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  ["project_date_type"]=>
  string(91) "Individual Participant-Level Data, which includes Full CSR and all supporting documentation"
  ["property_scientific_abstract"]=>
  string(1612) "Background; Simeprevir sodium (Sovriad), an antiviral drug for Hepatitis C Virus (HCV) infection, is a drug that 3 patients in Japan have died from already known Adverse Drug Reactions (ADR) of hyperbilirubinemia, leading to hepatic and renal failure. A possible reason for this is that various aspects of clinical trials are very different from those of routine clinical practice.
Objective; To identify different aspects between clinical trials and routine clinical practice of Simeprevir sodium and to identify factors contributing to different efficacy and safety outcomes of the drug.
Study design; A multi-centre retrospective study comparing various aspects of clinical trials and real-world clinical practice.
Participants; Subjects in pivotal clinical trials in Japan and real-world patients in Shimane Prefecture, Japan from marketing authorization of the drug in December 2013 to the issuing of a warning letter from the Japanese health authority in October 2014.
Main outcome measures; Frequency and severity of ADR, efficacy (Sustained Virological Response (SVR)) in routine clinical practice. Differences in demographic characteristics, disease severity, concomitant diseases, monitoring frequency, etc. between clinical trials and routine clinical practice. Factors contributing to the different effectiveness and safety outcomes between the two situations.
Statistical analysis; All parameters will be descriptively analyzed as appropriate. An explanatory approach will be used to identify the factors contributing to the different effectiveness and safety outcomes." ["project_brief_bg"]=> string(1613) "There have been many cases in Japan where just after a novel drug has been newly marketed, many patients have suffered from expected ADR, leading to serious outcomes including death. When serious ADR occur after the marketing authorization, the health authority and marketing authorization holders often alert healthcare professionals to the ADR with the Dear Healthcare Professional Letters of Rapid Safety Communications. However, the majority of these ADR had already occurred at the investigational stage and the risk of the ADR had been clearly stated on the product labels. Simeprevir sodium (Sovriad), an antiviral agent for HCV infection is one of these drugs, and 3 patients have died due to hyperbilirubinemia, leading to hepatic and renal failure.
A possible reason why these serious outcomes due to expected ADR cannot be prevented is that the inclusion and exclusion criteria of subjects and various other aspects of clinical trials are very different from routine clinical practice(1-3). However, there have been no studies investigating the actual differences between clinical trials and routine clinical practice before the Dear Healthcare Professional Letters of Rapid Safety Communications are issued.
It is crucial to identify the actual differences between clinical trials and routine clinical practice to determine the cause that serious outcomes due to expected ADRs cannot be prevented. The results of this project will present very important information for the health authority and healthcare professionals to prevent serious adverse outcomes due to known ADR of novel drugs." ["project_specific_aims"]=> string(1051) "Aim:
To identify different aspects between clinical trials and routine clinical practice of Simeprevir sodium (Sovriad) and to identify factors contributing to different efficacy and safety outcomes of the drug.
Objectives:
1. To identify precise differences between clinical trials and routine clinical practice of Simeprevir sodium (Sovriad) from full trial protocols of pivotal clinical trials in Japan and from medical records of patients who were administered the drug in routine clinical practice.
2. To categorize adverse drug events of the subjects in Individual Participant-level Data (IPD) and those in routine clinical practice according to MedDRA/J ver 15.0 PT and WHO toxicity grade and to compare the frequency and severity of these events.
3. To compare the effectiveness of the drug as SVR between the subjects in clinical trials and those in routine clinical practice.
4. To identify factors contributing to the different efficacy and safety outcomes of the drug between the two situations." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(3) { [0]=> array(2) { ["value"]=> string(49) "New research question to examine treatment safety" ["label"]=> string(49) "New research question to examine treatment safety" } [1]=> array(2) { ["value"]=> string(76) "Confirm or validate previously conducted research on treatment effectiveness" ["label"]=> string(76) "Confirm or validate previously conducted research on treatment effectiveness" } [2]=> array(2) { ["value"]=> string(69) "Confirm or validate previously conducted research on treatment safety" ["label"]=> string(69) "Confirm or validate previously conducted research on treatment safety" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> array(2) { ["value"]=> string(1) "R" ["label"]=> string(1) "R" } ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(596) "1. Subjects of pivotal clinical trials in Japan (NCT01366638, NCT01292239, NCT01290731, NCT01288209, NCT00996476) who were administered simeprevir sodium (Sovriad) with the same dose as the marketing authorization.
2. Patients who were administered simeprevir sodium (Sovriad) in routine clinical practice of medical institutions which were authorized for treatment of hepatitis by Shimane Prefectural local government from December 2013 to October 2014 (from when the drug came onto the market to the date the Dear Healthcare Professional Letter of Rapid Safety Communications was issued)." ["project_main_outcome_measure"]=> string(896) "1. Adverse drug events of the subjects in IPD and those in routine clinical practice will be categorized as follows;
(1) A trained investigator will categorize and quantify any adverse drug events that occurred both in the clinical trials and in routine clinical practice, according to MedDRA/J ver 15.0 PT and WHO toxicity grade. Causal relationships of the events will also be assessed.
(2) Adverse drug events of hyperbilirubinemia, as an event warned by the Dear Healthcare Professional Letter of Rapid Safety Communications, will be especially focused on, and subjects/patients clinical condition and outcome will be assessed in detail.
2. The following information will be obtained to assess the efficacy of the drug:
(1) The number of subjects/patients who achieved SVR for 12 weeks and for 24 weeks will be obtained in full CSR and in routine clinical practice." ["project_main_predictor_indep"]=> string(935) "1. The following information will be obtained to assess the proportion of patients in routine clinical practice who meet the inclusion /exclusion criteria of clinical trials:
(1) Baseline demographic characteristics, results of diagnostic studies of HCV infection, HCV RNA viral load, HCV genotype, IL28B genetic polymorphism (rs8099917), other concomitant hepatic diseases, other medical history, concomitant drugs and other drug history, results of laboratory tests and other precise inclusion and exclusion criteria of subjects in full Clinical Study Reports (CSR) of pivotal clinical trials in Japan. Unavailable information on patients in routine clinical practice will also be identified.
2. The information below will be obtained to identify precise differences between clinical trials and routine clinical practice:
(1) Frequency of medical institution visits, monitoring laboratory tests and other findings." ["project_other_variables_interest"]=> string(0) "" ["project_stat_analysis_plan"]=> string(1382) "All parameters will be descriptively analyzed as counts (percentage) for categorical variables, mean (standard deviation) or median (quartile range) for continuous or discrete variables as appropriate. The differences between the subjects in clinical trials and the patients in routine clinical practice will be analyzed by parametric or non-parametric tests (such as t-test, ?2 test etc.) as appropriate.
1. The number of patients who meet all inclusion/exclusion criteria of the clinical trials will be counted. And the number of patients who meet each inclusion/exclusion criterion will also be counted.
2. Baseline characteristics of the subjects in clinical trials and the patients in routine clinical practice will be compared and analyzed as appropriate.
3. Each adverse event categorized by MedDRA/J ver 15.0 PT and WHO toxicity grade of the subjects in clinical trials and the patients in routine clinical practice will be compared and analyzed as appropriate.
4. The number of identified ADRs (causal relationship is present) of the subjects in clinical trials and the patients in routine clinical practice will be compared and analyzed as appropriate.
5. The number of the subjects in clinical trials and the patients in routine clinical practice who achieved SVR for 12 weeks and for 24 weeks will be compared and analyzed as appropriate." ["project_timeline"]=> string(223) "Anticipated project start date: May 2020
Analysis completion date: Jan 2021
Date manuscript drafted and first submitted for publication: March 2021
Date results reported back to the YODA project: July 2021" ["project_dissemination_plan"]=> string(126) "The results will be published in a peer reviewed journal in the field of pharmacoepidemiology, drug safety or public health." ["project_bibliography"]=> string(740) "

1. van Deudekom FJ, Postmus I, van der Ham DJ, Pothof AB, Broekhuizen K, Blauw GJ, et al. External validity of randomized controlled trials in older adults, a systematic review. PLoS ONE 2017;12: e0174053.
2. Saunders C, Byrne CD, Guthrie B, Lindsay RS, McKnight JA, Philip S, et al. External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants? Diabet Med 2013; 30: 300-308.
3. Hutchinson-Jaffe AB, Goodman SG, Yan RT, Wald R, Elbarouni B, Rose B, et al. Comparison of Baseline Characteristics, Management and Outcome of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome in Versus Not in Clinical Trials. AmJ Cardiol 2010; 106: 1389-1396.

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pi affil
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products
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2020-4243

General Information

How did you learn about the YODA Project?: Conference

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT01366638 - A Phase III, Open-Label Study in Japan to Assess the Efficacy and Safety of TMC435 as Part of a Treatment Regimen Including Peginterferon Alfa-2b and Ribavirin in Hepatitis C, Genotype 1 Infected Subjects
  2. NCT01292239 - A Phase III, Randomized, Double-blind, Placebo-controlled Trial in Japan to Investigate the Efficacy and Safety of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Treatment-Naive, Genotype
  3. NCT01290731 - A Phase III, Open-label Trial in Japan to Investigate the Efficacy and Safety of TMC435 as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Genotype 1, Hepatitis C-infected Subjects Who Relapsed After Previous I
  4. NCT01288209 - A Phase III, Randomized, Open-label, Two-arm Trial in Japan to Investigate the Efficacy and Safety of TMC435 as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Hepatitis C, Genotype 1-Infected Subjects Who Failed to Respond to Previous IFN-based Therapy
  5. NCT00996476 - A Phase II, Randomized, Open-label Study in Japan to Investigate the Efficacy, Safety and Pharmacokinetics of TMC435 as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Treatment naïve, Genotype 1, Chronic Hepatitis C Subjects
What type of data are you looking for?:

Request Clinical Trials

Data Request Status

Status: Withdrawn/Closed

Research Proposal

Project Title: A comparative study of the effectiveness and safety of simeprevir sodium at the investigational stage and after marketing authorization.

Scientific Abstract: Background; Simeprevir sodium (Sovriad), an antiviral drug for Hepatitis C Virus (HCV) infection, is a drug that 3 patients in Japan have died from already known Adverse Drug Reactions (ADR) of hyperbilirubinemia, leading to hepatic and renal failure. A possible reason for this is that various aspects of clinical trials are very different from those of routine clinical practice.
Objective; To identify different aspects between clinical trials and routine clinical practice of Simeprevir sodium and to identify factors contributing to different efficacy and safety outcomes of the drug.
Study design; A multi-centre retrospective study comparing various aspects of clinical trials and real-world clinical practice.
Participants; Subjects in pivotal clinical trials in Japan and real-world patients in Shimane Prefecture, Japan from marketing authorization of the drug in December 2013 to the issuing of a warning letter from the Japanese health authority in October 2014.
Main outcome measures; Frequency and severity of ADR, efficacy (Sustained Virological Response (SVR)) in routine clinical practice. Differences in demographic characteristics, disease severity, concomitant diseases, monitoring frequency, etc. between clinical trials and routine clinical practice. Factors contributing to the different effectiveness and safety outcomes between the two situations.
Statistical analysis; All parameters will be descriptively analyzed as appropriate. An explanatory approach will be used to identify the factors contributing to the different effectiveness and safety outcomes.

Brief Project Background and Statement of Project Significance: There have been many cases in Japan where just after a novel drug has been newly marketed, many patients have suffered from expected ADR, leading to serious outcomes including death. When serious ADR occur after the marketing authorization, the health authority and marketing authorization holders often alert healthcare professionals to the ADR with the Dear Healthcare Professional Letters of Rapid Safety Communications. However, the majority of these ADR had already occurred at the investigational stage and the risk of the ADR had been clearly stated on the product labels. Simeprevir sodium (Sovriad), an antiviral agent for HCV infection is one of these drugs, and 3 patients have died due to hyperbilirubinemia, leading to hepatic and renal failure.
A possible reason why these serious outcomes due to expected ADR cannot be prevented is that the inclusion and exclusion criteria of subjects and various other aspects of clinical trials are very different from routine clinical practice(1-3). However, there have been no studies investigating the actual differences between clinical trials and routine clinical practice before the Dear Healthcare Professional Letters of Rapid Safety Communications are issued.
It is crucial to identify the actual differences between clinical trials and routine clinical practice to determine the cause that serious outcomes due to expected ADRs cannot be prevented. The results of this project will present very important information for the health authority and healthcare professionals to prevent serious adverse outcomes due to known ADR of novel drugs.

Specific Aims of the Project: Aim:
To identify different aspects between clinical trials and routine clinical practice of Simeprevir sodium (Sovriad) and to identify factors contributing to different efficacy and safety outcomes of the drug.
Objectives:
1. To identify precise differences between clinical trials and routine clinical practice of Simeprevir sodium (Sovriad) from full trial protocols of pivotal clinical trials in Japan and from medical records of patients who were administered the drug in routine clinical practice.
2. To categorize adverse drug events of the subjects in Individual Participant-level Data (IPD) and those in routine clinical practice according to MedDRA/J ver 15.0 PT and WHO toxicity grade and to compare the frequency and severity of these events.
3. To compare the effectiveness of the drug as SVR between the subjects in clinical trials and those in routine clinical practice.
4. To identify factors contributing to the different efficacy and safety outcomes of the drug between the two situations.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment safety Confirm or validate previously conducted research on treatment effectiveness Confirm or validate previously conducted research on treatment safety

Software Used: R

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: 1. Subjects of pivotal clinical trials in Japan (NCT01366638, NCT01292239, NCT01290731, NCT01288209, NCT00996476) who were administered simeprevir sodium (Sovriad) with the same dose as the marketing authorization.
2. Patients who were administered simeprevir sodium (Sovriad) in routine clinical practice of medical institutions which were authorized for treatment of hepatitis by Shimane Prefectural local government from December 2013 to October 2014 (from when the drug came onto the market to the date the Dear Healthcare Professional Letter of Rapid Safety Communications was issued).

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: 1. Adverse drug events of the subjects in IPD and those in routine clinical practice will be categorized as follows;
(1) A trained investigator will categorize and quantify any adverse drug events that occurred both in the clinical trials and in routine clinical practice, according to MedDRA/J ver 15.0 PT and WHO toxicity grade. Causal relationships of the events will also be assessed.
(2) Adverse drug events of hyperbilirubinemia, as an event warned by the Dear Healthcare Professional Letter of Rapid Safety Communications, will be especially focused on, and subjects/patients clinical condition and outcome will be assessed in detail.
2. The following information will be obtained to assess the efficacy of the drug:
(1) The number of subjects/patients who achieved SVR for 12 weeks and for 24 weeks will be obtained in full CSR and in routine clinical practice.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: 1. The following information will be obtained to assess the proportion of patients in routine clinical practice who meet the inclusion /exclusion criteria of clinical trials:
(1) Baseline demographic characteristics, results of diagnostic studies of HCV infection, HCV RNA viral load, HCV genotype, IL28B genetic polymorphism (rs8099917), other concomitant hepatic diseases, other medical history, concomitant drugs and other drug history, results of laboratory tests and other precise inclusion and exclusion criteria of subjects in full Clinical Study Reports (CSR) of pivotal clinical trials in Japan. Unavailable information on patients in routine clinical practice will also be identified.
2. The information below will be obtained to identify precise differences between clinical trials and routine clinical practice:
(1) Frequency of medical institution visits, monitoring laboratory tests and other findings.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:

Statistical Analysis Plan: All parameters will be descriptively analyzed as counts (percentage) for categorical variables, mean (standard deviation) or median (quartile range) for continuous or discrete variables as appropriate. The differences between the subjects in clinical trials and the patients in routine clinical practice will be analyzed by parametric or non-parametric tests (such as t-test, ?2 test etc.) as appropriate.
1. The number of patients who meet all inclusion/exclusion criteria of the clinical trials will be counted. And the number of patients who meet each inclusion/exclusion criterion will also be counted.
2. Baseline characteristics of the subjects in clinical trials and the patients in routine clinical practice will be compared and analyzed as appropriate.
3. Each adverse event categorized by MedDRA/J ver 15.0 PT and WHO toxicity grade of the subjects in clinical trials and the patients in routine clinical practice will be compared and analyzed as appropriate.
4. The number of identified ADRs (causal relationship is present) of the subjects in clinical trials and the patients in routine clinical practice will be compared and analyzed as appropriate.
5. The number of the subjects in clinical trials and the patients in routine clinical practice who achieved SVR for 12 weeks and for 24 weeks will be compared and analyzed as appropriate.

Narrative Summary: There have been many cases in Japan where just after a novel drug is newly marketed, many patients have suffered from already known Adverse Drug Reactions (ADR), leading to serious outcomes including death. The aim of this study is to identify actual differences between clinical trials and routine clinical practice to determine the cause that serious outcomes due to already known ADR cannot be prevented and to present very important information for the health authority and healthcare professionals to prevent serious adverse outcomes due to known ADR of a novel drug.

Project Timeline: Anticipated project start date: May 2020
Analysis completion date: Jan 2021
Date manuscript drafted and first submitted for publication: March 2021
Date results reported back to the YODA project: July 2021

Dissemination Plan: The results will be published in a peer reviewed journal in the field of pharmacoepidemiology, drug safety or public health.

Bibliography:

1. van Deudekom FJ, Postmus I, van der Ham DJ, Pothof AB, Broekhuizen K, Blauw GJ, et al. External validity of randomized controlled trials in older adults, a systematic review. PLoS ONE 2017;12: e0174053.
2. Saunders C, Byrne CD, Guthrie B, Lindsay RS, McKnight JA, Philip S, et al. External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants? Diabet Med 2013; 30: 300-308.
3. Hutchinson-Jaffe AB, Goodman SG, Yan RT, Wald R, Elbarouni B, Rose B, et al. Comparison of Baseline Characteristics, Management and Outcome of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome in Versus Not in Clinical Trials. AmJ Cardiol 2010; 106: 1389-1396.