Non-cancer Trials Research Articles

MP21-10 SEX BIAS IN CONTEMPORARY CLINICAL DRUG TRIALS IN UROLOGY

You have accessJournal of UrologyCME1 Apr 2023MP21-10 SEX BIAS IN CONTEMPORARY CLINICAL DRUG TRIALS IN UROLOGY Andres Guillen Lozoya, Candace Granberg, Vidit Sharma, Patricio Gargollo, and Kevin Koo Andres Guillen LozoyaAndres Guillen Lozoya More articles by this author , Candace GranbergCandace Granberg More articles by this author , Vidit SharmaVidit Sharma More articles by this author , Patricio GargolloPatricio Gargollo More articles by this author , and Kevin KooKevin Koo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003246.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite federal policies to foster equal representation of female and male participants, sex bias remains common in clinical trial enrollment, leading to underrepresentation of women among trial participants. The extent of sex bias in clinical trials in urology is not well characterized. This study aimed to evaluate enrollment rates by sex for clinical trials leading to new drug approvals in urology. METHODS: We retrospectively reviewed the US Food and Drug Administration database for new drug approvals for urological indications from 2016 through 2021. Published trials that supported these approvals were analyzed to determine enrollment rates of female participants. The sample was grouped and analyzed by demographic and clinical variables. To assess sex bias, we defined a “sex-matching ratio” as the proportion of female to male trial enrollees, where a ratio of 1.0 would indicate equal numbers of women and men. A ratio ≥0.9 was considered “optimal” based on prior published studies. RESULTS: Of a total of 20 trials supporting novel drugs in urology, 6 were excluded due to sex-specific conditions, leaving a total of 14 trials that enrolled 10,875 female and male participants. The clinical indications in the trials included urinary tract infection (4 trials, 29%), urothelial carcinoma (4 trials, 29%), renal cell carcinoma (1 trial,7%), and overactive bladder (1 trial, 7%). Women accounted for 43% of the total sample and had significantly less enrollment in trials for cancer indications; women were only 26% of enrollees in urothelial and renal cancer trials vs 45% in non-cancer trials (p<0.001). Five trials (36%) enrolled more women than men overall; however, the participants in these majority-women trials (3,215) only comprised 30% of total enrolled sample. In terms of sex bias, 7 of the trials (50%) achieved an optimal sex-matching ratio ≥0.9. Among the other 7 trials with suboptimal sex-matching ratios, 1 trial had a ratio of 0.75, while the remaining 6 trials had ratios <0.5 (range 0.26-0.42), indicating that women accounted for less than half the number of men in these trials. The total enrollees in the 7 trials with suboptimal sex-matching ratios was 6,728; of these, women (1,962) accounted for just 29% of the sample. CONCLUSIONS: Sex bias is common in contemporary clinical trials for new drugs in urology. In half the trials with the strongest sex bias, women accounted for just 29% of the study population. Renewed efforts are urgently needed to ensure inclusive drug trials in urology. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e289 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andres Guillen Lozoya More articles by this author Candace Granberg More articles by this author Vidit Sharma More articles by this author Patricio Gargollo More articles by this author Kevin Koo More articles by this author Expand All Advertisement PDF downloadLoading ...

Radiotherapy and newly approved cancer drugs – A quantitative analysis of registered protocols for drugs approved for the treatment of solid tumors

Background/purposeTo evaluate the usage of RT in trial protocols for anti-cancer drugs approved by the US Food and Drug Administration (FDA). MethodsDrugs which had been granted an FDA approval between 2010 and 2017 for the treatment of solid tumors in adults were identified. Use of RT in relation to each drug’s approval date was reviewed on ClinicalTrials.gov. ResultsOut of 42 drugs, none was initially approved for an indication which mandates RT. One drug (2.4%) has a post-approval label extension for sequential usage after RT. 5846 records were screened, exclusion of non-cancer trials and duplicates resulted in 4254 protocols out of which 2919 were industry-sponsored (68.6%). RT was tested in 350 (8.2%) studies. Out of 75 drug/RT trials which were initiated prior to approval, fourteen had not yet started recruitment, 45 were recruiting, one was completed, one prematurely terminated and fourteen fully-recruited but ongoing at approval time. Out of the fully-recruited or completed studies, results from four studies on three drugs were already published. In 52.4% of drugs, no patient had been treated with a drug/RT combination at the approval date. Drug/RT studies were less likely industry-sponsored (p < 0.001) and more likely initiated post-approval (p < 0.001) compared to drug-only trials. Despite this imbalance, pre-approval drug/RT trials were still mostly industry-sponsored (65.3%). ConclusionNo drug/RT data were publicly available in over 90% of newly approved anti-cancer drugs. These results indicate that clinicians must rely on postmarketing surveillance to identify drug/RT interactions as data from trials are unavailable at approval.

The Economic Contribution of Industry-Sponsored Pharmaceutical Clinical Trials.

In pharmaceutical clinical trials, industrial sponsors pay for study drugs and related healthcare services. We conducted a study to determine industry's economic contribution of these trials to the Alberta healthcare system. Methods: We used data from two trial centers for cancer and non-cancer trials at the University of Alberta. For each trial (cancer, non-cancer), we calculated the cost of drugs provided by the sponsors using the market price, the cost of clinical services, and the cost of administrative services that they paid. We extrapolated these results to all trials in Alberta based on information obtained from the registration website ClinicalTrials.gov. Results: Our sample consisted of 40 non-cancer and 39 cancer drug trials which were initiated in 2012. The monetary value of the industry sponsors' contribution was $799,055 per non-cancer and $630,243 per cancer drug trial. Drugs (in-trial and post-trial) accounted for 84% of the total contribution of the non-cancer drug trials whereas it represented 93% of all trial-related contributions in the cancer category. The total province-wide contribution of industry-sponsored drug trials which were initiated in 2012 was estimated to be $101 million, including open-label drugs in the non-cancer category. Conclusions: Industry-sponsored pharmaceutical trials represent a major economic contributor to clinical research within the province.

Combination Lymphoma Immunotherapy Using Checkpoint Blockade and Intratumoral Virus-like Particles Containing CpG TLR9 Agonist

Checkpoint blockade of immune inhibitory pathways is an exciting therapeutic approach for the treatment of a variety of cancers and has become a standard of care for melanoma and other malignancies. Preliminary results suggest anti-PD-1 has modest single agent activity in patients with non-Hodgkin lymphomas, however there remains considerable room for treatment optimization and improvement through the use of unique immunotherapeutic combinations.We explored one such combination of PD-1 checkpoint blockade and CMP-001, a virus-like particle (VLP) containing a novel immunostimulatory CpG oligodeoxynucleotide (ODN) TLR9 agonist. Clinical grade CMP-001 is available and has been evaluated in over 700 subjects in non-cancer trials. In both preclinical and clinical studies, CMP-001 stimulates a strong and prolonged local Th1 cytokine response designed to enhance antigen presentation. Thus, with intratumoral injection, CMP-001 could augment the development of a tumor-specific T cell response that can be maintained by anti-PD-1 therapy.Syngeneic, immunocompetent mice were inoculated on both the left and right flanks subcutaneously with lymphoma (either A20 B cell lymphoma or E.G7-OVA T cell lymphoma). Anti-PD-1, or isotype control, was delivered intraperitoneally (i.p.) starting one week after tumor challenge and continued twice weekly. CMP-001, or saline control, was delivered intratumorally (i.t.) into the tumor on one flank also starting one week after tumor challenge for a total of 3 doses. Tumor growth and survival was followed. This experimental design allowed us to assess the local (treated tumor) and abscopal (untreated tumor) effect of therapy in two different lymphoma models.Intratumoral CMP-001 enhanced survival, and reduced tumor growth of both the treated and untreated tumors in the A20 lymphoma model. Each of these effects was enhanced with the addition of anti-PD-1 therapy (Figure 1). The anti-tumor effect on both the treated and untreated tumor was lost with depletion of either CD4 or CD8+ T cells demonstrating both cell populations contributed to the therapeutic effect. In the E.G7 model, CMP-001 treatment reduced growth of the local tumor - an effect that was modestly enhanced by anti-PD-1 therapy and dependent on CD8+ T cells. There was no significant response to therapy observed in the untreated E.G7 tumor, perhaps due to the rapid growth of the tumor before an abscopal immune response could develop.We conclude the combination of systemic anti-PD-1 and intratumoral injection of CMP-001 can enhance development of a systemic anti-tumor T cell response and is a promising immunotherapy combination worthy of clinical evaluation. A Phase 1b clinical trial of the combination of anti-PD-1 and CMP-001 is underway in advanced melanoma, and a Phase 1 clinical trial of the same combination is planned in lymphoma, based in part on these results. [Display omitted] DisclosuresKrieg:Checkmate Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Weiner:Checkmate Pharmaceuticals: Consultancy, Research Funding.

Early phase drugs and biologicals clinical trials on worldwide leading causes of death: a descriptive analysis

To describe the global effort targeting the major causes of mortality in terms of "open" early phase clinical trials with drugs and biologicals. Sixteen of the 20 leading causes of death were chosen; 9 of these were also amongst the top 10 causes of death in low-income countries. Studies were identified from the ClinicalTrials.gov database and included phase 1 and/or 2 "interventional" "open" trials, i.e. those recruiting or about to start recruitment. Trials were considered in terms of sponsorship [industry, universities and other organisations (UNO), and US federal agencies (NIH included)], genders and age groups included, and whether they were conducted with drugs and/or biologicals. The search was performed in March 2010. A total of 2,298 (824 phase 1; 1,474 phase 2) trials were retrieved. Of these, 67% were on trachea, bronchus, and lung cancers (25%); diabetes mellitus (15%); colon and rectum cancers (14%); and HIV/AIDS (12%). In contrast, only 4% were trials on diarrhoeal disease, nephrosis and nephritis, liver cirrhosis, and prematurity and low birth weight. UNO were the first source of funding. Fifty-two percent of phase 1 non-cancer trials were on healthy volunteers. Twenty-nine percent of all trials were co-funded. There were 4.6 times as many drug trials as those with biologicals. Only 7% were conducted with a combination of drugs and biologicals, the majority (78%) on cancers. Discrimination in terms of gender or age group was not observed. Four of the 16 diseases considered represented 2/3 of early phase trials. Cancers were a top priority for all sponsors. Increasing attention should be given to conditions with current and projected global high mortality rates that had few "open" early phase trials.

Ethical aspects of clinical trials: the attitudes of participants in two non‐cancer trials

Abstract. Madsen SM, Holm S, Davidsen B, Munkholm P, Schlichting P, Riis P (Copenhagen University Hospital in Herlev, Slagelse County Hospital, Slagelse, Hvidovre Hospital, University of Copenhagen, Denmark and University of Manchester, UK). Ethical aspects of clinical trials: the attitudes of participants in two non‐cancer trials. J Intern Med 2000; 248: 463–474.Objectives. To investigate attitudes to clinical trials in non‐cancer trial participants.Design. Questionnaires at entry, during, and after participation in a clinical study.Setting. Participants in: (i) ROC: a clinical study comparing systemic interferon‐α‐2A treatment vs. prednisolone enemas in ulcerative colitis; and (ii) MRCRUC: a clinical study investigating low‐field magnetic resonance imaging as a new modality for the evaluation of patients with inflammatory bowel disease.Subjects. Thirty‐two patients in ROC and 47 patients in MRCRUC.Outcome measures. Attitudes towards different aspects of clinical research.Results. The majority found scientific testing of clinical methods necessary, having positive attitudes towards both participation by themselves and others. The creation of a personal moral problem by denying participation was rejected by a large majority, and still both personal and altruistic motives for participation were highly rated. An important motive for accepting inclusion was the expectation of being ‘a special patient’ during the trial. The presence of research ethics committees controlling clinical research had a significant positive impact on decisions to participate, and drawing lots and blinding were found problematic by only a minority. Patients valued their satisfaction with participation in the trials highly, and would almost all accept a request to participate in future trials. The most important reason for this was a feeling of receiving better care and information than expected outside a trial setting, primarily determined by the patients seeing only one physician during the trials. A pronounced wish to obtain follow‐up information was expressed.Conclusion. Attitudes towards medical research are positive with both altruistic and nonaltruistic motives for participation. Expectations of being treated as ‘a special patient’ in the trial were important in accepting to participate. Seeing the same physician at control visits was an important factor for satisfaction with participation.

DAB389IL-2 (Denileukin Diftitox, ONTAK): Review of Clinical Trials to Date

Clinical trials of DAB389IL-2 (denileukin diftitox, ONTAK) have been conducted in a variety of disease states as well as in normal volunteers. The individuals treated include 45 volunteers in pharmacokinetic testing, 195 patients with noncancer indications, and 216 patients with lymphoma, including ongoing trials. The noncancer trials involved patients with rheumatoid arthritis, psoriasis, HIV infection, and insulin-dependent diabetes mellitus. Two large trials involving 143 lymphoma patients provide the definitive data and formed the basis for seeking and receiving Food and Drug Administration approval for DAB389IL-2. The focus of this paper will be a review of the efficacy and toxicity trials with DAB389IL-2 completed to date in cancer, in particular those that involved patients with cutaneous T-cell lymphoma, as well as the rationale for these trials.