scholarly journals Remdesivir in treatment of COVID-19: A systematic benefit-risk assessment

2020 ◽  
Author(s):  
Miranda Davies ◽  
Vicki Osborne ◽  
Samantha Lane ◽  
Debabrata Roy ◽  
Sandeep Dhanda ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Clinical Trial ◽  
Safety Data ◽  
Clinical Trial Data ◽  
Standard Of Care ◽  
Serious Adverse Events ◽  
Current Time ◽  
Action Team ◽  
Benefit Risk Assessment ◽  
Clinical Trial Results

AbstractBackgroundThere is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk assessment was designed and conducted to strengthen the ongoing understanding of the benefit-risk balance for remdesivir in COVID-19 treatment by using a structured method which uses all available data.MethodsThe Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared to standard of care, placebo or other treatments. We searched PubMed,Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.ResultsSeveral key benefits and risks for use of remdesivir in COVID-19 compared to placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR=1.23, 95% CI: 0.87, 1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) comparted to the placebo group (26%), however more patients in the remdesivir group discontinued treatment as a result of an adverse event compared to those patients receiving placebo (12% vs 5%).ConclusionsPreliminary clinical trial results suggest a favourable benefit-risk profile for remdesivir compared to placebo, however there is limited safety data available at the current time. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment.

scholarly journals Systematic benefit-risk assessment for the use of chloroquine or hydroxychloroquine as a treatment for COVID-19: Establishing a dynamic framework for rapid decision-making

2020 ◽  
Author(s):  
Vicki Osborne ◽  
Miranda Davies ◽  
Sandeep Dhanda ◽  
Debabrata Roy ◽  
Samantha Lane ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Standard Of Care ◽  
Event Analysis ◽  
Dynamic Framework ◽  
Cox Proportional Hazard ◽  
A Value ◽  
Action Team ◽  
Benefit Risk Assessment ◽  
Risk Balance ◽  
Electrocardiogram Ecg

AbstractObjectivesGiven the current pandemic, there is an urgent need to identify effective, safe treatments for COVID-19 (coronavirus disease). A systematic benefit-risk assessment was designed and conducted to strengthen the ongoing monitoring of the benefit-risk balance for chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19 treatment.MethodsThe overall benefit-risk of the use of chloroquine or hydroxychloroquine as a treatment for COVID-19 compared to standard of care, placebo or other treatments was assessed using the Benefit-Risk Action Team (BRAT) framework. We searched PubMed and Google Scholar to identify literature reporting clinical outcomes in patients taking chloroquine or hydroxychloroquine for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.ResultsSeveral potential key benefits and risks were identified for use of hydroxychloroquine or chloroquine in COVID-19 treatment. Currently available results did not show an improvement in mortality risk; Cox proportional hazard ratio (HR) for death between patients who received HCQ alone vs. neither hydroxychloroquine or azithromycin was 1.08 (95% CI 0.63-1.85). A further study compared the incidence of intubation or death (composite outcome) in a time to event analysis between patients who received HCQ vs. those patients who did not (adjusted Cox proportional HR 1.00 (95% CI 0.76-1.32)). Risk of cardiac arrest, abnormal electrocardiogram (ECG) and QT prolongation was greater among patients taking HCQ (with or without azithromycin) compared to standard of care in the same study.ConclusionsOverall, based on the available data there does not appear to be a favourable benefit-risk profile for chloroquine or hydroxychloroquine compared to standard of care in treatment of severe COVID-19. As further data from clinical trials and real world use on these benefits and risks becomes available, this can be incorporated into the framework for an ongoing benefit-risk assessment.

scholarly journals Missing clinical trial data: the evidence gap in the safety of potential COVID-19 drugs

2020 ◽  
Author(s):  
Florence Rodgers ◽  
Toby Pepperrell ◽  
Sarai Keestra ◽  
Victoria Pilkington
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Severe Disease ◽  
Safety Information ◽  
Safety Data ◽  
Clinical Trial Data ◽  
Clinical Findings ◽  
Rapid Review ◽  
Clinical Trial Results

Abstract Background: Several drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of clinical trial results on public registries or through academic publication. We aimed to analyse the evidence gap in safety data by quantifying the number of missing clinical trial results for drugs potentially being repurposed for COVID-19 by conducting a rapid review of results posting on ClinicalTrials.gov and in academic publications. Methods: ClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for results and for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance. Results: Of 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. 1172 (31.2%) completed trials had tabular results on ClinicalTrials.gov. A further 1066 (28.4%) completed trials had results from the literature search, but did not report results on ClinicalTrials.gov. Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%). Conclusions: There is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause a large burden of additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.

scholarly journals Lopinavir-Ritonavir in treatment of COVID-19: A dynamic systematic benefit-risk assessment

2020 ◽  
Author(s):  
Vicki Osborne ◽  
Miranda Davies ◽  
Samantha Lane ◽  
Alison Evans ◽  
Jacqueline Denyer ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Acute Respiratory Distress Syndrome ◽  
Adverse Events ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Standard Of Care ◽  
Risk Profile ◽  
Serious Adverse Events ◽  
Benefit Risk Assessment

AbstractBackgroundCOVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required due to the urgent unmet public need. Importantly it allows additional data to be incorporated as it becomes available, and re-evaluation of the benefit-risk profile.MethodsA systematic benefit-risk assessment was conducted using the Benefit-Risk Action team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and EmBase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance.ResultsIn comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (HR=1.31, 95% CI:0.95, 1.80). There appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). In particular, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared to standard of care (13% vs 27%). Limited data were available for comparison of lopinavir-ritonavir to other treatments.ConclusionsBased on currently available data, there was no clear benefit for use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events, including acute respiratory distress syndrome. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.

scholarly journals Missing clinical trial data: the knowledge gap in the safety of potential COVID-19 drugs

2020 ◽  
Author(s):  
Florence Rodgers ◽  
Toby Pepperrell ◽  
Sarai Keestra ◽  
Victoria Pilkington
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Severe Disease ◽  
Safety Information ◽  
Safety Data ◽  
Clinical Trial Data ◽  
Clinical Findings ◽  
Knowledge Gap ◽  
Clinical Trial Results

AbstractObjectivesSeveral drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of clinical trial results on public registries or through academic publication. We aimed to analyse the knowledge gap in safety data by quantifying the number of missing clinical trial results for drugs potentially being repurposed for COVID-19.DesignClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched using the NCT number to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance.ResultsOf 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. 1172 (31.2%) completed trials had tabular results on ClinicalTrials.gov. A further 1066 (28.4%) completed trials had results from the literature search, but did not report results on ClinicalTrials.gov. Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%).ConclusionThere is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause a large burden of additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.

scholarly journals A systematic review of convalescent plasma treatment for COVID19

2020 ◽  
Author(s):  
Ville N. Pimenoff ◽  
Miriam Elfström ◽  
Joakim Dillner
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Recovery Time ◽  
Clinical Trial Data ◽  
Poisson Model ◽  
Clinical Report ◽  
Prolonged Recovery ◽  
Report Data ◽  
Using Data ◽  
Clinical Trial Results

ABSTRACTBackgroundTransfusion of convalescent immune plasma (CP) is commonly used in epidemics. Several articles now describe clinical report data of CP for treatment of SARS-CoV-2-induced COVID-19 disease.MethodsA systematic literature review was conducted using the NCBI curated COVID-19 related open-resource literature database LitCovid to identify studies using CP as treatment for COVID-19 patients. We retrieved and curated all COVID-19 related patient and treatment characteristics from previously reported studies. A Poisson model was developed to evaluate the association between age of the patients, older age being the most common risk factor for COVID-19 mortality, and recovery time since CP treatment using data extracted from the literature.ResultsFrom 18,293 identified COVID-19 related articles, we included ten studies reporting results of CP treatment for COVID-19 from a total of 61 patients. Decreased symptoms of severe COVID-19 and clearance of SARS-CoV-2 RNA were the most direct observations. We found that patients over the age of sixty who received CP treatment for COVID-19 had a significantly prolonged recovery estimated by viral clearance (from 10 to 29 days since first dose of CP) compared to younger patients, who recovered from the infection in less than a week after receiving CP treatment.ConclusionsLimited published results on plasma transfusion treatment for COVID-19 disease with concomitant treatments suggest that CP therapy for COVID-19 is well tolerated and effective. First randomized clinical trial results, however, revealed no improvements in recovery time for elderly patients with severe COVID-19 between standard treatment alone and added with convalescent plasma. Accordingly, we argue that older patients may need a significantly longer time for recovery. Further randomized clinical trial data for COVID-19 with rigorous ethical standards is urgently needed.

Cambia® (Diclofenac Potassium for Oral Solution) in the Management of Acute Migraine

US Neurology ◽  
2011 ◽  
Vol 07 (02) ◽  
pp. 139 ◽  
Author(s):  
Kevin Kahn ◽  
Keyword(s):  
Clinical Trial ◽  
Real World ◽  
Clinical Trial Data ◽  
Oral Solution ◽  
Comparable Efficacy ◽  
Migraine Treatment ◽  
The Past ◽  
The Us ◽  
Clinical Trial Results ◽  
Favorable Side Effect Profile

Migraine is a prevalent and disabling disorder involving central and peripheral neurologic processes that generate inflammatory mediated pain. Cambia® (diclofenac potassium for oral solution), a novel patented form of the anti-inflammatory medication diclofenac potassium, has been approved by the US Food and Drug Administration for the acute treatment of migraine. Clinical trial data have demonstrated that this formulation offers a four-fold decrease in time of onset of relief compared with conventional diclofenac, which has comparable efficacy to triptan medication. It has also proven effective in a real-world setting. Over the past few years, it has been established that migraine treatment that is administered early may prevent central sensitization and improve treatment outcomes. Given the importance of early intervention in migraine treatment, this medication offers rapid, convenient, and effective relief with a favorable side-effect profile. This review describes migraine pathophysiology, treatment rationale, clinical trial results, and real-world experience with the use of this new medication.

Influence of breast cancer CME on provider knowledge and competence.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 214-214
Author(s):  
T. B. Stacy ◽  
A. A. Heintz ◽  
K. Dopson ◽  
K. McLane ◽  
M. E. Haas
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Patient Care ◽  
Practice Patterns ◽  
Management Strategies ◽  
Safety Data ◽  
Treatment Strategies ◽  
Breast Cancer Patients ◽  
Provider Knowledge ◽  
Clinical Trial Results

214 Background: Due to the volume and pace of scientific advances within oncology, the timely dissemination of clinical trial results and discussion regarding the appropriate incorporation into therapeutic decision making is necessary to provide the highest quality patient care. Increasing awareness in the breast cancer community on similarities and differences amongst practice management strategies helps to identify practice patterns and benchmark individual knowledge and competence against one’s professional peers. Methods: During 2010 and 2011, educational outcomes assessments were gathered during 83 independent continuing medical education (CME) activities held within community and academic institutions across the USA. Participants were asked a series of case-based questions via an audience response system to assess baseline knowledge, competence, and identify practice patterns. Assessments were repeated post a 1-hour CME certified activity, with an additional 6-week electronic follow-up. Barriers to implementing the information learned were also captured. Educational gaps were identified through documentation and comparison of current best practices versus actual participant responses. Results: To date, a total of 1,515 healthcare providers have participated in the initiative. Number of years in practice ranged from <10 to >30. The number of breast cancer patients seen per month ranged from ≤10 to >40. Provider competency in applying recent literature to the patient care setting was both assessed and measured. Results of neoadjuvant data knowledge, adjuvant therapy selection, relapsed HER2+ disease treatment strategies, and competence in discussing efficacy and safety data from recent clinical trials will be presented. Participants reported a number of barriers to applying data learned at the activities into clinical practice. Responses included lack of reimbursement, treatment side effects, newness of treatment data, and perceived efficacy. Conclusions: The results suggest the education of providers on the most currently available clinical trial results and expert discussion of how to optimize translation of this information into patient care increases breast cancer provider knowledge and competence.

scholarly journals Convalescent Plasma in treatment of COVID-19: A review of evidence for a living systematic benefit-risk assessment

2020 ◽  
Author(s):  
Miranda Davies ◽  
Samantha Lane ◽  
Alison Evans ◽  
Jacqueline Denyer ◽  
Sandeep Dhanda ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Controlled Trial ◽  
Intervention Group ◽  
Case Series ◽  
Data Availability ◽  
Control Group ◽  
Small Subset ◽  
Summary Table ◽  
Current Time ◽  
Benefit Risk Assessment

Objectives: We aimed to review the evidence for a living systematic benefit risk assessment for convalescent plasma use amongst patients with severe COVID-19 disease, based on currently available data. Methods: The assessment used the Benefit-Risk Action Team (BRAT) framework. Convalescent plasma treatment in severe COVID-19 was compared to standard of care, placebo or other treatments. A literature search was conducted to identify published papers from January 1st, 2019 until July 8th, 2020. A value tree was constructed which included ranked key benefits and risks. Results: We screened 396 papers from PubMed and 127 papers from Embase. Four studies were eligible for inclusion as they contained comparative data. Results from a randomised controlled trial revealed a non-statistically significant shortening of time to clinical improvement of 2.15 days (95% CI, −5.28 to 0.99 days) in the intervention group compared with the control group, with a possible signal of increased efficacy amongst a small subset of patients with severe disease (but not life threatening disease), however this study may have been underpowered. Interpretation of findings amongst the three controlled non-randomised studies were limited by small patient numbers, lack of randomisation, and confounding by co-administration of other treatments. Limited data availability at the current time precluded construction of a data summary table and further quantitative analysis. Conclusions: There was insufficient evidence from controlled studies to complete a data summary table for a systematic benefit-risk assessment of the use of CP for severe COVID-19 disease at the current time, and as such a benefit-risk conclusion could not be made. Whilst uncontrolled case series have suggested positive findings with CP, results from these studies are very difficult to interpret. We provide a framework which can be updated when further data that have an impact on the benefit-risk become available.

scholarly journals Risk of Malignancies in Patients with Rheumatoid Arthritis Treated with Rituximab: Analyses of Global Postmarketing Safety Data and Long-Term Clinical Trial Data

2019 ◽  
Vol 7 (1) ◽  
pp. 121-131 ◽  
Author(s):  
Paul Emery ◽  
Daniel E. Furst ◽  
Petra Kirchner ◽  
Simone Melega ◽  
Stuart Lacey ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Trial ◽  
Safety Data ◽  
Clinical Trial Data ◽  
Trial Data

Transforming Clinical Trial Eligibility Criteria to Reflect Practical Clinical Application

2016 ◽  
pp. 83-90 ◽  
Author(s):  
Edward S. Kim ◽  
Jennifer Atlas ◽  
Gwynn Ison ◽  
Jennifer L. Ersek
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Diagnostic Testing ◽  
Standard Of Care ◽  
Trial Participation ◽  
Eligibility Criteria ◽  
Number Of Patients ◽  
Oncology Clinical Trials ◽  
Clinical Trial Accrual ◽  
Clinical Trial Results

Historically, oncology clinical trials have focused on comparing a new drug’s efficacy to the standard of care. However, as our understanding of molecular pathways in oncology has evolved, so has our ability to predict how patients will respond to a particular drug, and thus comparison with a standard therapy has become less important. Biomarkers and corresponding diagnostic testing are becoming more and more important to drug development but also limit the type of patient who may benefit from the therapy. Newer clinical trial designs have been developed to assess clinically meaningful endpoints in biomarker-enriched populations, and the number of modern, molecularly driven clinical trials are steadily increasing. At the same time, barriers to clinical trial enrollment have also grown. Many barriers contribute to nonenrollment in clinical trials, including patient, physician, institution, protocol, and regulatory barriers. At the protocol level, eligibility criteria have become a large roadblock to clinical trial accrual. Over time, eligibility criteria have become more and more restrictive. To accrue an adequate number of patients to molecularly driven trials, we should consider eligibility criteria carefully and attempt to reduce restrictive criteria. Reducing restrictive eligibility criteria will allow more patients to be eligible for clinical trial participation, will likely increase the speed of drug approvals, and will result in clinical trial results that more accurately reflect treatment of the population in the clinical setting.

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