Clinical Trial Safety Data Research Articles

Estimand Framework and Statistical Considerations for Integrated Analysis of Clinical Trial Safety Data.

Safety analyses play a pivotal role in drug development, ensuring the protection of patients while advancing innovative pharmaceuticals to market. A single study generally does not have sufficient sample size to evaluate all important safety events with reasonable precision and may not cover the full target population for the investigational treatment. Integrated analyses (pooled or meta-analysis) over several studies may be helpful in that regard. But without a structured conscious workflow accompanied with appropriate statistical methods for the integrated analysis, this can easily take a route compromising the interpretation. In this article we apply the ICH estimand framework to clinical trial integration and summarize respective critical statistical assumptions to ensure the integrated analyses are interpretable. The estimand framework is valuable for developing principles for a deeper understanding of the critical statistical aspects of planning an integrated safety analysis. Our principles address the clinical question of interest, estimand and estimation. Special focus was given to the criteria for inclusion and exclusion of the component studies in the integrated analysis, and to integration of estimates pertaining to signal detection. Performing an integrated analysis and its preparatory steps calls for a good understanding of the clinical question of interest and its estimand, care and sound practice, to enable interpretation and avoid introducing unnecessary bias. It is valuable to use the estimand framework not only for efficacy evaluations, but also for safety evaluations in clinical trials and for integrated safety analyses.

Anti-IL23/12 agents and JAK inhibitors for inflammatory bowel disease.

IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

Impact of eligibility criteria discordance on clinical trial accrual in diffuse large B-cell lymphoma (DLBCL).

e13707 Background: Excessively stringent clinical trial eligibility criteria may hinder trial accrual, differentially exclude racial-ethnic minority groups, and limit generalizability. This study reviewed the association between trial accrual and concordance of eligibility criteria with known drug safety data in DLBCL clinical trials. Methods: Eligibility criteria and accrual of completed phase II/III clinical trials for DLBCL that opened in the US between 2010-2020 were abstracted from ClinicalTrials.gov. Trials missing posted results or studying cellular therapy / transplant were excluded. Concordance with known safety data was assessed by comparing study eligibility criteria for QTc, renal, hepatic, and cardiac function to FDA labels and phase I safety signals of study drugs. Excessively strict discordant criteria (ExSDC) were defined as eligibility criteria without supporting safety signals. Logistic regression +/- dispersion was used for analysis. Results: 58 trials met criteria for inclusion, accruing 6,232 participants. 88% of studies involved a non-FDA-approved agent, 74% were multicenter, 55% were industry sponsored, 66% only accrued in the US, and 86% were phase II. Eligibility criteria were highly variable (Table). Discordance of renal, hepatic, cardiac function, and QTc criteria from known safety data occurred in 31%, 26%, 41%, and 29% of studies, respectively. Race and ethnicity data were not reported in 22% and 45% of studies, respectively. Trials after 2015 were more likely to report race (p=0.04) and ethnicity (p=0.01). In a multivariable model adjusted for international study sites, greater number of ExSDC was associated with a lower proportion of black patients in the trial (OR 0.45, CI 0.29-0.71, p=0.001). ExSDC in cardiac function were most associated with reduced accrual of this minority group (OR 0.17, CI 0.05-0.58, p=0.007). 11 studies (19%) had early termination for lack of accrual (ETLA). In multivariable analysis, greater number of ExSDC was independently associated with ETLA (OR 3.53, CI 1.45-8.64, p=0.006), while multicenter status protected against ETLA (OR 0.05, CI 0.01-0.31, p=0.002). Industry sponsor and concordance of cardiac criteria protected against ETLA in univariable analysis only. Other eligibility criteria were not associated. Conclusions: Eligibility criteria in DLBCL trials varied widely and were often discordant with known safety data. Higher number of ExSDC was associated with lower accrual of black patients and higher risk of ETLA. Optimizing concordance of eligibility criteria with safety data may improve trial accrual and diversity. [Table: see text]

Tree-temporal scan statistics for safety signal detection in vaccine clinical trials.

The evaluation of safety is critical in all clinical trials. However, the quantitative analysis of safety data in clinical trials poses statistical difficulties because of multiple potentially overlapping endpoints. Tree-temporal scan statistic approaches address this issue and have been widely employed in other data sources, but not to date in clinical trials. We evaluated the performance of three complementary scan statistical methods for routine quantitative safety signal detection: the self-controlled tree-temporal scan (SCTTS), a tree-temporal scan based on group comparison (BGTTS), and a log-rank based tree-temporal scan (LgRTTS). Each method was evaluated using data from two phase III clinical trials, and simulated data (simulation study). In the case study, the reference set was adverse events (AEs) in the Reference Safety Information of the evaluated vaccine. The SCTTS method had higher sensitivity than other methods, and after dose 1 detected 80 true positives (TP) with a positive predictive value (PPV) of 60%. The LgRTTS detected 49 TPs with 69% PPV. The BGTTS had 90% of PPV with 38 TPs. In the simulation study, with simulated reference sets of AEs, the SCTTS method had good sensitivity to detect transient effects. The LgRTTS method showed the best performance for the detection of persistent effects, with high sensitivity and expected probability of type I error. These three methods provide complementary approaches to safety signal detection in clinical trials or across clinical development programmes. All three methods formally adjust for multiple testing of large numbers of overlapping endpoints without being excessively conservative.

Apremilast for the Treatment of Psoriasis in Special Areas in Pediatric Patients in the SPROUT Study

Introduction & Objective: Psoriasis in special areas is difficult to treat and causes significant disease burden. Approved systemic therapies for moderate to severe plaque psoriasis in pediatric patients are limited and require subcutaneous injection. Apremilast, a unique oral immunomodulator that inhibits phosphodiesterase-4, is approved in multiple countries for use in adults with psoriasis, regardless of severity. In this study, the efficacy of apremilast for psoriasis in special areas in pediatric patients was assessed over 16 weeks. Materials & Methods: SPROUT (NCT03701763) is a phase 3, randomized, double-blind, placebo-controlled study in patients 6-17 years with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index ≥12, body surface area ≥10%, and static Physician Global Assessment [sPGA] ≥3) inadequately controlled by/inappropriate for topical therapy. Patients were stratified by age and randomized 2:1 to receive apremilast (weight-based 20 mg or 30 mg twice-a-day) or placebo for 16 weeks, then apremilast through week 52. Scalp Physician Global Assessment (ScPGA) response, modified sPGA of genitalia (sPGA-G) response, Whole Body Itch-Numeric Rating Scale (WBI-NRS) response, and change from baseline in Children’s Dermatology Life Quality Index (CDLQI) were assessed through week 16. Results: Of 245 randomized patients (apremilast: 163; placebo: 82), 101 (41.2%) were 6-11 years and 144 (58.8%) were 12-17 years; 120 (49.0%) patients weighed ≥20 to <50 kg and 125 (51.0%) weighed ≥50 kg. At baseline, 81.0% of the patients treated with apremilast and 84.1% of patients treated with placebo had moderate to severe scalp psoriasis (ScPGA ≥3). Significantly more patients achieved ScPGA response at week 16 with apremilast vs placebo (36.4% vs 18.8%; P=0.0091). At baseline, 110 patients (44.9%; 45.4% apremilast and 43.9% placebo) had moderate to severe genital psoriasis (sPGA-G ≥3). Achievement of sPGA-G response at week 16 was numerically greater with apremilast vs placebo (39.2% vs 25.0%), although not significant, possibly due to small sample size (apremilast: n=74; placebo: n=36). Significantly more patients achieved WBI-NRS response at week 16 with apremilast vs placebo (52.0% vs 32.1%; P=0.0110). Greater improvements in CDLQI were seen at week 16 with apremilast vs placebo (least-squares mean change from baseline −5.1 vs −3.2; P=0.0009). Adverse events were consistent with the known apremilast safety profile. In 21 patients vaccinated during the study (including for COVID-19, influenza, diphtheria, pertussis, tetanus, meningococcus, and hepatitis B), no new safety issues occurred. Conclusions: Apremilast significantly improved scalp psoriasis, itch, and quality of life in pediatric patients with moderate to severe psoriasis. At week 16, patients with moderate to severe genital psoriasis showed a trend toward improvement, although not significant due partially to the sample size.

Topical Clindamycin For Acne Vulgaris: Pharmacovigilance Safety Review and Retrospective Analysis of Gastrointestinal Events

Background: Clindamycin, a lincosamide antibiotic, was the 125th most prescribed medicine in the US in 2020. Topical formulations that combine clindamycin with benzoyl peroxide or a retinoid are commonly used for acne vulgaris (AV) treatment. While oral and topical clindamycin carry warnings/contraindications regarding the development of gastrointestinal (GI) adverse events (AEs), the real-world incidence of these AEs with topical clindamycin is unknown. The objective is to provide an overview of safety data for topical clindamycin when used for AV treatment.
 Methods: Safety data from published literature on PubMed® (case reports, clinical trials data, retrospective data), previously unpublished worldwide pharmacovigilance data (from January 1, 1900-December 31, 2022), and two unpublished retrospective cohort studies of US electronic medical records (EMR; January 1, 2011 to January 31, 2019) were reviewed, with a focus on inflammatory bowel disease (IBD) and GI AEs following topical clindamycin monotherapy or combination treatment
 Results: There have been only 4 published case reports of topical clindamycin-associated GI AEs, which were all published between the years 1981-1997. In 8 published pivotal phase 3 clinical trials of topical clindamycin monotherapy or combination treatment for AV, GI-related AEs were reported in 1.4% of clindamycin-treated participants (38/2,672; safety populations). According to the pharmacovigilance data, the rate of GI-related adverse drug reactions with topical clindamycin-containing products was 0.000045% (64/141,084,533). In 1 published retrospective report, there were 0 reports of colitis from the 1,124 patients estimated to have received topical clindamycin prescriptions in the years 1977-1980. In the first retrospective EMR study, results indicate that physicians prescribe topical clindamycin for AV treatment equally to patients with a history of IBD (19.0%; 98/515) or without (20.7%; 14,495/70,151). The second retrospective EMR study showed that among patients with AV and an initial prescription for topical clindamycin (monotherapy or combination; n=18,012), there were 3 (0.02%) incident cases of pseudomembranous colitis within 30 days; none of these cases had a history of IBD.
 Conclusions: A review of published case reports, clinical trials safety data, worldwide pharmacovigilance data, and retrospective US prescription data demonstrate that GI events—including colitis or pseudomembranous colitis—in patients exposed to topical clindamycin is extremely low, regardless of IBD history.
 Support: Ortho Dermatologics

Aloe Vera: A Potential Herb for Periodontitis Management

Background:: The Aloe Vera plant has been used in India for several decades for the treatment of periodontal disease. The plant has been considered to have antimicrobial and antiinflammatory properties, but it is still used for the treatment of periodontitis inflammation. Objective:: The study's goal was to assess the function of Aloe vera in the treatment of periodontitis. The article summarized numerous clinical research studies, clinical trials reports, patent reports, and safety data in addition to the mechanism of action to provide an overview of Aloe Vera’s usefulness in the treatment of periodontitis. Methods:: The information for their review articles was acquired by using Google Scholar and PubMed as search engines, as well as a number of publishers, including Springer Nature, Bentham Science, Taylor & Francis, and Elsevier. ClinicalTrials.gov.in was referred to study the clinical trials data, and Google Patents was used as a search engine for collecting patent reports. Results:: Aloe Vera is useful for Periodontitis prevention and treatment due to its antiinflammatory, antibacterial, and antioxidant features. Aloe Vera can be used as an alternative to treat periodontitis and its related physiological effects such as gingivitis and mucositis, and various pre-clinical and clinical studies have been summarized that have demonstrated that using Aloe Vera significantly improved the mentioned parameters. Conclusion:: Aloe Vera is an herb that may be used to treat periodontitis and its associated negative effects. However, more preclinical and clinical research, might contribute to raising awareness and managing periodontitis.

Prospective assessment of inter-rater reliability of a neonatal adverse event severity scale.

Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005-1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS.

Inflammatory Bowel Disease: Emerging Therapies and Future Treatment Strategies.

Inflammatory bowel disease (IBD) is a term used to represent a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are the two major clinical forms. The global incidence and prevalence of IBD have increased over the last 2-4 decades. Despite the specific etiopathogenesis of IBD still being unknown, it is widely recognized that immunological, genetic, and environmental factors are implicated. A greater understanding of the multiple signaling pathways involved has led to the development of biologic therapies in the last two decades. Although these treatments have dramatically transformed the course of IBD, there is not a definitive cure and available therapies may cause adverse events (AEs), limiting their use, or have an inadequate effect in some patients. In this context, emerging therapies addressing new specific pathogenetic mechanisms have shown promising efficacy and safety data in early clinical trials. The purpose of this review is to highlight the available clinical trial data for these new drugs, such as more preferential JAK inhibitors, anti-IL-23 antibodies, sphingosine-1-phosphate receptor modulators, anti-integrin therapies, and other small molecules that are currently under research. We will emphasize the potential significance of these agents in shaping future treatment options.

Therapeutic anti-amyloid β antibodies cause neuronal disturbances.

Recent published clinical trial safety data showed that 41% of Alzheimer patients experienced amyloid-related imaging abnormalities (ARIA), marks of microhemorrhages and edema in the brain, following administration of Biogen's Aduhelm/aducanumab (amino acids 3-7 of the Aβ peptide). Similarly, Janssen/Pfizer's Bapineuzumab (amino acids 1-5 of the Aβ peptide) and Roche's Gantenerumab (amino acids 2-11/18-27 of the Aβ peptide) also displayed ARIA in clinical trials, including microhemorrhage and focal areas of inflammation or vasogenic edema, respectively. The molecular mechanisms underlying ARIA caused by therapeutic anti-Aβ antibodies remain largely unknown, however, recent reports demonstrated that therapeutic anti-prion antibodies activate neuronal allergenic proteomes following cross-linking cellular prion protein. Here, we report that treatment of human induced pluripotent stem cells- derived neurons (HSCN) from a non-demented donor, co-cultured with human primary microglia with anti-Aβ1-6, or anti-Aβ17-23 antibodies activate a significant number of allergenic-related proteins as assessed by mass spectrometry. Interestingly, a large proportion of the identified proteins included cytokines such as interleukin (IL)-4, IL-12, and IL-13 suggesting a type-1 hypersensitivity response. Following flow cytometry analysis, several proinflammatory cytokines were significantly elevated following anti-Aβ1-6, or anti-Aβ17-23 antibody treatment. These results justify further and more robust investigation of the molecular mechanisms of ARIA during immunotherapy study trials of AD. Allergenic-related proteins are often linked with Alzheimer's disease (AD). We investigated the effects of amyloid beta (Aβ) immunotherapy on stem cell derived neurons and primary neuronal cells co-cultured with microglia. Anti-Aβ antibody treatment of neurons or neurons co-cultured with microglia led to activation of a substantial number of allergenic-related genes. These allergenic-related genes are associated with endothelial dysfunction possibly responsible for ARIA.

Depicting Risperidone Safety Profiles in Clinical Trials Across Different Diagnoses Using a Dopamine D2-Based Pharmacological Class Effect Query Defined by FAERS.

Current methods are not designed to relate the incidence of individual adverse events reported in clinical trials to the plurality of adverse events accumulated in spontaneous reporting databases during real-world use. We have previously reported on a pharmacological class-effect query of clinical trial data defined by a disproportionality analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) post-marketing data. The aim of the current analysis was to apply a dopamine D2-based pharmacological class-effect query to clinical trial safety data of an atypical antipsychotic tested across different patient populations. Patient-level adverse event data (n = 4400) from controlled clinical trials of the antipsychotic risperidone in schizophrenia, bipolar disorder, Alzheimer's disease psychosis, and autism were obtained through the Yale University Open Data Access (YODA) project. An Empirical Bayes Geometric Mean analysis was performed, and a three-fold threshold incidence level was applied to determine if a preferred term met criteria for being an antipsychotic class-related adverse event. In pooled data from seven trials of adult schizophrenia, class-specific adverse events were identified in 49% of patients treated with risperidone; in 49% of risperidone-treated patients in two trials in adolescent schizophrenia; in 65% of risperidone-treated patients in four trials in adult bipolar disorder; in 50% of risperidone-treated patients in two trials in adolescent schizophrenia; in 36% of risperidone-treated patients in one trial in Alzheimer's disease; and in 94% of risperidone-treated patients in one trial in autism. The cumulative curves of class-specific adverse events in risperidone clinical trials of schizophrenia were similar to those first reported for other atypical antipsychotic drugs. However, the class-specific adverse event curves were notably lower for Alzheimer's disease and higher for autism, suggesting that the diagnostic indication may have an important effect on the cumulative class-specific side-effect burden.

Biases in reporting of adverse effects in clinical trials, and potential impact on safety assessments in systematic reviews and therapy guidelines.

Clinical trials are an important source of adverse effects data, including analyses in systematic reviews and recommendations in therapy guidelines. Trial publication bias may have profound effects on safety perceptions. This MiniReview presents and discusses biases in reporting of safety data in clinical trials and the implications for systematic reviews and guidelines. The objectives of this work are to analyse risk of gastrointestinal bleeding in systemic corticosteroid trials and to assess adverse effects reporting in a fluoxetine trial in depression (Treatment for Adolescents With Depression Study [TADS]) and descriptions of adverse effects in adolescent depression therapy guidelines. We performed literature reviews and descriptive analyse of clinical trials with corticosteroids, and publications from the TADS trial. Risk of gastrointestinal bleeding from corticosteroids was analysed by meta-analysis. Gastrointestinal bleeding definitions varied considerably between trials. The incidence was significantly increased in hospitalized, but not in ambulant, patients compared to placebo. We identified several biases concerning TADS safety reporting, including severity thresholds and nonpublication of most adverse effects data beyond the initial 12 weeks. Therapy guidelines on adolescent depression mentioned suicidality risk, but many failed to mention other adverse effects. We identified several pitfalls in adverse effects reporting in clinical trials. These include heterogeneous disease definitions, reporting thresholds, and incomplete reporting. Trial bias may have great impact on risk assessments in systematic reviews and meta-analyses.

Review article: emerging drug therapies in inflammatory bowel disease.

The landscape of inflammatory bowel disease (IBD) treatment is rapidly expanding with the development of new therapeutic options. To review the mechanisms of action and the available clinical trial data on emerging drug therapies for IBD. Pubmed, Medline and Cochrane databases were queried up to July 2021 using keywords "inflammatory bowel disease," "IBD," "Crohn's disease," "ulcerative colitis" and "trial," "phase" and "study." In addition, we manually reviewed the grey literature including clinical trial registries and abstracts from major gastroenterology conferences in 2020 and 2021 to include pertinent information. In ulcerative colitis (UC), phase 2b and/or phase 3 studies met primary endpoints for S1P receptor agonists (estrasimod, ozanimod), anti-IL-23 agent (mirikizumab), anti-lymphocyte trafficking agents (ontamalimab, subcutaneous vedolizumab), JAK inhibitors (upadacitinib, filgotinib) and TLR9 agonist (cobitolimod). In Crohn's disease (CD), anti-IL-23 agents (risankizumab, mirikizumab, guselkumab), JAK inhibitors (upadacitinib, filgotinib) and anti-lymphocyte trafficking agents (ontamalimab, etrolizumab) met primary endpoints in randomised controlled clinical trials. Several new IBD drug therapies have positive efficacy and safety data in early clinical trials, and there are several drugs in the therapeutic pipeline. As more treatments for CD and UC are approved for clinical use, research to assess predictors of response to therapy and head-to-head trials is needed to inform providers on how to best position therapeutic options for patients with IBD.

Retrospective analysis of clinical trial safety data for pembrolizumab reveals the effect of co-occurring infections on immune-related adverse events.

Biologics targeting PD-1, PD-L1, and CTLA-4 immune checkpoint proteins have been used in a variety of tumor types including small and non-small cell lung cancers, melanoma, and renal cell carcinoma. Their anti-tumor activity is achieved through amplifying components of the patient's own immune system to target immune response evading cancer cells. However, this unique mechanism of action causes a range of immune related adverse events, irAEs, that affect multiple physiological systems in the body. These irAEs, depending on severity, often cause suspension or discontinuation of therapy and, in rare cases, may lead to fatal outcomes. In this study we focused on pembrolizumab, a PD-1 inhibitor currently approved for multiple types of cancer. We analyzed over ten thousand adverse event reports from Keynote clinical trials of pembrolizumab for various cancer indications with or without co-occurring infections, and observed a statistically significant 80% increase in the risk of developing an irAE in subjects with infections.

Classical Hodgkin Lymphoma; Real-World Observations from Physicians, Patients, and Caregivers on the Disease and Its Treatment (CONNECT): Physician First-Line Treatment Preferences for Stage III or IV Classical Hodgkin Lymphoma

BackgroundMainstay therapies for patients with stage III or IV classical Hodgkin lymphoma (cHL) include several multiagent chemotherapy regimens. A combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is commonly administered in the first-line (1L) setting; however, ~30% of patients with stage III or IV cHL will be refractory to or relapse following ABVD treatment. Brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD), a novel targeted therapy in combination with a standard chemotherapy regimen, is another option for 1L treatment of stage III or IV cHL. In the 5-year update of the ECHELON-1 trial (Straus, 2021), patients with stage III or IV cHL randomized to 1L A+AVD compared with ABVD continued to demonstrate progression-free survival (PFS) improvement with a 32% reduction in the risk of progression or death (HR=0.681, nominal P=0.002). To understand the decision-making process when selecting a 1L cHL treatment regimen for stage III or IV cHL, we surveyed physicians to gain insights into their preferred regimens and factors that influence their treatment choices as part of CONNECT, the first real-world observational survey in cHL that includes physicians, patients, and caregivers.MethodsPhysicians in the United States who treat patients with cHL were recruited to participate in an Institutional Review Board-approved, online anonymous survey from October 19, 2020-November 16, 2020. Eligible participants were medical oncologists, hematologist/oncologists, or hematologists with ≥2 years medical practice experience who, within the past 12 months, had treated ≥1 adult (aged ≥18 years) with stage III or IV cHL and ≥1 adult in the 1L setting.ResultsOf participating physicians (N=301), 62% were community-based and 80% identified themselves as a hematologist/oncologist, reporting a median of 15 years of experience. Participants saw a median (interquartile range) of 16 (7-40) patients with active, newly diagnosed cHL and 15 (8-40) cHL survivors in the 12 months preceding survey participation. The most important considerations (ranked 1 or 2) for cHL treatments were clinical trial efficacy and safety data (60%) and official guideline recommendations (58%). Specifically, efficacy attributes including overall survival (OS; 91%), long-term PFS (86%), curative potential (85%), and complete response (81%) were rated highest or as having the most essential impact. In contrast, patient personal goals (6%), treatment costs (4%), and patient financial support programs (4%) were endorsed by <10% of participants. When asked about acceptable long-term toxicity trade-offs for increased efficacy in patients with stage III or IV cHL, participants stated that an additional median of 8 months of OS and 6 months of PFS were worth the potential for downstream toxicity. Fifty percent of participants reported that disease stage was the most important patient characteristic to consider when deciding on 1L cHL treatment. In patients with newly diagnosed stage III or IV cHL, 37% to 50% of participants selected A+AVD as their first-choice regimen across various populations (Figure); no significant differences in preferences were noted between community and academic practice settings. Participants reported selecting intensive treatment regimens based on OS and PFS and less intensive regimens (e.g., AVD) based on age, comorbidities, and patient quality of life.ConclusionsEfficacy attributes, including OS and PFS; quality of life; and patient age were top reasons cited by surveyed participants for selecting a specific 1L treatment regimen in stage III or IV cHL. Treatment preferences for newly diagnosed stage III or IV cHL varied based on patient characteristics including presence of bulky mediastinal disease, disease stage, perceived risk of relapse, age, and comorbidities. [Display omitted] DisclosuresYu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Liu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Kumar: Seagen, Inc: Consultancy. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Flora: Seagen, Inc: Research Funding. Parsons: SeaGen: Consultancy.

Systematic Omission of Pregnant and Lactating Women from Malignant Haematology Trials Perpetuates a Cycle of Exclusion, Data Shortage and Disadvantage

Background: Pregnant or breastfeeding women are routinely excluded from clinical trials due to fear of teratogenicity and toxicity of therapeutic agents, despite a paucity of evidence to support this practice. In response to the diethylstilbesterol (DES) and thalidomide-induced embryopathy in the mid-20 th century, the US Food and Drug Administration (FDA) released new regulations excluding Women of Child-Bearing Potential (WoCBP) from phase I and II trial participation, followed by an introduction of a new pregnancy category labelling system in 1979. The legacy of these measures is a reliance on accidental exposure pregnancy data rather than rigorous clinical trial efficacy and safety data for medication use in pregnancy and lactation.WoCBP when enrolled in clinical trials are often subjected to prescriptive contraceptive requirements to mitigate the risk of accidental pregnancy, without informed consent for the contraceptive side effects. These barriers to trial participation for WoCBP, particularly in the setting of life-threatening haematological diseases, prevent timely access to therapies only accessible via clinical trial participation. Lymphoma and leukaemia in pregnancy occur with an approximate incidence of 1 in 6000 and 1 in 75,000-100,000 pregnancies respectively. We examined the rates and rationale for exclusion of these patients from clinical trials, as well as contraceptive requirements for WoCBP.Methods: We conducted a cross-sectional observational study of clinical trial protocols recruiting patients with potentially life-threatening haematological malignancies. We searched the clinicaltrials.gov clinical trials database for trial protocols enrolling acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), Hodgkin lymphoma (HL) and/or Diffuse Large B Cell lymphoma (DLBCL) between January 2016 and January 2021. Studies were included if they included WoCBP (15-55 years of age). Studies without complete electronic protocol access were excluded. The following data was collected: target disease, study phase, study location, age of patients, whether pregnant or lactating women were excluded (rationale if provided including evidence of teratogenicity), type of contraception and duration mandated and presence or absence of informed consent for contraception.Results: We identified 68 trials for AML, ALL, DLBCL and HL (40%, 26%, 21% and 13% respectively) (Table 1). Most were phase I-II studies (91%) of novel agents (90%) and of note, the majority were of non-chemotherapy agents (83%). The majority (97%) excluded pregnant women and (69%) without providing rationale. Only 2% cited evidence for embryopathy in either human or animal studies. Most studies (84%) explicitly excluded lactating women, of which 85% did not provide justification. Contraception was mandatory in 90% of the protocols, with 47% of these requiring at least two different forms of contraception for the entire study period. These included hormone-based contraception, barrier methods and abstinence. None of the protocols provided informed consent for the potential side effects of the mandated contraceptive methods in the context of the study.Conclusion: The theoretical harm from anti-cancer therapy to the foetus is typically given greater moral precedence than is a pregnant woman's autonomy. Pregnant and lactating women were almost universally excluded from the trials in this study with limited rationale provided. Study protocols frequently mandated contraception without informed consent of its associated risks in the context of the study. This perpetuates the lack of efficacy and safety data in this patient population, and drives a cycle of systematic exclusion, data shortage, and inequity.Pregnant and lactating women with life threatening haematological malignancies with no alternative treatment options should be eligible for clinical trials where this offers potentially life-saving therapy, with appropriate informed consent around the indefinable and potentially harmful effects on their foetus. We propose obligatory rationale for exclusion of pregnant and breastfeeding women in all clinical trials, using safety data from either human or animal studies and contraception informed consent. [Display omitted] DisclosuresHamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Biologics update: IL‐17 inhibitors

AbstractIntroductionPsoriasis is an immune‐mediated, multifactorial, systemic disease that has undergone a translational research revolution in the past two decades. As our understanding of the pathogenesis of psoriasis has improved, the interleukin‐17 (IL‐17) pathway has been elucidated as a key driver of chronic inflammation in psoriasis, which contributes to disease onset and progression. Biologic therapies targeting IL‐17 and its receptor have been developed to attenuate the IL‐17 pathway in patients with moderate‐to‐severe plaque psoriasis. This review includes a discussion on the IL‐17 pathway and biologics targeting IL‐17 in clinical trials and practice for the treatment of psoriasis.ObjectivesThe primary objective of this manuscript is to present safety and efficacy data from clinical trials released in 2018–2021 on IL‐17 therapies for the treatment of psoriasis. An update on the IL‐17 pathway will also be presented to inform the therapeutic development of IL‐17 biologics.MethodsReview of randomized controlled trials on the efficacy and safety of current and upcoming IL‐17 biologics via an electronic literature search on PubMed, The Cochrane Library, and ClinicalTrials.gov.ResultsA total of five IL‐17 biologics were included: secukinumab, ixekizumab, broadalumab, ustekinumab, and sonelokimab. The latest clinical trial safety and efficacy data are presented.ConclusionThe introduction of biologic IL‐17 therapies into clinical practice has ushered in a new era of treatment for psoriasis. With a greater understanding of the IL‐17 pathway and new IL‐17 biologics in clinical trials, physicians, and patients will have a greater number of options for more aggressive, targeted management of psoriasis.

Psoriasis medications: The future

AbstractIntroduction: Psoriasis is a chronic inflammatory skin disease characterized by dysregulation of keratinocytes and presenting as sharply demarcated, scaly, erythematous plaques and varying levels of systemic involvement.1‐3 The pathogenesis of the disease is multifactorial and includes immunologic, genetic, and environmental factors.3 Increased understanding of the involved immune‐mediated inflammatory pathways has led to the development of new targeted therapies.3 This review focuses on the safety and efficacy of novel topical, oral, and injectable therapeutic options for treatment of psoriasis.Objectives: The primary objective of this study is to present safety and efficacy data on current and upcoming topical, oral, and biologic therapies for the treatment of psoriasis.Methods: Review of randomized controlled trials on the efficacy and safety of current and upcoming topical, oral, and biologic therapies via an electronic literature search using PubMed, The Cochrane Library, ClinicalTrials.gov, and data presented at AAD VMX 2021.Results: A total of 15 oral, topical or biologic therapies were included and the latest clinical trial safety and efficacy data was presented for the following therapies: tapinarof, roflumilast, tofacitinib, deucravacitinib, baricitinib, abrocitinib, bimekizumab, sonelokimab, secukinumab, risankizumab, guselkumab, ustekinumab, ixekizumab, tildrakizumab, and brodalumab.Conclusion: There are many new and exciting topical, oral and biologic therapies for the treatment of psoriasis. With many novel biologics undergoing clinical trials, providers will have numerous options when deciding which therapy is best for each patient.

Assessing safety at the end of clinical trials using system organ classes: A case and comparative study.

Recent approaches to the statistical analysis of adverse event (AE) data in clinical trials have proposed the use of groupings of related AEs, such as by system organ class (SOC). These methods have opened up the possibility of scanning large numbers of AEs while controlling for multiple comparisons, making the comparative performance of the different methods in terms of AE detection and error rates of interest to investigators. We apply two Bayesian models and two procedures for controlling the false discovery rate (FDR), which use groupings of AEs, to real clinical trial safety data. We find that while the Bayesian models are appropriate for the full data set, the error controlling methods only give similar results to the Bayesian methods when low incidence AEs are removed. A simulation study is used to compare the relative performances of the methods. We investigate the differences between the methods over full trial data sets, and over data sets with low incidence AEs and SOCs removed. We find that while the removal of low incidence AEs increases the power of the error controlling procedures, the estimated power of the Bayesian methods remains relatively constant over all data sizes. Automatic removal of low-incidence AEs however does have an effect on the error rates of all the methods, and a clinically guided approach to their removal is needed. Overall we found that the Bayesian approaches are particularly useful for scanning the large amounts of AE data gathered.

Bleeding complications in patients with squamous cell carcinoma of the head and neck.

Hemorrhage in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) may be attributed to chemotherapy and local tumor irradiation. Evidence of the relationship between hemorrhage in R/M HNSCC and targeted therapies, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors, or immune checkpoint inhibitors, is limited. We aimed to identify epidemiological and clinical data related to the occurrence of hemorrhage in R/M HNSCC and to explore its relationship with various therapies. We describe information obtained from literature searches as well as data extracted from a commercial database and a database from the author's institution (Istituto Nazionale dei Tumori of Milan). Evidence suggests that most bleeding events in R/M HNSCC are minor. Clinical trial safety data do not identify a causal association between hemorrhage and anti‐EGFR agents or immune checkpoint inhibitors. In contrast, anti‐VEGF agents are associated with increased, and often severe/fatal, hemorrhagic complications.