단일기관 소아청소년 입원환자에서의 허가 외 약물 사용 현황 분석

신예지,김찬영,박근미,정주원,한혜원 한국병원약사회 2021 병원약사회지 Vol.38 No.3

Background : Because of the lack of clinical research and drug evaluation for children, off-label prescribing has been widely observed in children. However, studies on the prevalence of off-label prescribing in children are rare in Korea. The purpose of this study was to investigate the characteristics of off-label prescribing in pediatric inpatients at a tertiary university hospital in Korea. Methods : All pediatric patients age 0-18 years were included Jun 1-7, 2020 at Asan Medical Center. We retrospectively collected patient characteristics and medication profiles and off-label prescriptions were defined based on the Korea Food and Drug Administration–approved labeling. Results : Of the 286 inpatients, 229 (80.1%) patients received at least one off-label drug use. Additionally, 380 drugs were used, and 129 (33.9%) drugs are not approved in children. Of 1,784 prescriptions, 722 (40.5 %) were for off-label use. The proportion (n=107, 46.7%) of children under age two was higher in the off-label group than in the No off-label group. Gastrointestinal agents (n=183, 25.3%) were the most common causative drugs, followed by cardiovascular agents (n=111, 15.4%), and anti-Infective agents (n=82, 11.4%). Conclusion : Off-label prescribing is common among pediatric patients, especially in premature and neonates. Thus, pediatric pharmacists should be actively engaged in off-label drug use for safe and effective medication use in pediatric patients. A practical guideline for off-label drug use in children, and further research on adverse drug reactions from off-label drug use is needed.

의약품의 ‘허가사항 외 사용(Off-Label-Use)’으로 인한 손해배상책임 - 의사의 책임을 중심으로

전병남 사법발전재단 2014 사법 Vol.1 No.28

When pharmaceutical manufacturers wish to make and sell drugs, they must obtain permission from the Ministry of Food and Drug Safety. Also, the manufacturers must indicate the permission's details on their pharmaceutical labels. When medical professionals such as doctors use a medicine beyond the permission from Ministry of Food and Drug Safety, the act is referred to as ‘off-label use.’ If a doctor engages in off-label use, it is regarded as an act of negligence, provided that there is no valid reason for such use. If the government fails to conduct administrative guidance for pharmaceutical manufacturers, despite being aware of their off-label use, it should be held liable for damages inflicted on citizens, despite the knowledge of their off-label use. If the manufacturers fail to warn customers of the danger of off-label use on their labels, they should be held liable for their products. If a pharmacist has prepared a medicine despite the doctor's prescription suggesting off-label use, the pharmacist should be held liable for the consequences. However, the most important thing is to prevent such consequences, as the lives and health infringed by off-label use can never be fully compensated, no matter who takes responsibility. 의약품 제조업자가 의약품을 제조·판매하기 위해서는 식약처의 허가를 받아야 하고, 또한 그와 같은 허가사항을 의약품 첨부문서에 기재하여야 한다. 의사 등이 식약처의 허가사항 외로 의약품을 사용하는 것을 ‘허가사항 외 사용(Off-Label-Use)’이라고 한다. 의사가 의약품을 허가사항 외로 사용하는 경우에는, 허가사항 외로 사용할 수밖에 없는 특단의 합리적인 이유가 없는 한 과실이 추정된다. 국가는 의약품 제조업자 등이 허가사항 외로 사용하는 것을 알면서도 행정지도를 하지 아니하여 국민에게 손해가 발생한 경우에는 책임을 져야 한다. 의약품 제조업자는 첨부문서에 허가사항 외 사용으로 인한 위험성을 경고하지 아니한 경우에는 제조물책임을 진다. 약사는 의사가 발행한 처방전에 허가사항 외 사용을 의심할 수 있는 내용이 기재되어 있음에도 이를 확인하지 아니하고 조제하였다면 역시 손해배상책임을 진다. 그러나 위와 같이 손해가 전보되더라도 허가사항 외 사용으로 인하여 침해된 생명과 건강까지도 원상회복되는 것은 아니므로, 이를 예방하기 위한 노력이 필요하다.

의약품 ‘허가사항 외 사용’(Off-Label-Use)에 관한 공법적 고찰― 독일에서의 논의를 중심으로 ―

이세정 전남대학교 법학연구소 2014 법학논총 Vol.34 No.1

Der zulassungsüberschreitende Einsatz (Off-Label-Use) von Arzneimitteln wirdnicht von der zuständigen Behörde auf Nutzen und Risiko geprüft, daher gibt es kaumoder keine Beweise für Nutzen und Risiko, und ohne behördliche Zulassung können Ärzte über keine entscheidenden Informationen über Dosis und Darreichung derart verordneterArzneimittel verfügen. Folglich kann der Off-Label-Use zwangsläufig mit Risikoverbunden werden, und es stellt sich also die Frage, ob er zulassungsrechtlich erlaubtwerden soll. Und im Falle, dass ein Arzt den Off-Label-Use zur Heilung der Patientinnen undPatienten unvermeidlich vorgenommen hat, stellt sich sozialgesetzlich die Frage, ob dieanfallenden Kosten durch die gesetztlichen Krankenversicherungen erstattet werden sollenund unter welchen Voraussetzungen zugelassen werden soll. In diesem Zusammenhang wird heute in Deutschland über den Begriff des „Off-Label-Use“ und die Zulässigkeit des zulassungsüberschreitenden Einsatzes vonArzneimitteln und insbesondere über die Erstattungsfähigkeit derartig verordneterArzneimittel durch die gesetztlichen Krankenversicherungen umfassend diskutiert. In dieser Dissertation wird der Schwerpunkt auf die deutschen Auseinandersetzungen über den „Off-Label-Use“ gesetzt. Zuerst wird der Begriff des „Off-Label-Use“ untersuchtund mit den der „nicht zugelassenen Anwendung“ und der „Anwendung aus Mitgefühl“verglichen, und dabei werden die konkreten Fälle des „Off-Label-Use“ unter die Lupegenommen. Zweitens wird der Zusammenhang zwischen arzneimittelgesetzlicherZulassung und ärztlicher Verordnung von Arzneimitteln in Deutschland (die Zulässigkeitdes zulassungsüberschreitenden Einsatzes) untersucht. Drittens werden Urteile desBundessozialgerichts und Beschlüsse des Bundesverfassungsgerichts über dieErstattungsfähigkeit der im Sinne vom Off-Label-Use verordneter Arzneimittel durch diegesetztlichen Krankenversicherungen analysiert. Schließlich ergeben sich darausAndeutungen für Korea. 의약품 허가사항 외 사용은 그 유효성 및 안전성 등에 대하여 의약품행정청의 심사를 거치지 아니하므로 그 유효성 및 안전성에 대한 증거가 거의 또는 전혀 없는 실정이고, 의약품행정청의 허가가 없으면 의사는 의약품의 투여량, 투약방법 등에 관한 결정적인 정보를 갖지 못하게 된다. 결과적으로 의약품의 허가를 벗어나는 적용은 리스크와결부될 수밖에 없다는 문제가 있고, 그리하여 이를 허가법적 관점에서 허용할 것인지가문제된다. 또한 의사가 환자의 치료를 위하여 불가피하게 허가사항 외로 의약품을 사용한 경우사회법적 관점에서 허가사항 외로 사용된 의약품에 든 비용을 법정건강보험의 부담으로 하는 것을 허용할 것인지, 어떠한 전제요건에 따라 허용할 것인지가 문제된다. 이상의 관점에서 최근 독일에서는 의약품 ‘허가사항 외 사용’의 개념, 의약품 허가사항 외 사용의 허용성과 특히 허가사항 외로 사용된 의약품 비용의 법정건강보험 상환능력(가능성)에 대하여 광범한 논의가 진행 중이다. 이 논문에서는 의약품 ‘허가사항 외 사용’에 관한 독일에서의 논의를 중심으로 첫째,의약품 ‘허가사항 외 사용’의 개념, ‘미승인 사용’, ‘동정사용’ 등 유사 개념과의 비교 및‘허가사항 외 사용’의 구체적인 유형을 살펴보았다. 둘째, 독일 의약품법상 허가와 의사의 의약품 적용과의 관계(의약품 적용의 허용성)를 검토하였다. 셋째, 허가사항 외로 투여된 의약품 비용의 법정건강보험 상환능력에 관한 독일 연방사회법원의 판례 및 연방헌법재판소의 결정례를 분석하였다. 넷째, 결론으로서 우리나라에서 대한 시사점을 도출하였다.

의료과실의 판단기준으로서 의약품 첨부문서에 반하는 허가외 사용

박주현(Joo-Hyun Park) 중앙대학교 법학연구원 2012 法學論文集 Vol.36 No.1

Many types of new drugs have been developed in accordance with numerous advances in medicine. New drugs may be more effective than old ones, but they may sometimes provoke serious adverse reactions. Medical professionals should make efforts to acquire current knowledge via medical articles, conferences and by other means. Instructions on drug label are also important materials for doctors to prescribe drugs, and play significant roles in finding medical faults. They contain the highest level of information provided by pharmaceutical companies. When doctors prescribe medicine or pharmacists fill the prescription, the instructions must be noted first. Therefore, prescriptions of drugs contrary to the instructions on the drug label may lead to doubts about whether the doctor is at fault. In actual medical practice, doctors commonly prescribe drugs for off-label use Off-label use can be defined as the practice of prescribing drugs for an unapproved indication or in an unapproved age group, at an unapproved dose or in an unapproved form of administration. Although the off-label use of prescription drugs involves unpredictable risks, it may be necessary to treat some cases of diseases. In these cases, a higher duty of care is required compared to cases of the approved use of drugs. Especially where there are alterative approved medications, all of the information about off-label drug prescriptions has to be provided so that patients can decide upon their treatment. Doctors must let patients compare the benefits and risks of off-label use and must advise them to choose their own therapy. Patients have the right of self-determination, whereas doctors have the obligation to provide information to patients. This information has the role of not only in raising patients’ autonomy but also helping patients appropriately manage the adverse effects of off-label drug use. As drug information alerts patients to possible adverse effects, they can detect even subtle changes in their own body early after taking the drugs. Doctors have to instruct patients to cope with the adverse effects of drugs should they arise. Health care problems, such as outbreaks of antimicrobial resistant organisms and the rapid increase in health care expenditures, must be taken into account when doctors prescribe medicine. Therefore, legal policies for health care can be considered with the presumption of medical errors.

Five-year clinical outcomes of drug-eluting stents according to on-label and off-label use

( Kyu Hwan Park ),( Ung Kim ),( Chan Hee Lee ),( Jang Won Son ),( Jong Seon Park ),( Dong Gu Shin ),( Young Jo Kim ),( Jeong Hwan Cho ) 대한내과학회 2016 The Korean Journal of Internal Medicine Vol.31 No.4

Background/Aims: To compare the clinical outcomes of ‘on-label’ and ‘off-label’ drug-eluting stents (DESs) over a 5-year follow-up period. Methods: A total of 929 patients that underwent percutaneous coronary intervention with DESs were enrolled. Patients were divided into two groups according to on-label (n = 449) and off-label (n = 480) indications. Off-label use was defined as implantation of DESs for acute myocardial infarction (MI), very small vessel, a long stenotic lesion, chronic total occlusion, a bifurcation lesion, an ostial lesion, left main coronary artery disease, multivessel disease, a saphenous vein graft lesion, and a lesion with thrombus. Endpoints were composite of major adverse cardiac events (MACEs), which included all-cause death, ischemic-driven target vessel revascularization (Id-TVR), MI, and stent thrombosis (ST). Clinical outcomes in the two groups were compared for up to 5 years postimplantation. Results: At 1 year postimplantation, the off-label group had higher incidences of total MACEs (8.2% vs. 3.7%, p = 0.005), Id-TVR (5.0% vs. 1.6%, p = 0.004), and ST (1.7% vs. 0.3%, p = 0.042), and at 5 years postimplantation, the off-label group continued to have higher incidences of total MACEs (17.5% vs. 9.4%, p < 0.001), Id- TVR (13.1% vs. 5.8%, p = 0.024), and ST (2.1% vs. 0.3%, p = 0.021). Multivessel disease and diabetes were found to be independent risk factors of MACE in patients with an off-label indication. Conclusions: Patients treated with an on-label DES had better long-term clinical outcomes than those treated with an off-label DES.

단일기관 신생아중환자실에서의 허가외 약물 사용 현황

배혜정,신윤주,신현정,임정미,서성연,조윤희,조윤숙,신승한,최경희 한국병원약사회 2019 病院藥師會誌 Vol.36 No.3

Background : For a drug to be approved in a specific patient group, valid results are required through extensive clinical researches. However, it is often challenging to develop a drug for neonates due to distinct characteristics and limitations of clinical trials, making it often unavoidable to use off-label drugs in neonates. The objective of this study was to investigate the use of off-label drugs in neonatal intensive care unit (NICU) in a single institution in Korea. Methods : All neonates admitted to NICU of Seoul National University Children’s Hospital between January and June 2017 were retrospectively studied. Demographic data and patient medication profile were collected for the study. All the drugs were investigated with respect to: indications, dose, treatment route, duration of treatment, contraindications and warnings specified in the specific marketing authorization, and classified as licensed or off-label according to their licensing status. Results : 226 neonates were subjected to the study. Of the 226 neonates, 137 (60.6%) were preterm infants and 89 (39.4%) were term infants. Of the 1,797 prescriptions, 1,366 (76.0%) were used off-label drug, 155 (8.6%) were‘ Approved for neonatal and pediatric period but off-label use for dose and/or frequency’, 651 (36.2%) were ‘Off-label for neonatal period but on-label for pediatric period’, 481 (26.8%) were‘ Undetermined approval state for neonates and pediatric’, and 79 (4.4%) were‘ Contraindicated for neonates and pediatric’. Conclusions : Off-label drug use rates were as high as 76% of total prescriptions. Thus, the NICU pharmacist should be alert to this, and put more efforts to examine prescriptions, provide appropriate information through various literature reviews, and closely monitor drug side effects. In addition, further research should be done to obtain clinical evidence for the use of 'off-label drugs' in neonates.

의약품의 허가사항 외 사용으로 발생한 사고에 대한 의사와 제약회사의 책임

최상회 대한변호사협회 2009 人權과 正義 : 大韓辯護士協會誌 Vol.- No.400

Off-label use is the practice of prescribing pharmaceuticals for a purpose outside the scope of a drug’s approved label-an unproven, untested use - most often concerning the drug’s indication. In Korea, The pharmaceutical affairs law permit physician and other healthcare practitioners to prescribe approved medications for other than their intended indications. Marketing information for the drug will list one or more indications, that is, illnesses or medical conditions for which the drug has been shown to be both safe and effective. Pharmaceutical companies are not allowed to promote a drug for any other purpose without formal KFDA approval. However, once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that on their professional judgment is both safe and effective, and are not limited to official, KFDA approved indications. Off-label use dose not have a discussion in korea but Off-label use of medication is very common. Some drugs are used more frequently off-label than for their original KFDA-approved indications. And, there is usually extensive medical literature to support the off-label use. This paper have a think about a background of a difference between the perception in medical and law. And this paper is studying liability of a doctor and pharmaceutical company. 의약품의 허가사항 외 사용이란 약이 효용과 관련해서 대부분 증명되거나 실험되지 않은 허가범위 밖의 용도로 사용하는 것을 말한다. 우리나라 약사법에서는 의사가 식품의약품안전청이 승인한 의약품만을 처방하도록 하고 있다. 또한 약에 대한 시장정보는 약의 안전성과 유효성에 대한 질병이나 의학적 상황을 하나 이상 목록으로 만들수 있고 제약회사는 식품의약품안전청의 승인 없이 다른 목적으로 약을 판매하는 것은 허락하지 않는다. 그러나 일단 약이 한 가지 목적으로 판매에 대한 승인을 얻으면 의사들은 식품의약품안전청의 승인이나 공식적인 한계 없이 안전하고 효과적으로 그들의 전문적인 판단에 따라 다른 목적으로 자유롭게 처방한다. 우리나라의 경우 의약품의 허가사항 외 사용에 관한 논의가 많지 않지만 허가사항 외 사용은 많이 행해지고 있다. 그리고 어떤 약은 원래 식품의약품안전청에서 승인받은 것보다 허가사항 외 사용으로 더 많이 이용되는 것이 현실이며, 일반적으로 대부분의 의학보고서들은 통상 허가사항 외 사용을 지지하고 있다. 이 논문은 의학계와 법학계의 인식차이를 배경으로 해서 의약품의 허가사항 외 사용에 기인하여 사고가 발생한 경우에 그러한 방법에 의해 의약품을 투여한 의사와 제약회사의 책임문제를 검토하고, 의약품의 사용에 관한 사고처리의 방법을 생각해보고자 하였다.

시판후의약품 허가사항 초과사용(Off-Label Use)과 그 홍보활동으로 인한 법적 책임 : Qui Tam Action 도입론의 비판적 검토를 중심으로

강한철 梨花女子大學校 法學硏究所 2013 법학논집 Vol.17 No.3

The current rapid increase of health care costs, especially drugs expenses have encouraged some legal scholars in South Korea to assert that it is needed to introduce the prohibition of pharmaceutical companies’ off-label use promotions and qui tam actions used in case of violation of such prohibition in the United States to South Korea in order to control the expansion of the costs. However, pharmaceutical companies’ off-label use promotions can be legally admitted under the Enforcement Decree of the Pharmaceutical Affairs Act of South Korea, to the restricted extent in which such promotions have solid ground such as objective clinical trial literatures. Considering South Korea’s lenient attitude to the promotions could have positive functions in terms of pharmaceutical companies’ provision of medical information to and continued medical education for physicians, it seems that the introduction of the United States legal system stated above which is strange to the legal culture in South Korea would require more meticulous consideration and review. Furthermore, under the National Health Insurance Act. the risk of excessive use of drugs seems to be well refrained by the retribution of drug expenses and imposition of civil penalty on physicians who use drugs not in compliance with the prescription guideline provided by the government. Rather, it is needed to establish object standards to verify clinical trial data which is used for ground of pharmaceutical companies’ off-label use promotions by utilizing the achievement of the evidence-based medicine and set interpretation criteria which can lead to the fair division of liability between physicians and pharmaceutical companies in case of the retribution of drug expenses being implemented by the National Health Insurance Service. 최근 약제비를 포함한 보건의료비용이 급증하면서 이를 제어하기 위한 수단으로 미국의 시판후의약품 허가사항 초과사용 관련 홍보활동 금지 및 위반 시 사인에 의한 대행소송(Qui Tam Action)제도를 도입하여야 한다는 주장이 일부에서 제기되고 있다. 그러나 우리나라의 약사법 시행규칙을 보면 객관적인 임상문헌 등 엄격한 의학적 근거가 있는 경우에는 제약회사의 의약품 허가사항 초과사용 관련 홍보활동을 인정하고 있고 이는 제약회사의 의사에 대한 의․약학적 정보제공 필요성 측면에서 순기능이 인정되며 과도한 의약품 사용은 국민건강보험법 상의 약제비환수 및 과징금부과처분으로 규제할 수 있으므로 우리의 법률문화에 비추어 생소한 사인에 의한 대행소송까지 도입을 검토하여야 할 필요성은 절실하지 않다고 본다. 도리어 근거중심의학의 성과를 활용하여 제약회사 홍보활동의 인정요건이 되는 임상문헌의 가치를 검증할 수 있는 기준을 마련하고 약제비환수 등의 처분이 있을 경우 의사 및 의료기관과 제약회사 사이의 공평한 책임분담을 도모할 수 있는 해석론의 마련이 현재 제도의 장점을 극대화하고 불필요한 법적 혼란을 피할 수 있는 방안이 될 것이다.

소아청소년정신과에서의 허가 초과 및 비승인 약물 처방

이소영(Soyoung Irene Lee) 대한소아청소년정신의학회 2011 소아청소년정신의학 Vol.22 No.2

The purpose of licensing system is to ensure that the medicines are examined for safety, efficacy and quality. Nevertheless, offlabel or unlicensed drug usages in pediatric practice is widespread in Korea and worldwide. Psychotropics are one of the most commonly used off-label or unlicensed drugs. The most valid approach to face this dilemma will be to have more evidences from pediatric pharmacological studies. Clinicians, in addition, need to monitor closely their off-label or unlicensed drug prescriptions to minimize the trial and error in practice. Researchers should publish their experiences and provide guidelines. Pharmaceutical companies, regulatory authorities, and consumer organizations should endeavor altogether for the children’s right to get safe and efficacious drugs as adults do. Here, the definition as well as the current status of off-label and unlicensed drug prescriptions will be introduced. Critical issues regarding the off label drugs are discussed. In addition, I will describe the present condition as to the off-label and unlicensed drugs in child and adolescent psychiatry and the authorization process of off-label drug prescription in Korea. Lastly, direction we should like to take in this field will be mentioned.

Safety and Efficacy of Off-label and Unlicensed Medicines in Children

이지현,변효진,최승은,장영은,김은희,김진태,김희수 대한의학회 2018 Journal of Korean medical science Vol.33 No.37

Background: The aim of this study was to explore the use of off-label/unlicensed drugs to confirm the safety and efficacy of their prescription in children in Korea. Methods: In this retrospective study, we analyzed data of patients who received any of the 32 drugs between January–December 2014 in tertiary hospitals in Korea, including demographics, diagnoses, reasons for the medication, administration route, and details of adverse drug reactions. Additionally, the mortality in the cohort was assessed. The primary outcomes were efficacy and safety, including mortality, of these drugs in pediatric patients. The secondary outcomes were the current statuses of the use of off-label/unlicensed drugs in two centers. Results: Totally, 5,130 prescriptions were found in 2,779 patients. Age (73.5%) and indication (11.7%) were the most frequent reasons for prescriptions being off-labeled/unlicensed. Approximately 88% of the prescriptions were effective, and 19% of the patients developed adverse drug reactions. The number of prescriptions was significantly higher in children with adverse drug reactions than it was in those without (2.8 vs. 1.5; P < 0.001). The number of prescribed off-label/unlicensed medicines and age at prescription were independently associated with adverse drug events (odds ratio, 1.55 and 1.1; P < 0.001 and 0.034, respectively). Conclusion: Children are still prescribed medicines that are not authorized in terms of age, weight, indications, or routes of administration. Therefore, many old products require re-assessment of authorization. More prospective clinical studies should be performed to confirm the efficacy and safety of drugs in the pediatric population.