• Title, Summary, Keyword: surrogate endpoint

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The Role and Application of Biomarkers and Surrogate Endpoints for New Drug Development : Focused on Diabetes Mellitus and Osteoporosis (당뇨병 및 골다공증 치료제의 효율적인 신약개발을 위한 생체표지자 및 대리 결과 변수의 역할 및 활용)

  • Seong, Soo-Hyeon;Yun, Hwi-Yeol;Baek, In-Hwan;Kang, Won-Ku;Chang, Jung-Yun;Seo, Kyung-Won;Kwon, Kwang-Il
    • YAKHAK HOEJI
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    • v.52 no.5
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    • pp.331-344
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    • 2008
  • Recently, the FDA (Food and Drug Administration) of the United States and many advanced countries remark biomarkers and surrogate endpoints as a critical path tool on model based drug development. Economic, technical and social profit on model based drug development like a reduction of the length of research and development have been achieved. Therefore we summarize previous studies about biomarkers and surrogate endpoints and suggest a development direction of therapeutic agents. In diabetes mellitus (DM) and osteoporosis, there are remarkable increases in number of patients and most of patients take medicine during their whole lifetime. For this reason, many patients with DM and osteoporosis have a tolerance on their medicine. We expect that research and development on biomarkers and surrogate endpoints will contribute to new drug development on DM and osteoporosis. Biomarkers for DM are blood levels of glucose, insulin, ${HbA}_{1c}$, CRP, alpha-glucosidase, adiponectin and DPP-4. Among these, validated surrogate endpoints for DM are blood levels of glucose, insulin and ${HbA}_{1c}$ Biomarkers for osteoporosis are BMD, BMC, trabecular volume, ICTP, DPD, osteocalcin, the activity of osteoclast and production of osteoblast. The validated surrogate endpoints for osteoporosis are BMD only. This review summarizes all suggested biomarkers and surrogate endpoints in DM and osteoporosis. The biomarkers are classified by drugs, and the method of validation for surrogate endpoints is suggested. This information would contribute to suggest a direction of DM and osteoporosis therapeutic agent development.

Biomarkers and Surrogate Endpoints for Development of New Drug on Pulmonary Disease (폐질환 치료제의 효율적인 신약개발을 위한 생체표지자 및 대리결과 변수)

  • Seo, Jeong-Won;Lee, Byung-Yo;Chae, Jung-Woo;Son, Chu-Young;Kang, Won-Ku;Chae, Han-Jung;Kwon, Kwang-Il
    • YAKHAK HOEJI
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    • v.54 no.2
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    • pp.75-90
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    • 2010
  • Biomarkers are likely to be important in the study of various pulmonary diseases for many reasons. Research efforts in developing biomarkers and surrogate endpoints of lung diseases have resulted in the identification of new risk factors and novel drug targets, as well as the establishment of treatment guidelines. Government agencies, academic research institutions, diagnostic industries, and pharmaceutical companies all recognize the importance of biomarkers in new drug development and advancing therapies to improve public health. In drug development, biomarkers are used to evaluate early signals of efficacy and safety, to select dose, and to identify the target population. Identification of suitable end points not only would help investigators design appropriate clinical trials but would assist clinicians in caring for this patient population. Though the area of pulmonology has received much attention in the past decades, it still lags behind with regard to the development of biomarkers, particularly those of health effects and susceptibility. This review critically summarized several biomarker researches such as Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study with objectives of identifying the parameters that predict disease progression of COPD, as well as biomarkers that may serve as surrogate end-points.

Verification of the Correlation between Progression-free Survival and Overall Survival Considering Magnitudes of Survival Post-progression in the Treatment of Four Types of Cancer

  • Liu, Li-Ya;Yu, Hao;Bai, Jian-Ling;Zeng, Ping;Miao, Dan-Dan;Chen, Feng
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.3
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    • pp.1001-1006
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    • 2015
  • Background: With development and application of new and effective anti-cancer drugs, the median survival post-progression (SPP) is often prolonged, and the role of the median SPP on surrogacy performance should be considered. To evaluate the impact of the median SPP on the correlation between progression-free survival (PFS) and overall survival (OS), we performed simulations for treatment of four types of cancer, advanced gastric cancer (AGC), metastatic colorectal cancer (MCC), glioblastoma (GBM), and advanced non-small-cell lung cancer (ANSCLC). Materials and Methods: The effects of the median SPP on the statistical properties of OS and the correlation between PFS and OS were assessed. Further, comparisons were made between the surrogacy performance based on real data from meta-analyses and simulation results with similar scenarios. Results: The probability of a significant gain in OS and HR for OS was decreased by an increase of the SPP/OS ratio or by a decrease of observed treatment benefit for PFS. Similarly, for each of the four types of cancer, the correlation between PFS and OS was reduced as the median SPP increased from 2 to 12 months. Except for ANSCLC, for which the median SPP was equal to the true value, the simulated correlation between PFS and OS was consistent with the values derived from meta-analyses for the other three kinds of cancer. Further, for these three types of cancer, when the median SPP was controlled at a designated level (i.e., < 4 months for AGC, < 12 months for MCC, and <6 months for GBM), the correlation between PFS and OS was strong; and the power of OS reached 34.9% at the minimum. Conclusions: PFS is an acceptable surrogate endpoint for OS under the condition of controlling SPPs for AGC, MCC, and GBM at their limit levels; a similar conclusion cannot be made for ANSCLC.

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis

  • Cremolini, Chiara;Antoniotti, Carlotta;Pietrantonio, Filippo;Berenato, Rosa;Tampellini, Marco;Baratelli, Chiara;Salvatore, Lisa;Marmorino, Federica;Borelli, Beatrice;Nichetti, Federico;Bironzo, Paolo;Sonetto, Cristina;Bartolomeo, Maria Di;de Braud, Filippo;Loupakis, Fotios;Falcone, Alfredo;Maio, Massimo Di
    • Cancer Research and Treatment
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    • v.49 no.3
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    • pp.834-845
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    • 2017
  • Purpose The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). Materials and Methods A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination ($R^2$). Results Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, $R^2=0.539$, p < 0.001) and poor correlation (R=0.169, $R^2=0.029$, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. Conclusion Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.