The Science of Biosimilars-Updating Interchangeability.

This Viewpoint from the US Food and Drug Administration (FDA) summarizes a recent update to an FDA draft interchangeability guidance regarding the need for clinical switching studies to illustrate the FDA's ongoing efforts to streamline the development of biosimilar medications that are in line with the latest science.

Under-representation of black patients with multiple myeloma in studies supporting International Myeloma Working Group guidelines.

INTRODUCTION: Multiple myeloma (MM) is more common in Black persons when compared to non-Hispanic White persons. The International Myeloma Working Group (IMWG) provides consensus for diagnosis and treatment of MM. Our study aimed to assess the racial composition of supporting studies used by IMWG to publish their guidelines METHODS: We performed a cross sectional study that included all IMWG publications up to July 2022. References cited in each publication were reviewed. Review articles, comments, editorials, case reports, and animal-based studies were excluded. RESULTS: A total of 59 IMWG publications with 3956 references were reviewed. Final analysis included 2047 references of which 39 % (n = 804) were clinical trials, 35 % (n = 712) were observational studies, 20 % (n = 401) were diagnostic and or genetic testing-based studies, 3 % (n = 65) were population-based analysis and 3 % (n = 65) classified as others. Only 10.4 % of included references (n = 213/2047) reported race/ethnicity of studied patients. The total number of patients in all referenced studies were 5,747,920, only 2.6 % (n = 150,790) black patients. Of the trials referenced and done exclusively in the US, 41 out of 282 (14.5 %) reported race/ethnicity with a total number of patients of 38,050 of which 2493 (6.5 %) were black patients. CONCLUSION: IMWG guidelines were based mainly on studies that did not include enough Black patients. Guidelines should consider inclusion of observational, diagnostic and population-based studies with more black patients to allow for better reflection of disease prevalence, clinical characteristics and/or outcomes.

Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019.

Importance: After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. Objective: To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. Design, Setting, and Participants: This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Main Outcomes and Measures: Number and design of pivotal trials supporting both supplemental and original indication approvals. Results: From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. Conclusions and Relevance: These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

Guidelines for clinical evaluation of anti-cancer drugs.

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English.

Valve Academic Research Consortium 3: Updated Endpoint Definitions for Aortic Valve Clinical Research.

AIMS: The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research. METHODS AND RESULTS: Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs. CONCLUSIONS: Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

GRADE Guidelines: 29. Rating the certainty in time-to-event outcomes-Study limitations due to censoring of participants with missing data in intervention studies.

OBJECTIVES: To provide Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidance for the consideration of study limitations (risk of bias) due to missing participant outcome data for time-to-event outcomes in intervention studies. STUDY DESIGN AND SETTING: We developed this guidance through an iterative process that included membership consultation, feedback, presentation, and iterative discussion at meetings of the GRADE working group. RESULTS: The GRADE working group has published guidance on how to account for missing participant outcome data in binary and continuous outcomes. When analyzing time-to-event outcomes (e.g., overall survival and time-to-treatment failure) data of participants for whom the outcome of interest (e.g., death and relapse) has not been observed are dealt with through censoring. To do so, standard methods require that censored individuals are representative for those remaining in the study. Two types of censoring can be distinguished, end of study censoring and censoring because of missing data, commonly named loss to follow-up censoring. However, both types are not distinguishable with the usual information on censoring available to review authors. Dealing with individuals for whom data are missing during follow-up in the same way as individuals for whom full follow-up is available at the end of the study increases the risk of bias. Considerable differences in the treatment arms in the distribution of censoring over time (early versus late censoring), the overall degree of missing follow-up data, and the reasons why individuals were lost to follow-up may reduce the certainty in the study results. With often only very limited data available, review and guideline authors are required to make transparent and well-considered judgments when judging risk of bias of individual studies and then come to an overall grading decision for the entire body of evidence. CONCLUSION: Concern for risk of bias resulting from censoring of participants for whom follow-up data are missing in the underlying studies of a body of evidence can be expressed in the study limitations (risk of bias) domain of the GRADE approach.

Reporting of prior clinical studies in Investigator's Brochures did not adhere to the basic principles of evidence synthesis: a cross-sectional study.

OBJECTIVES: International regulations require Investigator's Brochures (IBs) to compile all available evidence that inform the risk-benefit assessment for the newly planned clinical trial. This study examined the adherence of IBs to the basic principles of evidence synthesis when compiling prior clinical studies. STUDY DESIGN AND SETTING: For 97 IBs for phase I/II trials reviewed at one German research ethics committee we assessed the reporting on search, appraisal, and synthesis procedures for prior clinical studies. For a random subsample of 30 IBs, we evaluated the quality of reporting of the compiled 247 prior clinical studies. RESULTS: Only 2% of all 97 IBs reported a comprehensive search strategy, provided a critical appraisal of the compiled prior clinical studies or presented respective study results in a structured manner. For the 247 prior clinical studies compiled in 30 IBs, the information required to appraise their risk of bias (eg, sample size calculation or baseline characteristics) was rarely reported. CONCLUSION: When compiling all available evidence supporting the rationale for the proposed clinical study IBs do not acknowledge the broadly established principles for reviewing and reporting evidence. This may impact negatively on the trustworthiness and efficiency of risk-benefit assessment.

Five Features to Look for in Early-Phase Clinical Intervention Studies.

Neurorehabilitation relies on core principles of neuroplasticity to activate and engage latent neural connections, promote detour circuits, and reverse impairments. Clinical interventions incorporating these principles have been shown to promote recovery and demote compensation. However, many clinicians struggle to find interventions centered on these principles in our nascent, rapidly growing body of literature. Not to mention the immense pressure from regulatory bodies and organizational balance sheets that further discourage time-intensive recovery-promoting interventions, incentivizing clinicians to prioritize practical constraints over sound clinical decision making. Modern neurorehabilitation practices that result from these pressures favor strategies that encourage compensation over those that promote recovery. To narrow the gap between the busy clinician and the cutting-edge motor recovery literature, we distilled 5 features found in early-phase clinical intervention studies-ones that value the more enduring biological recovery processes over the more immediate compensatory remedies. Filtering emerging literature through this lens and routinely integrating promising research into daily practice can break down practical barriers for effective clinical translation and ultimately promote durable long-term outcomes. This perspective is meant to serve a new generation of mechanistically minded and caring clinicians, students, activists, and research trainees, who are poised to not only advance rehabilitation science, but also erect evidence-based policy changes to accelerate recovery-based stroke care.

Physical therapy modalities in neurological disorders at developmental age - Assessment of the methodological value of research papers.

BACKGROUND: Physical therapy modalities are often applied in treatment of neurological conditions in children and adolescents. OBJECTIVE: Evaluation of the methodological quality of research focusing on the application of physical therapy modalities in children and adolescents with neurological conditions. METHODS: Papers published between 2007 and 2018 were included in the review. 149 papers were analyzed and finally 26 studies investigating the use of physical therapy modalities in children and adolescents with neurological conditions were included in the review. Jadad scale (0-5) was used to assess the methodological value of the studies. RESULTS: The mean Jadad score was 1.46 (researcher 1) and 1.38 (researcher 2). A score of 0 was awarded to nine (r1) and eight papers (r2). A score of 5 points was awarded to three (r1) and two papers (r2). CONCLUSION: 1. The evidence showing the effectiveness of the use of physical therapy modalities is mainly of low quality. 2. The Jadad scale is a valuable tool to assess the quality of research, although it does not always reflect the real value in the case children participate in studies. 3. The analyzed studies show that physical therapy modalities are effective in the treatment of children and adolescents with neurological disorders.

Outcome parameters in speech audiometry: retrospective analysis of data and reporting quality in clinical studies.

OBJECTIVES: The use of standardized outcome parameters is essential for the comparability of clinical studies. Pure-tone audiometry and speech audiometry are widely used, but there is no systematic evaluation of the outcome parameters in clinical application. Nevertheless, there is presumably a great heterogeneity especially in the field of speech audiometry. This study presents a snapshot of the current situation of documentation and usage of outcome parameters in otologic research. STUDY DESIGN: Retrospective study of existing literature analyzing common speech audiometric test material and procedure MAIN OUTCOME MEASURES: Intervention Studies from 2012 to 2016 concerning hearing ability were eligible for evaluation. Studies were analyzed with regard to study design, pathology and intervention, speech audiometric parameters, pure-tone audiometry, implementation of reporting standards and journal related data. RESULTS: 279 studies were included. Over 50% of the analyzed studies lacked proper documentation. In the remaining studies, there was a broad variance concerning the documented speech audiometric parameters, most often with a fixed presentation level of 65 dB SPL. CONCLUSION: The lack of generally used standards for reporting hearing outcomes makes it difficult to compare results of different clinical studies. An adequate description of the methods would be a first and important step in improving reports on audiological outcomes.

Balkan Clinical Research Registry: Established by Academy of Medical Sciences of Bosnia and Herzegovina.

BACKGROUND: From 2013 the World Medical Association's Declaration of Helsinki explicitly requires pre-registration of a study involving human subjects. The registration gives a chance for improvement of design and avoidance of bias. OBJECTIVE: The aim of this article was to describe process of bearing decision to create regional registry of clinical studies for Balkan countries. METHODS: After finding relevant studies about research registries and designing the concept and structure of future regional registry an article was published in IJBH journal. The article was than used as basis for discussion at 2020 meeting of Academy of Medical Sciences of Bosnia and Herzegovina (AMSBH), and final decision was made by the Academy to create the research registry. RESULTS: Regional registry of clinical studies will be under the auspices of AMSBH and web-based, with the option of online registration of new studies. The data required to be entered in the moment of registration relate to key elements of research plan: topic, variables, sample, type of the study and the study population. After applying for registration of a clinical study, the authors will soon receive the review made by the AMSBH expert committee. The application could be accepted, rejected or returned for major or minor revision. After an application is accepted, it will be deposited in the searchable database and given the registration number. CONCLUSION: The AMSBH's decision to create the regional registry of clinical studies will satisfy needs of researchers from Balkan countries in the first place, who share cultural and lingual similarities. It will also help with increasing standards of clinical research in the region.

Quantifying Sex Bias in Clinical Studies at Scale With Automated Data Extraction.

Importance: Analyses of female representation in clinical studies have been limited in scope and scale. Objective: To perform a large-scale analysis of global enrollment sex bias in clinical studies. Design, Setting, and Participants: In this cross-sectional study, clinical studies from published articles from PubMed from 1966 to 2018 and records from Aggregate Analysis of ClinicalTrials.gov from 1999 to 2018 were identified. Global disease prevalence was determined for male and female patients in 11 disease categories from the Global Burden of Disease database: cardiovascular, diabetes, digestive, hepatitis (types A, B, C, and E), HIV/AIDS, kidney (chronic), mental, musculoskeletal, neoplasms, neurological, and respiratory (chronic). Machine reading algorithms were developed that extracted sex data from tables in articles and records on December 31, 2018, at an artificial intelligence research institute. Male and female participants in 43 135 articles (792 004 915 participants) and 13 165 records (12 977 103 participants) were included. Main Outcomes and Measures: Sex bias was defined as the difference between the fraction of female participants in study participants minus prevalence fraction of female participants for each disease category. A total of 1000 bootstrap estimates of sex bias were computed by resampling individual studies with replacement. Sex bias was reported as mean and 95% bootstrap confidence intervals from articles and records in each disease category over time (before or during 1993 to 2018), with studies or participants as the measurement unit. Results: There were 792 004 915 participants, including 390 470 834 female participants (49%), in articles and 12 977 103 participants, including 6 351 619 female participants (49%), in records. With studies as measurement unit, substantial female underrepresentation (sex bias ≤ -0.05) was observed in 7 of 11 disease categories, especially HIV/AIDS (mean for articles, -0.17 [95% CI, -0.18 to -0.16]), chronic kidney diseases (mean, -0.17 [95% CI, -0.17 to -0.16]), and cardiovascular diseases (mean, -0.14 [95% CI, -0.14 to -0.13]). Sex bias in articles for all categories combined was unchanged over time with studies as measurement unit (range, -0.15 [95% CI, -0.16 to -0.13] to -0.10 [95% CI, -0.14 to -0.06]), but improved from before or during 1993 (mean, -0.11 [95% CI, -0.16 to -0.05]) to 2014 to 2018 (mean, -0.05 [95% CI, -0.09 to -0.02]) with participants as the measurement unit. Larger study size was associated with greater female representation. Conclusions and Relevance: Automated extraction of the number of participants in clinical reports provides an effective alternative to manual analysis of demographic bias. Despite legal and policy initiatives to increase female representation, sex bias against female participants in clinical studies persists. Studies with more participants have greater female representation. Differences between sex bias estimates with studies vs participants as measurement unit, and between articles vs records, suggest that sex bias with both measures and data sources should be reported.

The Qualification of an Enrichment Biomarker for Clinical Trials Targeting Early Stages of Parkinson's Disease.

As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson's Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.

Antibody-Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index.

Since the first approval of gemtuzumab ozogamicin (Mylotarg; Pfizer; CD33 targeted), two additional antibody-drug conjugates (ADC), brentuximab vedotin (Adcetris; Seattle Genetics, Inc.; CD30 targeted) and inotuzumab ozogamicin (Besponsa; Pfizer; CD22 targeted), have been approved for hematologic cancers and 1 ADC, trastuzumab emtansine (Kadcyla; Genentech; HER2 targeted), has been approved to treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, the toxicity profiles are comparable with those of standard-of-care chemotherapeutics, with dose-limiting toxicities associated with the mechanism of activity of the cytotoxic warhead. However, the enthusiasm to develop ADCs has not been dampened; approximately 80 ADCs are in clinical development in nearly 600 clinical trials, and 2 to 3 novel ADCs are likely to be approved within the next few years. While the promise of a more targeted chemotherapy with less toxicity has not yet been realized with ADCs, improvements in technology combined with a wealth of clinical data are helping to shape the future development of ADCs. In this review, we discuss the clinical and translational strategies associated with improving the therapeutic index for ADCs.

[How to perform a real world clinical study of surgery].

With the development of the methodology of clinical trials and the appearance of medical big data, the real-world study (RWS) presents its unique advantages, plays a role in clinical practice and research, and its importance is more and more recognized by scholars in recent years. In surgical research field, due to the specificity of surgical diseases and operational procedures, confounding factors and risk of bias are greatly higher than those of traditional medications. Therefore, using unique advantages of the RWS to solve the actual clinical problem in surgical field is the main goal of performing surgical RWS. This article will systematically elucidate how to perform the surgical RWS and the special matters of concern in carrying out surgical RWS.

Bridging the gap between the laboratory and the clinic for patients with sarcopenia.

Sarcopenia-the age-related loss of skeletal muscle mass and strength-is a major public health issue. Sarcopenia is associated with an increased risk of falls, disability, dependency, institutionalization, hospital stay and early death. Finding interventions to stabilize, reverse or prevent sarcopenia is therefore a key goal for clinical ageing research. If patients are to eventually benefit from discovery science on ageing skeletal muscle, we need to build a translational pipeline that facilitates progress from laboratory science and epidemiology, through feasibility testing to early-phase, and eventually late-phase clinical trials. A number of barriers need to be overcome to make this pipeline work-in particular challenges around identifying people with sarcopenia in routine clinical practice, ensuring that we study patients with clearly defined sarcopenia rather than related conditions such as functional impairment, developing capacity to run trials for older people, and selecting trial outcomes of relevance to older people with multimorbidity. A further key point is that interventions should ideally have pleiotropic actions-i.e. beneficial actions across multiple organ systems, rather than treating sarcopenia alone. Such pleiotropic interventions may be the only way to avoid the perils of polypharmacy and drug interactions that bedevil care for many older people. Maximising the potential for scientific discoveries in the biology of ageing muscle to improve health requires that discovery scientists, translational clinical scientists and clinicians come together to exchange findings and shape each others ideas within a shared culture.