Does biomarker use in oncology improve clinical trial failure risk? A large-scale analysis.

PURPOSE: To date there has not been an extensive analysis of the outcomes of biomarker use in oncology. METHODS: Data were pooled across four indications in oncology drawing upon trial outcomes from www.clinicaltrials.gov: breast cancer, non-small cell lung cancer (NSCLC), melanoma and colorectal cancer from 1998 to 2017. We compared the likelihood drugs would progress through the stages of clinical trial testing to approval based on biomarker status. This was done with multi-state Markov models, tools that describe the stochastic process in which subjects move among a finite number of states. RESULTS: Over 10000 trials were screened, which yielded 745 drugs. The inclusion of biomarker status as a covariate significantly improved the fit of the Markov model in describing the drug trajectories through clinical trial testing stages. Hazard ratios based on the Markov models revealed the likelihood of drug approval with biomarkers having nearly a fivefold increase for all indications combined. A 12, 8 and 7-fold hazard ratio was observed for breast cancer, melanoma and NSCLC, respectively. Markov models with exploratory biomarkers outperformed Markov models with no biomarkers. CONCLUSION: This is the first systematic statistical evidence that biomarkers clearly increase clinical trial success rates in three different indications in oncology. Also, exploratory biomarkers, long before they are properly validated, appear to improve success rates in oncology. This supports early and aggressive adoption of biomarkers in oncology clinical trials.

Inmunidad frente a SARS-CoV-2: caminando hacia la vacunación / Immunity against SARS-CoV-2: walking to the vaccination

Los coronavirus (CoVs) son un amplio grupo de virus en el que se encuentra el SARS-CoV-2 (familia Coronaviridae, subfamilia Coronavirinae, género Betacoronavirus y subgénero Sarbecovirus). Sus principales proteínas estructurales son la de membrana (M), la de envoltura (E), la nucleocápside (N) y la espicular (S). La respuesta inmune frente a SARS-CoV-2 implica la vertiente celular y humoral, con anticuerpos neutralizantes potencialmente defensivos fundamentalmente dirigidos frente al antígeno S. Aunque los datos de seroprevalencia se asumen muy frecuentemente como marcadores de protección, no necesariamentelo son. En España se estima que al menos cuatro quintas partes de la población deberían estar inmuno-protegidas para asegurar la inmunidad de grupo. Dada la alta tasa de letalidad por COVID-19, la adquisición de esta protección únicamente mediante el contagio natural no es asumible y se debe abogar por otras medidas como puede ser la inmunización masiva. En la actualidad existen varios prototipos de vacunas (que incluyen virus vivos, vectores virológicos, péptidos y proteínas y ácidos nucleicos) en diversas etapas de evaluación clínica. Se prevé que en breve alguna de estas nuevas vacunas se encuentre ya disponible en el mercado. En este texto se revisan aspectos relacionados con estos asuntos

The coronavirus are a wide group of viruses among that the SARS-CoV-2 is included (family Coronaviridae, subfamily Coronavirinae, genus Betacoronavirus and subgenus Sarbecovirus). Its main structural proteins are the membrane (M), the envelope (E), the nucleocapsid (N) and spike (S). The immune response to SARS-CoV-2 involves the cellular and the humoral sides, with neutralizing antibodies fundamentally directed against the S antigen. Although the seroprevalence data are frequently assumed as protection markers, no necessarily they are. In Spain, it is estimated that, to assure the herd immunity, at least four-fifths of the population should be immunoprotected. Due the high fatality rate of COVID-19, the acquisition of the protection only by the natural infection it not assumable and other measures as the mass immunization are required. Currently, there are several vaccine prototypes (including life virus, viral vectors, peptides and proteins and nucleic acid) in different phase of clinical evaluation. Foreseeably, some of these news vaccines would be soon commercially available. In this text, aspects related to these issues are reviewed

Study design: what's in a name?

The name of the study should properly reflect the actual conduct and analysis of the study. This short paper provides guidance on how to properly name the study design. The first distinction is between a trial (intervention given to patients to study its effect) and an observational study. For observational studies, it should further be decided whether it is cross-sectional or whether follow-up time is taken into account (cohort or case-control study). The distinction prospective-retrospective has two disadvantages: prospective is often seen as marker of higher quality, which is not necessarily true; there is no unifying definition that makes a proper distinction between retrospective and prospective possible.

[Immunity against SARS-CoV-2: walking to the vaccination]. / Inmunidad frente a SARS-CoV-2: caminando hacia la vacunación.

The coronavirus are a wide group of viruses among that the SARS-CoV-2 is included (family Coronaviridae, subfamily Coronavirinae, genus Betacoronavirus and subgenus Sarbecovirus). Its main structural proteins are the membrane (M), the envelope (E), the nucleocapsid (N) and spike (S). The immune response to SARS-CoV-2 involves the cellular and the humoral sides, with neutralizing antibodies fundamentally directed against the S antigen. Although the seroprevalence data are frequently assumed as protection markers, no necessarily they are. In Spain, it is estimated that, to assure the herd immunity, at least four-fifths of the population should be immunoprotected. Due the high fatality rate of COVID-19, the acquisition of the protection only by the natural infection it not assumable and other measures as the mass immunization are required. Currently, there are several vaccine prototypes (including life virus, viral vectors, peptides and proteins and nucleic acid) in different phase of clinical evaluation. Foreseeably, some of these news vaccines would be soon commercially available. In this text, aspects related to these issues are reviewed.

Current clinical trials on breast cancer in China: A systematic literature review.

With rapid advancement in clinical research, clinical trials on breast cancer in China have made great progress and are increasingly receiving worldwide recognition. Oncologists have been provided with an unprecedented opportunity to conduct clinical trials that offer both advantages and challenges. Investigator-initiated trials (IITs) and trials on domestic innovative drugs are still in the initial stages, with plenty of room to grow. The goal of this study was to systematically review time trends of the changing landscape of clinical drug development in China over the course of the last decade (from 2009 to 2018). The number of clinical trials specific to breast cancer has increased in a span of 10 years, from 36 trials in 2009 to 113 in 2018, and this trend is accompanied by an increase in publications, from 13 in 2009 to 52 in 2015. A total of 593 trials were conducted in breast cancer between 2009 and 2018. The distribution pattern of trial phases shows that phase 2 trials accounted for 34% of the total, followed by phase 3 trials at 21% and phase 1 trials at 20%. Academic trials or IITs were found to be the major sponsors, with 52% of trials being sponsored by them followed by pharmaceutical companies as a secondary sponsor (38%). Additionally, trials on chemotherapeutic agents constituted 50% of the trials followed by trials on targeted therapy (31%). The review provides insight on the effectiveness of the pharmaceutical industry and identify unmet clinical needs of stakeholders. With accumulated experience of Chinese oncologists and increasing support from the Chinese government, greater success could be anticipated in the near future.

Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers. MAIN OUTCOMES: Trial intervention, sponsorship, critical design elements and specified outcomes RESULTS: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020. CONCLUSIONS: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.

Reporting of randomized factorial trials was frequently inadequate.

OBJECTIVES: Factorial designs can allow efficient evaluation of multiple treatments within a single trial. We evaluated the design, analysis, and reporting in a sample of factorial trials. STUDY DESIGN AND SETTING: Review of 2 × 2 factorial trials evaluating health-related interventions and outcomes in humans. Using Medline, we identified articles published between January 2015 and March 2018. We randomly selected 100 articles for inclusion. RESULTS: Most trials (78%) did not provide a rationale for using a factorial design. Only 63 trials (63%) assessed the interaction for the primary outcome, and 39/63 (62%) made a further assessment for at least one secondary outcome. 12/63 trials (19%) identified a significant interaction for the primary outcome and 16/39 trials (41%) for at least one secondary outcome. Inappropriate methods of analysis to protect against potential negative effects from interactions were common, with 18 trials (18%) choosing the analysis method based on a preliminary test for interaction, and 13% (n = 10/75) of those conducting a factorial analysis including an interaction term in the model. CONCLUSION: Reporting of factorial trials was often suboptimal, and assessment of interactions was poor. Investigators often used inappropriate methods of analysis to try to protect against adverse effects of interactions.

Clinical trials for deep brain stimulation: Current state of affairs.

BACKGROUND: Deep brain stimulation (DBS) is a surgical neuromodulation procedure with a historically wide range of possible therapeutic indications, including movement disorders, neuropsychiatric conditions, and cognitive disorders. Ongoing research in this field is critical to gain further insights into the mechanisms of DBS, to discover novel brain targets for new and existing indications, and to refine targeting and post-operative programming techniques for the optimization of therapeutic outcomes. OBJECTIVE: To update on the state of DBS-related clinical human research by cataloging and summarizing clinical trials that have been completed or are currently ongoing in this field worldwide. METHODS: A search was conducted for clinical trials pertaining to DBS, currently listed on the ClinicalTrials.gov database. Trials were analyzed to generate a detailed overview of ongoing DBS-related research. Specifically, trials were categorized by trial start date, study completion status, clinical phase, projected subject enrollment, disorder, brain target, country of origin, device manufacturer, funding source, and study topic. RESULTS: In total, 384 relevant clinical trials were identified. The trials spanned 28 different disorders across 26 distinct brain targets, with almost 40% of trials being for conditions other than movement disorders. The majority of DBS trials have been US-based (41.9% of studies) but many countries are becoming increasingly active. The ratio of investigator-sponsored to industry-sponsored trials was 3:1. Emphasizing the need to better understand the mechanism of action of DBS, one-third of the studies predominantly focus on imaging or electrophysiological changes associated with DBS. CONCLUSIONS: This overview of current DBS-related clinical trials provides insight into the status of DBS research and what we can anticipate in the future concerning new brain targets, indications, techniques, and developing a better understanding of the mechanisms of action of DBS.

Differential Clinical Profiles, Exercise Responses, and Outcomes Associated With Existing HFpEF Definitions.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is currently no consensus on how to define HFpEF according to various society and clinical trial criteria. How clinical and hemodynamic profiles of patients vary across definitions is unclear. We sought to determine clinical characteristics, as well as physiologic and prognostic implications of applying various criteria to define HFpEF. METHODS: We examined consecutive patients with chronic exertional dyspnea (New York Heart Association class II to IV) and ejection fraction ≥50% referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. We applied societal and clinical trial HFpEF definitions and compared clinical profiles, exercise responses, and cardiovascular outcomes. RESULTS: Of 461 patients (age 58±15 years, 62% women), 416 met American College of Cardiology/American Heart Association (ACC/AHA), 205 met European Society of Cardiology (ESC), and 55 met Heart Failure Society of America (HFSA) criteria for HFpEF. Clinical profiles and exercise capacity varied across definitions, with peak oxygen uptake of 16.2±5.2 (ACC/AHA), 14.1±4.2 (ESC), and 12.7±3.1 mL·kg-1·min-1 (HFSA). A total of 243 patients had hemodynamic evidence of HFpEF (abnormal rest or exercise filling pressures), of whom 222 met ACC/AHA, 161 met ESC, and 41 met HFSA criteria. Over a mean follow-up of 3.8 years, the incidence of cardiovascular outcomes ranged from 75 (ACC/AHA) to 298 events per 1000 person-years (HFSA). Application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. CONCLUSIONS: Use of different HFpEF classifications variably enriches for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure highlights the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF subgrouping to test therapeutic interventions.

New NIH Regulations Say Most Basic Human Brain Research Is a Clinical Trial.

New NIH definitions classify virtually all human brain and behavioral research as clinical trials. The new definitions will change regulatory, reporting, and funding schemes for noninvasive studies such as neuroimaging. Resulting burdens threaten the viability of basic biobehavioral science research.

Automated classification of eligibility criteria in clinical trials to facilitate patient-trial matching for specific patient populations.

OBJECTIVE: To develop automated classification methods for eligibility criteria in ClinicalTrials.gov to facilitate patient-trial matching for specific populations such as persons living with HIV or pregnant women. MATERIALS AND METHODS: We annotated 891 interventional cancer trials from ClinicalTrials.gov based on their eligibility for human immunodeficiency virus (HIV)-positive patients using their eligibility criteria. These annotations were used to develop classifiers based on regular expressions and machine learning (ML). After evaluating classification of cancer trials for eligibility of HIV-positive patients, we sought to evaluate the generalizability of our approach to more general diseases and conditions. We annotated the eligibility criteria for 1570 of the most recent interventional trials from ClinicalTrials.gov for HIV-positive and pregnancy eligibility, and the classifiers were retrained and reevaluated using these data. RESULTS: On the cancer-HIV dataset, the baseline regex model, the bag-of-words ML classifier, and the ML classifier with named entity recognition (NER) achieved macro-averaged F2 scores of 0.77, 0.87, and 0.87, respectively; the addition of NER did not result in a significant performance improvement. On the general dataset, ML + NER achieved macro-averaged F2 scores of 0.91 and 0.85 for HIV and pregnancy, respectively. DISCUSSION AND CONCLUSION: The eligibility status of specific patient populations, such as persons living with HIV and pregnant women, for clinical trials is of interest to both patients and clinicians. We show that it is feasible to develop a high-performing, automated trial classification system for eligibility status that can be integrated into consumer-facing search engines as well as patient-trial matching systems.

Analysis of registered cancer clinical trials in Latin America and the Caribbean, 2007-2013.

Objective To characterize cancer clinical trials in Latin America and the Caribbean (LAC), with a focus on registration and enrollment trends. Methods Data were collected from 1 285 active cancer clinical trials registered up until 31 May 2014 in the World Health Organization's International Clinical Trial Registry Platform (ICTRP). The trials were categorized by six characteristics of the continuum of cancer control and care: 1) control and planning, 2) prevention, 3) detection and screening, 4) diagnosis, 5) treatment, and 6) survivorship and palliative care. The search strategy protocol included the use of optimized keywords combined with the names of the 43 countries selected for a descriptive analysis. Results A total of 973 registered and 972 enrolled cancer clinical trials between January 2007 and December 2013 were identified. Trends of growth were observed for both registration and enrollment of cancer treatment clinical trials; for other types of cancer clinical trials, trends for registration and enrollment varied in direction. Conclusions Growth trends in the registration of cancer treatment clinical trials indicate incremental adherence to cancer research reporting and improvements in cancer research transparency. The higher proportion of cancer treatment trials versus other types of cancer clinical trials indicates an imbalance in cancer research in the LAC region and suggests the need for more funding and incentives for other areas of research in order to achieve a more comprehensive approach to gaining knowledge on cancer issues.

[Same words, different meanings: How epidemiological terminology struggles with population health intervention research]. / À mêmes mots, sens différents--les difficultés de la terminologie épidémiologique avec la recherche en interventions en santé des populations.

Public health research differs from clinical epidemiological research in that its focus is primarily on the population level social and structural determinants of individual health and the interventions that might ameliorate them, rather than having a primary focus on individual-level risks. It is typically concerned with the proximal and distal causes of health problems, and their location within complex systems, more than with single exposures. Thus, epidemiological terms and concepts may have very different implications when used in the context of population health. This paper considers some key differences in relation to terms like 'population', 'baseline', 'control group' 'outcome' and 'adverse effects'. Even the concept of an 'intervention' often needs careful handling. The paper concludes that there is a need for an expanded, and more realistic use of these terms in the population health intervention research context.

Systematic characterization of gastrointestinal clinical trials.

BACKGROUND: Clinical guidelines are commonly based on inadequate evidence, suggesting deficiencies in the present portfolio of clinical research. AIMS: To investigate characteristics of clinical trials examining gastrointestinal (GI) diseases registered in ClinicalTrials.gov. METHODS: A cross-sectional analysis of 13,647 GI trials and 111,535 non-GI trials initiated between January 1997 and September 2013 was performed. Entries were sorted by operational status, purpose, interventions, trial design, and epochs to identify trends and interactions in trial properties. RESULTS: The global production of GI trials has remained static in recent years and a majority of research efforts are focused on a few diseases. While GI trials are generally produced by highly populated US states and countries, they are also seldom larger than 500 patients. The likelihood of using data monitoring committees, randomization, and double blinding in GI trials has increased over time, though a substantial fraction of GI trials still do not employ rigorous trial designs. While levels of GI trials correlate with disease burden, the explained variance of GI trials by disease burden worldwide is poor. CONCLUSION: GI trials are chiefly concentrated in few diseases and highly populated regions, exhibit heterogeneous trends and methodologies, and are sensitive to disease burdens, though more so within North America than worldwide.

Indirect Comparisons and Network Meta-Analyses.

BACKGROUND: Systematic reviews provide a structured summary of the results of trials that have been carried out on any particular subject. If the data from multiple trials are sufficiently homogenous, a meta-analysis can be performed to calculate pooled effect estimates. Traditional meta-analysis involves groups of trials that compare the same two interventions directly (head to head). Lately, however, indirect comparisons and network metaanalyses have become increasingly common. METHODS: Various methods of indirect comparison and network meta-analysis are presented and discussed on the basis of a selective review of the literature. The main assumptions and requirements of these methods are described, and a checklist is provided as an aid to the evaluation of published indirect comparisons and network meta-analyses. RESULTS: When no head-to-head trials of two interventions are available, indirect comparisons and network metaanalyses enable the estimation of effects as well as the simultaneous analysis of networks involving more than two interventions. Network meta-analyses and indirect comparisons can only be useful if the trial or patient characteristics are similar and the observed effects are sufficiently homogeneous. Moreover, there should be no major discrepancy between the direct and indirect evidence. If trials are available that compare each of two treatments against a third one, but not against each other, then the third intervention can be used as a common comparator to enable a comparison of the other two. CONCLUSION: Indirect comparisons and network metaanalyses are an important further development of traditional meta-analysis. Clear and detailed documentation is needed so that findings obtained by these new methods can be reliably judged.

Clinical Outcome Assessments: Conceptual Foundation-Report of the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force.

An outcome assessment, the patient assessment used in an endpoint, is the measuring instrument that provides a rating or score (categorical or continuous) that is intended to represent some aspect of the patient's health status. Outcome assessments are used to define efficacy endpoints when developing a therapy for a disease or condition. Most efficacy endpoints are based on specified clinical assessments of patients. When clinical assessments are used as clinical trial outcomes, they are called clinical outcome assessments (COAs). COAs include any assessment that may be influenced by human choices, judgment, or motivation. COAs must be well-defined and possess adequate measurement properties to demonstrate (directly or indirectly) the benefits of a treatment. In contrast, a biomarker assessment is one that is subject to little, if any, patient motivational or rater judgmental influence. This is the first of two reports by the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force. This report provides foundational definitions important for an understanding of COA measurement principles. The foundation provided in this report includes what it means to demonstrate a beneficial effect, how assessments of patients relate to the objective of showing a treatment's benefit, and how these assessments are used in clinical trial endpoints. In addition, this report describes intrinsic attributes of patient assessments and clinical trial factors that can affect the properties of the measurements. These factors should be considered when developing or refining assessments. These considerations will aid investigators designing trials in their choice of using an existing assessment or developing a new outcome assessment. Although the focus of this report is on the development of a new COA to define endpoints in a clinical trial, these principles may be applied more generally. A critical element in appraising or developing a COA is to describe the treatment's intended benefit as an effect on a clearly identified aspect of how a patient feels or functions. This aspect must have importance to the patient and be part of the patient's typical life. This meaningful health aspect can be measured directly or measured indirectly when it is impractical to evaluate it directly or when it is difficult to measure. For indirect measurement, a concept of interest (COI) can be identified. The COI must be related to how a patient feels or functions. Procedures are then developed to measure the COI. The relationship of these measurements with how a patient feels or functions in the intended setting and manner of use of the COA (the context of use) could then be defined. A COA has identifiable attributes or characteristics that affect the measurement properties of the COA when used in endpoints. One of these features is whether judgment can influence the measurement, and if so, whose judgment. This attribute defines four categories of COAs: patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes. A full description as well as explanation of other important COA features is included in this report. The information in this report should aid in the development, refinement, and standardization of COAs, and, ultimately, improve their measurement properties.

Differences between the real and the desired worlds in the results of clinical trials.

OBJECTIVE: We refer to the effectiveness (known as pragmatic or real world) and efficacy (known as explanatory or desired or ideal world) of interventions. However, these terms seem to be randomly chosen by investigators who design clinical trials and do not always reflect the true purpose of the study. A pragmatic-explanatory continuum indicator summary tool was thus developed with the aim of identifying the characteristics of clinical trials that distinguish between effectiveness and efficacy issues. We verified whether clinical trials used the criteria proposed by the indicator summary tool, and we categorized these clinical trials according to a new classification. METHOD: A systematic survey of randomized clinical trials was performed. We added a score ranging from 0 (more efficacious) to 10 (more effective) to each domain of the indicator summary tool and proposed the following classifications: high efficacy (<25), moderate efficacy (25-50), moderate effectiveness (51-75), and high effectiveness (<75). RESULTS: A total of 844 randomized trials were analyzed. No analyzed trials used the criteria proposed by the indicator summary tool. Approximately 44% of the trials were classified as having moderate effectiveness, and 43.82% were classified as having moderate efficacy. CONCLUSIONS: Most clinical trials used the term "efficacy" to illustrate the application of results in clinical practice, but the majority of those were classified as having moderate effectiveness according to our proposed score. The classification based on the 0-100 score is still highly subjective and can be easily misunderstood in all domains based on each investigator's own experiences and knowledge.