Poor correlation between preclinical and patient efficacy data for tumor targeted monotherapies in glioblastoma: the results of a systematic review.

PURPOSE: Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue. METHODS: We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006-2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests. RESULTS: A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0-33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models ('multiple models') had a significantly better median response rate than those tested using only one ('single model') or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027). CONCLUSION: Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.

Evaluation of supportive care needs, sexuality and quality of life in phase 1 trials: a prospective monocentric study.

PURPOSE: Patients enrolled in oncology phase 1 trials (ph1) usually have advanced heavily pre-treated cancers with few therapeutic options. Quality of life (QoL) is one of the key cancer-treatment outcome measures, especially in ph1, and sexuality is an important part of Qol but rarely explored. This prospective study aims to assess supportive care needs, QoL and sexuality in ph1. METHODS: Between September 2020 and June 2021, we prospectively recruited patients enrolled in ph1 at Gustave Roussy in France. Supportive care needs, QoL (EORTC QLQ-C30) and sexuality (female sexual function index for women, male sexual health questionnaire [MSHQ] for men) were assessed at baseline, one, three and 5 months. We performed multivariate analyses to identify associations between clinical characteristics, QoL and quality of sexual life over time. RESULTS: At baseline, we analyzed 187 patients (45% women (n = 84) and 55% men (n = 103)). Patients expressed the need for consultations in pain management, nutrition, psychology and sexology in 28%, 26%, 19% and 9%, respectively. Lower global QoL was independently associated with Royal Marsden Hospital score (p = 0.012), urogenital location tumor (p = 0.021), elevated CRP levels (p = 0.014) and pain intensity (p = 0.005). Ninety-two percent of women had sexual dysfunction. In men, a lower MSHQ score was independently associated with urogenital location tumor (p = 0.021), ECOG Performance Status (p = 0.006), comorbidity at risk (p = 0.024) and pain intensity (p = 0.004). CONCLUSIONS: There are significant needs for supportive care in ph1, especially in some subgroups of patients. New models of care should be developed to improve early phase pathways.

Consistency of the CRM when the dose-toxicity curve is not monotone and its application to the POCRM.

The continual reassessment method (CRM) is a well-known design for dose-finding trials with the goal of estimating the maximum tolerated dose (MTD), the dose with a given probability of toxicity. The standard assumption is that the probability of toxicity monotonically increases with dose. We show that the CRM can still be consistent and correctly identify the MTD even when the dose-toxicity curve is not monotone as long as there is monotonicity of the true toxicity probabilities right below and right above the true MTD. In the case of multiple therapies, where it is unclear how to order combinations of dose levels of multiple therapies, our findings provide insight into the performance of the partial order CRM (POCRM). To select the correct dose combination at the end of a trial, the POCRM does not have to select a monotone ordering of drug combinations. We illustrate the connection between our results for the CRM with a nonmonotone dose-toxicity curve and the POCRM via simulations.

Enrolment of older adults with cancer in early phase clinical trials-an observational study on the experience in the north west of England.

INTRODUCTION: older patients represent the majority of cancer patients but are under-represented in trials, particularly early phase clinical trials (EPCTs). MATERIAL AND METHODS: observational retrospective study of patients referred for EPCTs (January-December 2018) at a specialist cancer centre in the UK. The primary aim was to analyse the successful enrolment into EPCTs according to age (<65/65+). The secondary aims were to identify enrolment obstacles and the outcomes of enrolled patients. Patient data were analysed at: referral; in-clinic assessment and after successful enrolment. Among patients assessed in clinic, a sample was defined by randomly matching the older cohort with the younger cohort (1:1) by tumour type. RESULTS: 555 patients were referred for EPCTs with a median age of 60 years, of whom 471 were assessed in new patient clinics (38% were 65+). From those assessed, a randomly tumour-matched sample of 318 patients (159 per age cohort) was selected. Older patients had a significantly higher comorbidity score measured by ACE-27 (P < 0.0001), lived closer to the hospital (P = 0.045) and were referred at a later point in their cancer management (P = 0.002). There was no difference in suitability for EPCTs according to age with overall 84% deemed suitable. For patients successfully enrolled into EPCTs, there was no difference between age cohorts (20.1 vs. 22.6% for younger and older, respectively; P = 0.675) and no significant differences in their safety and efficacy outcomes. DISCUSSION: older age did not affect the enrolment into EPCTs. However, the selected minority referred for EPCTs suggests a pre-selection upstream by primary oncologists.

Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders.

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date.

Tozinameran (BNT162b2) Vaccine: The Journey from Preclinical Research to Clinical Trials and Authorization.

Vaccination development and production was an essential question for the prevention and global control of COVID-19. The strong support from governing authorities such as Operation Warp Speed and robust funding has led to the development and authorization of the tozinameran (BNT162b2) vaccine. The BNT162b2 vaccine is a lipid nanoparticle-encapsulated mRNA that encodes for SARS-CoV-2 spike protein, the main site for neutralizing antibodies. Once it binds with the host cells, the lipid nanoparticles enable the transfer of the RNA, causing S antigens' expression of the SARS-CoV-2, conferring immunity. The vaccine is administered as a 2-dose regime 21 days apart for individuals 16 years and older. Pfizer-BioNTech's BNT162b2 vaccine was the first candidate to receive FDA-Emergency Use Authorization (EUA) on December 11, 2020. During phase 2/3 clinical trials, 95% efficacy was reported among 37,706 participants over the age of 16 who received the BNT162b2 vaccination; additionally, 52% efficacy was noted 12 days following the administration of the first dose of BNT162b2, reflecting early protection of COVID-19. The BNT162b2 vaccine has exhibited 100% efficacy in clinical trials of adolescents between the ages of 12 and 15. Clinical trials in pregnant women and children under the age of 12 are expected to also exhibit promising results. This review article encompasses tozinameran (BNT162b2) vaccine journey, summarizing the BNT162b1 and BNT162b2 vaccines from preclinical studies, clinical trial phases, dosages, immune response, adverse effects, and FDA-EUA.

Landscape of phase 1 clinical trials for minors with cancer in the United States.

OBJECTIVES: Understanding trends in characteristics of early phase trials that allow minors with cancer to participate may inform additional efforts to improve cancer drug development for young people. METHODS: We accessed data for oncology phase 1 or phase 1/2 trials in the United States from ClinicalTrials.gov with lower age bound for eligibility <18 years. Descriptive statistics were calculated and trends over time evaluated using logistic and multinomial logistic regression. RESULTS: Six hundred twelve trials met inclusion criteria. Sixty-five percent of trials were for older adults that also allowed minors, while 9% were exclusively for patients ≤18 years of age. Eighty-three percent of trials included at least one novel agent, while 17% studied only conventional therapies. Fifty-eight percent of trials studied treatments not yet Food and Drug Administration (FDA) approved (48% if exclusively for patients ≤18 years). Fifteen percent of trials for which dose-escalation method could be determined, utilized a model-based design. Eighteen percent of all trials were industry sponsored (48% if exclusively for patients ≤18 years). Forty-nine percent of all trials were multicenter (69% if exclusively for patients ≤18 years). There was an increase in trials exclusively focused on patients with central nervous system (CNS) tumors over the study period (P ≤ .02). No other temporal trends were seen. The median times from first-in-adult to first-in-pediatric for monotherapy and combination trials were 5.7 and 3.3 years, respectively. CONCLUSION: The paucity of clear temporal trends highlights the need for innovation in early drug development for young people. Our analysis serves as a benchmark against which to evaluate initiatives to improve pediatric cancer drug development.

Lack of value of juvenile animal toxicity studies for supporting the safety of pediatric oncology phase I trials.

Toxicity studies in juvenile animals (JAS) are sometimes performed to support clinical trials in pediatric oncology patients, and there are differing conclusions on the value of JAS for pediatric drug development. This manuscript provides a review of the pediatric clinical data for 25 molecularly-targeted and 4 biologic anticancer therapeutics. Other publications that evaluated the value of JAS in pediatric drug development focus on differences in toxicity between juvenile animals and adult animals. The present paper examines pediatric-specific clinical findings to focus on dose setting in pediatric oncology patients and safety monitoring in terms of the potential value of JAS. Our assessment demonstrates that pediatric starting doses were safe for all 29 therapeutics examined in that no life-threatening toxicities occurred in the first cohort, and overall the ratio of the pediatric maximum tolerated dose (MTD) to the recommended adult dose was close to 1. In addition, the 4 serious adverse events (SAEs) that weren't detectable with standard monitoring plans for pediatric oncology trials would not have been detectable in a standard JAS. This review demonstrates that safe starting doses in pediatric oncology patients for these therapeutics could have been solely based on adult doses without any knowledge of findings in JAS.

Analysis of esophagogastric cancer patients enrolled in the National Cancer Institute Cancer Therapy Evaluation Program sponsored phase 1 trials.

BACKGROUND: In phase 1 trials, an important entry criterion is life expectancy predicted to be more than 90 days, which is generally difficult to predict. The Royal Marsden Hospital (RMH) prognostic score that is determined by lactate dehydrogenase level, albumin level, and number of metastatic sites of disease was developed to help project patient outcomes. There have been no systematic analyses to evaluate the utility of the RMH prognostic score for esophagogastric cancer patients. METHODS: All nonpediatric phase 1 oncology trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program that began between 2001 and 2013 were considered in this review. RESULTS: Of 4722 patients with solid tumors, 115 patients were eligible for our analysis; 54 (47 %) with cancer of the esophagus, 14 (12 %) with cancer of the esopagogastric junction, and 47 (41 %) with stomach cancer. Eighty-six patients (75 %) had a good RMH prognostic score (0 or 1) and 29 patients (25 %) had a poor RMH prognostic score (2 or 3). Disease control rates were significantly different between patients with good and poor RMH prognostic scores (49 % vs 17 %; two-sided Fisher's exact test P = 0.004). The median treatment duration and overall survival for good and poor RMH prognostic score patients were significantly different (median treatment duration 2.1 months vs 1.2 months respectively, P = 0.016; median overall survival 10.9 months vs 2.1 months respectively, P < 0.001). In the multivariate analysis, age (60 years or older), Eastern Cooperative Oncology Group performance status (2 or greater), and the RMH prognostic score (2 or 3) were significant predictors of poor survival. CONCLUSIONS: The RMH prognostic score is a strong tool to predict the prognosis of esophagogastric cancer patients who might participate in a phase 1 trial.

Regulatory experience of TOPS: an internet-based system to prevent healthy subjects from over-volunteering for UK clinical trials.

PURPOSE: The aim was to review the use of The Over-volunteering Prevention System (TOPS) since the HRA began hosting it in 2013, and the Medicines and Healthcare products Regulatory Agency (MHRA) experience of monitoring its use by UK clinical research units. METHODS: The HRA searched the TOPS database for the number, type and location of units and the number of entries. The MHRA inspectors reviewed their findings from routine inspections. RESULTS: Twenty-two additional UK units registered to use TOPS during 2013-2016, making a total of 84 units since TOPS was established in 2002. Use of TOPS is now a condition of research ethics committee approval of a phase 1 study and fulfils MHRA accreditation requirements for preventing over-volunteering. The total number of entries by all active units during 2013-2016 was 89,335, of which 84% were UK citizens and 16% non-UK citizens. The total number of entries during 2002-2016 was 249,612. Only 15 of 24,531 subjects (1/1600) and 18 of 18,745 subjects (1/1040) entered in 2015 and 2016, respectively, were deemed potential over-volunteers. CONCLUSIONS: The findings continue to support the concept that TOPS not only helps to prevent over-volunteering, but also deters subjects from trying to do so. Regulation of TOPS by the HRA and MHRA has enhanced its effectiveness, benefited all users and helped to improve the safety of volunteers who participate in non-therapeutic trials in the UK. The UK is still the only country with a national database to prevent over-volunteering that has published data on its widespread use and effectiveness.

Access to Children's Oncology Group and Pediatric Brain Tumor Consortium phase 1 clinical trials: Racial/ethnic dissimilarities in participation.

BACKGROUND: Phase 1 clinical trials introduce new therapies to humans with the goal of establishing their safety. A prior Children's Oncology Group (COG) study analyzed the proportional enrollment of patients by race, ethnicity, sex, and age for all trial phases. The current study evaluated the representation of patients by race, ethnicity, sex, and age in phase 1 clinical trials. METHODS: This study evaluated 1348 children with 128 diagnoses enrolled in COG and Pediatric Brain Tumor Consortium phase 1 clinical trials in the United States from February 28, 2000 to December 29, 2008. Observed and expected proportions were calculated according to an established methodology with a representative population from Surveillance, Epidemiology, and End Results data, which included 27,766 children with the same International Classification of Diseases for Oncology (third edition) diagnostic codes. RESULTS: Underrepresentation in phase 1 trials was seen for lymphohematopoietic (LH) tumors (9.3% observed vs 37% expected) versus solid tumors (90.6% observed vs 63% expected). Although representation was fairly proportional, Hispanics (12.6% observed vs 27% expected), particularly Hispanic females (6% observed vs 18% expected), were significantly underrepresented. The 0- to 4-year age group was underrepresented (11.7% observed vs 36.5% expected). By tumor type, the most significantly underrepresented groups were 0- to 4-year-old children and Hispanics for both solid cancers (11% observed vs 34.4% expected for 0- to 4-year-old children and 12% observed vs 24% expected for Hispanics) and LH cancers (16% observed vs 40% expected for 0- to 4-year-old children and 19.4% observed vs 33% expected for Hispanics). CONCLUSIONS: Although sex and racial/ethnic groups are mostly proportionally represented in phase 1 trials, some specific subgroups such as Hispanic children are underrepresented and may benefit from focused accrual. Cancer 2016;122:3207-14. © 2016 American Cancer Society.

A study of motivations and expectations of patients seen in phase 1 oncology clinics.

BACKGROUND: To better inform clinical practice, this study was aimed at capturing patients' motivations for enrolling in phase 1 trials and at quantifying their expectations of the benefits, risks, and commitment associated with clinical trials and the impact of the initial consultation on their expectations. METHODS: This was a single-center, prospective, quantitative study of newly referred adult patients considering their first phase 1 oncology trial. Participants completed questionnaires before they were seen and an abbreviated follow-up version after their consultation. RESULTS: Questionnaires were completed by 396 (99%) and 301 (76%) before and after the clinic, respectively. Participants ranked the possibility of tumor shrinkage (84%) as the most important motivation for considering a phase 1 trial; this was followed by no alternative treatments (56%), their physician's recommendation (44%), and the fact that the research might benefit others (38%). When they were asked about the potential personal benefit, 43% predicted tumor shrinkage initially. After the consultation, this increased to 47%. Fourteen percent of patients expected a cure. When asked about risks, 71% of the participants expected moderate side effects. When asked about expectations of time commitments, a majority of patients did not anticipate weekly visits, although this was understood by 93% of patients after the consultation. Overall, patients were keen to consider trials and when asked before and after the consultation 72% and 84% were willing to enroll in studies, respectively. CONCLUSIONS: This study reports that more than 80% of patients enroll in early-phase clinical oncology trials motivated by the potential of a clinical benefit, with approximately half expecting tumor shrinkage and approximately a tenth anticipating a cure. The typical phase 1 response rate is 4% to 20%, and this discrepancy exemplifies the challenges faced by patients and healthcare professionals during their interactions for phase 1 studies. Cancer 2016;122:3501-3508. © 2016 American Cancer Society.

How do researchers decide early clinical trials?

Launch of clinical investigation represents a substantial escalation in commitment to a particular clinical translation trajectory; it also exposes human subjects to poorly understood interventions. Despite these high stakes, there is little to guide decision-makers on the scientific and ethical evaluation of early phase trials. In this article, we review policies and consensus statements on human protections, drug regulation, and research design surrounding trial launch, and conclude that decision-making is largely left to the discretion of research teams and sponsors. We then review what is currently understood about how research teams exercise this discretion, and close by laying out a research agenda for characterizing the way investigators, sponsors, and reviewers approach decision-making in early phase research.

Description of the types and content of phase 1 clinical trial consent conversations in practice.

BACKGROUND OR AIMS: All agree that informed consent is a process, but past research has focused content analyses on post-consent or on one conversation in the consent series. Our aim was to identify and describe the content of different types of consent conversations. METHODS: We conducted a secondary analysis of 38 adult oncology phase 1 consent conversations, which were audio-recorded, transcribed, coded, and qualitatively analyzed for type and content. RESULTS: Four types of consent conversations were identified: (1) priming, (2) patient-centered options, (3) trial centered, and (4) decision made. The analysis provided a robust description of the content discussed in each type of conversation. Two themes, supportive care and prognosis, were rarely mentioned. Four themes clustered in the patient-centered (type 2) conversations: affirmation of honesty, comfort, progression, and offer of supportive care. CONCLUSION: We identified and described four types of consent conversations. Our novel findings include (1) four different types of conversations with one (priming) not mentioned before and (2) a change of focus from describing the content of one phase 1 consent conversation to describing the content of different types. These in-depth descriptions provide the foundation for future research to determine whether the four types of conversations occur in sequence, thus describing the structure of the consent process and providing the basis for coaching interventions to alert physicians to the appropriate content for each type of conversation. A switch from a focus on one conversation to the types of conversations in the process may better align the consent conversations with the iterative process of shared decision making.

Are phase 1 trials therapeutic? Risk, ethics, and division of labor.

Despite their crucial role in the translation of pre-clinical research into new clinical applications, phase 1 trials involving patients continue to prompt ethical debate. At the heart of the controversy is the question of whether risks of administering experimental drugs are therapeutically justified. We suggest that prior attempts to address this question have been muddled, in part because it cannot be answered adequately without first attending to the way labor is divided in managing risk in clinical trials. In what follows, we approach the question of therapeutic justification for phase 1 trials from the viewpoint of five different stakeholders: the drug regulatory authority, the IRB, the clinical investigator, the referring physician, and the patient. Our analysis shows that the question of therapeutic justification actually raises multiple questions corresponding to the roles and responsibilities of the different stakeholders involved. By attending to these contextual differences, we provide more coherent guidance for the ethical negotiation of risk in phase 1 trials involving patients. We close by discussing the implications of our argument for various perennial controversies in phase 1 trial practice.

Similar genetic profile in early and late stage urothelial tract cancer.

INTRODUCTION: Urothelial tract cancer (UTC) ranks as the tenth most prevalent cancer and holds the seventh position in terms of mortality worldwide. Despite its prevalence and mortality ranking, there are still gaps in the knowledge of the mutational landscape in patients with advanced disease who have limited therapeutic options after multiple lines of prior treatment. This study compares the genomic and transcriptomic landscape, and targeted treatment options between metastatic UTC (mUTC) patients treated with multiple lines of therapy compared to newly diagnosed, untreated Muscle Invasive Bladder Cancer (MIBC). METHODS: We compared genomic and clinical data from two cohorts: mUTC patients who received multiple lines of therapy and were referred to the Copenhagen Prospective Personalized Oncology (CoPPO) project at Rigshospitalet, University of Copenhagen. Data for MIBC UTC patients were acquired from the Cancer Genome Atlas Bladder Cancer (TCGA BLCA) cohort. Biopsies in CoPPO were performed at the time of enrollment. 523 highly important cancer-related genes (TrueSight Oncology-500 targeted sequencing panel) were used from both cohorts for comparative analysis. Analyses included RNA count data to compare predicted molecular subtypes in each cohort separately. RESULTS: Patients from the CoPPO cohort had a lower median age at first-line treatment than the TCGA BLCA cohort, with no significant gender disparity. The predominant histology was urothelial cell carcinoma in both cohorts. Genomic analysis revealed no significant difference between the top mutated genes in the two cohorts, specifically looking into DNA damage repair genes. Molecular subtyping indicated a higher frequency of neuroendocrine differentiation in the CoPPO cohort. 13% of patients in the CoPPO cohort received targeted therapy based on genomic findings, and 16% received non-targeted treatment, totaling 29% receiving CoPPO treatment (9 patients). The remaining 71% received best supportive care. Kaplan-Meier analysis showed a non-significant survival benefit for the intervention group in the CoPPO cohort. CONCLUSION: When focusing on 523 highly relevant cancer genes, the mutational profile of mUTC patients who have undergone numerous treatment lines resembles that of newly diagnosed MIBC. These alterations can be targeted, indicating the potential advantage of early genomic testing for personalized treatment within clinical trials.

More may not be better: reconsidering early clinical trial design in the era of targeted cancer therapeutics.

The advent of a new generation of targeted cancer drugs requires a radically different design of early clinical trials. Here, René Bernards discusses why new clinical trial designs are needed and what is being done to achieve this. Such innovative trials can lead to similar outcomes for cancer patients with fewer side effects while at the same time reducing the cost of cancer care.

Hope and meaning-making in phase 1 oncology trials: a systematic review and thematic synthesis of qualitative evidence on patient-participant experiences.

BACKGROUND: Phase 1 drug trials are popular treatment options for patients with advanced disease, despite the greater levels of uncertainty associated with them. However, their meaning and consequences for patient-participants remains under-explored. This review synthesises the qualitative evidence of patients' experiences of participating in phase 1 oncology trials, exploring their decisions to take part and the impacts of these trials on patient wellbeing. METHODS: A comprehensive literature search involving medical subject headings (MeSH) and keywords was undertaken in the following databases: MEDLINE, EMBASE, PsycINFO, Scopus, CINAHL, and Cochrane CENTRAL, with supplementary searches also conducted. Studies were independently screened for inclusion by two researchers. Included studies were critically appraised and data extracted using standardised forms. Qualitative results were analysed using thematic synthesis. RESULTS: Three main themes were identified across 13 studies: decision-making and joining the trial; experiences of taking part in the trial and hope and coping. Patients primarily joined trials hoping for therapeutic benefits, sentiments which prevailed and shaped their experiences across their trial journey. Rather than indicate therapeutic misconception based on poor understanding, patient perspectives more commonly pointed to differences between hope and expectation and cultural narratives of staying positive, trying everything and trusting in experts. CONCLUSIONS: These findings challenge information-based models of consent, favouring coping frameworks which account for the role of hope and meaning-making during serious illness. Personalised consideration of existential and quality-of-life matters before and during trials is recommended, including palliative and supportive care alternatives to active treatment. REVIEW REGISTRATION: The review was registered with PROSPERO international prospective register of systematic reviews (CRD 42020163250).

The animal model of human disease as a core concept of medical research: Historical cases, failures, and some epistemological considerations.

This article uses four historical case studies to address epistemological issues related to the animal model of human diseases and its use in medical research on human diseases. The knowledge derived from animal models is widely assumed to be highly valid and predictive of reactions by human organisms. In this contribution, I use three significant historical cases of failure (ca. 1890, 1960, 2006), and a closer look at the emergence of the concept around 1860/70, to elucidate core assumptions related to the specific practices of animal-human knowledge transfer, and to analyze the explanations provided by historical actors after each of the failures. Based on these examples, I argue that the epistemological status of the animal model changed from that of a helpful methodological tool for addressing specific questions, but with precarious validity, to an obligatory method for the production of strong knowledge on human diseases. As a result, there now exists a culture of biomedical research in human disease that, for more than a century, has taken the value of this methodological tool as self-evident, and more or less beyond question.

Decision-making about clinical trial options among older patients with metastatic cancer who have exhausted standard therapies.

OBJECTIVES: Older adults under-enroll in early phase cancer clinical trials. There are limited data on their trial experiences, which hampers our ability to understand potential reasons and responses to under-enrollment. We aimed to explore older adults' experiences and deliberations with phase 1 trials. MATERIALS AND METHODS: We analyzed 101 in-depth interviews with 39 adults (average 2.6 interviews per participant) about their experiences with phase 1 trials. All respondents were ≥ 65 years and had advanced cancer. Interviews lasted 60-90 min and were audio-recorded, transcribed, and analyzed to identify respondents' understanding of clinical research, perceptions of early phase trials, and experiences with enrollment. RESULTS: Clinical trial participation was an interactive process that unfolded over time. Older adults relied on ongoing guidance and discussion with their oncologist to navigate the process. Respondents were generally interested in life-prolonging therapies, including enrollment in early phase clinical trials, but did not necessarily state this explicitly to their oncologist. While respondents did not mention age as a limitation to trials participation, participants age > 70 were less enthusiastic about participation and more often discussed their quality of life and weighed benefits of trial participation in the context of their remaining months of life. CONCLUSION: Early phase clinical trial enrollment is complex, and older adults rely on their oncologist to navigate this process. Acknowledging this complexity through shared decision-making may ensure that older adults have appropriate opportunities to enroll in early phase clinical trials and guard against inappropriate under-enrollment.