Trends in the approval of cancer therapies by the FDA in the twenty-first century.

The cancer treatment landscape has changed dramatically since the turn of the century, resulting in substantial improvements in outcomes for patients. This Review summarizes trends in the approval of oncology therapeutic products by the United States Food and Drug Administration (FDA) from January 2000 to October 2022, based on a categorization of these products by their mechanism of action and primary target. Notably, the rate of oncology indication approvals has increased in this time, driven by approvals for targeted therapies, as has the rate of introduction of new therapeutic approaches. Kinase inhibitors are the dominant product class by number of approved products and indications, yet immune checkpoint inhibitors have the second most approvals despite not entering the market until 2011. Other trends include a slight increase in the share of approvals for biomarker-defined populations and the emergence of tumour-site-agnostic approvals. Finally, we consider the implications of the trends for the future of oncology therapeutic product development, including the impact of novel therapeutic approaches and technologies.

Abuse liability assessment of atomoxetine in a drug-abusing population.

BACKGROUND: Atomoxetine is a non-amphetamine medication approved to treat ADHD in children, adolescents, and adults. Previous studies demonstrated low abuse potential for atomoxetine in recreational drug users. This study assessed the abuse potential of atomoxetine in stimulant-preferring drug abusers compared to methylphenidate and phentermine as positive controls and desipramine and placebo as negative controls. METHODS: Forty male and female, 32-53 years old stimulant-preferring drug abusers completed this balanced Latin-square designed study. Subjects received acute, double-blind doses of placebo, desipramine (100 and 200 mg), methylphenidate (90 mg), phentermine (60 mg), and atomoxetine (45, 90, and 180 mg). Subjective and physiological effects were collected for 24 h following each drug treatment. RESULTS: Methylphenidate and phentermine were liked significantly more than placebo, atomoxetine, or desipramine. No atomoxetine dose was liked significantly more than placebo and liking scores for atomoxetine were similar to, or significantly lower than, desipramine, as assessed by the Drug Rating Questionnaire-Subject. While atomoxetine 45 and 180 mg did not significantly change any Addiction Research Center Inventory (ARCI) scores, atomoxetine 90 mg significantly increased A and BG stimulant scores of the ARCI and both methylphenidate and phentermine produced greater A and BG increases than any atomoxetine dose and also increased MBG (euphoria) scores relative to placebo. CONCLUSIONS: Atomoxetine has significantly less abuse liability than methylphenidate or phentermine and no greater abuse liability than desipramine.

Atomoxetine treatment of adults with ADHD and comorbid alcohol use disorders.

OBJECTIVE: Adults with attention-deficit/hyperactivity disorder (ADHD) have higher rates of alcohol and drug use disorders than adults without ADHD. The study aim was to determine if atomoxetine was superior to placebo in improving ADHD and alcohol use in recently abstinent adults with ADHD and comorbid alcohol use disorder. METHODS: Adults with DSM-IV diagnoses of ADHD and alcohol abuse and/or dependence were abstinent from alcohol at least 4 days (maximum 30 days) before study randomization. Participants received atomoxetine (25-100mg daily) or placebo for 12 weeks. ADHD symptoms were assessed using ADHD Investigator Symptom Rating Scale (AISRS) total score. Time-to-relapse to heavy alcohol use was analyzed using a 2-sided log-rank test based on Kaplan-Meier estimates and cumulative heavy drinking events over time were evaluated post hoc with recurrent-event analysis. RESULTS: Subjects received atomoxetine (n=72) or placebo (n=75) and 80 subjects completed the 12-week double-blind period (n=32 and 48, respectively). ADHD symptoms were significantly improved in the atomoxetine cohort compared to placebo (AISRS total score mean [S.D.], atomoxetine: -13.63 [11.35], P<.001; placebo: -8.31 [11.44], P<.001, difference: P=.007; effect size=0.48). No significant differences between treatment groups occurred in time-to-relapse of heavy drinking (P=.93). However, cumulative heavy drinking days were reduced 26% in atomoxetine-treated subjects versus placebo (event ratio=0.74, P=.023). There were no serious adverse events or specific drug-drug reactions related to current alcohol use. CONCLUSIONS: This 3-month, double-blind, placebo-controlled study of atomoxetine in adults with ADHD and comorbid alcohol use disorder demonstrates clinically significant ADHD improvement, and inconsistent effects on drinking behavior.

Long-term, open-label safety and efficacy of atomoxetine in adults with ADHD: final report of a 4-year study.

OBJECTIVE: Previously, data from 97 weeks of open-label atomoxetine treatment of adults with attention-deficit/hyperactivity disorder (ADHD) were reported. This final report of that study presents results from over 4 years of treatment. METHOD: Results were derived from the study of 384 patients (125 patients remaining in the open-label trial since the interim report), receiving up to 221 weeks of treatment. Primary efficacy measure was the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) Total ADHD Symptom score. Adverse events and vital signs were assessed. RESULTS: CAARS-Inv:SV Total ADHD Symptom scores decreased 30.2% (p < .001) during treatment. Similar, significant decreases were noted for the secondary efficacy measures, including the Sheehan Disability Scale Total score, which improved 25.3% (p < .001). Adverse events consisted primarily of pharmacologically (noradrenergic) expected effects. CONCLUSIONS: Results of this open-label study support the long-term efficacy, safety, and tolerability of atomoxetine for the treatment of adult ADHD.

High-dose atomoxetine treatment of ADHD in youths with limited response to standard doses.

OBJECTIVE: To assess the utility and tolerability of higher than standard atomoxetine doses to treat attention-deficit/hyperactivity disorder (ADHD). METHOD: Two randomized, double-blind trials of atomoxetine nonresponders ages 6 to 16 years were conducted comparing continued treatment with same-dose atomoxetine to treatment using greater than standard efficacious doses (study 1: up to 3.0 mg . kg . day; study 2: up to 2.4 mg . kg . day). RESULTS: The primary outcome measure for both studies was mean ADHD Rating Scale (ADHD RS) total score. For study 1 (N = 122), decreases in ADHD RS total scores were not significantly different between treatment groups (mean change [SD]: continued same dose, -8.9 [11.2]; high dose, -9.8 [13.1]; p = .595). Likewise, for study 2 (N = 125), treatment groups did not differ (mean change [SD]: continued same dose, -6.2 [12.2]; high dose, -8.9 [10.0], p =.110). Tolerability was not significantly different between the continued same-dose and high-dose groups. CONCLUSIONS: These studies provide evidence that current dose recommendations are appropriate for most patients, suggesting no systematic advantage to increasing atomoxetine doses beyond current guidelines. In both studies, continued treatment, whether at a higher dose or the previous dose, was associated with improved outcomes in patients who demonstrated incomplete/inadequate response to acute ADHD treatment, although without a placebo arm, we cannot rule out the possibility that expectancy played a role in symptom improvement.

Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: an interim analysis.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is an early-onset neuropsychiatric disorder that affects 3% to 7% of school-age children and 4% of adults. Its pathophysiology is thought to involve the dopaminergic and nor-adrenergic pathways associated with attention control and impulsivity. These symptoms have largely been defined in the childhood population, but the course of the condition and expression in the adult population are not as well characterized. METHOD: This is an ongoing, 3-year, open-label study consisting of adults with DSM-IV ADHD who were previously enrolled in 1 of 2 double-blind, acute-treatment studies of atomoxetine. The results of the interim analysis reported here were derived from the study of 384 patients at 31 sites who had been studied for a period of up to 97 weeks. The primary efficacy measure was the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) total ADHD symptom score. In addition, safety, adverse events, and vital sign measurements were assessed. RESULTS: Significant improvement was noted with atomoxetine therapy, with mean CAARS-Inv:SV total ADHD symptom scores decreasing 33.2% from 29.2 (baseline of open-label therapy) to 19.5 (endpoint of open-label therapy) (p < .001). Similar and significant decreases were noted for the secondary efficacy measures. Adverse events consisted primarily of pharmacologically (noradrenergic) expected effects, such as increases in heart rate and blood pressure and a slight decrease in weight. CONCLUSION: The results of this interim analysis of an ongoing, open-label study of adults with ADHD support the long-term efficacy, safety, and tolerability of atomoxetine for the treatment of adult ADHD.

Ethnographic methodologic assessment of pain perceptions by verbal description.

This study was designed to use known anthropologic methods to gather and analyze qualitative data about verbal descriptors of pain among 25 Chinese, and 60 Western subjects (25 Anglo-Americans and 35 Scandinavians). The sample consisted of 54 patients and 31 dentists. Key pain descriptors from each cultural context were selected for construction of pain assessment instruments which allowed multidimensional statistical techniques to translate these data into cross-cultural quantitative indices. Results revealed dimensions of pain which were universal in all cultures examined. These included time, intensity, location, quality, cause and curability. More culture-specific dimensions included the Chinese concept suantong, a multidimensional concept of bone, muscle, joint, tooth and gingival pain. 'Real' and 'imagined' pains were contrasts described by Western subjects, especially dentists; 'imagined pain' being the conversion of fear or anxiety into perceived pain. These data indicate that the data gathering and data analytic methods were reliable and sensitive to cultural variables and that ethnicity played a stronger role in determining perceptions of pain description than professional socialization for this population sample of Chinese and Western subjects.

Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure.

The purpose of this study was to examine the time course of changes in dopamine D(1)- and D(2)-like receptor densities in monkeys self-administering cocaine. Experimentally naïve adult male rhesus monkeys (n = 22) were divided into a food reinforcement group (n = 6), in which responding was maintained by food presentation, or into four cocaine self-administration groups (n = 4/group), based on dose (0.03 or 0.3 mg/kg per injection) and duration of exposure (5 or approximately 100 sessions). After the last session, monkeys were euthanized, brains were removed, frozen, and coronal sections through the striatum, rostral to the anterior commissure, were processed for D(1) ([3H]SCH23390) and D(2) ([3H]raclopride) receptor autoradiography. Compared with controls, there was no effect of 5 days of cocaine self-administration on D(1) and D(2) receptors. In monkeys with extensive cocaine histories, D(1) receptor densities were significantly increased relative to controls in some parts of the striatum, while D(2) receptor densities were significantly decreased throughout the striatum. These findings demonstrate that chronic cocaine self-administration produces neuroadaptations in dopamine systems, but that these changes do not occur in a parallel fashion.

Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response.

OBJECTIVE: Response to atomoxetine, a nonstimulant norepinephrine-specific reuptake inhibitor, was compared with the effect of osmotic-release oral methylphenidate, a long-acting methylphenidate preparation, in patients with attention deficit hyperactivity disorder (ADHD). METHOD: In a large placebo-controlled, double-blind study, patients ages 6-16 with ADHD, any subtype, were randomly assigned to receive 0.8-1.8 mg/kg per day of atomoxetine (N=222), 18-54 mg/day of osmotically released methylphenidate (N=220), or placebo (N=74) for 6 weeks. The a priori specified primary analysis compared response (at least 40% decrease in ADHD Rating Scale total score) to osmotically released methylphenidate with response to atomoxetine and placebo. After 6 weeks, patients treated with methylphenidate were switched to atomoxetine under double-blind conditions. RESULTS: The response rates for both atomoxetine (45%) and methylphenidate (56%) were markedly superior to that for placebo (24%), but the response to osmotically released methylphenidate was superior to that for atomoxetine. Each medication was well tolerated, with completion rates and discontinuations for adverse events not significantly different from those for placebo. Of the 70 subjects who did not respond to methylphenidate, 30 (43%) subsequently responded to atomoxetine. Likewise, 29 (42%) of the 69 patients who did not respond to atomoxetine had previously responded to osmotically released methylphenidate. CONCLUSION: Response was significantly greater with osmotically released methylphenidate than with atomoxetine. One-third of patients who received methylphenidate followed by atomoxetine responded better to one or the other, suggesting that there may be preferential responders.

Atomoxetine for the treatment of attention-deficit/hyperactivity disorder and oppositional defiant disorder.

OBJECTIVE: In this study we examined the effectiveness of atomoxetine for the treatment of oppositional defiant disorder comorbid with attention-deficit/hyperactivity disorder. METHODS: Patients were aged 6 to 12 years and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnostic criteria for attention-deficit/hyperactivity disorder with a Swanson, Nolan, and Pelham Rating Scale-Revised attention-deficit/hyperactivity disorder subscale score above age and gender norms; Clinical Global Impressions-Severity Scale score of > or = 4; and Swanson, Nolan, and Pelham Rating Scale-Revised oppositional defiant disorder subscale score of > or = 15. Patients were randomly assigned in a 2:1 ratio to receive 1.2 mg/kg per day of atomoxetine (n = 156) or placebo (n = 70) for 8 weeks. Treatment effect on oppositional defiant disorder and attention-deficit/hyperactivity disorder symptoms was measured by using the investigator-rated Swanson, Nolan, and Pelham Rating Scale-Revised. RESULTS: Repeated-measures analysis demonstrated a statistically significant difference favoring atomoxetine over placebo in the reduction of Swanson, Nolan, and Pelham Rating Scale-Revised oppositional defiant disorder total scores. There were significant pairwise treatment differences at weeks 2 and 5 but not at week 8 postbaseline. A last-observation-carried-forward analysis showed Swanson, Nolan, and Pelham Rating Scale-Revised scores at endpoint for the atomoxetine and placebo groups were significantly different for attention-deficit/hyperactivity disorder symptoms but not for oppositional defiant disorder symptoms. Atomoxetine was superior to placebo in a last-observation-carried-forward analysis of Clinical Global Impression-Improvement and Clinical Global Impression-Severity scores. CONCLUSIONS: This study confirms previous findings that patients with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder show statistically and clinically significant improvement in attention-deficit/hyperactivity disorder symptoms and global clinical functioning when treated with atomoxetine. It remains uncertain, however, whether atomoxetine exerts a specific and enduring effect on oppositional defiant disorder symptoms.

Low-dose atomoxetine for maintenance treatment of attention-deficit/hyperactivity disorder.

OBJECTIVE: Data from acute studies of atomoxetine in patients with attention-deficit/hyperactivity disorder suggest that a dose of approximately 1.2 mg/kg per day is required to attain a maximal symptom response. However, lower doses could be effective during maintenance treatment, which would reduce drug exposure and potential problems related to tolerability during chronic treatment. METHODS: Patients 6 to 16 years of age who had a robust response to an initial acute trial of atomoxetine were assigned randomly under double-blind conditions to continue treatment for up to 8 months with either the dose to which they had responded acutely (1.2-1.8 mg/kg per day, N = 116, continued same dose) or a lower dose (0.5 mg/kg per day, N = 113, low dose). The primary outcome measure was relapse, defined as an Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score returned to > or = 90% of the original baseline value (before acute treatment) for 2 consecutive visits. Mean change in Attention-Deficit/Hyperactivity Disorder Rating Scale total score was assessed as a secondary outcome. RESULTS: At randomization, symptom severity was low and similar in both groups. At end point, relapse rates did not differ between the groups. Mean change in Attention-Deficit/Hyperactivity Disorder Rating Scale total score from the conclusion of acute treatment to end point also was not different between groups. Reports of affective lability were higher in the patients in the low-dose group. Also, increases in heart rate (compared with when atomoxetine was started) were higher in the patients in the continued same-dose group than in the low-dose group. Finally, increases in weight over the course of the trial were greater for the low-dose group than the continued same-dose group. CONCLUSIONS: For patients who experience a robust response to atomoxetine, it may be possible to retain the response during maintenance treatment with a reduced dose of atomoxetine.

Quality of life assessment in adult patients with attention-deficit/hyperactivity disorder treated with atomoxetine.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has its onset during childhood and is estimated to affect 3% to 7% of school-aged children. Unfortunately, the disorder frequently persists into adult life. The burden of this disorder is considerable and is often characterized by academic (or occupational) impairment and dysfunction within the family and society. Despite the existence of research demonstrating the effects of ADHD on certain aspects of life, the clinical trials of treatments for this disorder have focused primarily on efficacy and safety. METHODS: Atomoxetine was approved in the United States in November 2002 for the treatment of ADHD in children, adolescents, and adults. The present study uses data from a clinical trial of atomoxetine in adult patients with ADHD that incorporated a measure of health-related quality of life (the Medical Outcomes Study 36-item short-form health survey [SF-36]) as part of the overall assessment of the success of this relatively new treatment. The primary outcome measure for ADHD symptoms was the Conners Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS) ADHD total symptom score. RESULTS: In agreement with previous studies, adult patients with ADHD treated with atomoxetine at typical doses showed significant amelioration of ADHD symptoms, as measured on the CAARS. At baseline, the measures of overall mental health (one aspect of quality of life) of adult patients with ADHD were below the average level, as measured on the SF-36. Treatment with atomoxetine significantly improved the measures of mental health and ameliorated the ADHD symptoms. In addition, the 2 measures were correlated. CONCLUSIONS: These data suggest that pharmacological intervention with atomoxetine not only ameliorates ADHD symptoms in adult patients but also improves their perceived quality of life.

Direct Raman imaging techniques for study of the subcellular distribution of a drug.

Direct Raman imaging techniques are demonstrated to study the drug distribution in living cells. The advantage of Raman imaging is that no external markers are required, which simplifies the sample preparation and minimally disturbs the drug mechanism during imaging. The major challenge in Raman imaging is the weak Raman signal. In this study, we present a Raman image model to describe the degradation of Raman signals by imaging processes. Using this model, we demonstrate special-purpose image-processing algorithms to restore the Raman images. The processing techniques are then applied to visualize the anticancer agent paclitaxel in living MDA-435 breast cancer cells. Raman images were obtained from a cancer cell before, during, and after drug treatment. The paclitaxel distribution illustrated in these images is explained by means of the binding characteristics of the paclitaxel and its molecular target-the microtubules. This result demonstrates that direct Raman imaging is a promising tool to study the distribution of a drug in living cells.

Preclinical antitumor activity and pharmacokinetics of methyl-2-benzimidazolecarbamate (FB642).

Methyl-2-benzimidazolecarbamate (carbendazim, FB642) is an anticancer agent that induces apoptosis of cancer cells. In vitro, FB642 demonstrated potent antitumor activity against both the murine B16 melanoma (IC50 = 8.5 microm) and human HT-29 colon carcinoma (IC50 = 9.5 microm) cell lines. FB642 was also highly active against both murine tumor models and human tumor xenografts at varying doses and schedules. In the murine B16 melanoma model, T/C values > 200 were observed. In the human tumor xenograft, FB642 produced tumor growth inhibition of greater than 58% in five of the seven xenograft models evaluated. Partial and complete tumor shrinkage was noted with FB642 against the MCF-7 breast tumor model. Pharmacokinetic studies in rats demonstrated that oral absorption of FB642 was variable and may be saturated at the 2000 mg/kg dose level since higher doses failed to produce a further increase in the area under the time concentration curve. Toxicity of FB642 in vivo appeared to be dose-dependent. Lower doses in the range of 2,000-3,000 mg/kg were better tolerated, while still preserving antitumor activity. Evaluation of FB642 in phase I clinical trials of adult patients with advanced malignancies is currently ongoing.