Defining estimands for efficacy assessment in single arm phase 1b or phase 2 clinical trials in oncology early development.

The addendum of the ICH E9 guideline on the statistical principles for clinical trials introduced the estimand framework. The framework is designed to strengthen the dialog between different stakeholders, to introduce greater clarity in the clinical trial objectives and to provide alignment between the estimand and statistical analysis. Estimand framework related publications thus far have mainly focused on randomized clinical trials. The intention of the Early Development Estimand Nexus (EDEN), a task force of the cross-industry Oncology Estimand Working Group (www.oncoestimand.org), is to apply it to single arms Phase 1b or Phase 2 trials designed to detect a treatment-related efficacy signal, typically measured by objective response rate. Key recommendations regarding the estimand attributes include that in a single arm early clinical trial, the treatment attribute should start when the first dose is received by the participant. Focusing on the estimation of an absolute effect, the population-level summary measure should reflect only the property used for the estimation. Another major component introduced in the ICH E9 addendum is the definition of intercurrent events and the associated possible ways to handle them. Different strategies reflect different clinical questions of interest that can be answered based on the journeys an individual subject can take during a trial. We provide detailed strategy recommendations for intercurrent events typically seen in early-stage oncology. We highlight where implicit assumptions should be made transparent as whenever follow-up is suspended, a while-on-treatment strategy is implied.

Estimands for overall survival in clinical trials with treatment switching in oncology.

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention-to-treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment-policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross-industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation.

Ethical Considerations in Adaptive Design Clinical Trials.

Adaptive design clinical trial methodologies offer both opportunities and challenges for observing basic ethical principles in human subject research. Using both published and unpublished adaptive design clinical trials, we have selected and reviewed examples of clinical trials with different design adaptations to discuss the ethical obstacles presented and often successfully resolved by these approaches, including (1) confirmatory trials for treatments widely accepted on the basis of uncontrolled case series or open-label trials (clinical equipoise and "justice" in the sense of which trial groups will "receive the benefits of research and bear its burdens") (infantile hemangioma/propranolol); (2) interim results analysis by unblinded data monitoring committees ("withholding information necessary to make a considered judgment" ["respect for persons"] versus compromising the trial's scientific basis) (BIG 1-98); (3) adaptations involving sample size reassessment or dose adjustment via dropping or adding treatment arms, allowing fewer subjects to produce statistically significant results, fewer subjects treated with ineffective/toxic doses, and more subjects given doses showing tolerance and treatment activity ("beneficence" or "protecting from harm and making efforts to secure wellbeing") (ECMO, Neuromyelitis Optica); (4) adaptive randomization inferential problems balanced against ethical benefits (trastuzumab vs taxane in advanced gastric cancer; ADVENT); (5) more efficient allocation of societal resources for research, in both public and commercial realms, versus uncertain regulatory acceptance (indicaterol; VALOR); and (6) platform, umbrella, and basket trials offering additional efficiencies (I-SPY II, BATTLE, Lung-MAP). The importance of careful design, meticulous planning, and rigorous ethical review of adaptive design trials on a case-by-case basis cannot be overemphasized.

Factors influencing prostate-specific antigen response among men treated with testosterone therapy for 6 months.

INTRODUCTION: Factors influencing prostate-specific antigen (PSA) changes in men undergoing testosterone (T) therapy have not been well studied. AIM: The aim of this study was to assess the influence of selected variables on PSA changes in hypogonadal men administered with 1.62% testosterone gel (T-gel) for 6 months. METHODS: A double-blind, placebo-controlled study of 274 (234 T-gel, 40 placebo) hypogonadal men >18 years of age, with baseline T concentrations <300 ng/dL, PSA ≤2.5 ng/mL, and negative digital rectal examination. Subjects received once-daily T-gel for T therapy. MAIN OUTCOME MEASURES: Changes in mean serum PSA, percentage of free PSA (%fPSA), and T from baseline to 6 months (182 days). RESULTS: Mean age was 53.5 years and baseline mean values were total T 247 ng/dL, PSA 0.9 ng/mL, and %fPSA 24.6%. Among men treated with T-gel, T increased to 499 ng/dL and PSA increased by 0.1 ng/mL (P = 0.0012). PSA increased ≥0.3 ng/mL in 26.3%, <0.3 ng/mL in 73.7%, including a decline from baseline in 33.0%. In the placebo group, T increased 29 ng/dL to 274 ng/dL, and PSA decreased 0.1 ng/mL, compared with baseline. A greater increase in PSA was noted in men ≥60 years old than in men <60 years old (0.4 vs. 0.05 ng/mL, respectively; P = 0.0006). Mean PSA did not change in men with baseline serum T >250 ng/dL, whereas it increased by 0.2 ng/mL in men with T ≤250 ng/dL (P = 0.0031). PSA increased 0.3 ng/mL in men with baseline %fPSA <20% and 0.1 ng/mL in men with %fPSA ≥20%. CONCLUSIONS: Overall, T-gel treatment was associated with a minor increase in PSA, of questionable clinical significance. Factors predicting greater PSA increases included age ≥60 years, baseline T ≤250 ng/dL, and %fPSA <20%. Men with T >250 ng/dL and age <60 years demonstrated minimal or no PSA change.

A 6-month observational study of energy, sexual desire, and body proportions in hypogonadal men treated with a testosterone 1% gel.

AIMS AND METHODS: This was a 6-month, open label, multinational, observational study in hypogonadal men treated with daily titrated dose of 50, 75, or 100 mg 1% testosterone gel (AndroGel®) in community practice. Primary outcome was effect of treatment on hypogonadal symptoms and quality of life as assessed by Aging Males' Symptoms (AMS) scale. Secondary objectives included erectile dysfunction (International Index of Erectile Function [IIEF]), fatigue (Multidimensional Fatigue Inventory [MFI]), and surrogates for body composition (waist circumference, body mass index [BMI]). RESULTS: Seven hundred and ninety-nine of the 1053 men enrolled had follow-up data at 6 months, 81.2% had ≥1 testosterone value in the normal range during the study. Substantial and significant improvements were observed in mean AMS score (-29%), IIEF score (+115.7%), and MFI scores (-21.5%). Further beneficial effects were significant decreases in mean BMI (-0.8 kg/m(2)) and waist circumference (-3.3 cm). Younger age quartiles showed greater improvements in AMS, MFI, BMI, and waist circumference than older quartiles. IIEF scores, however, did not differ significantly by age category. CONCLUSIONS: Substantial improvements in hypogonadal symptoms, quality of life, fatigue, erectile dysfunction, and libido/sexual desire were observed. Adverse drug reactions were experienced by 7.5% of the safety population over the 6-month study period.

A multicenter, open-label, observational study of testosterone gel (1%) in the treatment of adolescent boys with klinefelter syndrome or anorchia.

PURPOSE: To assess the safety and clinical outcomes of 6-month treatment with testosterone gel 1% therapy in adolescent boys with primary hypogonadism resulting from Klinefelter syndrome (KS) or anorchia. METHODS: This was a subgroup analysis of a multicenter, open-label study of adolescent boys (N = 86) with delayed puberty who received .5-5.0 g testosterone gel 1% daily for ≤6 months. Adolescent boys 12-17 years of age with KS (n = 21) or anorchia (n = 8), bone age ≥10.5 years, and baseline growth data ≥6 months were included in this analysis. Serum hormone levels (total/free testosterone, luteinizing hormone, dihydrotestosterone, follicle-stimulating hormone, and estradiol) were measured using validated assays. Safety was assessed through adverse events (AEs). RESULTS: At baseline, patients with KS were taller, weighed more, and had higher total testosterone levels (mean 174 vs. 19 ng/dL) than patients with anorchia. At 6 months, total and free testosterone and dihydrotestosterone levels increased 1.8- to 2.3-fold in the KS group and eight- to 10-fold in anorchia patients. Estradiol levels increased 1.9-fold in the anorchia group and 1.4-fold in the KS group after treatment. No clinically significant changes were noted for luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin concentrations in either group. Cough was the most common AE (eight of 29), followed by acne and headache (both four of 29). One anorchia and two KS patients discontinued prematurely. CONCLUSIONS: Once-daily testosterone gel application increased serum testosterone levels into the pubertal range and maintained pubertal testosterone levels during 6-month treatment. In this study, testosterone gel 1% raised testosterone levels and was associated with cough as the most common AE.

Testosterone replacement with 1% testosterone gel and priapism: no definite risk relationship.

INTRODUCTION: Although testosterone replacement therapy (TRT) is the preferred treatment for hypogonadism, information for patients using testosterone includes too frequent or prolonged erections as a potential side effect. AIM: To assess the frequency and risk of priapism or related adverse events (AEs) in hypogonadal men treated with a 1% testosterone gel. METHODS: Safety and tolerability data for AndroGel 1% were assessed, including three randomized, controlled clinical trials in varying populations of hypogonadal or near hypogonadal men. Study 1 was a Phase 3 trial of AndroGel 1% 5 g, 7.5 g, or 10 g once daily for 6 months (N = 227). Study 2 was a Phase 2 trial of AndroGel 1% 7.5 g once daily titrated as needed vs. placebo for 26 weeks in men with type 2 diabetes (N = 180). Study 3 was a Phase 4 trial of AndroGel 1% 5 g once daily vs. placebo for 12 weeks in men previously unresponsive to sildenafil 100 mg monotherapy and receiving concomitant sildenafil 100 mg (N = 75). Postmarketing AndroGel pharmacovigilance reporting data from 2001 to 2011 was searched for events coded as priapism. MAIN OUTCOME MEASURES: The incidence of priapism and/or related symptoms reported as urogenital or reproductive system AEs. RESULTS: In the 283 men exposed to AndroGel 1% over the three trials, mean exposure ranged from 84 days to 149 days. No AEs described as priapism or related symptoms were reported in the three trials. In the postmarketing data, representing 40 million units sold, eight cases described as priapism were reported. Of the six cases with accompanying data, all were judged as possibly related to AndroGel. CONCLUSIONS: Safety data from the clinical trials for AndroGel 1% did not report any cases of priapism, and its incidence in the postmarketing pharmacovigilance data is extremely low, indicating a minimal risk of inducing priapism.