Plan to waive Phase 3 for comb therapies for HTN and DYS

If both treatments have been proven, through meta-analysis data, to not affect efficacy and safety

MFDS clarified the exemption in the revision plan for the guidelines for clinical trials of combination drugs

Ministry of Food and Drug Safety (MFDS)

The Ministry of Food and Drug Safety (MFDS) has announced an exemption for Phase 3 clinical trials of combination therapies targeting hypertension and dyslipidemia, provided the components do not mutually interfere with efficacy or safety. This exemption is also expected to extend to triple-combination therapies that include diuretics.

However, the MFDS explained that Phase 3 data will be waived only if meta-analysis data confirm that treatments for hypertension and dyslipidemia do not affect each other’s therapeutic effects or safety profiles.

The MFDS has prepared a revision to the 'Guidelines for Clinical Trials of Combination Drugs' and is collecting industry feedback through January 13.

The new addition outlines a plan to rationalize data submission requirements for developing combination drugs intended for comorbid conditions, organized in a Q&A format within the guidelines.

According to the guidelines, the MFDS stated, "Regarding combination drugs for the treatment of comorbid hypertension and dyslipidemia, we have determined that therapeutic confirmatory clinical trials (Phase 3) can be exempted for specific drug classes based on the results of meta-analysis performed on accumulated domestic clinical trial data."

The MFDS added, "To date, hypertension + dyslipidemia combinations developed in Korea have primarily consisted of ARBs (Angiotensin II Receptor Blockers) or CCBs (Calcium Channel Blockers) for hypertension, and Statins or Ezetimibe for dyslipidemia," and explained," Meta-analysis of previously submitted clinical results indicate that these hypertension and dyslipidemia treatments do not mutually affect therapeutic efficacy or safety."

Based on these findings, the MFDS has finalized a policy to exempt therapeutic confirmatory clinical trial data for companies developing combination drugs composed of ARB or CCB and Statin or Ezetimibe. Nevertheless, the MFDS noted that even within these classes, toxicological patterns or pharmacokinetic profiles may vary by specific active pharmaceutical ingredient (API).

The MFDS explained that a therapeutic confirmatory clinical trial may be requested in some cases because the toxicity profile and pharmacokinetics may vary depending on APIs. 

The MFDS stated, ​"Developers must present a review of the impact on safety and efficacy based on trial data regarding absorption, distribution, metabolism, and excretion (ADME), as well as pharmacokinetic drug-drug interaction studies," the MFDS added. "If significant drug-drug interactions are observed in pharmacokinetic studies and are judged to potentially affect safety or efficacy, a therapeutic confirmatory clinical trial may be requested."

Regarding triple-combination drugs that include a diuretic in addition to these two components, the MFDS explained that while Phase 3 data submission is the general rule, exemptions are possible under specific conditions.

The MFDS stated, "For hypertension-dyslipidemia combinations containing drugs in addition to the mentioned classes (e.g., diuretics), therapeutic confirmatory clinical trials must be submitted as before. However, if meta-analysis data for the specific drug class being developed confirms that the hypertension and dyslipidemia treatments do not influence each other's efficacy and safety, the requirement for Phase 3 data may be waived."

In cases where the combination includes a new drug ingredient or involves changes to dosage and administration, additional safety and efficacy data will be required. The MFDS advised, "If a new drug is included in the proposed combination or if it deviates from the approved labeling (dosage, administration, etc.) of the individual treatments, additional safety and efficacy evaluations may be necessary," and added, "We encourage companies to consult with the Ministry in advance."