MFDS specifies guidelines on the biosimilars Phase 3 trial waiver

The guidelines for evaluating biosimilars has been established, and feedback will be received until September 22

After implementing a July revision that significantly relaxed submission requirements for Phase 3 clinical trials (comparative efficacy clinical studies) and animal testing data in biosimilar (generics) approvals, the Ministry of Food and Drug Safety (MFDS) issued detailed evaluation criteria to apply these standards to regulatory reviews.

According to industry sources on the 14th, the Biosimilar Division of the National Institute of Food and Drug Safety Evaluation (NIFDS) drafted a revision to the "Guideline on the Evaluation of Biosimilars," reflecting domestic and international biosimilar development and approval experience as well as the latest globally harmonized regulatory requirements, and has begun receiving feedback from the pharmaceutical industry through Tuesday, September 22.

This revision follows the "Regulation on the Approval and Review of Biological Products," which was revised and implemented on July 14. The NIFDS explained that the revision reflects advances in sophisticated physicochemical and functional analytical techniques and global regulatory trends led by bodies such as the World Health Organization (WHO), reducing unnecessary testing burdens on developers and supporting faster market entry.

The revision stated, "Comparative efficacy clinical trials are not mandatory"

The main focus of this revised guideline is the formal removal of the mandatory requirement for "comparative efficacy clinical trials (Phase 3)," which previously required substantial time and capital in biosimilar development.

The revision explicitly states, "When biosimilarity can be demonstrated through quality, nonclinical, and pharmacokinetic (PK) study results, comparative efficacy clinical trials are not required." Furthermore, it clarified that a paradigm shift in clinical evaluation by stating that "the MFDS does not presume that comparative efficacy clinical trials must be routinely conducted."

Comparative efficacy clinical evaluations are required for exceptional supplementary measures, reserved solely for specific situations where "residual uncertainty" remains unresolvable through quality, nonclinical, and pharmacokinetic evaluations alone, or where conducting pharmacokinetic evaluations is unfeasible.

Additionally, the MFDS stated that waiving comparative efficacy clinical trials does not signify a "relaxation of quality standards."

The guideline clearly states that when meaningful differences in quality attributes compared to the reference product occur during the quality comparability assessment stage, comparative efficacy clinical trials cannot be used to justify such discrepancies. In particular, if differences are identified in critical quality attributes (CQAs) that directly reflect the drug's mechanism of action, such as "potency" or "biological activity," they cannot be resolved via Phase 3 clinical data; developers must instead optimize the manufacturing process or reassess the overall development strategy.

In other words, to qualify for a Phase 3 trial waiver, developers must rigorously demonstrate biosimilarity upfront through precision structural and functional characterization.

To support this framework, the revision incorporates extensive new provisions, including: ▲ risk assessments considering clinical impact and uncertainty by quality attribute (Tier classification) ▲ methods for calculating statistical comparability acceptance criteria (Quality Range) ▲ batch requirements for the proposed biosimilar (minimum of 6 batches) and the reference product (recommended minimum of 10 batches) ▲ a standardized reporting format for quality comparability evaluations (CTD 3.2.R).

Established criteria for waiving nonclinical animal studies and immunogenicity testing

In addition to the Phase 3 clinical trial waiver, the guidelines establish criteria for waiving nonclinical and early-stage clinical requirements.

The revision states that in vivo animal studies, such as repeat-dose toxicity studies, may be omitted if in vitro comparative evaluations are sufficient and leave no residual uncertainty. Furthermore, the guideline established clear rationales for omitting clinical immunogenicity testing altogether for well-characterized, low-risk biologics such as insulin, somatropin, filgrastim, and teriparatide.

An official from the pharmaceutical industry stated, "This guideline revision is expected to shorten development timelines and save tens of billions of won in Phase 3 clinical trial expenses. It is expected to enhance the global competitiveness of the domestic biosimilar industry."