Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials.

Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.

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.

"The ignored pain" - experiences of encounters with healthcare from the perspective of women with pain persisting after childbirth - a qualitative study.

INTRODUCTION: Although the prevalence of pain persisting after pregnancy or labour decreases with time, up to 35 % of women report pain 8 months to 12 years after childbirth. To prevent the development and reduce the impact of chronic pain, researchers and clinicians emphasize the importance of early diagnosis as well as timely and appropriate treatment. Previous studies have shown that when women with post-childbirth morbidities consult healthcare professionals during the first year following birth, their problems are often neglected, and they do not receive adequate treatment. OBJECTIVE: To explore how women with pain persisting for eight months after childbirth experienced encounters with healthcare. METHODS: A descriptive qualitative design with 20 face-to-face, semi-structured interviews. Data were analysed using inductive qualitative content analysis. RESULTS: "Pain ignored by healthcare" was identified as an essential theme and included four categories: "Questioned pain experience," "Inadequate pain management," "Lost in healthcare," and "Insufficient postpartum care " CONCLUSION: The women experienced that their pain was often not recognized or adequately treated, but instead ignored or trivialized. Recurring were descriptions of experienced knowledge gaps among the healthcare providers regarding pain and its management. There was an overall desire among women for a well-defined and well-functioning chain of care with better accessibility and scope.

Disease Progression in Multiple System Atrophy-Novel Modeling Framework and Predictive Factors.

BACKGROUND: Multiple system atrophy (MSA) is a rare and aggressive neurodegenerative disease that typically leads to death 6 to 10 years after symptom onset. The rapid evolution renders it crucial to understand the general disease progression and factors affecting the disease course. OBJECTIVES: The aims of this study were to develop a novel disease-progression model to estimate a population-level MSA progression trajectory and predict patient-specific continuous disease stages describing the degree of progress into the disease. METHODS: The disease-progression model estimated a population-level progression trajectory of subscales of the Unified MSA Rating Scale and the Unified Parkinson's Disease Rating Scale using patients in the European MSA natural history study. The predicted disease continuum was validated via multiple analyses based on reported anchor points, and the effect of MSA subtype on the rate of disease progression was evaluated. RESULTS: The predicted disease continuum spanned approximately 6 years, with an estimated average duration of 51 months for a patient with global disability score 0 to reach the highest level of 4. The predicted continuous disease stages were shown to be correlated with time of symptom onset and predictive of survival time. MSA motor subtype was found to significantly affect disease progression, with MSA-parkinsonian (MSA-P) type patients having an accelerated rate of progression. CONCLUSIONS: The proposed modeling framework introduces a new method of analyzing and interpreting the progression of MSA. It can provide new insights and opportunities for investigating covariate effects on the rate of progression and provide well-founded predictions of patient-level future progressions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Disempowering women-a mixed methods study exploring informational support about pain persisting after childbirth and its consequences.

BACKGROUND: Access to information is essential to achieving individual empowerment; meaning the ability to exercise control, manage one's own condition and make informed decisions. However, studies have shown that information provided to women regarding physiological changes during the postpartum period and postpartum health was inadequate, incorrect, or inconsistent. METHODS: The aim of this study was to explore informational support about pain persisting after childbirth and its consequences. A sequential explanatory mixed methods design was used. In the first, quantitative phase, 1,171 women, who gave birth eight months earlier, completed a self-administered questionnaire. In the second, qualitative phase, 20 women who experienced chronic pain were interviewed. Descriptive statistics and qualitative content analysis were used to analyse the data. RESULTS: The majority of the women did not receive information about pain persisting after childbirth, or the information was insufficient or incorrect. They did not know when and where to seek help and did not consult health care professionals. In addition, the lack of information had a negative impact on women's psychological well-being. All women expressed the need to be informed by health care professionals, irrespective of the individual risk of developing chronic pain. CONCLUSIONS: Health services should ensure availability of information to give the women opportunity to achieve empowerment to make good health decisions, increase control over their health and well-being as well as to enhance their self-efficacy. We propose that a booklet or leaflet with relevant information about the risk of developing chronic pain, symptoms and treatment, along with advice about appropriate health care settings should be provided as part of antenatal or postnatal care.

Sensitivity to Change and Patient-Centricity of the Unified Multiple System Atrophy Rating Scale Items: A Data-Driven Analysis.

BACKGROUND: The Unified Multiple System Atrophy Rating Scale (UMSARS) is a commonly used semiquantitative rating scale to assess symptoms and measure disease progression in multiple system atrophy (MSA). However, it is currently incompletely understood which UMSARS items are the most sensitive to change and most relevant to the patient. OBJECTIVE: The objective of this study was to assess sensitivity to change and patient-centricity of single UMSARS items. METHODS: Data were taken from the European Multiple System Atrophy Study Group Natural History Study and the Rasagiline for Multiple System Atrophy trial. Sensitivity of change of an item of the UMSARS was assessed by calculation of a sensitivity-to-change ratio using its mean slope of progression divided by the standard deviation of the slope when modeling its progression over time. Patient-centricity was assessed through correlation of UMSARS items with quality-of-life measures. RESULTS: Progression rates above the mean in at least one of the two studies examined here were seen for seven items of UMSARS I and 11 items of UMSARS II. These items related to key motor functions such as swallowing, speech, handwriting, cutting food, hygiene, and dressing or walking, whereas items related to autonomic dysfunction were generally less sensitive to change in either data set. More UMSARS I items were identified as patient-centric compared with UMSARS II items, and items most strongly impacting patients' quality of life were those affecting verbal communication skills, personal hygiene, and walking. CONCLUSION: The present results illustrate the potential to optimize the UMSARS to enhance sensitivity to change and patient centricity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Grieving over the past and struggling forward - a qualitative study of women's experiences of chronic pain one year after childbirth.

OBJECTIVE: To describe women's experiences of chronic pain related to childbirth approximately one year after labour. DESIGN: A qualitative design with face-to-face interviews analysed using inductive qualitative content analysis. PARTICIPANTS: Twenty women who reported chronic pain, with onset during pregnancy and/or following labour, approximately one year after childbirth. FINDINGS: The analysis revealed an essential theme, "Grieving over the past and struggling forward", and three categories "Mourning the losses", "Struggling with the present" and "Managing the future". CONCLUSIONS: This study provides new knowledge about women's experiences of chronic pain one year after childbirth. The pain severely reduced women´s previous ability to perform physical and social activities, negatively impacted psychological well-being and altered their self-image. Most of the women adopted a positive attitude and hoped for improved health in the future, although constantly struggling with the pain and its consequences. IMPLICATIONS FOR PRACTICE: This knowledge is particularly important as chronic pain may not diminish with time in predisposed individuals who may need help and support from health professionals in their endeavour to manage their pain. Healthcare providers, i.e. midwives, gynaecologists and general practitioners need to understand women´s experiences of chronic pain from their own perspective to improve identification and treatment of pain following childbirth, thus preventing women's suffering and potential long-term health problems. Future studies are warranted to further explore and discuss women's coping strategies, health seeking behaviour and experiences of health care.

Building clinically relevant outcomes across the Alzheimer's disease spectrum.

Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a "clinically meaningful outcome" in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity. The AARR meeting on November 19-20, 2019, reviewed current approaches to defining clinical meaningfulness from various perspectives including those of patients and care partners, clinicians, regulators, health economists, and public policymakers. Participants discussed approaches that may confer clinical relevance at each stage of the disease continuum and fostered discussion about what should guide us in the future.

Simultaneous modeling of Alzheimer's disease progression via multiple cognitive scales.

Analyzing the progression of Alzheimer's disease (AD) is challenging due to lacking sensitivity in currently available measures. AD stages are typically defined based on cognitive cut-offs, but this results in heterogeneous patient groups. More accurate modeling of the continuous progression of the disease would enable more accurate patient prognosis. To address these issues, we propose a new multivariate continuous-time disease progression (MCDP) model. The model is formulated as a nonlinear mixed-effects model that aligns patients based on their predicted disease progression along a continuous latent disease timeline. The model is evaluated using long-term follow-up data from 2152 participants in the Alzheimer's Disease Neuroimaging Initiative. The MCDP model was used to simultaneously model three cognitive scales; the Alzheimer's Disease Assessment Scale-cognitive subscale, the Mini-Mental State Examination, and the Clinical Dementia Rating scale-sum of boxes. Compared with univariate modeling and previously proposed multivariate disease progression models, the MCDP model showed superior ability to predict future patient trajectories. Finally, based on the multivariate disease timeline estimated using the MCDP model, the sensitivity of the individual items of the cognitive scales along the different stages of disease was analyzed. The analysis showed that delayed memory recall items had the highest sensitivity in the early stages of disease, whereas language and attention items were sensitive later in disease.

Clinician- and Patient-reported Endpoints in CNS Orphan Drug Clinical Trials: ISCTM Position Paper on Best Practices for Endpoint Selection, Validation, Training, and Standardization.

OBJECTIVE: The International Society of CNS Clinical Trials Methodology (ISCTM) Working Group on Rare Disease/Orphan Drug Development is dedicated to improving and streamlining trials to best develop new treatments for rare diseases. The rarity of these disorders requires a drug development strategy that differs from those of nonrare conditions. Rare disease drug development programs are challenged with small sample sizes, heterogeneous clinical presentations, and few, if any, off-the-shelf endpoints. When disease-specific clinical endpoints exist, they might not be validated and are typically not well known or broadly used in clinical practice. This paper aims to provide an overview of the special issues surrounding endpoints in rare disease drug development, with guidance, practical applications, and discussion. DISCUSSION: The paper covers regulatory considerations in endpoint selection; identification of relevant measurement domains; methods of quantifying clinical meaningfulness; incorporation of patient- and clinician-reported outcomes; considerations for global clinician- and patient-rated clinical assessments; cognition assessment challenges in rare diseases; translation considerations; training, standardization, and calibration of assessors; and endpoint quality assurance. Additionally, it provides guidance and resources for those involved in drug development for rare diseases. CONCLUSION: In keeping with the mission of ISCTM and the rare disease/orphan drug development working group, this article is designed to encourage thoughtful consideration and provide insight and guidance to promote and further efforts in in central nervous system (CNS) rare disease drug development efforts.

Raising awareness about chronic pain and dyspareunia among women - a Swedish survey 8 months after childbirth.

Background and aims Although several studies have been conducted, knowledge about chronic pain and dyspareunia after childbirth is still limited. The aim of this study was to explore the prevalence of chronic pain 8 months after childbirth in a cohort of Swedish women. The characteristics of chronic pain, such as, pain intensity, localization and frequency as well as pain interference with daily activities were examined. An additional aim was to describe the prevalence and intensity of dyspareunia. Methods Data were obtained through two self-administered questionnaires and the patient record system, Obstetrix. The first questionnaire was distributed on the maternity ward, 24-36 h after labour, to Swedish-speaking women who had given birth to a living child (n = 1,507). The second questionnaire was sent by post 8 months after childbirth. We collected data about demographic and social characteristics, pain presence and its onset, as well as pain intensity, frequency, bodily localization and pain interference with activities of women's daily life. Results In total, 1,171 (77.7%) responded to both questionnaires and were included in the analysis. Eight months after giving birth, totally 16.7% (195/1,171) of the women reported chronic pain related to childbirth. Of these, 9.1% (106/1,171) of women reported chronic pain with onset during pregnancy, 4.5% (53/1,171) experienced chronic pain with onset following labour and 3.1% (36/1,171) of women had both chronic pain with onset during pregnancy and chronic pain with onset following labour (each participant could only appear in one of the groups). Women reported a lower prevalence of chronic pain after vaginal delivery than caesarean section (61/916, 6.7% vs. 28/255, 11%, p = 0.021, OR 1.73, 95% CI 1.1-2.8). Moreover, 19.2% (211/1,098) of women experienced dyspareunia. There was no difference regarding prevalence of dyspareunia and the mode of delivery. Of those women who had a vaginal delivery, 19.5% (167/858) experienced pain during intercourse and the corresponding number for women after caesarean section was 18.3% (44/240) (p = 0.694, OR 0.929, CI 0.6-1.3). Approximately 80% of women with chronic pain, and 60% of women that experienced dyspareunia, rated their worst pain as moderate or severe (NRS 4-10). The corresponding number regarding average chronic pain was between 50 and 70%. More than 35% of the women with chronic pain scored pain interference with daily activities as ≥4 on a 0-10 NRS. Conclusions In our study, chronic pain 8 months after childbirth was reported by one in six women and one in five of the women experienced dyspareunia. The intensity of both chronic pain and dyspareunia was reported as moderate to severe in a significant proportion of women and chronic pain interfered considerably with daily activities. Implications There is a need to raise awareness among healthcare providers of this clinical problem as well as to revise and upgrade education regarding pain after childbirth to prevent potential long-term health problems, women's suffering and increased need for health care. The development of strategies for prevention, follow-up and treatment of pain is warranted. More research, including women's experiences of pain as well as intervention studies, are also needed.

Differential effects of depressive symptoms on prospective and retrospective memory in old age.

The effects of depressive symptoms on prospective and retrospective memory were examined in a population-based sample of elderly persons (n = 404). Depression was assessed using the Comprehensive Psychopathological Rating Scale and treated as a continuous variable. The variation in depressive symptoms ranged from no symptoms to presence of a clinical depression. Depressive symptoms had a negative effect on consolidation and retrieval in retrospective memory. However, the retrospective, but not the prospective, component of prospective memory was affected by depression. The findings are discussed in light of medial-temporal lobe alterations in depression.

Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis.

To determine the size of the impairment across different cognitive domains in preclinical Alzheimer's disease (AD), a meta-analysis based on 47 studies involving 9,097 controls and 1,207 preclinical AD cases was conducted. There were marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; somewhat smaller deficits in verbal ability, visuospatial skill, and attention; and no preclinical impairment in primary memory. Younger age (< 75 years) and shorter follow-up intervals (< 3 years) were associated with larger effect sizes for both global cognitive ability and episodic memory. For global cognitive ability, studies that used population-based sampling yielded larger effect sizes; for episodic memory, larger differences were seen in studies that preidentified groups in terms of baseline cognitive impairment. Within episodic memory, delayed testing and recall-based assessment resulted in the largest effect sizes. The authors conclude that deficits in multiple cognitive domains are characteristic of AD several years before clinical diagnosis. The generalized nature of the deficit is consistent with recent observations that multiple brain structures and functions are affected long before the AD diagnosis.

Alzheimer's disease and depression: preclinical comorbidity effects on cognitive functioning.

Both Alzheimer's disease (AD) and depression (D) are prevalent disorders in old age and may co-occur in the same individual. The present study examined whether a diagnosis of D in AD has negative effects on cognitive functioning in the preclinical stage of the diseases, as well as at the time when the diagnoses were rendered. Population-based samples of 13 individuals with incident AD and D, 109 incident AD cases without D, and 179 normal older adults were followed over a three-year period. The groups were compared preclinically and at the time of diagnosis on global cognitive functioning using the MMSE total and the specific item scores, as well as the occurrence of depressive symptoms. As expected, there were clear AD-related deficits preclinically, which were exacerbated at follow-up. In addition, there were D-related deficits on three MMSE items (i.e., following commands, reading, and writing). The poorer performance on the three MMSE items was linked to an elevation of depressive symptoms. However, D was not associated with greater decline in cognitive functioning over the three-year follow-up period. Thus, although depressive symptoms may result in slight cognitive deficits in preclinical AD, at the time of the dementia diagnosis these effects may be absorbed by the neurodegenerative process.

Negligible effects of depression on verbal and spatial performance in Alzheimer's disease.

We examined whether a diagnosis of depression affects verbal and visuospatial performance in Alzheimer's disease (AD). Using data from a population-based study, persons with AD and depression (AD/D), AD alone and a control group of normal older adults were compared in two tests of verbal ability (category and letter fluency) and two tests of visuospatial skill (block design and clock drawing). As expected, there were clear AD-related deficits across all cognitive tasks. More importantly, the AD and AD/D groups were indistinguishable on all task variables. The lack of effects of depression was discussed relative to the view that those symptoms of this disease which are especially detrimental to cognitive functioning (e.g. concentration difficulties, lack of interest, loss of energy) may already be present in AD as a result of the neurodegenerative process.