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Pink Sheet – LPAD Approval Pathway Is Not Saving Antimicrobial Development

Pink Sheet – LPAD Approval Pathway Is Not Saving Antimicrobial Development

Executive Summary

US FDA and CMS explore reimbursement ideas to strengthen business case for antimicrobial development; new approval pathway likely is only needed in special situations.

Bundle of money and pack of medication tablets or drug pills, close-up. Expensive health care concept, selective focus

One of the US FDA’s newest weapons to help spur antimicrobial development may not be as vital as initially thought. However, industry still needs incentives and now the agency is moving into the reimbursement area to fight against antimicrobial resistance.


The Limited Population Antibacterial Drug (LPAD) pathway allows antibiotics to be approved and labeled for small populations with unmet needs. The program is intended to allow smaller clinical trials and allow products on the market where risks may otherwise outweigh benefits for large patient groups.


After several years of stakeholder debates, Congress created the program in the 2016 21st Century Cures Act. (Also see “Antibiotic Guidance: Limited Populations Do Not Include Rare Infections” – Pink Sheet, 12 Jun, 2018.)


Ed Cox, director of FDA’s Office of Antimicrobial Products, said Nov. 14 that agency officials thought many antimicrobials under development during the last five years would use the pathway, but it turned out not to be necessary, in part because increasing resistance made it easier to show the new products were better.


“We essentially thought all those drugs would be LPAD drugs if you look back say five or 10 years ago, but some of those drugs actually almost showed superiority … and part was because resistance was chipping away at the efficacy of the comparator option,” Cox said during Biopharma Congress IV, sponsored by Prevision Policy and the Friends of Cancer Research. “The drugs are coming along and they’re actually doing better than expected. The degree of uncertainty is really not so large, even though it is a small clinical trial, because the drug is quite effective.”


Cox said that it appears LPAD is not going to be an extremely popular approval route for new antibiotics.


“LPAD will play a specific role in probably limited circumstances,” he said. “It’s a pathway that sort of needs to fit the characteristics of the drug, the results of the clinical trial, and then we have to be able to identify a specific patient population where the benefit-risk is appropriate. To have all those factors aligned is something that will happen in a limited number of cases.”


The limited use of LPAD may be a relief for some at FDA, who worried that the products may be prescribed off-label and endanger patients unnecessarily. (Also see “FDA Worries About Off-Label Use, Stewardship With Limited-Population Approval Pathway” – Pink Sheet, 11 Feb, 2013.)


Insmed Inc.’s Arikayce (amikacin liposome inhalation suspension) is the only drug approved using LPAD to date. The product received an indication for Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial regimen when patients do not achieve negative sputum cultures after at least six consecutive months of multidrug background regimen therapy. (Also see “LPAD As An Afterthought? Insmed’s Arikayce Reaches US Market Thanks To Limited Population Pathway” – Pink Sheet, 3 Oct, 2018.)

FDA, CMS Explore Antimicrobial Economics

At the same time, FDA also is working with CMS to come up with reimbursement ideas that may improve the business case for antimicrobial development.


“It really is this recognition that this is probably the next factor that needs to be addressed in some way with a solution that will allow for antibacterial drugs to have an economic circumstance that allows the enterprise to essentially be sustained,” Cox said.


He added that often antibiotic approvals were not greeted with celebrations from the company in their public announcements. In some cases, he said press releases announced staff reductions or restructuring.


FDA and CMS are discussing ideas to address the economic challenges, but so far have not found any answers.


“We have talked about some of the different things that they might think about, how they might fit into trying to address some of the economic issues that are out there with regards to trying to make antibacterial drug development once something is approved more sustainable,” Cox said. “We don’t have solutions yet, but I can tell you we’re working on this and really trying to come up with ideas.”


Indeed, while FDA engagement with CMS is not new, discussions related to reimbursement and market sustainability appear to be another extension beyond FDA’s traditional boarders and further into drug development.


FDA talks with CMS are in their early stages as each side better understands the other’s operations.


“The first step is obviously trying to learn each other’s languages,” Cox said. “We’ve been working with our CMS colleagues explaining some about antibacterial drug approvals and they’ve been educating us too on some of the issues around payment.”


Even convincing a government agency to invest can be difficult. An official at the Biomedical Advanced Research and Development Authority (BARDA), which was created to help develop antibiotics and other drugs for use during a pandemic or biological attack, recently said non-traditional antibiotics may be too risky to warrant use of its funds. (Also see “BARDA Official Worries About How Non-Traditional Antibiotics Will Get To Market” – Pink Sheet, 20 Jun, 2018.)

New Ideas To Add To Existing Incentives

Payments for antibiotics typically are very low compared to other drugs, making recouping development costs difficult. At the same time, stakeholders don’t want newly approved products used unless necessary so resistance does not develop, making sales challenging.


De-linking volume from revenue for antimicrobials is one idea being considered. Cox said the administration wants to create a payment structure that recognizes a product’s value, but still fosters stewardship.


FDA Commissioner Scott Gottlieb recently suggested a subscription-like model, where facilities would pay an annual fee to access a pre-determined supply of the antibiotic, similar to how computer software is marketed. (Also see “Gottlieb Floats New Antibiotic Payment Model In LPAD Announcement” – Pink Sheet, 12 Jun, 2018.)


Antibiotic sponsors also have suggested that more up-front incentives would encourage development since exclusivity and other perks already in place tend to reward sponsors later. (Also see “Best Of BIO: Policy & Regulatory Updates From BIO 2017” – Pink Sheet, 23 Jun, 2017.)


The agency already offers the qualified infectious disease product (QIDP) designation, which promises additional exclusivity and other benefits. (Also see “US FDA Joins Chorus Of Concerns About Results Of GAIN Act” – Pink Sheet, 5 Feb, 2018.)


Developing antibiotics for small populations using LPAD also may open them to orphan drug incentives, Center for Drug Evaluation and Research Director Janet Woodcock has said. (Also see “Orphan Antibiotics? Woodcock Says It May Be Possible If IDSA’s New Pathway Is Implemented” – Pink Sheet, 31 Mar, 2012.)…