Final FDA LPAD guidance: Same substance, useful clarifications

Dear All,

FDA have released the final version of their LPAD (Limited Population Pathway for Antibacterial and Antifungal Drugs, really should be LPPAAAD) guidance. You can get it here. I have generated a comparison with the Jul 2018 draft version that you can get here.

As a reminder, the central concept of the LPPAAAD pathway (OK, so I like the extra letters … sing it aloud to appreciate the melisma!) is that “FDA’s determination of safety and effectiveness take into account the severity, rarity, or prevalence of the infection a drug is intended to treat and the lack of alternative treatment in the limited population for which the drug is intended.”

Specifically, “FDA may approve a drug under the LPAD pathway based upon a conclusion of a positive benefit-risk balance in the limited population, even though insufficient data exist to conclude that there is a favorable benefit-risk profile in a broader population” because “drugs with risks that would be unacceptable for a broad population may be acceptable for patient populations with serious diseases that do not have other treatment options.”

The final LPAD guidance doesn’t offer anything really new (nor was that expected), but there are some useful clarifications:

• A drug can have both LPAD and non-LPAD indications (Section III, definition of LPAD): “There may be cases when a drug is approved under the LPAD pathway for certain indications and may be approved under a non-LPAD pathway for other indications.  The labeling will make clear the indications approved under the LPAD pathway (see section VII., Conditions for Approval Under the LPAD Pathway).”
• The use has to be in a limited population (Section III.A.2): “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.”
• LPAD isn’t for all drugs (Section V): “If an applicant submits a request for approval of an application under the LPAD pathway, but the drug instead can be approved under the traditional approval pathway or the accelerated approval pathway alone, FDA will approve the application, but not under the LPAD pathway.  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.”

It’s great to have this final guidance on LPAD and I hope to see more use of it in the future. If you want to dig deeper into LPAD, follow these links:

• Per discussions at this week’s antifungal R&D workshops, only two drugs have thus far used the LPAD pathway: Arikayce (link) and pretomanid (link).
• See also this wonkish note (link) from FDA’s 12 Jul 2019 Public Meeting on the LPAD pathway in which I’ve further explored the history of LPAD.

All best wishes, –jr

PS: Superb article yesterday on CARB-X by Maryn McKenna in the Boston Globe Magazine — read it here! Thank you, Maryn, for working to tell the story so clearly for our non-technical colleagues!

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.