterial and antifungal drugs for serious or life-threatening infections in limited populations of patients with unmet needs. The FDA does not define limited population as meaning that there needs to be a small number of patients affected, but instead that the intended condition is a subset of a broader type of infection. Drugs approved through the pathway must meet the usual standards for safety and effectiveness but the benefit-risk assessment within LPAD takes into account the intended limited patient population, the severity of the infection, and the lack of treatment alternatives. Drugs approved through this pathway are also labeled to reflect that the drug is safe and effective for use only in the limited population.
The LPAD program does not include financial incentives, but sponsors may be eligible for other FDA programs that expedite drug review or provide incentives. For instance, the Qualified Infectious Disease Product Designation could qualify the drug for a five-year extension of any exclusivity that the application qualifies for at the time of approval.
Drug approvals so far
Since the LPAD creation in 2016, just four drug developers have sought approval through the pathway. The FDA approved two of the drugs through LPAD and one drug was approved outside of LPAD for a different indication.
In 2018, the FDA approved Arikayce, which is indicated for treatment of a bacterial infection called refractory mycobacterium avium complex (MAC) lung disease in adults who have limited or no alternative treatment options, through the LPAD. Pretomanid, which was approved through LPAD in 2019, is indicated for treatment of specific types of highly treatment-resistant tuberculosis.
For both drugs, the clinical development was already underway when the LPAD program was established. According to the GAO report, both sponsors made the request for LPAD after FDA officials suggested it during the review of their marketing applications.
LPAD shortfalls
GAO reported that five of the ten industry stakeholders they interviewed said that LPAD “had fallen short of their expectations.” One issue highlighted is that FDA does not determine a drug’s eligibility for LPAD until after a marketing application has been submitted. The industry commenters said this creates uncertainty during drug development because sponsors don’t know if they can plan more streamlined clinical trials that enroll fewer patients.
But the GAO reported that FDA officials said they could not make a definitive determination of eligibility without reviewing the clinical data in the marketing application. “Agency officials stated that if there is interest in developing a drug for a limited population, drug sponsors should ideally notify FDA of their intent to request LPAD during development. If drug sponsors do so, agency officials said that they will work with the drug sponsor to ensure that the population is clearly defined in a clinically meaningful way,” according to the GAO report.
Industry stakeholders also noted the need for additional clarity in FDA guidance about LPAD, including more information on trial design and what clinical data would meet standards for approval.
GAO report on antimicrobial drug development


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