Design of a long-term follow-up effectiveness,immunogenicity and safety study of women who received the 9-valent human papillomavirus vaccine

The 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets four HPV types (6/11/16/18) also covered by the quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). Vaccine efficacy to prevent HPV infection and disease was established in a Phase III clinical study in women 16–26 years of age. A long-term follow-up (LTFU) study has been initiated as an extension of the Phase III clinical study to assess effectiveness of the 9vHPV vaccine up to at least 14 years after the start of vaccination. It includes participants from Denmark, Norway and Sweden and uses national health registries from these countries to assess incidence of cervical pre-cancers and cancers due to the 7 oncogenic types in the vaccine (HPV 16/18/31/33/45/52/58). Incidences will be compared to the estimated incidence rate in an unvaccinated cohort of similar age and risk level. This LTFU study uses a unique design: it is an extension of a Phase III clinical study and also has elements of an epidemiological study (i.e., endpoints based on standard clinical practice; surveillance using searches from health registries); it uses a control chart method to determine whether vaccine effectiveness may be waning. Control chart methods which were developed in industrial and manufacturing settings for process and production monitoring, can be used to monitor disease incidence in real-time and promptly detect a decrease in vaccine effectiveness. Experience from this innovative study design may be applicable to other medicinal products when long-term outcomes need to be assessed, there is no control group, or outcomes are rare.     

Hybrid clinical trials to generate real-world evidence: design considerations from a sponsor's perspective

Randomized controlled trials have traditionally been the gold standard for evaluating efficacy and safety of medical products and for regulatory decision-making. With the advancement of information technologies, vast amounts of data pertinent to patient health status and health care delivery are becoming available from a variety of real-world sources, including electronic health records, medical claims, patient registries, and patient-generated data. In 2016, the United States Congress passed the 21st Century Cures Act, mandating the U.S. FDA to establish a program to evaluate the potential use of real-world evidence (RWE) for regulatory purposes. In 2018, the FDA published the framework on its RWE program. One particular study type identified in the framework is the hybrid design – integration of a traditional randomized controlled trial with pragmatic design aspects to collect real-world data on patients. This design preserves the benefit of randomization, provides real-world outcome data while potentially accelerating product development and lowering the cost of data collection and patient follow-up. Here we focus on design considerations for hybrid trials to support regulatory decisions and provide a sponsor's perspective. While applicable to all medical products, we emphasize vaccine development where such hybrid designs are particularly useful given the low incidence rate of some vaccine-preventable clinical outcomes. We propose program strategies on how such hybrid designs may be integrated into a clinical development plan, illustrated by three examples. Major challenges are discussed and recommendations provided. Given the promise of hybrid designs and the challenges in implementation, we encourage proactive discussion with health authorities.     

Effectiveness on high-grade cervical abnormalities and long-term safety of the quadrivalent human papillomavirus vaccine in Japanese women

This study for the first time assessed quadrivalent human papillomavirus (qHPV) vaccine effectiveness against HPV6/11/16/18-related high-grade cervical disease in Japanese women (16–26 years old), as previously demonstrated in overseas trials, and vaccine safety in a longer term (48-month) open-label study (NCT01544478). Participants received three doses of qHPV vaccine (Day 1, Month 2, Month 6). Effectiveness endpoints, assessed in the per-protocol population, included incidence of HPV6/11/16/18-related cervical intraepithelial neoplasia (CIN) Grade 2 or worse (CIN Grade 2 and 3, adenocarcinoma in situ, and/or cervical cancer) as primary endpoint and incidence of external genital lesions (EGLs). Disease related to other high-risk HPV types was also assessed. Adverse events (AEs) and serious AEs (SAEs) were collected from Days 1–15 after any vaccination; vaccine-related SAEs, deaths, and new medical conditions were collected throughout the study. A total of 1030 women received at least one vaccination. No cases of CIN2 or worse or EGLs were reported in the per-protocol population. Injection site-related AEs were reported in 14.5% of participants; most were mild and resolved within 15 days. Vaccine-related systemic AEs occurred in 8.6% of participants, most commonly headache (2.3%), malaise (1.7%), and pyrexia (1.3%). There were no vaccine-related SAEs; one participant discontinued due to a vaccine-related AE of mild uticaria. Overall, qHPV vaccine effectiveness against HPV6/11/16/18-related high-grade cervical disease and EGLs was indicated in Japanese women. The vaccine was well-tolerated, without new safety signals throughout the 48-month study period. Findings are consistent with overseas qHPV vaccine pivotal trials.Clinical trial registryclinicaltrials.gov; NCT01544478.     

Design of a large outcome trial for a multivalent human papillomavirus L1 virus-like particle vaccine

BackgroundThe 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets the four HPV types (6/11/16/18) covered by the licensed quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). A large outcome trial of 9vHPV vaccine was conducted.MethodsAn active control (qHPV vaccine) was used because a placebo is not ethically acceptable. Since qHPV vaccine is (and 9vHPV vaccine was anticipated to be) highly efficacious against HPV 6/11/16/18, low incidence of HPV 6/11/16/18-associated disease was expected. Consequently, an efficacy comparison of 9vHPV versus qHPV vaccine for HPV 6/11/16/18 would have been prohibitively large in size. Moreover, no minimum antibody level predicting protection against infection or disease is defined for HPV vaccination. As an alternative approach, the two vaccines were compared using immunogenicity bridging for HPV 6/11/16/18 and clinical efficacy for HPV 31/33/45/52/58.ResultsThe two co-primary objectives were to demonstrate: (1) non-inferior anti-HPV 6/11/16/18 antibody response; and (2) superior efficacy in HPV 31/33/45/52/58-related clinical outcome, for 9vHPV vaccine versus qHPV vaccine. For HPV 6/11/16/18, supportive analyses included a non-inferiority assessment of the percent risk reduction (compared to historical placebo) for 9vHPV versus qHPV vaccine.ConclusionsA Phase III study of 9vHPV vaccine was successfully implemented. Experience from this study design may be applicable when developing a multivalent vaccine covering the same serotypes as an existing vaccine plus additional serotypes and there is no immune correlate of protection. Also, this study established that efficacy of a new HPV vaccine may be demonstrated using immunogenicity endpoints, which may open new options in HPV vaccine development.     

Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: The TARGET-NASH study

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. NAFLD comprises the spectrum from simple steatosis (nonalcoholic fatty liver, NAFL), to steatosis with inflammation (nonalcoholic steatohepatitis, NASH). Current primary therapy recommended for NAFLD is weight loss induced by lifestyle modification. The difficulty in achieving this has led to robust pharmacological therapy development. While new drugs may show efficacy in selected phase II/III clinical trial populations, their real-world effectiveness is unknown. TARGET-NASH is a 5-year, longitudinal, observational study of patients with NAFLD designed to evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. A biological specimen repository is included in TARGET-NASH for translational studies of genomics and biomarkers of disease activity. Patients are enrolling at adult and pediatric sites representing multiple specialties. All patients being managed for NAFLD are eligible, whereas those in other NASH registries or clinical trials will be excluded. Enrolled patients range in age from 6 and up and will have 3 years of clinical data reviewed. Patient comorbidities, concomitant medications, disease progression and off-label interventions will be assessed, and adverse outcomes, monitored. Confirming the use, safety and effectiveness of NAFLD interventions in children and adults and establishing pragmatic methods of assessing disease progression under real-world conditions are key study outcomes. Ultimately, TARGET-NASH will establish a large, diverse registry of NAFLD patients at academic and community practices to be leveraged to improve health and reduce development of cirrhosis and hepatocellular carcinoma.     

癌症患儿随访体验的系统评价

目的 系统评价癌症患儿随访体验的质性研究,为提高癌症患儿随访质量提供参考依据。方法 计算机检索PubMed、Embase、Web of Science、Cochrane Library、CINAHL、中国知网、中国生物医学文献数据库、维普、万方数据库中关于癌症患儿随访体验和需求的质性研究,检索时限为建库至2021年6月。采用澳大利亚乔安娜布里格斯研究所循证卫生保健中心质性研究质量评价标准对文献质量进行评价,采用汇集性整合方法进行结果整合。结果 共纳入12篇文献,提炼60个研究结果,归纳形成10个新类别,合成3个整合结果：癌症患儿身心俱疲、人际关系紧张,但仍然心怀希望,渴望得到家庭和社会支持;癌症患儿疾病管理需求未得到满足以及与医护人员沟通不畅,导致其日常生活受限;尽管癌症患儿对随访的认知不足,但参与动机强烈,期待获得全面的随访。结论 医护人员应关注癌症患儿这一特殊群体,重视其随访体验,及时给予医疗信息、情感和社会支持,同时需加大对专业人员规范化培训的力度,丰富随访内容及参与形式,以确保随访的可持续性,帮助癌症患儿更好地适应社会。     

Effectiveness of 7-valent pneumococcal conjugate vaccine: A meta-analysis of post-marketing studies

AIM:To investigate the 7-valent pneumococcalconjugate vaccine(PCV7)effectiveness.METHODS:A systematic literature review of studies which evaluated the effectiveness of PCV7 vaccine was performed searching the keyword"heptavalent pneumococcal conjugate vaccine"in PubM ed and Scopus until March 16,2013.The selection of potential eligible articles was done by two researchers independently on the basis of abstract and title and only post-marketing studies were included in the systematic review.Data extraction was carried out by two researchers with respect to invasive pneumococcal diseases due to both all and vaccine serotypes in pre-vaccine and postvaccine periods in children less than 5 years.Results of studies which were considered suitable for meta-analysis were combined by means of relative risk(RR)with95%CI.Vaccine effectiveness was calculated as(1-RR)×100.Heterogeneity was assessed by I2 and a random effects model was used to combine data in the case of heterogeneity.RevM an 5 was used to pool data.RESULTS:On the whole,757 eligible papers were identified from the literature search in PubM ed and Scopus.Of them,62 were finally considered in the systematic review and 38 were included in the meta-analysis.In all post-marketing studies included in the systematic review the incidence of invasive pneumococcal diseases due to vaccine serotypes declined significantly with the exception of few studies showing stability or a slight,but not significant,increase.Furthermore most of studies highlighted also a reduction in the incidence of invasive pneumococcal diseases due to all serotypes.With regards to meta-analysis,a random effects model was used to combine data because of the high heterogeneity.Data combination showed that the effectiveness of PCV7in reducing invasive pneumococcal diseases due to vaccine serotypes and to all serotypes was 84%(95%CI:74%-90%)and 53%(95%CI:46%-59%)respectively.These results are confirmatory with respect to the efficacy of PCV7 against invasive pneumococcal diseasesdue to vaccine serotypes.CONCLUSION:PCV7 implementation determines a significant decrease of invasive pneumococcal diseases.     

Möglichkeiten der internetbasierten Versorgungsforschung

Data from registries have gained increasing relevance for assessment of safety and efficacy and are one of the most important study types in the field of clinical healthcare research in addition to prospective randomized studies. In the modern digital world, web-based applications are an attractive method to evaluate patient outcome and to create data for clinical registries. These applications provide an easy and efficient possibility to contact patients and thus to collect clinical data. Against this background the cartilage register of the German Trauma Society (KnorpelRegister DGOU) was established in October 2013. Using a similar technical platform the German-speaking arthroscopy register (DART) is now also ready to be launched. The current article provides an overview of the background, previous experiences and the present state of development and also discusses potential problems associated with this new form of data collection. These issues can be data protection and especially verification of the validity of the collated scientific data.     

Key considerations in the design of real-world studies

Randomized controlled clinical trials (RCTs) are the gold standard for evaluating the safety and efficacy of pharmaceutical drugs, but in many cases their costs, duration, limited generalizability, and ethical or technical feasibility have caused some to look for real-world studies as alternatives. However, real-world studies may be less convincing due to the lack of randomization and blinding. In this article, we discuss some key considerations in the design of real-world studies, which include experimental studies (e.g., hybrid or pragmatic clinical trials and non-randomized single-arm clinical trials with external controls) and non-experimental studies (e.g., cohort studies, cross-sectional studies, and case-control studies). Causal inference plays a critical role in the derivation of robust real-world evidence (RWE) from the analysis of real-world data (RWD). Therefore, we apply the hypothetical strategy, along with the concept of potential outcome, to lay out these key considerations, and we hope these considerations are helpful for the design, conduct, and analysis of real-world studies.     

Predictors of Missed Follow-up Visits in the National Traumatic Brain Injury Model Systems Cohort Study

ObjectiveTo identify key variables that could predict risk of loss to follow-up (LTFU) in a nationally funded longitudinal database of persons with traumatic brain injury.DesignSecondary analysis of a prospective longitudinal cohort study.SettingTraumatic Brain Injury Model System (TBIMS) Centers in the US.ParticipantsA total of 17,956 TBIMS participants (N=17,956) with interview status data available were included if eligible for 1-, 2-, 5-, 10-, 15-, or 20-year follow-ups between October 31, 1989, and September 30, 2020.InterventionsNot applicable.Main Outcome MeasuresFollow-up data collection completion status at years 1, 2, 5, 10, 15, and 20.ResultsInformation relevant to participants’ history, injury characteristics, rehabilitation stay, and patterns of follow-up across 20 years were considered using a series of logistic regression models. Overall, LTFU rates were low (consistently <20%). The most robust predictors of LTFU across models were missed earlier follow-ups and demographic factors including Hispanic ethnicity, lower education, and lack of private health insurance.ConclusionsEfforts to retain participants in such social disadvantaged or minority groups are encouraged given their disproportionate rate of LTFU. Repeated attempts to reach participants after a previously missed assessment are beneficial because many participants that missed 1 or more follow-ups were later recovered.     

Observation of health technologies after their introduction into clinical practice: a systematic review on data collection instruments

Rationale, aims and objectives Early assessment of health technologies after they are covered by the health system is deemed crucial to promptly identify and analyse unforeseen problems that may arise when these are used in real world settings. This paper aims to describe the various instruments which could be used for collecting information intended for prospective observation of health technologies, so as to choose the specific instrument best suited to each context. Methods Systematic review of the medical literature aimed at retrieving general reference documents on data collection instruments for post-introduction observation of health technologies. A purpose-designed systematic bibliographic search was elaborated for the main three data collection instruments identified. Results The three instruments are briefly described along with the main results of the studies retrieved, in terms of the advantages, drawbacks and considerations to be borne in mind when it comes to use these tools in post-introduction observation of new technologies. Conclusions At present, the most appropriate data collection method for conducting post-introduction observation of new technologies is the use of prospective clinical registries. Electronic clinical records may replace clinical registries in the near future, but currently there are still many doubts as to the quality of the information retrieved.     

Real-World Effectiveness and Safety of a Live-Attenuated Herpes Zoster Vaccine: A Comprehensive Review

Herpes zoster (HZ) is a common, painful and debilitating disease caused by the reactivation of latent varicella-zoster virus in ganglia. This clinical event occurs more frequently in the elderly and those who are immunocompromised. The most common complication of HZ is post-herpetic neuralgia (PHN) which is responsible for the highest HZ-related burden of illness and is challenging to treat. Due to the important clinical and economic impact of HZ and PHN, and the suboptimal treatments that are currently available, HZ vaccination is an important approach to reduce the burden of illness. Currently, one-dose, live-attenuated vaccine is licensed in the United States and Europe to prevent HZ and it is included in some national immunization programs. The clinical efficacy, safety and tolerability of the vaccine has been demonstrated in two large phase III clinical trials, involving more than 38,000 and 22,000 individuals aged ≥60 and 50–59 years, respectively. This comprehensive review summarizes the extensive “real-world” effectiveness and safety data from both immunocompetent and immunocompromised individuals. These data confirm those from the clinical trials, supporting the use of HZ vaccine in clinical practice and provide evidence that the current recommendations for immunocompromised individuals should be revised. Funding: Funding for the editorial assistance, article processing charges, and open access fee for this publication was provided by Sanofi Pasteur MSD.     

A state-of-art review on collagenase Clostridium Histolyticum and Peyronie’s disease: drug profile,clinical evidence and safety outcomes

ABSTRACT

Introduction: Collagenase clostridium histolyticum (CCH) is the first and only licensed medical treatment for men with Peyronie’s disease (PD). Published literature shows intralesional CCH injection as an effective and safe minimally invasive treatment in a specific subgroup of PD patients.

Areas covered: The authors discuss pharmacodynamics and pharmacokinetics as well as clinical outcomes and safety profile from major CCH studies in PD. All relevant CCH studies published in PubMed and EMBASE databases up to June 2019 were included.

Expert opinion: Given the variability in treatment schedule and drug access coupled with the potential need for further treatment, strict patient selection and the use of adjunctive strategies are key determinants to maximize clinical efficacy of intralesional CCH. Furthermore, longer-term follow-up data on the clinical outcomes, safety and durability of CCH in larger multi-center studies and post-marketing surveillance data are necessary to provide a comparison to other standard PD treatment options.     

A Cost-Utility Analysis of Pregabalin Versus Duloxetine for the Treatment of Painful Diabetic Neuropathy

ABSTRACT

The objective of the current study was to determine the cost-utility of pregabalin versus duloxetine for treating painful diabetic neuropathy (PDN) using a decision tree analysis. Literature searches identified clinical trials and real-world studies reporting the efficacy, tolerability, safety, adherence, opioid usage, health care utilization, and costs of pregabalin and duloxetine. The proportions of patients reported in the included studies were used to determine probabilities in the decision tree model. The base-case model included the Food and Drug Administration (FDA)-approved doses of pregabalin (300 mg/day) and duloxetine (60 mg/day), whereas “real-world” sensitivity analyses explored the effects over a range of doses (pregabalin 75–600 mg/day, duloxetine 20–120 mg/day). A 6-month time horizon and a US third-party payer perspective were chosen for the study. Outcomes from the model were expressed as cost per quality-adjusted life-year (QALY). In the base-case model, duloxetine cost less and was more effective than pregabalin (incremental cost ?$187, incremental effectiveness 0.011 QALYs). Results from two real-world sensitivity analyses indicated that duloxetine cost $16,300 and $20,667 more per additional QALY than pregabalin. Using a decision tree model that incorporated both clinical trial and real-world data, duloxetine was a more cost-effective option than pregabalin in the treatment of PDN from the perspective of third-party payers.     

Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician

Real-world studies have become increasingly important in providing evidence of treatment effectiveness in clinical practice. While randomized clinical trials (RCTs) are the “gold standard” for evaluating the safety and efficacy of new therapeutic agents, necessarily strict inclusion and exclusion criteria mean that trial populations are often not representative of the patient populations encountered in clinical practice. Real-world studies may use information from electronic health and claims databases, which provide large datasets from diverse patient populations, and/or may be observational, collecting prospective or retrospective data over a long period of time. They can therefore provide information on the long-term safety, particularly pertaining to rare events, and effectiveness of drugs in large heterogeneous populations, as well as information on utilization patterns and health and economic outcomes. This review focuses on how evidence from real-world studies can be utilized to complement data from RCTs to gain a more complete picture of the advantages and disadvantages of medications as they are used in practice.Funding: Sanofi US, Inc.     

Development of new Japanese encephalitis vaccine

We have developed the new inactivated Japanese encephalitis vaccine derived from virus-infected Vero cells cultured on microcarriers. The safety and effectiveness of this new vaccine were compared with those of current mouse-brain-derived vaccine that have some intrinsic demerits such as possible contamination of adventitious agents. The results of pre-clinical and clinical trials suggested that the safety and effectiveness of new vaccine are approximate equivalent to those of currently conventional vaccine in humans and animals, and that the availability of Vero cell-derived vaccine is anticipated.     

Meningococcal tetravalent conjugate vaccine

Background: Neisseria meningitidis is a leading cause of meningitis and sepsis worldwide. Since 1981, a tetravalent meningococcal polysaccharide vaccine has been available in the US but it has been limited to high-risk patients and outbreak settings. In 2005, a tetravalent polysaccharide meningococcal conjugate vaccine (MCV4) was licensed for routine use in the US. Objective: To assess the immunogenicity and safety of MCV4, and to extrapolate the anticipated clinical effectiveness of MCV4 using data from other polysaccharide conjugate vaccination programs. Methods: All published controlled studies of MCV4 immunogenicity, safety and cost-effectiveness are analyzed. Publicly-available clinical trial data and the Advisory Committee on Immunization Practices guidelines were also reviewed. Conclusion: MCV4 is as safe and immunogenic as the previously available polysaccharide vaccine, and seems to provide longer lasting protection against meningococcal disease. Long-term studies are continuing and will shed further light on the effectiveness of MCV4 at the population level.     

Quantitative coronary analysis in the Nordic Bifurcation studies

Quantitative coronary analysis (QCA) of bifurcation lesions in the Nordic Bifurcation studies was performed using software dedicated to bifurcating vessels. By now, pre-PCI, post-PCI and 8-month follow-up angiograms of 957 patients have been analyzed in the first three Nordic Bifurcation studies. Large scale clinical studies with specific areas of interest require QCA software with high intra- and inter observer reproducibility, an efficient workflow, flexible features of analysis, a detailed output, and facilities for data export. Recently, a dedicated second generation 2D QCA bifurcation software became commercially available. We used this new software in the third Nordic Bifurcation study for efficient and tailored analysis. Despite widespread automation of the analysis process and experienced observers, an elaborate standard operating procedure is still essential for standardized high quality QCA analysis of bifurcation lesions.     

Review of orthostatic tests on the safety of tamsulosin, a selective alpha1A-adrenergic receptor antagonist, shows lack of orthostatic hypotensive effects

Two phase III studies with tamsulosin, a selective alpha1A-adrenergic receptor antagonist, were conducted to evaluate the safety and efficacy of the standard treatment doses of 0.4 mg/day and 0.8 mg/day in patients with symptoms of benign prostatic hyperplasia (BPH). These large-scale clinical trials were the first to include extensive testing for possible drug-induced orthostatic hypotension (OH). The frequency of positive orthostatic tests and magnitude of vital sign changes were compared among tamsulosin and placebo-treated groups. The results indicate that tamsulosin up to 0.8 mg/day does not induce higher risk of OH than that of placebo. Data from post-marketing surveillance (PMS) studies of tamsulosin indicate that the incidence of hypotension and syncope is extremely low in community-dwelling elderly men treated for BPH. From the results of the phase III studies, PMS studies and an active-controlled clinical pharmacology study, we conclude that the orthostatic test is a useful and convenient method to evaluate the risk of OH and syncope during the investigational stage.     

Deconstructing the Pharmacovigilance Hype Cycle

Data science is making increasing contributions to pharmacovigilance. Although the technical innovation of these works are indisputable, efficient progress in real-world pharmacovigilance signal detection may be hampered by corresponding technology life cycle effects, with a resulting tendency to conclude that, with large enough datasets and intricate algorithms, “the numbers speak for themselves,” discounting the importance of clinical and scientific judgment. A practical consequence is overzealous declarations regarding the safety or lack of safety of drugs. We describe these concerns through a critical discussion of key results and conclusions from case studies selected to illustrate these points.