Approval Letter Other 215040 (Jan 1, 2024)

Summary

This is a Complete Response Letter from the FDA to Galephar Pharmaceutical Research Inc. regarding their New Drug Application (NDA) 215040 for Legubeti (acetylcysteine) for oral solution. The FDA has determined that the application cannot be approved in its present form due to several deficiencies related to clinical data, regulatory compliance, and safety information.

Key points

• Conduct palatability and tolerability studies for Legubeti at clinically relevant doses, including a fit-for-purpose patient reported outcomes (PRO) instrument, with agreement from the Division of Clinical Outcomes Assessment (DCOA) on the PRO.
• Provide additional information (e.g., published literature or a study) to justify the safety of L-lysine exposure in pediatric patients down to 1 kg for the proposed indication.
• Address the reliance on Cetylev for Physician Labeling Rule (PLR) and Pregnancy and Lactation Labeling Rule (PLLR) by either citing and providing original publications not based on FDA's finding of a listed drug, or by complying with legal/regulatory requirements for reliance on Cetylev (e.g., establishing a scientific bridge, patent certification).
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies, detailing significant changes or findings in the safety profile, presenting new and combined safety data, comparing adverse event frequencies, providing case report forms and narrative summaries for deaths or serious adverse events, describing changes in common adverse events, providing updated exposure information, and summarizing worldwide safety experience with English translations of foreign labeling.
• Resubmit the proposed proprietary name, Legubeti, when responding to the application deficiencies.
• Provide a comprehensive summary of clinical pharmacology information for N-acetylcysteine and L-Lysine available in the published literature along with the original articles.
• Resubmit the application or take other actions available under 21 CFR 314.110 within one year, clearly marking the resubmission as 'RESUBMISSION' and stating it is a complete response to the deficiencies.
• You have not provided data to demonstrate the tolerability of Legubeti, the lysine salt of acetylcysteine, for the full range of loading and maintenance doses for patients with all body weights proposed in labeling. The data to address the effect of the lysine on the palatability of Legubeti is inadequate, as the completed relative bioavailability study with 1 gm of acetylcysteine is not sufficient for higher doses (up to 15 gm). This uncertainty places patients at increased risk of acetaminophen-induced toxicity.

Cited reasons

• Inadequate Tolerability and Palatability Data for Legubeti
• Insufficient Safety Information for L-lysine in Pediatric Patients
• Regulatory Compliance for Labeling Reliance in 505(b)(2) Application
• The application for Legubeti (acetylcysteine) for oral solution received a Complete Response due to critical deficiencies in clinical data regarding product tolerability and palatability, insufficient safety information for L-lysine in pediatric patients, and regulatory non-compliance for labeling reliance in a 505(b)(2) pathway.

Recommended actions

• Conduct palatability and tolerability studies for Legubeti at clinically relevant doses, including a fit-for-purpose patient reported outcomes (PRO) instrument, with agreement from the Division of Clinical Outcomes Assessment (DCOA) on the PRO.
• Provide additional information (e.g., published literature or a study) to justify the safety of L-lysine exposure in pediatric patients down to 1 kg for the proposed indication.
• Address the reliance on Cetylev for Physician Labeling Rule (PLR) and Pregnancy and Lactation Labeling Rule (PLLR) by either citing and providing original publications not based on FDA's finding of a listed drug, or by complying with legal/regulatory requirements for reliance on Cetylev (e.g., establishing a scientific bridge, patent certification).
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies, detailing significant changes or findings in the safety profile, presenting new and combined safety data, comparing adverse event frequencies, providing case report forms and narrative summaries for deaths or serious adverse events, describing changes in common adverse events, providing updated exposure information, and summarizing worldwide safety experience with English translations of foreign labeling.
• Resubmit the proposed proprietary name, Legubeti, when responding to the application deficiencies.
• Provide a comprehensive summary of clinical pharmacology information for N-acetylcysteine and L-Lysine available in the published literature along with the original articles.
• Resubmit the application or take other actions available under 21 CFR 314.110 within one year, clearly marking the resubmission as 'RESUBMISSION' and stating it is a complete response to the deficiencies.

Deficiency summary

The application for Legubeti (acetylcysteine) for oral solution received a Complete Response due to critical deficiencies in clinical data regarding product tolerability and palatability, insufficient safety information for L-lysine in pediatric patients, and regulatory non-compliance for labeling reliance in a 505(b)(2) pathway.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

505(b)(2) of the Federal Food, Drug, and Cosmetic Act

Impact

Impact score

0.95

Estimated delay

540 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The application was not approved due to significant clinical data gaps concerning product tolerability/palatability and pediatric safety, coupled with regulatory issues regarding the appropriate reliance on listed drugs for labeling in a 505(b)(2) submission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%