HLB Determined to Retry Liver Cancer Drug Approval: "Multiple Cases of FDA Approval After Three CRLs"

HLB, which recently received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) during the approval review process, is expected to make another attempt to gain approval for its new liver cancer drug. As the main reason cited in the CRL appears to be related to certain pharmaceutical manufacturing quality management standards (cGMP) at some manufacturing facilities, rather than issues of clinical efficacy or safety, there is growing interest in the company's timeline for resubmission.

Industry experts emphasize that the nature of the deficiencies pointed out by the FDA is more important than the mere receipt of a CRL. This is because the likelihood of future approval and the appropriate response strategy may differ significantly depending on whether the CRL is due to fundamental deficiencies in clinical efficacy or safety, or instead relates to procedural matters such as manufacturing, quality, or facilities that must be addressed prior to approval.

According to a Wells Fargo report analyzing 268 CRLs issued by the FDA since 2018, manufacturing-related CRLs are more likely to be successfully addressed than those related to clinical issues. The report found that, among resubmitted applications that had received a CRL between 2018 and 2021, the overall approval rate was 55%. While the approval rate for applications that received a CRL due to clinical deficiencies was only 24%, it was as high as 89% for those with manufacturing-related deficiencies.

The probability of approval after resubmission was also relatively high. According to the Wells Fargo report, among resubmitted applications for which a final FDA decision was confirmed, the approval rate reached 74%. The average resubmission period for manufacturing or product quality-related CRLs was 224 days, which was shorter than the 373-day average for clinical deficiency CRLs.

The report states, "Manufacturing-related CRLs can generally be addressed, even if received two or three times, whereas clinical-related CRLs are not as easily resolved." In cases similar to HLB, where a third CRL was received, 6 out of 9 resubmitted applications—equivalent to 67%—eventually gained final FDA approval.

There are many confirmed cases of FDA approval after a third CRL. Verrica Pharmaceuticals, for example, received three CRLs in 2020, 2021, and 2022 for its molluscum contagiosum treatment 'Ycanth.' The second and third CRLs were both due to manufacturing facility issues at the same contract manufacturing organization (CMO). After resolving these facility issues, the company obtained FDA approval in July 2023.

Mallinckrodt/Ikaria also experienced three delays in approval for its hepatorenal syndrome treatment 'Terlivaz' due to product quality and facility deficiencies, but obtained FDA approval in September 2022 after resubmitting in June of the same year.

Braeburn Pharmaceuticals/Camurus likewise received three CRLs due to third-party manufacturing facility issues for its opioid use disorder treatment 'Brixadi.' The company resubmitted in November 2022 and received FDA approval in May 2023.

Additionally, IntelGenx/Gensco received a CRL for its migraine treatment 'Rizaport/RizaFilm,' and Sun Pharmaceutical Industries received a CRL for its glaucoma and ocular hypertension treatment 'Xelpros' due to GMP manufacturing facility issues. Both companies ultimately received approval in 2018 after addressing the deficiencies.

These cases indicate that the most important factor following the receipt of a CRL is not the number of CRLs, but whether the issues identified by the FDA are of a nature that can be resolved.

In particular, it is a common view in the industry that manufacturing facility or product quality-related CRLs are fundamentally different from those that require additional proof of clinical efficacy. Many precedents show that when the issues involve production facility quality management systems, manufacturing processes, testing facilities, or labeling, approval has often followed once the deficiencies were addressed.

In HLB's case, the main deficiencies cited in the CRL are understood to be related to the cGMP compliance of manufacturing facilities and matters concerning commercial production. There have been no newly identified issues regarding clinical efficacy, safety, or clinical data.

Accordingly, HLB's U.S. subsidiary, Elevar Therapeutics, plans to review the relevant materials with its partner company Hansoh Pharmaceutical, carefully examine the supplemental information requested by the FDA and the necessary future procedures, and proceed with resubmission of the approval application.

An HLB representative stated, "An FDA CRL is not a decision that denies the possibility of approval itself, but rather a process of notifying the applicant of deficiencies that need to be addressed before approval. In particular, since this CRL appears to be related to manufacturing and quality rather than clinical efficacy or safety issues, we will work with our partner company to promptly address the required procedures and consult with the FDA to pursue resubmission."

This content was produced with the assistance of AI translation services.