Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development.

This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.

Caregiver Preferences for the Treatment of Males with Fragile X Syndrome.

OBJECTIVE: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. The objective of this study was to determine the relative importance that caregivers place on improving different phenotypic traits observed in males with FXS to better understand the greatest medical needs for developing and evaluating FXS treatments. METHOD: Fragile X syndrome caregivers (n = 614) compared hypothetical treatments in a discrete-choice experiment. The treatments varied in their effects on 6 outcomes associated with FXS: learning and applying new skills, explaining needs, controlling behavior, taking part in new social activities, caring for oneself, and paying attention. The relative importance was calculated for improving severe or moderate levels of disability and transformed to a 10-point scale. Relative importance was also quantified by patient age group (child, adolescent, and adult). RESULTS: Most important to caregivers were controlling behavior (10.0) and caring for oneself (9.9). Least important was taking part in new social activities (4.2). A partial improvement in controlling behavior or self-care was more important than full resolution of the least important disabilities. This was consistent across age groups. Improvements from severe to moderate disability were more important than from moderate to no disability. CONCLUSION: Caregivers expressed strong preferences for improvement in self-care and behavioral control, independent of the age of the individual with FXS. These data may be helpful when designing studies to test the efficacy of FXS treatments because small treatment effects on very important outcomes may be valued more than large treatment effects on less valued outcomes.

SEP-225289 serotonin and dopamine transporter occupancy: a PET study.

UNLABELLED: SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy. METHODS: Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2ß-carbomethoxy-3ß-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events. RESULTS: Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported. CONCLUSION: At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about indication, dose, and therapeutic potential.

Assessing the onset of antidepressant-induced sexual dysfunction using interactive voice response technology.

BACKGROUND: Sexual dysfunction is a symptom of major depression, as well as a common complication of treatment with many classes of antidepressants. Nonetheless, the various forms of sexual dysfunction continue to be underreported in clinical practice, despite the availability of validated scales such as the Changes in Sexual Functioning Questionnaire (CSFQ). The current study was designed to evaluate the validity of obtaining CSFQ data using interactive voice response (IVR) technology. METHOD: Sexually active, healthy male volunteers (N = 99; mean age of 31 years) were randomly assigned to 3 weeks of double-blind, parallel-group treatment with paroxetine (20 mg/day); CP-448,187 (3 mg/day); or placebo. Patients completed both paper-and-pencil and IVR versions of the 14-item CSFQ at baseline and on treatment days 8, 15, and 21. Additional IVR assessments were obtained at days 2, 4, and 6, permitting assessment of changes between office visits. This study was conducted between March and May 2001. RESULTS: The overall correlation between the paper and IVR CSFQ total score was r = 0.96 (p < .0001). Similarly, high correlations were found between paper and IVR assessment methods on the individual CSFQ subscales: pleasure (r = 0.88), frequency (r = 0.88), interest (r = 0.93), arousal (r = 0.89), and orgasm (r = 0.92; p < .0001 for all comparisons). Both assessment methods were able to detect a statistically significant between-group difference in sexual functioning by day 8, which remained significant throughout the remainder of the study. Both assessment methods found SSRI-related sexual dysfunction to include significant effects on all CSFQ domains. Assessments using IVR collected from subjects at home on days 2, 4, and 6 identified onset of sexual dysfunction by day 4, before it was detected during scheduled office visits. CONCLUSION: Interactive voice response assessment of sexual dysfunction on the CSFQ was found to be highly correlated with previously validated paper-and-pencil assessment. Interactive voice response provides a valid, easy-to-administer alternative method for obtaining systematic data on the impact of antidepressant treatment on sexual functioning. More frequent assessment by IVR enables more precise evaluation of symptom onset.

Birthweight-discordance and differences in early parenting relate to monozygotic twin differences in behaviour problems and academic achievement at age 7.

This longitudinal monozygotic (MZ) twin differences study explored associations between birthweight and early family environment and teacher-rated behaviour problems and academic achievement at age 7. MZ differences in anxiety, hyperactivity, conduct problems, peer problems and academic achievement correlated significantly with MZ differences in birthweight and early family environment, showing effect sizes of up to 2%. As predicted by earlier research, associations increased at the extremes of discordance, even in a longitudinal, cross-rater design, with effect sizes reaching as high as 12%. As with previous research some of these non-shared environmental (NSE) relationships appeared to operate partly as a function of SES, family chaos and maternal depression. Higher-risk families generally showed stronger negative associations.

Sibling relationships in early/middle childhood: links with individual adjustment.

The overarching goal of the study was to identify links between sibling relationship quality in early/middle childhood with children's adjustment, having accounted for the effects of parent-child relationship quality. The sample consisted of 101 working and middle-class 2-parent English families with 2 children ages 4-8 years. Parents provided reports of sibling relationship quality, the parent-child relationship, and the children's prosocial and problematic behaviors. The children also provided reports of their familial relationships with a puppet interview. Results indicated that sibling relationship quality was associated with the older siblings' adjustment, controlling for the children's relationships with parents. In addition, the pattern of findings suggested that positivity within the sibling relationship was more strongly linked with child adjustment than was sibling conflict.

Nonshared environmental influences on individual differences in early behavioral development: a monozygotic twin differences study.

The monozygotic (MZ) twin differences method was used to investigate nonshared environmental (NSE) influences independent of genetics. Four-year-old MZ twin pairs (N = 2,353) were assessed by their parents on 2 parenting measures (harsh parental discipline and negative parental feelings) and 4 behavioral measures (anxiety, prosocial behavior, hyperactivity, and conduct problems). Within-pair differences in parenting correlated significantly with MZ differences in behavior, with an average effect size of 3%. For the extreme 10% of the parenting-discordant and behavior-discordant distributions, the average NSE effect size was substantially greater (11%), suggesting a stronger NSE relationship for more discordant twins. NSE relationships were also stronger in higher risk environments, that is, families with lower socioeconomic status, greater family chaos, or greater maternal depression.