Kyungwan Hong

Background/aims: Rare disease drug development faces unique challenges, such as genotypic and phenotypic heterogeneity within small patient populations and a lack of established outcome measures for conditions without previously successful drug development programs. These challenges complicate the process of selecting the appropriate trial endpoints and conducting clinical trials in rare diseases. In this descriptive study, we examined novel drug approvals for non-oncologic rare diseases by the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research over the past decade and characterized key regulatory and trial design elements with a focus on the primary efficacy endpoint utilized as the basis of approval. Methods: Using the Food and Drug Administration’s Data Analysis Search Host database, we identified novel new drug applications and biologics license applications with orphan drug designation that were approved between 2013 and 2022 for non-oncologic indications. From Food and Drug Administration review documents and other external databases, we examined characteristics of pivotal trials for the included drugs, such as therapeutic area, trial design, and type of primary efficacy endpoints. Differences in trial design elements associated with primary efficacy endpoint type were assessed such as randomization and blinding. Then, we summarized the primary efficacy endpoint types utilized in pivotal trials by therapeutic area, approval pathway, and whether the disease etiology is well defined. Results: One hundred and seven drugs that met our inclusion criteria were approved between 2013 and 2022. Assessment of the 107 drug development programs identified 150 pivotal trials that were subsequently analyzed. The pivotal trials were mostly randomized (80%) and blinded (69.3%). Biomarkers (41.1%) and clinical outcomes (42.1%) were commonly utilized as primary efficacy endpoints. Analysis of the use of clinical trial design elements across trials that utilized biomarkers, clinical outcomes, or composite endpoints did not reveal statistically significant differences. The choice of primary efficacy endpoint varied by the drug’s therapeutic area, approval pathway, and whether the indicated disease etiology was well defined. For example, biomarkers were commonly selected as primary efficacy endpoints in hematology drug approvals (70.6%), whereas clinical outcomes were commonly selected in neurology drug approvals (69.6%). Further, if the disease etiology was well defined, biomarkers were more commonly used as primary efficacy endpoints in pivotal trials (44.7%) than if the disease etiology was not well defined (27.3%). Discussion: In the past 10 years, numerous novel drugs have been approved to treat non-oncologic rare diseases in various therapeutic areas. To demonstrate their efficacy for regulatory approval, biomarkers and clinical outcomes were commonly utilized as primary efficacy endpoints. Biomarkers were not only frequently used as surrogate efficacy endpoints in accelerated approvals, but also in traditionally approved rare disease drugs. The choice of primary efficacy endpoints varied by therapeutic area, approval pathway, and understanding of disease etiology.

Objectives To synthesise research investigating data and code sharing in medicine and health to establish an accurate representation of the prevalence of sharing, how this frequency has changed over time, and what factors influence availability. Design Systematic review with meta-analysis of individual participant data. Data sources Ovid Medline, Ovid Embase, and the preprint servers medRxiv, bioRxiv, and MetaArXiv were searched from inception to 1 July 2021. Forward citation searches were also performed on 30 August 2022. Review methods Meta-research studies that investigated data or code sharing across a sample of scientific articles presenting original medical and health research were identified. Two authors screened records, assessed the risk of bias, and extracted summary data from study reports when individual participant data could not be retrieved. Key outcomes of interest were the prevalence of statements that declared that data or code were publicly or privately available (declared availability) and the success rates of retrieving these products (actual availability). The associations between data and code availability and several factors (eg, journal policy, type of data, trial design, and human participants) were also examined. A two stage approach to meta-analysis of individual participant data was performed, with proportions and risk ratios pooled with the Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis. Results The review included 105 meta-research studies examining 2 121 580 articles across 31 specialties. Eligible studies examined a median of 195 primary articles (interquartile range 113-475), with a median publication year of 2015 (interquartile range 2012-2018). Only eight studies (8%) were classified as having a low risk of bias. Meta-analyses showed a prevalence of declared and actual public data availability of 8% (95% confidence interval 5% to 11%) and 2% (1% to 3%), respectively, between 2016 and 2021. For public code sharing, both the prevalence of declared and actual availability were estimated to be Conclusions The review found that public code sharing was persistently low across medical research. Declarations of data sharing were also low, increasing over time, but did not always correspond to actual sharing of data. The effectiveness of mandatory data sharing policies varied substantially by journal and type of data, a finding that might be informative for policy makers when designing policies and allocating resources to audit compliance. Systematic review registration Open Science Framework doi:10.17605/OSF.IO/7SX8U.

Background/Aims: Inadequate description of trial interventions in publications has been repeatedly reported, a problem that extends to the description of placebo controls. Without describing placebo contents, it cannot be assumed that a placebo is inert. Pharmacologically active placebos complicate accurate estimation and interpretation of efficacy and safety data. In this study, we sought to assess whether placebo contents are described in study protocols and publications of trials published in high-impact medical journals. Methods: We identified all placebo-controlled randomized clinical trials (RCTs) published in 2016 in Annals of Internal Medicine, The BMJ, the Journal of the American Medical Association (JAMA), The Lancet, and the New England Journal of Medicine (NEJM). We included all trials with publicly available study protocols. From journal publications and associated study protocols, we searched and recorded: description of placebo contents; the amount of each placebo ingredient; and investigators’ stated rationale for selection of placebo ingredients. Results: We included 113 placebo-controlled RCTs. Of the 113 trials, placebo content was described in 22 (19.5%) journal publications and 51 (45.1%) study protocols. The amount of each placebo ingredient was described in 15 (13.3%) journal publications and 47 (41.6%) study protocols. None of the journal publications explained the rationale for the choice of placebo ingredients, whereas a rationale was provided in 4 (3.5%) study protocols. The stated rationales were to ensure the placebo was visually indistinguishable from the experimental intervention ( N = 3) and ensure comparability with a previous study ( N = 1). Conclusion: There is no accessible record of the composition of placebos for approximately half of high-impact RCTs, even with access to study protocols. This impedes reproducibility and raises unanswerable questions about what effects—beneficial or harmful—the placebo may have had on trial participants, potentially confounding an accurate assessment of the experimental intervention’s safety and efficacy. Considering that study protocols are unabridged, detailed documents describing the trial design and methodology, the fact that less than half of the study protocols described the placebo contents raises concerns about clinical trial transparency. To improve the reproducibility and potential of placebo-controlled RCTs to provide reliable evidence on the efficacy and safety profile of drugs and other experimental interventions, more detail regarding placebo contents must be included in trial documents.

Objectives: Many meta-research studies have investigated rates and predictors of data and code sharing in medicine. However, most of these studies have been narrow in scope and modest in size. We aimed to synthesise the findings of this body of research to provide an accurate picture of how common data and code sharing is, how this frequency has changed over time, and what factors are associated with sharing. Design: Systematic review with meta-analysis of individual participant data (IPD) from meta-research studies. Data sources: Ovid MEDLINE, Ovid Embase, MetaArXiv, medRxiv, and bioRxiv were searched from inception to July 1 ^st , 2021. Eligibility criteria: Studies that investigated data or code sharing across a sample of scientific articles presenting original medical and health research. Data extraction and synthesis: Two authors independently screened records, assessed risk of bias, and extracted summary data from study reports. IPD were requested from authors when not publicly available. Key outcomes of interest were the prevalence of statements that declared data or code were publicly available, or ‘available on request’ (declared availability), and the success rates of retrieving these products (actual availability). The associations between data and code availability and several factors (e.g., journal policy, data type, study design, research subjects) were also examined. A two-stage approach to IPD meta-analysis was performed, with proportions and risk ratios pooled using the Hartung-Knapp-Sidik-Jonkman method for random-effects meta-analysis. Three-level random-effects meta-regressions were also performed to evaluate the influence of publication year on sharing rate. Results: 105 meta-research studies examining 2,121,580 articles across 31 specialties were included in the review. Eligible studies examined a median of 195 primary articles (IQR: 113-475), with a median publication year of 2015 (IQR: 2012-2018). Only eight studies (8%) were classified as low risk of bias. Useable IPD were assembled for 100 studies (2,121,197 articles), of which 94 datasets passed independent reproducibility checks. Meta-analyses revealed declared and actual public data availability rates of 8% (95% CI: 5-11%, 95% PI: 0-30%, k=27, o=700,054) and 2% (95% CI: 1-3%, 95% PI: 0-11%, k=25, o=11,873) respectively since 2016. Meta-regression indicated that only declared data sharing rates have increased significantly over time. For public code sharing, both declared and actual availability rates were estimated to be less than 0.5% since 2016, and neither demonstrated any meaningful increases over time. Only 33% of authors (95% CI: 5-69%, k=3, o=429) were estimated to comply with mandatory data sharing policies of journals. Conclusion: Code sharing remains persistently low across medicine and health research. In contrast, declarations of data sharing are also low, but they are increasing. However, they do not always correspond to the actual sharing of data. Mandatory data sharing policies of journals may also not be as effective as expected, and may vary in effectiveness according to data type - a finding that may be informative for policymakers when designing policies and allocating resources to audit compliance.

Objective: This study examined the extent to which trials presented at major international medical conferences in 2016 consistently reported their study design, end points and results across conference abstracts, published article abstracts and press releases.Design: Cross-sectional analysis of clinical trials presented at 12 major medical conferences in the USA in 2016. Conferences were identified from a list of the largest clinical research meetings aggregated by the Healthcare Convention and Exhibitors Association and were included if their abstracts were publicly available. From these conferences, all late-breaker clinical trials were included, as well as a random selection of all other clinical trials, such that the total sample included up to 25 trial abstracts per conference.Main outcome measures: First, it was determined if trials were registered and reported results in an International Committee of Medical Journal Editors-approved clinical trial registry. Second, it was determined if trial results were published in a peer-reviewed journal. Finally, information on trial media coverage and press releases was collected using LexisNexis. For all published trials, the consistency of reporting of the following characteristics was examined, through comparison of the trials’ conference and publication abstracts: primary efficacy endpoint definition, safety endpoint identification, sample size, follow-up period, primary end point effect size and characterisation of trial results. For all published abstracts with press releases, the characterisation of trial results across conference abstracts, press releases and publications was compared. Authors determined consistency of reporting when identical information was presented across abstracts and press releases. Primary analyses were descriptive; secondary analyses included χ²tests and multiple logistic regression.Results: Among 240 clinical trials presented at 12 major medical conferences, 208 (86.7%) were registered, 95 (39.6%) reported summary results in a registry and 177 (73.8%) were published; 82 (34.2%) were covered by the media and 68 (28.3%) had press releases. Among the 177 published trials, 171 (96.6%) reported the definition of primary efficacy endpoints consistently across conference and publication abstracts, whereas 96/128 (75.0%) consistently identified safety endpoints. There were 107/172 (62.2%) trials with consistent sample sizes across conference and publication abstracts, 101/137 (73.7%) that reported their follow-up periods consistently, 92/175 (52.6%) that described their effect sizes consistently and 157/175 (89.7%) that characterised their results consistently. Among the trials that were published and had press releases, 32/32 (100%) characterised their results consistently across conference abstracts, press releases and publication abstracts. No trial characteristics were associated with reporting primary efficacy end points consistently.Conclusions: For clinical trials presented at major medical conferences, primary efficacy endpoint definitions were consistently reported and results were consistently characterised across conference abstracts, registry entries and publication abstracts; consistency rates were lower for sample sizes, follow-up periods, and effect size estimates.Registration: This study was registered at the Open Science Framework (https://doi.org/10.17605/OSF.IO/VGXZY).

노인이 증가하고 있는 현재와 빠른 증가가 예상되는 미래에 여가산업의 확대는 불가피할 것이다. 특히 여가활동과 관련한 관광산업에 있어서 노년기 여성은 중요한 소비계층으로 부상하고 있다. 그러나 여행동기는 육체적·정신적으로 허약한 노년기 여성들의 여행 참여에 막대한 영향을 미칠 것이다. 지금까지의 선행연구는 노인 관광객 제약요인에 의한 여행상품 구매행동 연구, 노인복지관광의 활성화 방안에 대한 연구, 실버계층의 관광 참여동기가 만족과 행동의도에 미치는 영향 등 실버층 전체를 대상으로 한 연구들이 다수를 차지하였지만, 노년기 여성에 초점을 맞춰 진행한 체계적인 연구는 거의 이루어지지 않은 상황이다. 본 연구에서는 기존 학자들이 제기한 모형과 이론을 바탕으로 노인이 증가하고 있는 현재와 빠른 증가가 예상되는 미래에 노년기 여성이 중요한 소비계층으로 부상할 것이라는 전망을 전제로, 관광수요가 상대적으로 왕성한 중국 랴오닝성 선양시 노년기 여성을 대상으로 실증적 연구를 통해 노년기 여성 관광객의 관광 행동 제약 또는 촉진에 대한 이론적인 이해와 실무적인 시사점을 제시하는 데 연구의 목적을 두고 있다. 이에 본 연구에서는 선행연구에 대한 고찰을 통해 연구모형과 가설을 설정하고, 이를 토대로 설문 문항을 구성하였다. 본 연구의 목적을 달성하기 위해 노인이라는 전체 모집단에서 중국의 퇴직정책과 연금수혜 연령을 고려하여 여행에 잠재적 수요를 가진 55세 이상의 노년기 여성을 조사대상으로 설정하였고 자기기입식 설문방법을 활용하였다. 조사 기간은 2020년 9월부터 10월까지 랴오닝성 선양시에 거주하고 있으며 여행 경험이 있는 노년기 여성들을 대상으로 유효 설문지 564부를 수집하여 실증분석을 실시하였다. 실증분석은 빈도분석, 신뢰도 분석, 탐색적 요인분석, 확인적 요인분석, 집중타당성과 판별타당성 분석, 매개분석 등을 통해 결론을 도출하였다. 본 연구의 결과에 따르면 전반적으로 노년기 여성의 여행동기는 여가제약 요인에 영향을 미치고 여행동기와 여가 제약 요인이 참여의도에 각각 영향을 미치며 여가제약 요인은 여행동기와 참여의도 사이에서 매개 역할을 하는 것으로 확인되었다. 본 연구는 여행동기와 여가제약 요인이 노년기 여성의 여행 참여의도에 미치는 영향의 중요성을 인식하고 실무적으로 노년기 여성의 여행동기를 유발하며 여가제약 요인을 해소하여 노년기 여성의 적극적인 사회참여, 노후 생활의 질적 향상, 나아가 관광시장의 발전과 활성화를 위한 기초자료를 제공하고 후속 연구를 위한 학문적인 시사점을 제시하였다.

Background: Patient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions.Methods: We included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted.Results: Of 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers’ comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods.Conclusions: Despite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.