In the pharmaceutical industry of Korea, ‘re-examination’ is a system that re-evaluates the safety and efficacy of new drugs or drugs equivalent to new drugs by investigating and verifying adverse events that did not appear during the approval process, within the re-examination period from the initial approval date. ‘Post-marketing study’ refers to studies such as use-result surveys, special investigations, and post-marketing clinical trials conducted during the re-examination period by the license holder to collect, review, confirm, or verify information necessary for the safe and effective use of re-examination subject drugs. ‘Use-result survey’ is a study conducted without specifying the conditions of the subjects to understand the safety and efficacy of the drug in routine clinical practice, necessary for the re-examination application.
In summary, ‘Re-examination’ is a system for evaluating the safety and efficacy of new drugs, ‘Post-Marketing Surveillance (PMS)’ is a study conducted during the re-examination period in accordance with this system, and ‘Use Result Surveillance’ is the most representative research method in post-marketing studies. Re-examination is a condition of drug licensing, so post-marketing surveillance is an obligation of pharmaceutical companies, and they must undergo re-examination during the re-examination period to maintain their product license.
The ‘Re-examination Criteria for New Drugs, etc.’ were established in 1995, making the history of the re-examination system long. The background and purpose of this system are well explained in the ‘Re-examination Business Guidelines for New Drugs, etc.’
Pre-marketing clinical trials have limitations in observation periods and subject numbers, applying strict selection criteria, making it difficult to apply the results to all patients. There is a high possibility of serious adverse events not found in clinical trials when a variety of patients take the medication over a long period post-marketing. Therefore, the purpose is to re-examine new information about adverse events and their occurrence situations, factors affecting safety and efficacy, etc., by observing early drug usage patterns in a wide range of patients for a certain period, and to reflect this in the licensing matters.
Under this background and purpose, Article 32 (Re-examination of New Drugs, etc.) of the Pharmaceutical Affairs Law legislates that drugs classified as new drugs among those that have received product licensing must undergo re-examination by the Minister of the MFDS after 4 to 6 years from the date of licensing. For re-examination, Article 23 (Application for Re-examination of Drugs, etc.) of the Safety Regulations requires the applicant to submit a re-examination application form with regular report data and comprehensively analyzed and evaluated data.
The ‘Re-examination Criteria for New Drugs, etc.’ were announced by the MFDS to specify matters related to the number of subjects for re-examination subject products, requirements for re-examination data, and the method of preparing investigation data to ensure appropriateness in re-examination business. The ‘Re-examination Business Guidelines for New Drugs, etc.’ were established by the MFDS in 2011 to specify necessary matters for methods and procedures of re-examination by providing recommendations and examples. Employees or safety managers in charge of post-marketing studies must be familiar with the re-examination criteria and business guidelines.
The license holder intending to conduct a post-marketing study must submit a post-marketing study plan to the Minister of the MFDS one month before marketing. For multinational pharmaceutical companies, there was time to prepare the study plan due to the time required for drug import and hospital listing after licensing. However, since July 2015, the Risk Management Plan (RMP) was introduced for new drugs and orphan drugs, and pharmaceutical companies must submit an RMP to minimize adverse effects and risk factors of the drug when applying for product licensing.
Pharmaceutical companies usually choose post-marketing studies as the ‘additional pharmacovigilance plan’ of the RMP, so they must include an overview of the post-marketing study in the RMP. Therefore, multinational pharmaceutical companies need to obtain approval for the post-marketing study plan from the headquarters in advance when preparing the licensing data and include the plan in the RMP when applying for product licensing, which has advanced the preparation schedule.
Two significant changes occurred with the most recent revision of the Re-examination Criteria in December 2020: the addition of a post-marketing database study as part of the special investigation in post-marketing studies and the removal of the fixed case number item (3000 for new drugs, 600 for other new drugs and drugs requiring data submission) in the post-marketing study plan. The ‘Post-marketing Database Study’ mentioned as one of the special investigations uses medical information databases to conduct research aimed at detecting and confirming information on the occurrence of adverse drug reactions by disease type and quality, efficacy, and safety of the drug. Medical information databases systematically computerize patient medical records, health insurance claims data, patient registration systems, and other patient health status data collected over a certain period. The MFDS is preparing related guidelines, hoping for a variety of post-marketing study methods beyond traditional use-result surveys, including the use of big data.
The number of subjects for the investigation is determined by considering the characteristics of the indication of the product and calculated for each product. If it’s not 3000 or 600, pharmaceutical companies must submit objective and valid evidence for calculating the number of subjects. Evidence can include the domestic prevalence of the relevant indication, actual patient numbers, prescription counts or medical claim amounts of similar products, drug adverse reactions corresponding to key safety review items, and occurrence rates. If adjustment of the number of subjects is necessary during the re-examination period, it can be applied for after at least half of the re-examination period has elapsed from the product licensing date and at least one year before the expiry of the re-examination period. Pharmaceutical companies can decide the number of subjects considering the product’s characteristics, the number of patients with the disease, and registration feasibility, reducing the burden on companies and avoiding future adjustments to the number of subjects.
Since the introduction of the Risk Management Plan (RMP) in 2015 for full-cycle drug safety management, 78% of RMP products were also designated for re-examination, raising the need for improvements in duplicative data submission and systematic post-marketing drug safety management. Consequently, the MFDS prepared the ‘Improvement Plan for Post-Marketing Drug Safety Management System,’ planning to abolish the re-examination system by 2022 (stopping new designations for re-examination from 2023) and operate it integrated with the RMP.
The improvement plan is progressively implemented as shown in the figure below. The first phase (until 2020) resolves duplicative data submission between the RMP and re-examination, the second phase (until 2021) strengthens the efficiency of the RMP, and the third phase (until 2022) unifies post-marketing safety management with the RMP. Especially since re-examination is related to data protection that blocks the entry of generic drugs, a separate data protection system is planned to be established along with the abolition of re-examination by 2022.
Multinational pharmaceutical companies must explain the re-examination system to the headquarters and obtain approval for the post-marketing study plan and budget each time they prepare for a post-marketing study. It was difficult to persuade the headquarters to approve Korea-specific post-marketing studies when licensing new drugs, but if the re-examination system is unified with the RMP, pharmaceutical companies can focus on the RMP, and work coordination with the headquarters will be facilitated through international harmonization of post-marketing safety management.
References
- Re-examination Business Guidelines for New Drugs, etc. MFDS (Ministry of Food and Drug Safety) Guide for Applicants. Dec 2019.
- Re-examination Criteria for New Drugs, etc. MFDS Notification. Dec 14, 2020.
- Pharmaceutical Affairs Law Article 32 (Re-examination of New Drugs, etc.). Oct 8, 2020.
- Rules on the Safety of Drugs, etc. Article 23 (Application for Re-examination of New Drugs, etc.). Dec 12, 2019.
- Guidelines for the Risk Management Plan of Drugs. MFDS Guide for Applicants. Dec 2019.
- MFDS Press Release. Department of Drug Safety Evaluation, Pharmaceutical Safety Bureau. Jul 16, 2020.
Uthando Nethemba 