Considerations for development of an evidence dossier to support the use of mobile sensor technology for clinical outcome assessments in clinical trials.

BACKGROUND: Mobile sensors offer enormous potential for the collection of informative clinical endpoints in clinical trials to support regulatory decision making and product labelling. There are currently no specific guidelines on the information needed to enable regulators to review and accept proposed endpoints derived from mobile sensors for use in drug development trials. OBJECTIVE: The purpose of this working group report is to recommend the structure and content of an evidence dossier intended to support whether a clinical endpoint derived from mobile sensor data is fit-for-purpose for use in regulatory submissions for drug approvals. EVIDENCE DOSSIER: The structure and content of a dossier to provide evidence supporting the use of a sensor-derived clinical endpoint is described. Sections include clinical endpoint definition and positioning, the concept of interest, the context of use, clinical validation and interpretation, study implementation, and analytical validity with sensor performance verification in support of the selected sensor. CONCLUSIONS: In the absence of definitive regulatory guidance, this report provides a considered approach to compiling a comprehensive body of evidence to justify acceptance of mobile sensors for support of new drug applications.

Assessing disability progression with the Multiple Sclerosis Functional Composite.

BACKGROUND: The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event. OBJECTIVE: Evaluate a new method for analyzing disability progression using the MSFC. METHODS: MSFC progression was defined as worsening from baseline on scores of at least one MSFC component by 20% (MSFC Progression-20) or 15% (MSFC Progression-15), sustained for >or=3 months. Progression rates were determined using data from natalizumab clinical studies (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]). Correlations between MSFC progression and other clinical measures were determined, as was sensitivity to treatment effects. RESULTS: Substantial numbers of patients met MSFC progression criteria, with MSFC Progression-15 being more sensitive than MSFC Progression-20, at both 1 and 2 years. MSFC Progression-20 and MSFC Progression-15 were related significantly to Expanded Disability Status Scale (EDSS) score change, relapse rate, and the SF-36 Physical Component Summary (PCS) score change. MSFC Progression-20 and MSFC Progression-15 at 1 year were predictive of EDSS progression at 2 years. Both MSFC progression end points demonstrated treatment effects in AFFIRM, and results were replicated in SENTINEL. CONCLUSION: MSFC Progression-20 and MSFC Progression-15 are sensitive measures of disability progression; correlate with EDSS, relapse rates, and SF-36 PCS; and are capable of demonstrating therapeutic effects in randomized, controlled clinical studies.

Distribution of GABA(C)-like responses among acutely dissociated rat retinal neurons.

GABAergic responses of acutely dissociated rat retinal neurons, including both bipolar cells (BCs) and other, morphologically round cells (RCs), were assayed with the fluorescent (FL), voltage-sensitive probe oxonol DiBaC4(5). Using intensified video microscopy and simultaneous recording, GABA responses were identified in one-third of cells in a typical microscope field; of these 85% hyperpolarized (0.05-0.3 log unit FL decreases) while the remainder depolarized (0.05-0.2 log unit FL increases). GABA-sensitive cells were also TACA-sensitive (trans-4-Aminocrotonic acid), and these ligands appeared interchangeable in ability to evoke responses. In RCs, an asymmetric co-responsive pattern was observed between GABA- and muscimol-evoked events. Muscimol-sensitive RCs responded well to GABA, but not all GABA-sensitive RCs responded to muscimol. In GABA-sensitive BCs, muscimol responses were typically weak or absent. Few BCs or RCs responded to CACA (cis-4-Aminocrotonic acid). Bicuculline-resistant GABA responses occurred in approximately 80% of GABA-responsive RCs and BCs. Both bicuculline-sensitive (GABA(A)-like) and bicuculline-insensitive (GABAc-like) responses were resistant to picrotoxin. Although a small minority of GABA-sensitive cells hyperpolarized in response to R(+)baclofen, bicuculline-insensitive responses were not antagonized by 2-hydroxysaclofen, and were abolished in low [Cl-]o. Results suggested (1) that bicuculline-insensitive, Cl(-)-dependent, GABAc-like responses were broadly distributed and predominant among dissociated rat retinal neurons; (2) that muscimol was a particularly weak agonist for rat retinal BCs; and (3) that oxonol was a sensitive probe for retinal GABA responses.

Astrocytes regulate developmental changes in the chloride ion gradient of embryonic rat ventral spinal cord neurons in culture.

1. Embryonic rat ventral spinal cord neurons were dissociated at day 15 and grown on: (i) poly-D-lysine (PDL); (ii) a confluent monolayer of type I astrocytes; or (iii) PDL in astrocyte-conditioned medium (ACM) to examine the influence of astroglia on the regulation of GABAA receptor/Cl- channel properties. 2. Potentiometric oxonol dye recordings of intact cells indicated that embryonic neurons were uniformly depolarized by muscimol. The depolarizing effects disappeared in cells dissociated during the early postnatal period and recovered in culture for 24 h. Similar recordings using the calcium-imaging dye fura-2 AM revealed that GABA or muscimol triggered a sustained rise in cytosolic Ca2+ (Ca2+c ) in embryonic neurons that was dependent on extracellular Ca2+, blocked by bicuculline and nifedipine and sensitive to changes in extracellular chloride. The incidence and amplitude of the Ca2+ response decreased with time in vitro and was accelerated in neurons cultured on astrocytes compared with those on PDL. 3. Perforated patch-clamp recordings revealed that GABA depolarized neurons in a Cl--dependent and bicuculline-sensitive manner. Both the resting membrane potential and the GABA equilibrium potential became more hyperpolarized with time in vitro. 4. Astrocytes and ACM accelerated the transformation of GABAergic potential responses from depolarizing to hyperpolarizing. The change occurred over the first 4 days in co-culture or in ACM but took more than 2 weeks in neurons cultured on PDL alone. 5. The intrinsic, elementary properties of GABAA receptor/Cl- channels including open time and unitary conductance changed independently of the presence of astrocytes or ACM. Mean open time of the dominant kinetic component decreased and conductance increased with time in vitro. 6. In sum, astrocytes accelerate the developmental change in the Cl- ion gradient extrinsic to GABAA receptor/Cl- channels, which is critical for triggering Ca2+ entry, without influencing parallel changes in the intrinsic properties of the channels.

Sodium channels, GABAA receptors, and glutamate receptors develop sequentially on embryonic rat spinal cord cells.

It is not well understood when during embryonic development the elements of a cell's responsiveness first appear, nor the factors controlling their appearance. A strategy to approach this issue is to determine which aspects of neuronal development are highly stereotyped in presence, timing, or pattern across a variety of cell types, and which are more diversified by cell type, region, or other parameters. We have used a fluorescent potentiometric oxonol dye in conjunction with a digital video imaging system to record the emergence and distribution of specific forms of excitability in dissociated embryonic rat spinal cord cells. We studied the expression of responses to veratridine, a sodium channel activator; muscimol, a GABAA receptor agonist; and kainic acid, an agonist at a class of glutamate receptors. Responses were consistently detectable in a percentage of cells dissociated from the earliest age examined, embryonic day 13, and increased progressively in later ages. Cells were examined from four regions, with cervical-lumbosacral and ventrodorsal distinctions. In the population of cells from each region, functional sodium channels appeared prior to GABAA receptors, which in turn emerged prior to kainate-activated glutamate receptors. This pattern was common to all spinal cord regions and revealed ventrodorsal and rostrocaudal gradients reflecting the known pattern of spinal cord neurogenesis. Analysis of the individual cell responses indicated that the stereotypical pattern of sequential channel development occurs individually on most cells in each region.

A collaborative practice model for the clinical nurse specialist.

This article describes a model of advanced nursing practice, jointly funded through nursing and medicine. The model is based on a matrix reporting structure with the clinical nurse specialist reporting to both a physician and a director of nursing. The authors discuss how the various role components are enacted and the benefits of the model to the specialist, institution, physicians, staff, and patients and their families.

Experimental study of the conducted action potential in cardiac Purkinje strands.

Conduction velocity is a complex physiological process that integrates the active and passive properties of the excitable cell. The relations between these properties in determining the conduction velocity are not intuitively obvious, and models have been used frequently to illustrate important relationships. To study the relationships of important parameters and to evaluate commonly used models, we changed conduction velocity experimentally in sheep cardiac Purkinje strands by reducing extracellular Na systematically. Cable analyses were also performed to obtain passive membrane and cable properties. Resting membrane resistance and capacitance did not change, nor did core resistance. Active properties measured in addition to conduction velocity included maximal upstroke velocity, action potential height, time constant of the foot, peak inward current, and upstroke power. With reduction in extracellular Na, all of these parameters of the action potential changed nonlinearly and not in direct proportion to the change in conduction velocity. The only simple relation found was a linear relationship between maximal upstroke velocity and peak inward current, normalized by the capacity of the foot. Models based on the cable equation and the wave equation offer a basis for quantitative analysis of conduction, and these data can be used to test the models.

The conducted action potential. Models and comparison to experiments.

Propagation of the action potential is a complex process, and the relationships among the various factors involved in conduction have not been clear. We use three mathematical models of uniform conduction in a cable to clarify some of these relationships. One model is newly derived here, and two have been previously derived by Hunter et al. (1975, Prog. Biophys. Mol. Biol., 30:99-144). These models were able to simulate individual experimental action potential upstrokes previously obtained (Walton and Fozzard, 1983, Biophys. J., 44:1-8). The models were then utilized to provide relationships between measures of conduction. Among these were that maximal upstroke velocity (Vmax) is directly proportional to peak inward ionic current normalized by capacitance that is filled during the upstroke (I/Cf), and that conduction velocity was directly related to the square root of either Vmax or I/Cf. These relationships were shown to be model independent and to predict the experimental results, thus providing validated quantitative relationships that were not discernible through use of experimental data alone. The concept of safety factor was considered and a parameter was proposed that may be related to safety factor.