Between May 4, 2023 and May 14, 2023, a cross-sectional, web-based survey of 261 hematooncologists active in the field and full members of the KSMO was conducted. All responders were invited via an e-mail that included a link to the survey and were fully informed of the overall purpose of our survey prior to participation. Microsoft Forms (https://forms.office.com) was used to build the online survey. All authors, as the leaders of the KSMO Health Care Policy and Government Relations Committee, supervised the entire investigation, ensured data reliability, and analyzed the results.

This survey was intended as an exploratory tool to capture the perspectives of KSMO members on the pre-application system. The goal was to gather preliminary insights for discussion and hypothesis generation at the KSMO Policy Symposium, rather than to create a validated questionnaire for generalized conclusions. The survey encompassed 19 questions designed to capture the nuanced experiences of oncologists in the pre-application process for off-label use of anti-cancer drugs, which were grouped into three categories.

The categories and questions are as follows (Supplementary Material):

(1) Personal characteristics and work environment: duration in subspecialty practice; type of medical practice institution; cancer of primary interest and number of patients seen per week; geographical area of practice.

(2) Questionnaire about pre-application process: satisfaction with the pre-application process system itself; experience with the pre-application process. For those with experience in pre-application for an unapproved drug that had not been previously applied for by another organization, the following questions were posed: “time spent on the application” and “whether you have ever had an application rejected.” If a prior application was denied, the following questions were posed: “whether you were fully informed of the reasons for the denial”; “how you felt when you realized the rejection”; “the degree of displeasure experienced when rejected”; “the impact of rejection on subsequent applications.”

(3) Post-approval experience with the off-label use of anti-cancer drugs: whether you have ever discontinued a patient’s treatment despite its effectiveness due to cost concerns; opinion on selective reimbursement of prior-application therapies, which would provide health insurance coverage if disease is controlled for a period of time after use of the prior-application therapy.

We employed descriptive statistics to summarize the demographic and professional characteristics of survey participants, as well as the responses to individual survey questions. To evaluate factors associated with satisfaction levels regarding the pre-application system, we used a chi-squared test for univariate analysis and multivariate logistic regression to identify independent predictors of satisfaction. We conducted all statistical analyses using IBM SPSS Statistics ver. 21 (IBM Corp.).

Over two weeks, 110 members (42.1%) answered the survey. The baseline characteristics of the survey respondents are presented in Table 1. A significant majority of respondents (70.9%) have been certified specialists for more than 10 years, indicating a cohort of medical professionals with considerable experience. Most respondents (70.0%) are employed in tertiary hospitals. Furthermore, over 50% physicians treat more than 150 patients per week, with 15.5% managing more than 250 patients weekly. This highlights the high patient load and the intensive nature of their practice. Additionally, 93.6% respondents (n=103) have utilized the pre-application system, indicating widespread familiarity and experience with this administrative process.

Most respondents (67.3%) (Fig. 1) expressed moderate to extreme dissatisfaction with the pre-application process; only 12.7% of respondents indicated ‘very satisfied’. The reasons why the pre-application system is unsatisfactory were submitted as an open-ended questionnaire, and 96 individuals (87.3%) provided their opinions. Procedure-related issues in the pre-application process that caused dissatisfaction among members included (Table 2): the amount of paperwork and complexity of the process (n=22, 20.0%), a long duration from application to approval (n=27, 24.5%), overly stringent approval criteria (n=21, 19.1%), lack of consistency and transparency in the review process (n=9, 8.2%), strict requirements for eligible institutions for application including the need to have an internal review body (n=6, 5.5%), and problems with the composition of the Cancer Disease Review Committee (n=3, 2.7%). The following reasons were provided for why the pre-application process is superfluous: (1) it encroaches upon the professionalism of experts and the autonomy of patients to make treatment decisions (n=5, 4.5%), (2) it is not covered by health insurance in principle, thus precluding any role for governmental involvement (n=3, 2.7%), and (3) the expert opinion is re-evaluated by another expert whose qualifications are questionable (n=2, 1.8%).

Among 103 respondents with experience in pre-application, most (73.8%) reported making ≥ 3 applications per year (Fig. 2A) and 60 respondents (58.2%) had experience of pre-application for an unapproved drug that had not been previously applied for by other institutions (first-time pre-application). The time taken to complete the first-time pre-application document is shown in Fig. 2B. Briefly, 74.4% of members reported that it took them more than 3 hours to complete the first-time pre-application, and 31.6% reported that it took them more than 7 hours. This is to be expected since these pre-applications are made in the absence of sufficient medical evidence, in the absence of alternative treatments, or for rare cancers.

A notable number of pre-applications were not approved: 41 out of 60 respondents (68.3%) who had pre-applied for the first use experience rejection (Fig. 3A). Among these, 28 respondents (68.2%) reported that they were not fully informed of the reasons why their application was not approved (Fig. 3B). Emotional responses to disapproval varied, with some understanding the decision (12.2%) and others feeling unpleasant or extremely displeased as their opinions were ignored (70.8%) (S1 Table). The respondents identified other reasons for this frustration as: (1) inconsistent approval criteria (n=3, 7.3%), (2) evaluation by non-specialists (n=2, 4.9%), (3) lack of reward for the time spent on paperwork associated with the application process (n=2, 4.9%), and (4) lack of explanation for denials (n=1, 2.4%) (S1 Table). The intensity of displeasure varied, but 68.3% of respondents reported moderate or great discomfort. Notably, 26.8% reported experiencing extreme discomfort by the disapproval (Fig. 4). Out of the 41 respondents who experienced a first-time pre-application disapproval, 61.0% (n=25) indicated that they would reapply and use the off-label anti-cancer drugs if pre-application was necessary, whereas 39.0% (n=16) stated that they would not pre-apply and would give up further treatment (S2 Fig.).

The statistical analysis demonstrated that none of the examined factors showed a statistically significant influence on satisfaction with the pre-application system. These factors included experience with application for prior authorization (p=0.291), the number of pre-applications per year (p=0.103), clinical burden/patient load (p=0.526), type of cancer of primary interest, and type of medical facility (p=0.285). Furthermore, there were no significant associations between satisfaction and experience with first-time application status (p=0.546), its rejection (p=0.081), or the time taken to complete pre-application documents (p=0.161).

The use of off-label anti-cancer drugs is generally not covered by health insurance, leaving patients with a significant financial burden to maintain treatment, even if they respond to treatment. Most respondents (97.8%, 90/92) (S3 Fig.) experienced treatment discontinuation due to the costs associated with using approved off-label anti-cancer drugs. Most respondents (86.0%, 80/93) supported selective reimbursement for the use of pre-approved off-label anti-cancer drugs if the disease did not progress for a certain period, while others (6.5%, n=6) supported reimbursement irrespective of disease control (S4 Fig.). The preferred timing for applying health insurance coverage was predominantly after 3-6 months of disease control.

The results of the survey indicate that a significant number of oncologists perceive the pre-application process for off-label use of anti-cancer drugs to be overly complex and time-consuming. In fact, 67.3% of respondents indicated moderate or great dissatisfaction with the pre-application process itself. A total of 58.2% of respondents indicated that they had a first-time pre-application experience, and about 74.4% of them reported that the first pre-application paperwork took more than three hours to complete, with 13.3% taking more than 12 hours. Even though it takes several hours to complete, the preparation work for these applications is not classified as a medical practice fee and therefore cannot be billed at all.

In Korea, pre-applications for off-label use of anti-cancer drugs are subject to a two-step review process. It must first pass through a multidisciplinary committee of experts from the applicant institution, and if it passes, it must then pass through the Cancer Disease Review Committee (CDRC) of the HIRA. This results in a minimum eight weeks for pre-approval of an off-label anti-cancer drug. The complexity, relatively long time to approval, and lack of reward not only burdens healthcare providers, but also delays the start of potentially life-saving treatments for patients. The digitization of application forms and streamlining the application process can reduce the administrative burden on oncologists and facilitate the provision of timely treatment to patients.

Strict approval criteria for off-label use of anti-cancer drugs was one of the main sources of dissatisfaction among respondents. Cited by 19.1% of respondents, many oncologists felt that the criteria were overly stringent, limiting their ability to prescribe off-label medications even when clinical judgment indicated potential benefit to patients. The CDRC’s criteria for evaluating off-label anti-cancer therapies are as follows: (1) medical rationale: assessed based on whether it is documented in textbooks, specified in treatment guidelines, the existence of clinical research literature, and expert opinion from relevant societies; (2) availability of alternative therapies: an assessment of the availability of alternatives anti-cancer drugs in terms of indicated population, disease stage, and regimens; (3) additional cost-effectiveness if an alternative therapy exists: If an alternative is determined to be available, the CDRC would consider the cost-effectiveness and economic burden. These criteria are stringent enough to resemble the criteria for reimbursement of new drugs rather than minimal efficacy and safety assessments. Even if a prior authorization to use the off-label anti-cancer drugs is granted, patients are responsible for the full cost of using the drug. Deciding whether to approve an off-label anti-cancer drug for use based on cost-effectiveness without the government bearing responsibility for the costs could be considered an abuse of discretion.

According to the 2020 National Audit Office data, although detailed reason for the disapproval was not reported, the rejection rate for off-label pre-applications for anti-cancer drugs is 56.9%, which is higher than the rejection rate for other off-label non-cancer uses (3.8%) [16]. Overly stringent approval criteria are one of the main reasons for the high rejection rate. In our survey, 68.3% of respondents with first-time pre-application experienced rejection, and 68.2% of them reported moderate to severe displeasure, and 26.8% reported very severe displeasure, as their expert opinion was ignored and patients lost the opportunity to receive potentially effective treatment. Some experts (39%) reported that this experience led them to abandon the application altogether, despite the need for pre-application.

The financial burden associated with off-label drug use, which is generally not covered by health insurance in Korea, was the primary reason for treatment discontinuation. Most respondents (96.8%) reported instances where patients had to halt treatment due to financial constraints, despite the treatment’s efficacy. This financial obstacle not only impacts patient outcomes, but also places significant emotional and ethical strain on oncologists who are unable to provide optimal care. Implementing selective reimbursement policies, where health insurance covers off-label drugs if the disease is controlled for a certain period, is an effective solution to this issue and supports sustained treatment. The survey results are clear: 86% respondents stated that patients who benefit from off-label cancer drug treatment should be eligible for selective reimbursement. Furthermore, 7.5% of respondents insist that a drug approved under current stringent standards should be covered by the National Health Insurance, regardless of whether patients benefit from the treatment or not.

With the widespread use of next generation sequencing (NGS) technology to analyze large amounts of personal genetic information and the development of molecularly targeted therapeutics, precision medicine is becoming the new norm for research, development, and clinical practice worldwide. Unlike in South Korea, the United States, the United Kingdom, and Australia, etc. leave the use of drugs beyond the scope of their approval to the discretion of the physician. Thus, there is no separate application system for such use, and there are no administrative obstacles to implementing MGTO [3,4,9,10]. Though many patients have been genomically analyzed as NGS tests are reimbursed at least in part in Korea, one of the problems hindering precision medicine implementation and development is that even if a specific oncogene mutation is identified, there is no authorized system to immediately administer targeted anti-cancer drugs. The current off-label pre-application system for anti-cancer drugs cannot meet this need and needs to be fundamentally improved. Currently, the KSMO and the Korean Cancer Study Group (KCSG) have established the Korean Precision Medicine Networking Group (KPMNG) to advance the realization of precision medicine in cancer care in Korea, and have designed and conducted the KOSMOS-II study [17]. In the KOSMOS-II study, a centralized molecular tumor board (MTB) of multiple cancer experts, including medical oncologists, pathologists, and bioinformaticians, analyzes patients’ NGS test results, clinical and imaging information to recommend the most appropriate treatment for patients with difficult diagnosis and treatment. Based on the MTB’s recommendations, patients will be enrolled in an appropriate clinical trial, treated with an investigational drug (a licensed drug approved for a different indication) supplied by a pharmaceutical company, or receive personalized treatment with other anti-cancer drugs. The initial analysis of 489 patients were recently presented in an international meeting [18]. Of these, 59.5% patients were eligible for molecular guided treatment, and 34.8% showed clinical benefit. Implementing precision medicine cannot rely on the goodwill of medical oncology societies and the support of pharmaceutical companies. The Ministry of Health and Welfare must establish a legal system that allows immediate use of therapies recommended through these MTBs regardless of indications approved and provide financial support. It must also establish a large database of patients who have received such treatments and continuously update the drug compendium based on the evidence, as seen in the United States [19].

Based on the survey findings, several recommendations can be made to improve the prior authorization system. These include simplifying the application process, revising the approval criteria to be more flexible, standardizing the review process to ensure consistency and transparency, and addressing the financial barriers to treatment continuation through selective reimbursement policies. These suggestions are in line with the Korean Alliance of Patients Organization’s statement on improving the system for the prompt and safe use of off-label anti-cancer drugs and over-the-counter drugs [15]. Additionally, involving oncologists in the development and continuous improvement of these policies can ensure that the system meets the needs of both healthcare providers and patients [19]. By addressing these discussion points and recommendations, policymakers can create an efficient, fair, and supportive system for the off-label use of anti-cancer drugs, ultimately improving patient outcomes and oncologists’ satisfaction.

It is essential to recognize the constraints of this study in order to contextualize the findings and to inform future research. Firstly, the current survey items were not subjected to formal validation procedures. The survey items were not developed using formal validation procedures, as the primary objective was to rapidly ascertain the perspectives of KSMO members for the purposes of hypothesis generation and exploratory analysis. While this approach was appropriate for achieving the study’s objectives, future research should prioritize the development and validation of a reliable and accurate instrument to enhance the reliability and accuracy of the findings. Secondly, the limitations of web-based surveys and self-reported data must be acknowledged. The use of web-based surveys offers a number of practical advantages, including cost-effectiveness and ease of dissemination, which are particularly beneficial when collecting data from busy professionals. However, this format may prove less effective than face-to-face or structured interviews in capturing the depth and nuance of participants’ opinions. In future research, integrating qualitative methods such as in-depth interviews with key stakeholders could provide richer insights and complement quantitative findings. Furthermore, it would be beneficial to include patient input in future studies, as the pre-application system ultimately affects patient access to care. Incorporating patient surveys or focus groups in future research would provide a more comprehensive evaluation of the system.

In conclusion, the current study reveals significant dissatisfaction among Korean oncologists with the current prior authorization system for off-label anti-cancer drugs, citing complexity, lengthy application times, and stringent criteria as major issues. Despite these challenges, the system’s critical role in oncology is evident. The system may be improved by simplifying the process, enhancing transparency, and implementing selective reimbursement policies to reduce financial burdens on patients. Involving oncologists in policy development and leveraging advances in precision medicine can create a supportive and efficient framework, ultimately improving patient care and clinician satisfaction.